[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO1999006397A2 - Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists - Google Patents

Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists Download PDF

Info

Publication number
WO1999006397A2
WO1999006397A2 PCT/US1998/015479 US9815479W WO9906397A2 WO 1999006397 A2 WO1999006397 A2 WO 1999006397A2 US 9815479 W US9815479 W US 9815479W WO 9906397 A2 WO9906397 A2 WO 9906397A2
Authority
WO
WIPO (PCT)
Prior art keywords
loweralkyl
hydrogen
aryl
benzodioxol
methoxyphenyl
Prior art date
Application number
PCT/US1998/015479
Other languages
French (fr)
Other versions
WO1999006397A3 (en
Inventor
Martin Winn
Steven A. Boyd
Charles W. Hutchins
Hwan-Soo Jae
Andrew S. Tasker
Thomas W. Von Geldern
Jeffrey A. Kester
Bryan K. Sorensen
Bruce G. Szczepankiewicz
Kenneth J. Henry
Gang Liu
Steven J. Wittenberger
Steven A. King
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/905,913 external-priority patent/US6162927A/en
Priority to SK145-2000A priority Critical patent/SK1452000A3/en
Priority to JP2000505155A priority patent/JP2001512119A/en
Priority to PL98342500A priority patent/PL342500A1/en
Priority to HU0003484A priority patent/HUP0003484A3/en
Priority to NZ502395A priority patent/NZ502395A/en
Priority to BR9815296-3A priority patent/BR9815296A/en
Priority to IL13417598A priority patent/IL134175A0/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to AU85921/98A priority patent/AU748469B2/en
Priority to EP98937139A priority patent/EP1003740A2/en
Priority to CA002297894A priority patent/CA2297894A1/en
Publication of WO1999006397A2 publication Critical patent/WO1999006397A2/en
Publication of WO1999006397A3 publication Critical patent/WO1999006397A3/en
Priority to NO20000542A priority patent/NO20000542L/en
Priority to BG104216A priority patent/BG104216A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and 20 compositions for antagonizing endothelin.
  • ET Endothelin
  • Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility i_n vit ro, stimulate mitogenesis in vascular smooth muscle cells i n vitro.
  • non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus i n v itro, increase airway resistance i n vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor i n vitro and i n vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release
  • vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 41 1 (1988), FEBS Letters 23J. 440 (1988) and Biochem. Biophys. Res. Commun. 1 54 868 (1988)).
  • An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial 5 effects in a variety of therapeutic areas.
  • an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J.
  • an anti-endothelin antibody attenuated the nephrotoxic i o effects of intravenously administered cyclospori ⁇ (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 1 14 (1990)).
  • a nonpeptide ET-A/B antagonist prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally.
  • SAH subarachnoid hemorrhage
  • Z is -C(Ri 8)(Ri 9)- or -C(O)- wherein R ⁇ ⁇ and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
  • R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is 20 (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R 3 is (a) R 4 -C(0)-R 5 - , R4-R ⁇ a- , R4-C(0)- R 5 -N(R 6 )- , R 6 -S(0) 2 -R7- or R 2 6-S(0)-R 2 7- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R o)-R8- or -R 8a -N(R 20 )-R 8 - wherein R 8 and R 8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R 9a -0-R 9 - wherein R9 and R 9a are independently
  • R ⁇ a is (i) alkylene or (ii) alkenylene;
  • R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i )-R ⁇ o- or -R 1 0a -N(R2i )-R ⁇ o- wherein R10 and R 1 0a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi;
  • R4 and Re are independently selected from the group consisting of (i) (Rn )(Ri2)N- wherein R- ⁇ and R12 are independently selected from
  • R26 is (i) loweralkyl, (ii) haloalkyi, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyi, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyi, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyi; and
  • R27 is alkylene or alkenylene
  • a preferred embodiment of the invention is a compound of formula ( I I )
  • substituents -R2, -R and -R1 exist in a trans, trans relationship and Z, n, R, R1 , R2, and R3 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- , R6-S(0)2-R7- or R26-S(0)-R27- wherein R 4 , R 5 , R 6> R 7 , R 26 and R 27 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or aikoxyalkoxyalkyi.
  • a more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- wherein R4 is (R- ⁇ ⁇ )(Ri2)N- as defined above and R5 is alkylene or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein R7 is alkylene, R27 is alkylene and RQ and R26 are defined as above.
  • Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R -C(0)-N(R2o)-R ⁇ - or R 6 -S(0)2-N(R ⁇ )-R ⁇ o- wherein R 8 and R , o are alkylene and R4, Re, R20 and R21 are defined as above.
  • An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is
  • R 1 and R are independently selected from (i) loweralkyl, (ii) cycloalkyi, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyi, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N- alkylaminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (R- ⁇ ⁇ )(R-i2)N- wherein R ⁇ and R 12 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalk
  • a yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
  • R 2 is substituted or unsubstituted
  • R 3 is R 4 -C(0)-N(R 2 o)-R ⁇ - or R6-S(0) -N(R ⁇ )-R ⁇ o- wherein R 8 and R 1 0 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and RQ is loweralkyl, haloalkyi, alkoxyalkyl, aryl or arylalkyi.
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
  • R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R ⁇ - wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R ⁇ and R 1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
  • R 16 wherein R 16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) aryl, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluor
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl, (vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 3-fluoro-4-e
  • R3 is R6-S(0)2-N(R2i)-R ⁇ o- wherein R-i o is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi.
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl or haloalkyi, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyi,, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic
  • a still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R-
  • R 2 is 1 ,3-benzodioxolyl
  • R3 is R4-C(0)-R ⁇ - wherein R5 is alkylene and R4 is (R ⁇ ⁇ )(Ri 2)N- wherein R- d and R 12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R-
  • a most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, be
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzo
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4- methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyi, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N- alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (R- ⁇ ⁇ )(R-i2)N- wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R and R 12 is alkyl.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-R ⁇ - wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is loweralkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkenyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is heterocyclic (alkyl), and R3 is R4-C(0)-Rs- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is arylalkyi, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryl, and R3 is R4-C(0)-R ⁇ - wherein R4 is (R- ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is (N- alkanoyl-N-alkyl)aminoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • the present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
  • the present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
  • the invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
  • the compounds of the invention comprise two or more asymmetrically substituted carbon atoms.
  • racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.
  • S and R configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp.
  • a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference.
  • Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No.
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference.
  • carboxy protecting groups are Ci to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyi; alkenyl; cycloalkyi and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentyimethyl and the like; arylalkyi, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like
  • alkanoylaminoalkyl such as acetylaminomethyl and the like
  • heterocycliccarbonyloxyalkyl such as 4-methylpiperazinylcarbonyloxymethyl and the like
  • dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl
  • 5-(loweralkyl)-2-oxo-1 ,3- dioxolen-4-yl)alkyl such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4- yl)methyl and the like
  • 5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
  • N-protecting group or "N-protected” as used herein
  • N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyi, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
  • sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyioxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methyiethoxycarbonyl, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzy
  • N-protecting groups are formyl, acetyl, benzoyi, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • alkanoyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group.
  • alkanoyl include acetyl, propionyl and the like.
  • alkanoylamino refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
  • alkanoylaminoalkyl refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
  • alkanoyloxyalkyl refers to R30-O-R31- wherein R30 is an alkanoyl group and R31 is an alkylene group.
  • alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 - methyl-2-buten-1 -yl and the like.
  • alkenyloxy refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-0-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. i o
  • alkoxy refers to R41O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
  • alkoxyalkoxy refers to R 8u 0-R 8 -
  • aikoxyalkoxyalkyi refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
  • Representative examples of aikoxyalkoxyalkyi groups include 20 methoxyethoxyethyl, methoxymethoxymethyl, and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. 25
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • alkoxycarbonylalkenyl refers to an 30 alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
  • alkoxycarbonylalkyl refers to R34-C(0)-R35- wherein R34 is an alkoxy group and R35 is an alkylene 35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
  • alkoxycarbonylaminoalkyl refers to R3 8 -C(0)-NH-R39- wherein R3 8 is an alkoxy group and R39 is an alkylene group.
  • alkoxycarbonyloxyalkyl refers to R 3 6-C(0)-0-R37- wherein R36 is an alkoxy group and R37 is an alkylene group.
  • (alkoxycarbonyl)thioalkoxy refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
  • Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
  • alkoxyhaloalkyl refers to a haloalkyi radical to which is appended an alkoxy group.
  • alkyl and “loweralkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • (N-alkanoyl-N-alkyl)aminoalkyP refers to R ⁇ 5C(0)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
  • alkylamino refers to R51 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • alkylaminoalkyl refers to a loweralkyl radical to which is appended an alkylamino group.
  • alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
  • alkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylaminoalkyl refers to R40-C(O)-NH-R4i- wherein R40 is an alkylamino group and R41 is an alkylene group.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -,
  • alkylsulfonylamidoalkyl refers R88S(0)2NHR89- wherein R88 is loweralkyl and R ⁇ 9 is alkylene.
  • alkylsulfonylamino refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(0)2-NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond.
  • alkynylene include -C ⁇ C-, -C ⁇ C-CH 2 -, -C ⁇ C-CH(CH 3 )- and the like.
  • aminoalkyl refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
  • aminocarbonyl refers to H2N-C(0)- .
  • aminocarbonylalkenyl refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkoxy refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkoxy examples include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkyl refers to (R90)(R91 )(R92)N(Rg3)- wherein R90, R91 , and R92 are independently selected from loweralkyl and R93 is alkylene.
  • aroyloxyalkyl refers to R32-C(0)-0-R33- wherein R 3 2 is an aryl group and R33 is an alkylene group.
  • Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyi, haloalkoxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyciic)alkoxy, hydroxy, hydroxalkoxy, phenyl
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
  • arylalkoxy refers to R42O- wherein R42 is an arylalkyi group, for example, benzyloxy, and the like.
  • arylalkoxyalkyl refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
  • arylalkyi refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
  • aryloxy refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the like.
  • arylalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R 62 C(0)0- wherein R 62 is an arylalkyi group).
  • aryloxyalkyl refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
  • carboxydehyde refers to a formaldehyde 5 radical, -C(0)H.
  • carboxy refers to a carboxylic acid radical, -C(0)OH.
  • carboxyalkenyl refers to a carboxy group as previously defined appended to an alkenyl radical as previously i o defined.
  • Examples of carboxyalkenyl include 2-carboxyethenyl, 3- carboxy-1 -ethenyl and the like.
  • carboxyalkoxy refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, 15 carboxyethoxy and the like.
  • cyanoalkoxy refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group.
  • cyanoalkoxy examples include 3-cyanopropoxy, 4-cyanobutoxy and the like.
  • cycloalkanoyloxyalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R 60 -C(O)-O- wherein R 60 is a cycloalkyi group).
  • cycloalkyi refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not 25 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyi groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and 3o carboxamide.
  • cycloalkylalkyl refers to a cycloalkyi group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl .
  • dialkylamino refers to R56R57N- 35 wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
  • dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent 5 molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
  • dialkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group. i o
  • dialkylaminocarbonylalkyl refers to
  • R50-C(O)-R5i- wherein R50 is a dialkylamino group and R51 is an alkylene group.
  • halo or halogen as used herein refers to I, Br, Cl or F.
  • haloalkenyl refers to an alkenyl radical 15 to which is appended at least one halogen substituent.
  • haloalkoxy refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
  • haloalkoxyalkyi refers to a loweralkyl radical to which is appended a haloalkoxy group.
  • haloalkyi refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or 25 pentafluoroethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7- membered ring containing one, two or three nitrogen atoms; one oxygen 30 atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds.
  • the 35 nitrogen heteroatoms can be optionally quatemized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
  • Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl
  • Heterocyclics also include compounds of the formula where X * is -CH 2 - or -O- and Y * is -C(O)- or [-C(R") -] V where R" is hydrogen or C ⁇ -C4-alkyl and v is 1 , 2 or 3 such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
  • nitrogen containing heterocycles can be N-protected.
  • (heterocyclic)alkoxy refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
  • Examples of (heterocyclic)alkoxy include 4- pyridylmethoxy, 2-pyridylmethoxy and the like.
  • (heterocyclic)alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocycliccarbonyloxyalkyl refers to R46-C(0)-0-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
  • hydroxy refers to -OH.
  • hydroxyalkenyl refers to an alkenyl radical to which is appended a hydroxy group.
  • hydroxyalkoxy refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group.
  • hydroxyalkoxy include 3-hydroxypropoxy, 4- hydroxybutoxy and the like.
  • hydroxyalkyi refers to a loweralkyl radical to which is appended a hydroxy group.
  • leaving group refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
  • mercapto refers to -SH.
  • methylenedioxy and "ethylenedioxy” refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the
  • tetrazolyl refers to a radical of the formula
  • tetrazolylalkoxy refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.
  • thioalkoxy refers to R70S- wherein R70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • thioalkoxyalkoxy refers to R 8u S-R 8 -
  • alkoxyalkoxy groups include CH 3 SCH 2 0-, EtSCH 2 0-, t-BuSCH 2 0- and the like.
  • thioalkoxyalkoxyalkyi refers to a thioalkoxyalkoxy group appended to an alkyl radical.
  • aikoxyalkoxyalkyi groups include CH 3 SCH 2 CH 2 OCH 2 CH 2 -, CH 3 SCH 2 OCH 2 -, and the like.
  • trans, cis refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
  • Preferred compounds of the invention are selected from the group consisting of: 5 fra ⁇ s-?ra/7s-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[3-(N- propyl-N-A7-pentanesulfonylamino)propyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-(4-Me ⁇ hoxy methoxyphenyl) -4- ( 1 ,3-benzodioxol-5-yl)---
  • trans trans-2- ( (2- Methoxyph en oxy)-methy I) -4- (1 ,3-benzodioxol-5-yl)- ⁇ o 1 -[(N-b utyl-N-(4-di methy la mi no butyl) ami no)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, trans-2-((2-W ⁇ ei oxyp he noxy)- methy I) -4- (7-methoxy-1 ,3- benzodioxol-5-yl)-1 - (N,N-di(n-buty I) am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; 15 trans, fra
  • Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -CO2H.
  • a ⁇ -ketoester J_, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • the condensation product 3_ is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst).
  • the resulting amine cyclizes to give the dihydro pyrrole 4_.
  • Reduction of 4. for example, sodium cyanoborohydride or catalytic hydrogenation and the like
  • a protic solvent such as ethanol or methanol and the like
  • Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans, trans and cis, trans isomers which is further elaborated.
  • the cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans, trans isomer and then carried on as described below.
  • the pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(0)- or R ⁇ -S(0)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(0)- or R6-S(0)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the
  • Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1 , m is 0, Z is -CH2- and W is -CO2H.
  • a substituted benzyl chloride 9_ is reacted with a lithio dithiane 1_ in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct U..
  • the anion of compound J_L is formed using a base such as n-butyllithium and then reacted with R1 -CH2-X' wherein X' is a WO 99/06397 " 4 ? " PCT/US98/15479
  • Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -CO2H.
  • ⁇ -Keto ester 2_0 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an ⁇ -haloester 2J_ (where J is lower
  • 25 bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 2j4.
  • Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1 , Z is -CH2- and W is -CO2H.
  • the trans,trans compound Z, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is
  • a preferred embodiment is shown in Schemes V and VI.
  • a benzoyi acetate 2_6 is reacted with a nitro vinyl benzodioxolyl compound 2J_ using 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to i o give compound 2J3.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 2_9.
  • the double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 3_0 as a mixture of cis-cis, trans, trans and cis, trans isomers.
  • Scheme VI illustrates the further elaboration of the trans, trans isomer.
  • the mixture (3 1) of trans, trans and cis, trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in
  • Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 3_5 is reacted with lithio dithiane 3_6 to give the alkylated compound 3_Z. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium
  • Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid.
  • Compound 5_5 which can be prepared by the procedures described in Scheme IV, is converted (for
  • carboxamide 5_6 20 example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 5_6.
  • the carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 5_7.
  • Nitrile 5_7 under standard tetrazole forming conditions (sodium azide
  • tetrazole 5_8 25 and triethylamine hydrochloride or trimethylsilylazide and tin oxide is reacted to give tetrazole 5_8.
  • nitrile 5_Z is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF,
  • a base for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH
  • amidoxime 5_9 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium
  • a conventional organic solvent such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine
  • a base for example, triethylamine, pyridine, potassium carbonate and sodium
  • a carboxylic acid 6_2 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N- dimethylformamide to give the acid chloride.
  • Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the ⁇ -chloroketone 63.
  • Pyrrolidine ester 5. where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the ⁇ -chloroketone 6.3 to provide alkylated pyrrolidine 6_4.
  • Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 6_5.
  • Scheme XI illustrates the preparation of "reverse amides and sulfonamides".
  • the carboxy protected pyrrolidine 5. prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6_6.
  • X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6_6.
  • Treatment of 6_6 with an amine (R20NH2) affords secondary amine 6_7.
  • This amine (67) can be reacted with an activated acyl compound (for example, R4-C(0)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 6_8-
  • amine 6_7 can be reacted with an activated sulfonyl compound (for example, R 8 -S(0)2-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 6_9_.
  • Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate.
  • General structures such as compound 70 are known to add to unsaturated esters such as Zl to provide pyrrolidines such as compound 7_2 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 5_2 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn.
  • Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 8J , which can be further elaborated on the pyrrolidine nitrogen.
  • Intermediate racemic pyrrolidine ester J_7 (for example, prepared by the procedure described in Scheme V) is Boc- nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyi pyrrolidine carboxylic acid 7_8.
  • the carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
  • This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 7_9_.
  • the pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 8_0.
  • the pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 8_1
  • optically active compound 8_1 The use of (-)-cinchonine will give the opposite enantiomer.
  • Scheme XIV describes another procedure for preparation of pyrrolidines.
  • Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc, Perkin Trans. 1 , 5: 1091-97 (1991 ).
  • the azomethine ylide precursor 8_2 (where R55 is hydrogen or methyl) is condensed with a substituted acrylate 8_3 (wherein R2 is as described herein and R56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 8_4.
  • the N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85. which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 8j6. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 8_Z
  • Nitro vinyl compound 5 (8_8) is reacted with beta-keto ester 8_9 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a i o temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 9_Q.
  • Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day
  • reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like,
  • pyrrolidine compound 9_2 as the c/s,c/s-isomer.
  • Epimerization at C-3 is effected by treatment of compound 9_2 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the
  • (+)-isomer of compound 9_3 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 9_3 with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.
  • the (+)-isomer of 9_3 selectively crystallizes as the salt, leaving the (-)-isomer of 9_3 in solution.
  • the substantially pure (i.e., 5 at least 95% of the desired isomer) optically active (-)-isomer of compound 9_3 can be selectively crystallized by reaction of a mixture of the
  • (+)-isomer and the (-)-isomer of 9_3 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired i o (-t-)-isomer of compound 9J3 in solution.
  • Compound 93 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like
  • ester 15 in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 9_4.
  • the ester can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide
  • Grignard reagent for example, propylmagnesium bromide
  • unsaturated ester for example, ethyl 3,3-dimethylacrylate.
  • the resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding ⁇ -ketoester, for example by activation using
  • olefinic ⁇ -ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired ⁇ -ketoester.
  • N-alkyl,0-alkyl bromohydroxamates are prepared according to
  • N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium catalyst.
  • the resultant amine is acylated, for example using bromoacetyl bromide.
  • the ⁇ -ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII.
  • Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH.
  • base for example DBU or potassium t-butoxide
  • the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH.
  • a mixture of isomers are generated, in which the trans- trans is generally preferred.
  • Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above.
  • Treatment with a chiral acid for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can be further enriched through recrystallization.
  • the salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product.
  • the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.
  • Activation of the acid for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically.
  • a similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
  • Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4- heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-( ⁇ - hydroxyalkyl)-N-alkyl haloacetamide.
  • Hydrolysis of the resultant ester for example using sodium hydroxide in aqueous alcohol, provides the product.
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonyl alky I, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R aa is aryl or arylalkyi
  • R b is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R-, and
  • R 2 is other than hydrogen; or a salt thereof; or a compound of the formula:
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • R i and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,
  • Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1 ;
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi,
  • V I (V I ) wherein n is 0 or 1 ; m is 0 to 6; R 5b is alkylene;
  • Q is a leaving group
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl , dialkylaminocarbonylalkyl , aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,
  • Q is a leaving group
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
  • Ri and R2 are independently selected from hydrd ' gen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl,
  • Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein m is zero or 1 ; R 5b is alkylene;
  • Q is a leaving group
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula
  • Q is a leaving group
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group
  • Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl,
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R 5b is alkylene
  • R 0a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • R aa is aryl or arylalkyi
  • R bb is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R-, and
  • R 2 is other than hydrogen; or a salt thereof.
  • Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1 ;
  • R 5b is alkylene
  • R 2 0 a ' s hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0;
  • R 5b is alkylene
  • R 20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is -CO 2 -G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyI, 3-fluoro-4-methoxyphen
  • Boc for tert-butyloxycarbonyl
  • Cbz for benzyloxycarbonyl
  • DBU for 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • EDCI for 1-(3- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride
  • EtOAc for ethyl acetate
  • EtOH for ethanol
  • HOBt 1-hydroxybenzotriazole
  • Et3N for triethylamine
  • TFA trifluoroacetic acid
  • THF for tetrahydrofuran.
  • Example A Ethyl 2-(4-methoxybenzov ⁇ -4-nitromethyl-3-(1.3-benzodioxole-5-v ⁇ butyrate
  • ethyl (4-methoxybenzoyl)acetate 23.0 g, 0.104 mol
  • 5-(2- nitrovinyl)-1 ,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 ml_ of toluene and heated to 80 °C was added 1 ,8-diazabicyclo[5,4,0] undec-7- ene (DBU, 0.65 g) with stirring.
  • DBU 1,8-diazabicyclo[5,4,0] undec-7- ene
  • Example 1 D Using the method described in Example 1 D, 300 mg of the mixture of 64% trans, trans- and 34% c/s, fra ⁇ s-pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrile to give 291 mg of a mixture of trans, trans- and cis, trans- N-alkylated esters. A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis, trans- ethyl ester.
  • Example 3 fra ⁇ s. l *rans-2-(4-Methoxyphenvn-4-f 1.3-benzodioxol-5-vn-1 -(4-fluorobe ⁇ zvn- pyrrolidine-3-carboxylic acid
  • 300 mg of the mixture of 64% trans, trans- and 34% cis, trans- pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans, trans- and c/s, fra ⁇ s-N-alkylated esters.
  • Example 4 fra ⁇ s. fra ⁇ s-2-f4-Metho ⁇ yphenyl -(1 ,3-benzodioxol-5-yl)-1-(2-ethoxyethyO- pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg.
  • Example 5 trans.frans-2-(4-Methoxyphenv ⁇ -4-f 1.3-benzodioxol-5-vn-1 -(2-Dropoxyethv ⁇ - pyrrolidine-3-carboxylic acid
  • 520 mg of the mixture resulting from Example 1 C 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans, trans- and c/s, frans-esters.
  • Example 6B rrat7s.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-yl;-1-[2- ⁇ 2- methoxyethoxy)ethyl)-pyrrolidine-3-carboxylic acid
  • -250 mg of the compound resulting from Example 6A 150 mg of 2-(2- methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the frans, fra ⁇ s-ester.
  • Example 7 frans. rat7S-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-y ⁇ -1 - 2-(2-pyridyl)ethyl]- pyrrolidine-3-carboxylic acid
  • 2-vinyl pyridine 355 mg
  • acetic acid was dissolved in 2- methoxyethanol, and stirred at 100 °C for 2.5 hours.
  • Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated.
  • Example 8 5 fra ⁇ s, frans-2-(4-MethoxyphenylM-(1 ,3-benzodioxol-5-vO-1 -(morpholin-4- ylcarbonyl)-pyrrolidine-3-carboxylic acid
  • To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1 -morpholinocarbonyl chloride. The mixture i o was stirred 3 hours at room temperature. Toluene- was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester.
  • Example 10 fra ⁇ s.fra ⁇ s-2- ( 4-Methoxyphenyl - ⁇ .3-benzodioxol-5-v ⁇ -1 -(4- ' methoxyphenylaminocarbonyl)-3-pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 6A (300 mg) was treated with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9.
  • the resulting ester was hydrolyzed with NaOH using the method described in Example 1 D to give 279 mg of the title compound, m.p. 185-187 °C.
  • Example 1 fra ⁇ s.frat7S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y ⁇ -1-acetylpyrrolidine-3- carboxylic acid
  • the compound resulting from Example 6A 250 mg in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1 D to give 21 1 mg of the title compound, m.p. 248-250 °C.
  • Example 12 frans.frans-2-(4-Methoxyphenvn-4-(1 .3-benzodioxol-5-vn-1 -(2-furovn-pyrrolidine-3- carboxyiic acid
  • the mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester.
  • the ester was hydrolyzed by the procedure described in Example 1 D to give 269 mg of the title compound as an amorphous powder.
  • Example 13 frans. frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-yl )-1- (phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid
  • phenyl i o isocyanate Starting with the compound resulting from Example 6A, phenyl i o isocyanate and the procedures described in Example 9, the title compound was prepared, m.p. 209-21 1 °C.
  • Example 14 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yO-1- (allylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound 20 was prepared, m.p. 138-140 °C.
  • Example 15 fra ⁇ s.rrans-2-(4-Methoxypheny ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-fn- butylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 105-107 °C. 1 H NMR (CDCI3, 300 MHz) ⁇ 0.90 (t, 3H), 30 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1 H), 2.87-3.35 (m, 6H), 3.62 (m, 1 H),
  • Example 17 fra ⁇ s.fra ⁇ s-2-f4-Methoxypheny ⁇ -4-(1.3-benzodioxol-5-yl;-1-(pyrrolidin-1 - ylcarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid.
  • H NMR (CDCI3, 300 MHz) ⁇ 1.40- 1.70 (m, 6H), 2.80 (d, 1 H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1 H), 6.80-6.90 (m, 3H),
  • Example 18 frat7S,fra ⁇ 5-2-(4-Methoxyphenv ⁇ -4-f1.3-benzodioxol-5-y ⁇ -1- (isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 175-177 °C. 1 H NMR (CD3OD, 300 MHz) ⁇ 0.87 (dd, 6H), 1.75 (septet, 1 H), 2.85 (d, 1 H), 2.90-3.10 (m, 4H), 3.23 (d, 1 H), 3.40
  • Example 20 fra ⁇ s. fra/7S-2-(4-Methoxyphenyl -(1.3-benzodioxol-5-yu-1 -(morpholin-4- ylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid.
  • Example 21 frans. frans-2-(4-Methoxyphenyl -(1 ,3-benzodioxol-5-yO-1 -(2-phenoxyethyl)- pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid.
  • Example 22 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y0-1 -(2- methoxyethylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 107-109 °C.
  • Example 25 frans.rrans-2-(1.3-Benzodioxol-5-yn-4-(4-methoxyphenyn-1 -(2-propoxyethyn- pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4- methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2- nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound, m.p. 67- 69 °C.
  • Example 26 frans.frans-2-(1.3-Benzodioxol-5-v ⁇ -4-(4-metho ⁇ yphenv ⁇ -1 -[2-(2- methoxyethoxy ) ethyl)l-pyrrolidine-3-carboxylic acid Using the procedures . described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2- methoxyethoxy)ethytbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 85-86 °C.
  • Example 29 frans.frans-2-(4-Methoxyphenyl)-4-(1.4-benzodioxan-6-y ⁇ -1-(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • 6-(2- nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, m.p. 74-76 °C. Rotational isomers are seen in the NMR.
  • Example 30 frans.fra ⁇ s-2-t4-Metho ⁇ yphenyl ⁇ -4-f1.3-benzodioxol-5-vn-1-fN-methyl-N- butylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. Rotational isomers are seen in the NMR.
  • Example 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(1.3-benzodioxol-5-y0-pyrrolidine-
  • Example 31 B frans. ra ⁇ s-2-(4-Methoxy-2-methoxymethoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1 -(N- methyl-N-butylaminocarbonylmethyl ⁇ -pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 31 A was epimerized by the procedure described in Example 6A.
  • the resulting trans, trans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example 1 D substituting N-methyl-N-butyl bromoacetamide for N- propyl bromoacetamide to give the title compound (75 mg, 62%).
  • Example 32A Ethyl 2-(4-methoxybenzoyl ⁇ -3-carbornethoxy-1 ,3-benzodioxole-5-propionate
  • ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1 ,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 L of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.
  • Example 32B Ethyl 1 -(3-ethoxypropylV2-(4-methoxyphenvn-4-H .3-benzodioxol-5-v0-4.5-dihvdro- 5-QXO-1 H-pyrrole-3-carboxylate
  • Example 32C Ethvl 1-f3-ethoxypropvlV2-(4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pvrrolidin-5- one-3-carboxylate
  • the compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature.
  • the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
  • Example 32D frans.frans-2-f4-Methoxypheny ⁇ -4-f1.3-benzodioxol-5-y ⁇ -1-(3-ethoxypropy ⁇ - pyrrolidin-5-one-3-carboxylic acid
  • To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 % sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour.
  • Example 33 frans.fra ⁇ s-2-(4-Metho ⁇ yphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-(3-methoxybenzy ⁇ - pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, 65%). m.p. 150-152 °C. 1 H NMR (CD3OD ,
  • Example 34 frans.frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-yn-1-(N.N- diisoamylaminocarbonylmethyl»-pyrrolidine-3carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 35 frat7g,frans-2-(4-Meth ⁇ >xyphenyl)-4-(1 ,3-benz ⁇ >diQXQl-5-yl)-1-(N,N- dipentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 36 frans.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1-(N.N-di(2- methoxyethv ⁇ aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 120-122 °C. 1 H NMR (CDCI3, 300 MHz) ⁇ 2.82 (d,
  • Example 39 frans.frans-2-(4-MethoxyPhenvn-4-(1.3-benzodioxol-5-vn-1-(N-cvclopropylmethyl- N-propylaminocarbonylmethyl)-pyrrplidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the NMR.
  • Example 39 frans.rrans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-y ⁇ -1 -(N-methyl-N- pentylaminocarbonylmethvn-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1 . Rotational isomers were seen in the NMR.
  • Example 40 fra ⁇ s.frans-2-(4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1 -(N.N- diisobutylaminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 141-143 °C.
  • Example 41 frans.frans-2- 4-Methoxyphenvn-4-f1.3-benzodioxol-5-yl ⁇ -1-fN-methyl-N- ⁇ 2- propynyl)aminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
  • Example 42 frans.f-ans-2-f4-Metho ⁇ yphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-(N-methyl-N-(n- hexyl)aminocarbony!methy0-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 43 frans.fra ⁇ s-2-r4-Methoxyphenyl.-4-f1.3-benzodioxol-5-yl ⁇ -1-t ⁇ . ⁇ /-cy/Yn- butvnaminocarbonylmethyl -o ⁇ /rro ⁇ d ⁇ r ⁇ e-3-ca ⁇ box ⁇ c acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 123-125 °C. 1 H NMR (CDCI 3 , 300 MHz) ⁇ 0.79 (t,
  • Example 46 rrans.frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1 -(N-methyl-N- cyclohexylaminocarbonylmethvn- p yrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the
  • Example 47 frans.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-y ⁇ -1-(N.N-dim- propyl)aminocarbonylmethylVpyrroHdine-3-carboxylic acid i o
  • the title compound was prepared using the -procedures described in Example 1. m.p. 170-172 °C.
  • Example 48 fra ⁇ s.fra ⁇ s-2-f4-MethoxyphenylV4-(1.3-benzodioxol-5-v ⁇ -1 -(N-methyl-N- isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 20
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
  • Example 49A E-2-(3.4-Methylenedioxyphenyl)-1-nitroethene
  • piperonal 75g, 500 mmol
  • methanol 35 120 mL
  • sodium hydroxide 21 g, 525 mmol, 1.05 eq
  • Example 49B Ethyl 2-(4-methoxyphenvhoxo-4-nitro-3-(3.4-methylenedioxyphenyl ⁇ butyrate To a stirred solution of the nitrostyrene resulting from Example
  • Example 50 ffans.frans-2-r4-Methoxyphenyn-4-(1.3-benzodioxol-5-yl,-1-ft- butyloxycarbonylmethyl.-pyrrolidine-3-carboxylic acid
  • acetonitrile 2 mL
  • diisopropylethylamine 70 ⁇ L, 0.40 mmol, 1.5 eq
  • t-butyl bromoacetate 48 ⁇ L, 0.29 mmol, 1.1 eq
  • Example 52B fra ⁇ s.frans-2-f4-Methoxypheny ⁇ -4-f2.3-dihvdrobenzofuran-5-y ⁇ -1-(N-methyl-N- propyl,aminocarbonylmethyn-pyrrolidine-3-carboxylic acid
  • Example 53 frans.rran5-2.4-Bisf4-methoxyphenyh-1-(N-methyl-N-propy ⁇ aminocarbonylmethv ⁇ - pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • Example 54 trans. frans-2-»4-Methoxyphenv ⁇ -4-(3.4-dimethoxyphenv ⁇ -1-fN-methyl-N- propyl ⁇ aminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid
  • Example 55 rans.fran5-2-f4-Methoxyphenyn-4-f3-methoxyphenyn-1-(N-methyl-N- propy ⁇ aminocarbonylmethylVpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • Example 56 fra ⁇ s.frans-2-(4-Metho ⁇ yphenyl ' )-4-f2-naphthyl>-1-(N-methyl-N-
  • Dr ⁇ Dylteminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) ⁇ 7.82 (4H, m), 7.69 (1 H, m>, 7.47 (2H, m), 7.37
  • Example 57 frans. frans-2-(4-Methoxyphenyl ⁇ -4-M .3-benzodioxol-5-yl I -f2-(ethylsulfinv ⁇ ethyl ' >- pyrrolidine-3-carboxylic acid
  • 2-chloroethyl ethyl sulfide 67.5 mg, 0.5 mmol, 2 equivalents
  • Kl 0.5 mmol, 2 equivalents
  • Example 59 frans.frans-2-(4-Methoxypheny ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-(2-(isobutoxy ⁇ ethy ⁇ - pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 1 D from the compound resulting from Example 1 C and 2- (isobutoxy) ethyl bromide, m.p. 68-70 °C.
  • Example 60 fra ⁇ s.frans-2-f4-Methoxyphenv ⁇ -4-f1.3-benzodioxol-5-v ⁇ -1 -fbutylsulfonyl)-
  • the ester 120 mg, 0.244 mmol was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid, m.p. 67-69 °C.
  • Example 61 frar7S.?rans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -,2-(N-methyl-N- isopropylcarbonylamino')ethv ⁇ -pyrrolidine-3-carboxylic acid
  • Example 61 A frans.frans-2-f4-Methoxy p henyn-4-M .3-benzodioxol-5-vn-1-(2-bromoethyl,- pyrrolidine-3-carboxylic acid ethyl ester
  • trans pyrrolidines resulting from Example 1 C 400 mg
  • dissolved in 9 mL of 1 ,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide.
  • Example 61 B frans.fra ⁇ s-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -(2-fmethylamino l ethyl,- pyrrolidine-3-carboxylic acid ethyl ester
  • EtOH aqueous methylamine
  • sodium iodide 50 mg
  • Example 61 C fra ⁇ s.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-yn-1-r2-rN-methyl-N- isobutyrylamino ⁇ ethy ⁇ -pyrrolidine-3-carboxylic acid
  • the solution was cooled to -40 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.
  • Example 62 rra ⁇ s.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1- ⁇ 2-(N-methyl-N- propionylamino)ethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61 C.
  • Example 64 rans.frans-2- ⁇ 4-MethoxyDhenyl)-4-f1.3-benzodioxol-5-v ⁇ -1-fN-ethyl-N- butylaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared.
  • Example 65 rrans.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-yl;-1- ⁇ N-methyl-N-(2.2- dimethylpropynaminocarbonylmethyn-pyrrolidine-3-carboxylic acid
  • Example 66 trans. frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-ylV1-(2-(N-methyl-N- butylsulfonylamino ⁇ ethy ⁇ -pyrrolidine-3-carboxylic acid
  • Example 61 B To the compound resulting from Example 61 B (60 mg, 0.13 mmol) dissolved in 5 mL of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1 .1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 :1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound, m.p. 64-66 °C.
  • Example 67 s frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-yl)-1-.2-(N-methyl-N- propylsulfonylaminotethyn-pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 66 substituting 1-propanesuIfonyl chloride for 1- butanesulfonyl chloride, m.p. 69-70 °C. 1 H NMR (CDCI 3 .
  • Example 69 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1-f2- (propylsulfonv ⁇ ethyl -pyrrolidine-3-carboxylic acid
  • 1-propanethiol 3.5 g, 46.05 mmol
  • 632 mg 26.32 mmol
  • NaH sodium hydride
  • the mixture was heated at 60-70 °C for 1 hours.
  • To this mixture was added the compound resulting from Example 61 A (180 mg, 0.38 mmol) in 2 mL THF.
  • Example 69B rrans-5-Methylhex-2-en-1 -ol
  • the compound resulting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath.
  • Example 69C frans-1 -Bromo-5-rnethylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C for two hours. The solution was poured onto ice, the-layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).
  • Example 70 frans.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1-N-(frans-3.5- dimethylhex-2-env ⁇ -Pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olefins.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 71 A 1 -Chioro-3-propyl-2-hexanone To 2-propylpentanoic acid (156.6 ⁇ l, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 ⁇ L, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 ⁇ L, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature.
  • reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere.
  • Hydrogen chloride as a 4 N solution in dioxane (275 ⁇ L, 1.10 mmol) was added dropwise over a few minutes.
  • the reaction was stirred 18 hours while warming to ambient temperature.
  • the reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
  • Example 71 B fra ⁇ s. fra ⁇ s-Ethyl 2-(4-methoxyphenyl )-4-M .3-benzodioxol-5-yh- 1 -> 4- heptylcarbonylmethyl ⁇ -pyrrolidine-3-carboxylate
  • Example 71 A To the compound resulting from Example 71 A (1.00 mmol, maximum theoretical yield) was added a solution of the trans, trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 % solution in toluene), diisopropylethylamine (700 ⁇ L, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole %), and the reaction mixture was stirred 18 hours 5 under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole %) and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours.
  • Example 71 C trans. trans-2-( 4- Methoxyp hen yh-4-M .3-benzodioxol-5-v0-1 -(4- 5 heptylcarbonylmethvn-pyrrolidine-3-carboxylic a£id
  • Example 71 B To the compound resulting from Example 71 B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium 0 hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL).
  • Example 72A 1-Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
  • Example 72B fra ⁇ s. fra ⁇ s-Ethyl 2-(4-methoxyphenyl ,-4-M .3-benzodioxole-5-vn-1 (valerylmethvn-pyrrolidine-3-carboxylate Substituting the compound resulting from Example 72A for 1- chloro-3-propyl-2-hexanone and using the procedure described in Example 71 B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil.
  • Example 72C frans. frar7s-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1 - (valerylmethvh-pyrrolidine-3-carboxylic acid
  • Example 73A trans.trans- and c/s.fra ⁇ s-2-(4-Methoxyphenyn-4-f 1 ,3-benzodioxol-5- yl )-1 -f(3.4-dimethoxybenzyl )aminocarbonylmethyl )pyrrolidine-3- carboxylic acid ethyl ester
  • Example 1 D, paragraph 1 substituting 3,4- dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
  • Example 73B trans.trans- and c;s.fra ⁇ s-2-(4-Methoxyphenyl ⁇ -4-M .3-benzodioxol-5- y ⁇ -1 -(N- ⁇ 3.4-dimethoxybenzyn-N- methylaminocarbonylmethyl )pyrrolidine-3-carboxylic acid ethyl ester
  • Example 73A The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 ⁇ L, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et2 ⁇ ) indicated incomplete reaction.
  • Example 73C The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound.
  • Example 75B fra ⁇ s.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-yn-1 -((1 RV1 -(N.N- dipropylaminocarbonyl ⁇ -1 -butv ⁇ pyrrolidine-3-carboxylic acid ethyl ester
  • the resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours.
  • the reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to give 81.4 mg (96%) of the crude acid as a white solid.
  • Example 75C o 2R.3R.4R ,-2-(4-Methoxyphenyn-4-(1 .3-benzodioxol-5-yn-1 -(( 1 R ,-1 -
  • Example 73C (N.N-dipropylaminocarbony ⁇ -1 -buty ⁇ pyrrolidine-3-carboxylic acid
  • Example 75B substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield.
  • Example 73C The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield.
  • Trifluoromethanesulfonic anhydride (95 ⁇ L, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and 5 at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 ⁇ L, 75 mg, 0.58 mmol) in 3 mL of CH2CI2 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature.
  • Example 77B ⁇ 2S.3S.4S)-2-(4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1 -fn S 1-fN.N- dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product 5 from Example 73B, to provide the title compound in 100% yield.
  • Example 79 frans.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-vn-1-/ r /V./V-rJ/Yn- butyl)aminocarbonylmethyl)-3-(5-tet ⁇ azoM)ov ⁇ o ⁇ d r ⁇ e
  • Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound, m.p. 194-196 °C.
  • Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature.
  • Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3- carbonitrile compound.
  • Example 90 frans.fra ⁇ s-2-(4-Fluorophenvn-4-n .3-benzodioxol-5-vn-1- ⁇ ./V-fi/rn- ⁇ ;fv/)a / ⁇ ocarb ⁇ n t77ef/7v/)pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3-benzodioxoIe using the procedures described in Examples 1 and .43.
  • Example 81 fra ⁇ s.frans-2-(4-Methoxyphenv ⁇ -4- ⁇ .3-benzodioxol-5-vn-1-fN.N-di(n- butvflaminocarbonylmethvOpyrrolidine-3-carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C.
  • Example 82 rrans.rrans-2-(4-Methoxyphenyn-4-n .3-benzodioxol-5-vn-1 -fN-n-butvn-N-m- propvnaminocarbonvlmethvnpvrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C.
  • Example 83 fra ⁇ s.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -f2-fN.N-di(n- propy ⁇ aminocarbonv ⁇ ethyl]pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 6A 250 mg, 0.677 mmol
  • diallyl acrylamide Polysciences, Inc.
  • 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
  • the diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere.
  • the catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
  • Example 84 frans.fra ⁇ s-2-(4-Methoxyphenyn-4- ⁇ .3-benzodioxol-5-yl,-1-fN.N-dirn- butvnaminocarbonyl.pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyi chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material.
  • Example 87 frans.frans-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1-(2-rN-fN.N-dim- butvnaminocarbonvn-N-methylamino1ethyl)pyrrolidine-3-carboxylic acid
  • Dibutyl carbamoyi chloride (135 mg) was added to the compound resulting from Example 61 B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2S ⁇ 4 and concentrated.
  • Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours. After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%) of the title compound, m.p.
  • Example 89 frans.frans-2-(4-MethoxvphenvlV4-f1.3-benzodioxol-5-vn-1-fN.N-di.n- butv ⁇ aminocarbo ⁇ ylmethyl ⁇ pyrrolidine-3- N-benzenesulfonv ⁇ carboxamide
  • the compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 °C for a sample recrystallized from acetonitrile.
  • Example 90 frans. frans-2-f4-Methoxyphenv ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-rN.N-di(n-butv ⁇ aminosulfonylmethyl]-pyrrolidine-3-carboxylic acid Chloromethyl sulfenyl chloride, prepared by the method of
  • N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans, trans-2- ⁇ 4- Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[N, N-di(n- butyl)aminosulfenylmethyl]-pyrroiidine-3-carboxylate.
  • This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett.
  • Example 91 A i ⁇ Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH2CI2, the solution was cooled to 0 °C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature.
  • Example 91 B trans.trans- and c/s.frans-2- 4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1- ⁇ (N.N- dim-butv ⁇ amino ⁇ carbonyl-1-ff?SVethyliPyrrolidine-3-carboxylic acid ethyl ester
  • a solution of the resultant mixture of trans.trans and cis.trans compounds from Example 1C 232 mg, 0.628 mmol
  • the resultant compound from Example 91 A 183 mg, 0.693 mmol
  • 2 mL of CH3CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol).
  • the solution was stirred at 60-80 °C under a N2 atmosphere for 16 hours.
  • the reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et2 ⁇ and 10 mL of 1 M aqueous Na2C03 solution.
  • the organic phase was washed with 20 mL water and 20 mL brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude).
  • the product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 4 diastereomers.
  • Example 91 C frans. fran5-2-f4-Methoxyphenyn-4-n.3-benzodioxol-5-ylV1-f.N.N- dibutylamino)carbonyl-1-(f?S)-ethyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73C was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield.
  • Example 92 fra ⁇ s.fra ⁇ s-2-(Pentyl -4-( 1.3-benzodioxol-5-yB-1 -(N.N-dim- butyl,aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
  • Example 92A Methyl 2-(4-hexenoylt-4-nitro-3-(1.3-benzodioxole-5-yl)butyrate
  • a solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1 ,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 ⁇ L, 0.15 mmol) was added.
  • the resulting reddish solution was stirred at room temperature for 20 minutes.
  • TLC ethyl acetate-hexane, 1 :3) indicated complete consumption of ketoester.
  • Example 92B Methyl frans.fra ⁇ s-2-fpentyl.-4-f1.3-benzodioxol-5-ynpyrrolidine-3-carboxylate
  • Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example 1 B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions.
  • a solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol).
  • the resultant solution was heated at reflux for 18 hours.
  • the reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated N HC ⁇ 3 diluted with 10 mL water and 30 mL of CH2CI2.
  • the aqueous phase was extracted (2 x 30 mL CH2CI2), then the combined organic phases were washed with 20 mL brine, dried over Na2S ⁇ 4, filtered and the filtrate concentrated under reduced pressure to afford the crude product.
  • Example 92C frans.frans-2-fPentvn-4-f1.3-benzodioxol-5-yl,-1-(N.N-difn- butv ⁇ aminocarbonylmethyflpyrrolidine-3-carboxylic acid
  • Example 1 B-1D The procedures of Example 1 B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam.
  • Methyl frans.frans-2-(Pentvn-4-(1.3-benzodioxol-5-yn-1-[2-fN-propyl-N- propylsulfonylamino)ethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 ⁇ mol) in 1 mL EtOH was treated with propylamine (60 ⁇ L, 0.73 mmol). The solution was warmed to 80 °C for 4 hours.
  • the reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M. aqueous Na2C ⁇ 3. The organic phase was washed with 15 mL brine, then dried over Na2S04, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg).
  • the crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 ⁇ L, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 ⁇ L, 0.26 mmol). The solution was stirred at room temperature for 4 hours.
  • Example 71 C rans-2-fPentyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-propyl-N- pro p ylsurfonylamino thyl]pyrrolidine-3-carboxylic acid
  • Example 94 trans. trans-2-( Propyl -f 1.3-benzodioxol-5-yl;-1 -f N.N-di - butyltaminocarbonylmethv ⁇ py ⁇ Olidine-3-carboxylic acid
  • Example 94A Ethyl 2-(4-butanovn-4-nitro-3-( 1.3-benzodioxole-5-ynbutyrate
  • Example 94C frans.frans-g-fPropvn ⁇ -n .S-benzodioxol-S-vlVI-.fN.N-dim- butyl ⁇ aminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid
  • the procedure of Example 92C was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound.
  • Example 95A fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl - ⁇ .3-benzodioxol-5-ylV1 -( tert- butyloxycarbonylaminocarbonylmethyllpyrrolidine-3-carboxylic acid
  • the resulting mixture of 64% trans, trans- and cis, trans- pyrrolidines resulting from Example 1 C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride.
  • Example 95B f2R.3R.4S,-(+,-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-(tert- butyloxycarbonylaminocarbonylmethvB-pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam.
  • This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1 H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate.
  • Example 95C ( 2R.3R.4S)-f-i- l -Ethvl 2-f4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pyrrolidine-3- carboxvlate
  • the compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol.
  • the resulting solution was heated at 50 °C. with stirring for 18 hours at which point all of the precipitated solid had dissolved.
  • the reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL).
  • Example 95B Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
  • Example 61 The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C.
  • the product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid.
  • Example 61 (ethylaminocarbonynamino)ethvnpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl isocyanate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • the title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :4 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 99 frans.frans-2-(4-Methoxyphenv ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-[2-(N-propyl-N- ethoxycarbonylamin ⁇ )ethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 100 frans.fra/7S-2-f4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-methyl-N-f2- ethylbutyryl ⁇ amin ⁇ )ethyl]pyrrolidine-3-carboxylic acid
  • HOBt 60 mg
  • EDCI 85 mg
  • N- methylmorpholine 50 ⁇ L
  • DMF 2 mL
  • Example 101 frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-ylV1-r2-(N-methyl-N-(2- propytvaleryl)aminotethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2- ethylbutyric acid.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid.
  • Example 102 rrans.frat7S-2-f4-Methoxvphenyn-4-n .3-benzodioxol-5-vn-1-r2-fN-propyl-N-.tert- butyloxycarbonylmethyl.amino.ethyllpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and t-butyl bromoacetate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • Example 103 frans.fra ⁇ s-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-[2-(N-propyl-N-(n- propylaminocarbonylmethyl)amin ⁇ ethyl1pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 61 C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 61 but substituting propylamine for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a whjje solid.
  • Example 105 rans.fra ⁇ s-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-r2-fN-propyl-N-(4- methoxybenzovnamino ethyHpyrrolidine-3-carboxylic acid
  • Example 61 The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 106 frar7S.frans-2-(4-Methoxyphenyn-4-M .3-benzodioxol-5-yl,-1-f2-(N-propyl-N- benzoylamino.ethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzoyi chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 1Q7 fra ⁇ s.frans-2-,4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -r2-(N-propyl-N- benzyloxycarbonylamino ⁇ ethyllpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C 18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 61 substituting propylamine for methylamine in Example 61 B and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61C.
  • the title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA.
  • the desired fractions were Iyophilized to give the product as a white solid.
  • Example 110 fra ⁇ s.fra ⁇ s-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-r2-(N-butyl-N- propoxycarbonylamino ethyl]pyrrolidine-3-carboxylic aci '
  • the title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 111 frans.frar>s-2- 4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1-f2-.N-propyl-N- propoxvcarbonylamino)ethv ⁇ pvrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 112 fra ⁇ s.frans-1-fN.N-Di(n-butyl ⁇ aminocarbonylmethylV2.4-dif1.3-benzodioxol-5- yl)Pyrrolidine-3-carboxylic acid
  • Ethyl (3,4-methylenedioxybenzoyl)acetate prepared by the method of Krapcho et al., Org. Syn. 42, 20 (1967) starting with 3,4- methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid, m.p. 58-60 °C. 1 H NMR (CDCI3.
  • Example 113 fra ⁇ s.frans-1-(2-fN-m-Butvn-N-propylsulfonylamino)ethvn-2-f4-methoxyphenyn-4- (1 r 3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 64-65 °C.
  • Example 114 fra ⁇ s.fra ⁇ s-1-fN.N-Di(n-butynaminocarbonylmethyl>-2-(4-metho ⁇ yphenvn-4-M .3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid, m.p. 74 76 °C. 1 H NMR
  • Example 115 frans.frans-1-f2-fN-Propyl-N-propylsulfonylamino ⁇ ethyn-2-f4-methoxyphenvn-4- (1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73 °C. 1 H NMR (CDCI3.
  • Example 116 trans, frans-1 -(2-fN-Butyl-N-butylsulfonylamino ethvn-2-(4-metho ⁇ yphenvn-4- ⁇ .3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 62-63 °C.
  • Example 118 fra ⁇ s.frans-1-f2-fN.N-Dim-butyl aminocarbonylmethvn-2-(4-hydroxyphenvn-4-(1.3- benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid hydrochloride salt
  • the compound resulting from Example 1 16 was treated with concentrated HCI in 1 :1 THF-isopropanol to give the title compound as a white solid, m.p. 211-212 °C. 1 H NMR (CD3OD.
  • Example 121 trans.trans-1 -(2-(N-(4-Methoxybenzenesulfonvn-N-propylamino ethyl ⁇ -2-(4- methoxyphenyl ;-4-(1.3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid
  • Example 122 ra ⁇ s.frans-1 -fN.N-Dim-butynaminocarbonylmethyn-2-(2-methoxyethoxy-4- methoxyphenvn-4-(1.3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid
  • 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2- methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid, m.p. 63-65 °C.
  • Example 123 frans.frans-1-f2-fN-Propyl-N- l 2.4-dimethylbenzenesurfonynamino.ethvn-2-(4- methoxyphenyn-4-f1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-90 °C.
  • Example 124 frans.frans-1- l 2-fN-Propyl-N-(3-chlcropropylsulfonvnaminoiethvn-2-(4- methoxyphenyn-4-M .3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 75-76 °C.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof, is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

Description

ENDOTHELIN ANTAGONISTS
This is continuation-in-part application of U.S. patent application 5 Serial No. 08/905,913, filed August 4, 1997 which is a continuation-in- part of U.S. patent application Serial No. 08/794,506, filed February 4, 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/600,625, filed February 13, 1996, which is a continuation-in- part of U.S. patent application Serial No. 08/497,998, filed August 2, i o 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/334,717, filed November 4, 1994, which is a continuation-in-part of U.S. patent application Serial No. 08/293,349, filed August 19, 1994.
1 5
Technical Field
The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and 20 compositions for antagonizing endothelin.
Background of the Invention
Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val
25 bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility i_n vit ro, stimulate mitogenesis in vascular smooth muscle cells i n vitro.
30 contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus i n v itro, increase airway resistance i n vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor i n vitro and i n vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release
35 of renin i n vitro and stimulate release of gonadotropins i n vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 41 1 (1988), FEBS Letters 23J. 440 (1988) and Biochem. Biophys. Res. Commun. 1 54 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial 5 effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 8_3 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic i o effects of intravenously administered cyclosporiπ (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 1 14 (1990)).
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-
15 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber
20 after SAH has also been recently reported (S.ltoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 1 95: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.
25 Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease. For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309. 261 -269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9., 201 -207) have
30 demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 5J., 1 2-27) .
35 Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate cancer (Nelson et al, Nature Medicine 1995, 1 , 944-949), suggesting a role of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists bind tightly to plasma 5 proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.
i o Disclosure of the Invention
In accordance with the present invention there are compounds of the formula (I):
Figure imgf000005_0001
15 wherein
Z is -C(Ri 8)(Ri 9)- or -C(O)- wherein Rι β and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is 20 (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
(d) -CN,
25 (e) -C(0)NHR-| 7 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, 30 (j) alkoxy,
(k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 wherein Rι 6 is loweralkyl, haloalkyl, aryl or dialkylamino, (m) -S(0)2NHC(0)Ri6 wherein R16 is defined as above,
Figure imgf000006_0001
rf o
S
"\
HO
(o)
Figure imgf000006_0002
NT \ s=o
-^ H
(s) H
Figure imgf000006_0003
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-j and R is other than hydrogen;
R3 is (a) R4-C(0)-R5- , R4-Rδa- , R4-C(0)- R5-N(R6)- , R6-S(0)2-R7- or R26-S(0)-R27- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R o)-R8- or -R8a-N(R20)-R8- wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-0-R9- wherein R9 and R9a are independently selected from alkylene;
Rδa is (i) alkylene or (ii) alkenylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i )-Rι o- or -R1 0a-N(R2i )-Rι o- wherein R10 and R1 0a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi;
R4 and Re are independently selected from the group consisting of (i) (Rn )(Ri2)N- wherein R-π and R12 are independently selected from
( 1 ) hydrogen,
(2) loweralkyl,
(3) haloalkyi, (4) -alkoxyalkyl,
(5) haloalkoxyalkyi ,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyl , (9) cycloalkylalkyl ,
( 1 0) aryl ,
(1 1 ) heterocyclic, (12) arylalkyi,
(13) (heterocyclic)alkyl,
(14) hydroxyalkyi,
(15) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl, and
(20) carboxyalkyl, ϋ) loweralkyl, iii) alkenyl, iv) alkynyl, v) cycloalkyi, vi) cycloalkylalkyl, vii) aryl, viii) arylalkyi, ix) heterocyclic, x) (heterocyclic)alkyl, xi) alkoxyalkyl, xii) hydroxyalkyi, x i i i ) haloalkyi, xiv) haloalkenyl, xv) haloalkoxyalkyi, xvi) haloalkoxy, xvii) alkoxyhaioalkyl, xviii) alkylaminoalkyl, xix) dialkylaminoalkyl, xx) alkoxy, and
Figure imgf000008_0001
(xxi) wherein z is 0-5 and R7a is alkylene; R26 is (i) loweralkyl, (ii) haloalkyi, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyi, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyi, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyi; and
R27 is alkylene or alkenylene;
(b) R22~0-C(0)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond,
(ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl,
(c) loweralkyl, (d) alkenyl,
(e) alkynyl,
(f ) cycloalkyi,
(g) cycloalkylalkyl, (h) aryl, ( i ) arylalkyi,
( j ) aryloxyalkyl,
(k) heterocyclic,
( I ) (heterocyclic)alkyl,
(m) alkoxyalkyl, (n) aikoxyalkoxyalkyi, o r
(0) R1 3-C(0)-CH(R1 4)- wherein R13 is amino, alkylamino or dialkylamino and R1 4 is aryl or R-| 5-C(0)- wherein R15 is amino, alkylamino or dialkylamino ; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula ( I I )
Figure imgf000009_0001
wherein the substituents -R2, -R and -R1 exist in a trans, trans relationship and Z, n, R, R1 , R2, and R3 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- , R6-S(0)2-R7- or R26-S(0)-R27- wherein R4, R5, R6> R7, R26 and R27 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or aikoxyalkoxyalkyi.
A more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- wherein R4 is (R-ι ι )(Ri2)N- as defined above and R5 is alkylene or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein R7 is alkylene, R27 is alkylene and RQ and R26 are defined as above.
Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R -C(0)-N(R2o)-Rδ- or R6-S(0)2-N(R ι )-Rι o- wherein R8 and R , o are alkylene and R4, Re, R20 and R21 are defined as above.
An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is
-C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH -,
R 1 and R are independently selected from (i) loweralkyl, (ii) cycloalkyi, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyi, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N- alkylaminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (R-ι ι )(R-i2)N- wherein R^ and R12 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl, arylalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R5 is alkylene; or R3 is R4-C(0)-N(R2o)-Rδ- or Rβ-S(0)2-N(R2i )-Rι o- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and Re is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi, R8 and R10 are alkylene and R20 and R21 are loweralkyl; or R3 is R8-S(0)2-R7- or R26-S(0)-R27- wherein RQ is loweralkyl or haloalkyi, R7 is alkylene, R26 is loweralkyl and R27 is alkylene.
A yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
(iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyi,
(xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted
1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-N(R2o)-Rδ- or R6-S(0) -N(R ι)-Rι o- wherein R8 and R1 0 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and RQ is loweralkyl, haloalkyi, alkoxyalkyl, aryl or arylalkyi.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
(iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl,
3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- methoxyphenyl,
3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyi,
(xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rδ- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R^ and R1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl, arylalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(0)2R16 wherein R16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) aryl, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R^ is loweralkyl and R-| 2 is aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl, (vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,
1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl,
8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2i)-Rι o- wherein R-i o is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
NHS(0)2R16 wherein R16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) substituted or unsubstituted
4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl o r
1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyi, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl, or (ix) phenyl, R2 is substituted or unsubstituted
1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R8-S(0)2-N(R2i )-Rι o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi.
Another yet more preferred embodiment of the invention is a = compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0)2R1 6 wherein R1 6 is loweralkyl or haloalkyi, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyi,, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
A still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R-| 6 wherein R1 6 is loweralkyl or haloalkyi, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,
4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,
(ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl,
(vi) arylalkyi, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl, or (ix) phenyl, R2 is 1 ,3-benzodioxolyl,
1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rδ- wherein R5 is alkylene and R4 is (Rι ι )(Ri 2)N- wherein R-d and R12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0)2R-| 6 wherein R1 6 is loweralkyl or haloalkyi, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyi, (N- alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
A most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rι ι )(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl .
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rδ- wherein R5 is alkylene and R4 is (Rι ι )(R-i 2)N- wherein R^ is loweralkyl and R1 2 is aryl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4- methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2i)-Rι o- wherein R-i o is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi and R21 is loweralkyl, haloalkyi or alkoxyalkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyi, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-Rδ- wherein R5 is alkylene and R4 is (Rι ι )(R-i 2)N- wherein R is alkyl and R1 2 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N- alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (R-ι ι )(R-i2)N- wherein R and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R and R12 is alkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rδ- wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is loweralkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkenyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is heterocyclic (alkyl), and R3 is R4-C(0)-Rs- wherein R4 is (Rι ι )(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is arylalkyi, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryl, and R3 is R4-C(0)-Rδ- wherein R4 is (R-ι ι)(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is (N- alkanoyl-N-alkyl)aminoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rι ι )(Ri2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (Rι ι )(Ri2)N- as defined therein and R5 is alkylene.
The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30. The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981 ), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are Ci to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyi; alkenyl; cycloalkyi and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentyimethyl and the like; arylalkyi, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaieryloxymethyl, 1 - (propionyloxy)-l -ethyl, 1 -(pivaloyloxyl)-l -ethyl, 1 -methyl-1 - (propionyloxy)-l-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxy methyl, cyclobutylcarbonyloxymethyl, 5 cyclopentylcarbonyloxymethyl, cyciohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2- benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 - ι o methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 - ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and
15 the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl,
2o diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1 ,3- dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4- yl)methyl and the like; and (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein
25 refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby
30 incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyi, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
35 sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyioxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methyiethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyi, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like. The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
The term "alkanoyloxyalkyl" as used herein refers to R30-O-R31- wherein R30 is an alkanoyl group and R31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 - methyl-2-buten-1 -yl and the like. The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -
5 CH2CH=CHCH2-, and the like.
The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-0-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. i o The term "alkoxy" as used herein refers to R41O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term "alkoxyalkoxy" as used herein refers to R8u0-R8-| 0- wherein R8u is loweralkyl as defined above and R8ι is alkylene. 15 Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term "aikoxyalkoxyalkyi" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative examples of aikoxyalkoxyalkyi groups include 20 methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. 25 The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. The term "alkoxycarbonylalkenyl" as used herein refers to an 30 alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like. The term "alkoxycarbonylalkyl" as used herein refers to R34-C(0)-R35- wherein R34 is an alkoxy group and R35 is an alkylene 35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like. The term "alkoxycarbonylaminoalkyl" as used herein refers to R38-C(0)-NH-R39- wherein R38 is an alkoxy group and R39 is an alkylene group.
The term "alkoxycarbonyloxyalkyl" as used herein refers to R36-C(0)-0-R37- wherein R36 is an alkoxy group and R37 is an alkylene group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term "alkoxyhaloalkyl" as used herein refers to a haloalkyi radical to which is appended an alkoxy group.
The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "(N-alkanoyl-N-alkyl)aminoalkyP as used herein refers to Rδ5C(0)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
The term "alkylamino" as used herein refers to R51 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like. The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group. The term "alkylaminocarbonylaminoalkyl" as used herein refers to R40-C(O)-NH-R4i- wherein R40 is an alkylamino group and R41 is an alkylene group.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH2-,
-CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2C(CH3)2CH2- and the like.
The term "alkylsulfonylamidoalkyl" as used herein refers R88S(0)2NHR89- wherein R88 is loweralkyl and Rβ9 is alkylene. The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(0)2-NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like. The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -C=C-H, H-C≡C-CH2-, H-C≡C-CH(CH3)- and the like.
The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C≡C-, -C≡C-CH2-, -C≡C-CH(CH3)- and the like.
The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
The term "aminocarbonyl" as used herein refers to H2N-C(0)- .
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH2C(0)-) group. The term "aminocarbonylalkoxy" as used herein refers to
H2N-C(0)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH2C(0)-) group. The term "trialkylaminoalkyl" as used herein refers to (R90)(R91 )(R92)N(Rg3)- wherein R90, R91 , and R92 are independently selected from loweralkyl and R93 is alkylene.
The term "aroyloxyalkyl" as used herein refers to R32-C(0)-0-R33- wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyi, haloalkoxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyciic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
The term "arylalkoxy" as used herein refers to R42O- wherein R42 is an arylalkyi group, for example, benzyloxy, and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "arylalkyi" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "aryloxy" as used herein refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the like.
The term "arylalkylcarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R62C(0)0- wherein R62 is an arylalkyi group). The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde 5 radical, -C(0)H.
The term "carboxy" as used herein refers to a carboxylic acid radical, -C(0)OH.
The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously i o defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3- carboxy-1 -ethenyl and the like.
The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, 15 carboxyethoxy and the like.
The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group.
Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
20 The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R60-C(O)-O- wherein R60 is a cycloalkyi group).
The term "cycloalkyi" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not 25 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyi groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and 3o carboxamide.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyi group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl .
The term "dialkylamino" as used herein refers to R56R57N- 35 wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like. The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent 5 molecular moiety through a carbonyl (-C(O)-) linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group. i o The term "dialkylaminocarbonylalkyl" as used herein refers to
R50-C(O)-R5i- wherein R50 is a dialkylamino group and R51 is an alkylene group.
The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.
The term "haloalkenyl" as used herein refers to an alkenyl radical 15 to which is appended at least one halogen substituent.
The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like. 20 The term "haloalkoxyalkyi" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.
The term "haloalkyi" as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or 25 pentafluoroethyl and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7- membered ring containing one, two or three nitrogen atoms; one oxygen 30 atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The 35 nitrogen heteroatoms can be optionally quatemized. The term
"heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
Heterocyclics also include compounds of the formula
Figure imgf000028_0001
where X* is -CH2- or -O- and Y* is -C(O)- or [-C(R") -]V where R" is hydrogen or Cι -C4-alkyl and v is 1 , 2 or 3 such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=0), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyi, cycloalkyi, aryl, arylalkyi, -COOH, -SO3H , alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term "(heterocyclic)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4- pyridylmethoxy, 2-pyridylmethoxy and the like. The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above. The term "heterocycliccarbonyloxyalkyl" as used herein refers to R46-C(0)-0-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
The term "hydroxy" as used herein refers to -OH. The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4- hydroxybutoxy and the like.
The term "hydroxyalkyi" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term "leaving group" as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
The term "mercapto" as used herein refers to -SH.
The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the
formation of a benzodioxolyl radical. O Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl
radical
Figure imgf000029_0001
The term "substantially pure" as used herein means 95% or more of the specified compound.
The term "tetrazolyl" as used herein refers to a radical of the formula
N- N
Λ-V' N or a tautomer thereof. The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like. The term "thioalkoxy" as used herein refers to R70S- wherein R70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The term "thioalkoxyalkoxy" as used herein refers to R8uS-R8-| 0- wherein R8u is loweralkyl as defined above and R8ι is alkylene. Representative examples of alkoxyalkoxy groups include CH3SCH20-, EtSCH20-, t-BuSCH20- and the like.
The term "thioalkoxyalkoxyalkyi" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of aikoxyalkoxyalkyi groups include CH3SCH2CH2OCH2CH2-, CH3SCH2OCH2-, and the like.
The term "trans, trans " as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
Figure imgf000030_0001
The term "trans, cis" as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
Figure imgf000030_0002
. This definition encompasses both the case where R and R2 are cis and R and R1 are trans and the case where R2 and R are trans and R and R1 are cis. The term "cis, cis" as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
Figure imgf000031_0001
Preferred compounds of the invention are selected from the group consisting of: 5 fraπs-?ra/7s-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[3-(N- propyl-N-A7-pentanesulfonylamino)propyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-(4-Me\hoxy methoxyphenyl) -4- ( 1 ,3-benzodioxol-5-yl)--
(2-(N-propyl-N-t7-pentanesulfonylamino)ethyl]pyrrolidine-3- ι o carboxylic acid; trans, trans-2- (3, 4-Dimethoxy phenyl) -4- (1 ,3-benzodioxol -5-yl)-1 -[2-
( N-p ropy l-N-π-pen tan esu If ony lam ino)ethy I] pyrrol idine-3- carboxylic acid; ?rat7S,fra/7s-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2- 15 (N-propyl-N-A7-hexanesulfonylamino)ethyl]pyrrolidine-3- carboxyiic acid; tτaA7s, "a/7s-2-(4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N- propyl-N-/7-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; 20 /τat7S, ft-a/7s-2-(3,4-Difl uorophenyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -(N, N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, rraπs-2-(3,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N- propyl-N-π-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; 25 trans, trans-2-(3 -Fluoro-4-methoxyp he ny I )-4-(1 ,3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-/7-hexanesulfonylamino)ethyl]pyrrolidine-3- carboxylic acid; ?ra/7s, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)- 30 pyrrolidine-3-carboxylic acid ; trans, raπs-2-(3-Fiuoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-isobutyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; WO 99/06397 _ 3°" PCT/US98/15479
frans, rrat7S-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; frat7s, fra/7s-2-(4-Methoxy-3-fl uorophenyl)-4-(7-methoxy-1 ,3- 5 benzodioxol-5-yl)-1 -[2-(N-propyl-N-(/7- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; tra ns, trans-2- (3- Fluoro-4-methoxy phenyl) -4- (1 ,3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-(2, 2,3,3, 3-pentaf luoropropoxyeth anesulf onyl)- amino)ethyl]pyrrolidine-3-carboxylic acid; i o trans, trans-2-(Λ ,4-Benzodioxan-6-yl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)- 1 -[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; tra t7s,ιτa/7S-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3- 15 carboxylic acid;
?rat7s,ιτat7s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)- ethyl)pyrrolidine-3-carboxylic acid; trans, fraπs-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 20 1 -(2-(N-(2-methoxyethyl)-N-
(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; frat7s, fraπs-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)su lfonyl)amino)- ethyl]pyrrolidine-3-carboxylic acid; 25 fra/7s,frat7s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)- pyrrolidine-3-carboxylic acid; fra/7s,frat7s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5- yl)-1 -[2-(N-propyl-N-(2- 3o methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- (3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3- carboxylic acid; fra/7s, ?rat7s-2-(2-Methylpentyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -(N ,N-di(n- 35 butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, rra/7S-2-(2,2-Dimethylpentyl)-4-( 1 ,3-benzodioxol-5-y I)- 1 -(N , N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, fra/7s-2-(2-(1 , 3-D ioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-y I)- 1 -
(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, frat?s-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1 ,3-benzodioxol- 5-yl)- 1 - (N,N-di( n-buty I) aminocarbonyl methyl) -pyrrol id ine-3- carboxylic acid; trans, tτaπs-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frat7S,?/-at7S-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(N,N-di(π-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-{2-{ ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -
[[Λ/-4-heptyl-Λ/(2 methyl-3-fluorophenyl)] amino carbonylmethylj- pyrrolidine-3-carboxylic acid; trans, trans-2-{2-( ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; fraπs, raπs-2-((2-Methoxyphenoxy)-methyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -( N, N-d i (n-b uty I) am inocarbony I methyl) -pyrrol id ine-3 -carboxy lie acid; t'2S, 3 .,4S;-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-4- heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; frat7s, raπs-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, trans-2-{2-{λ ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluo ro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; raπs,?rans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5- y I)- 1 -(N, N-d i (n-b uty I) aminocarbonyl methyl ) -pyrrol idine-3- carboxylic acid; trans, trans-2- (2, 2-di met hylpentyl)-4-(2, 3-d i hydro-be nzofuran-5-y I) -
1 -(N, N-d i(n-butyl)am inocarbony I methyl)-pyrro I idine-3-carboxy lie acid; frans, fraπs-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(7- methoxy-1 ,3-benzodioxol-5-yl)-1 -(N,N-di(n- buty I) am inocarbony I methyl)-pyrrolidine-3-carboxy lie acid; ιτaA7S, £τaπs-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)- 5 1 -(N,N-di(n-buty I) am inocarbony I methyl)-pyrrolidine-3-carboxy lie acid; trans, rrans-2-(2,2-Dimethyl-3-(fJ-pentenyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; i o trans, frat7S-2-(2-(2-pyridyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -(N, N- di( n-b uty l)am inocarbony I methyl)-pyrrolidine-3-carboxy lie acid; (2S, 3R, 4S -2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5- y I)- 1 -(N, N-d i( n-b uty I) am inocarbony I methyl ) -pyrrol id in e-3- carboxylic acid; 15 {2S, 3R, 4S)-2-(2-(2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 - (N-4-heptyl-N-(4-f l uoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, fraπs-2- (2-( 1 -pyrazoly I) ethyl) -4- (1 ,3-benzodioxol-5-yl)-1 -(N ,N- 20 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (4- Methoxyp he ny I )-4-(1 ,3-benzodioxo l-5-yl)- 1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; f.? :?,3/:?,4S -2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl) 1 - 25 (2-( N-p ropy l-N-pentanesu If ony lam in o) ethyl) -pyrrol idine-3- carboxylic acid; rans; frans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -((N- butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; 3o trans, trans-2- (2, 2-Dimethylpenty I) -4-(7-methoxy-1 ,3-benzodioxol-5- yl)- 1 -(N-4-heptyl-N-(4-f l uoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans, ?rans-2- (2, 2-Dimethylpenty I) -4- (7-methoxy- 1 ,3-benzodioxol-5- 35 yl)-1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; frans, .τat7S-2-(2,2-Dimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -
(N-4-heptyi-N-(4-f I uoro-3-methylpheny I)) am inocarbony Imethyl)- pyrrolidine-3-carboxylic acid; fraπs, fraπs-2- (2, 2-Dimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-1 - 5 ((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; frans, frat7s-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N, N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; i o fraπs, ?raπs-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fraπs, frans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3- 15 benzodioxol-5-yl)-1 -((N-butyl-N-(4- d i met hy la mi no)b uty I )am inocarbony I methyl ) -pyrrol idine-3- carboxylic acid; frans, £τat7s-2-(2,2,4-Trimethyipent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N-4-heptyl-N-(4-fluoro-3- 20 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frat7s, fraπs-2-(2,2,4-Trimethylpent-3-enyl)-4-( 1 ,3-benzodioxol-5-yl)-
1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; 25 trans, trans-2-(2, 2 , 4-Tri methyl pent-3-eny I )-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; fra/7s, frans-2-(2 ,2 ,4-Trimethylpent-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4-fluoro-3- 30 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra/7s, ?rans-2-(2 ,2 ,4-Trimethylpent-3-enyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -((N-butyl-N-(4- dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3- 35 carboxylic acid; trans , fraπs-2-(2-(1 ,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1
[(N-butyl-N-(4-di methy lam inobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- 5 benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; fraπs, fraπs-2-(2, 2, -Dimethyl-2-(1 , 3-Dioxol-2-yl)ethyl)-4-( 1 , 3- benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4-fluoro-3- ι o methy Iphe ny I) )am inocarbony I methy I) -pyrro lid ine-3-carboxy lie acid; trans, ?raπs-2-(2 ,2-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- 15 carboxylic acid; trans, trans-2-(2, 2, -Di methy l-2-(1 ,3-Dioxo l-2-yl)ethyl)-4- (7- methoxy-1 ,3-benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 20 trans, trans-2- (2, 2-Dimethyl-2-( 1 ,3-dioxolan-2-y l)ethyl)-4-(7- methoxy-1 ,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; fraπs,rra is-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)- 25 1 - (N-4-heptyl-N- (4-fluoro-3- methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)-
1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- 30 pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 - (N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, ?ra/7s-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1 ,3- 35 benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, t rans-2- (2- (2-Methoxy phenyl) -ethyl) -4- (7- methcxy-1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; 5 trans, trans-2-( (2- Methoxyphenoxy) -met hyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))amino)carbonyl methy l]-pyrrolidine-3-carboxy lie acid; trans, trans-2- ( (2- Methoxyph en oxy)-methy I) -4- (1 ,3-benzodioxol-5-yl)- ι o 1 -[(N-b utyl-N-(4-di methy la mi no butyl) ami no)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, trans-2-((2-WΛei oxyp he noxy)- methy I) -4- (7-methoxy-1 ,3- benzodioxol-5-yl)-1 - (N,N-di(n-buty I) am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; 15 trans, fra/7s-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fraπs, .τat7s-2-(2-(2-Methoxyphe noxy )-methyl)-4-(7-methoxy- 1 ,3- 20 benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-(2-{2-Oxo 1 ,2-dihydro pyridin-1 -yl)-ethyl)-4-(1 ,3- benzodioxol-5-y I)- 1 -(N,N-di(n-buty I) am inocarbony I methy I) - 25 pyrrolidine-3-carboxyiic acid; trans, trans-2-(2- (2-Oxo py rid in- 1 -yl)-ethyl)-4-( 1 ,3-benzodioxol-5- yl)- 1 -[ (N-4-hepty l- N-(4-f l uo ro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid ; 30 trans, fraπs-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-(1 ,3-benzodioxol-5- yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; fra 7S, frat7s-2-(2-(2-Oxopyridin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)- 1 -(N,N-di(N-butyl)aminocarbonylmethyl)- 35 pyrrolidine-3-carboxylic acid ; frans, frat7s-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-(2-Oxopyridin- 1 -yl)-ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; <τaπs, .rat7s-2-(2(-2-Oxopiperidin-1 -yl)-ethyl)-4-( 1 ,3-benzodioxol-5- yl)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, fraπs-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, /raπs-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3- be nzodioxol-5-y I)- 1 -(N,N-di(N-buty l)am inocarbony Imethyl)- pyrrolidine-3-carboxylic acid; trans, frat7s-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frat7S; fra/7s-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; fratjs, rat7s-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)-1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid ; tτa/7S, tτaπs-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; i7at7s, tτa/7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; frans, "a/7S-2-(2- (2-Oxo pyrro I idin- 1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 -[(N-butyl-N-(4- trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; 5 ?raπs, rrat7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, /τa/7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(3- ι o hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, tτa/7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic 15 acid; rrat7s, fra/7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-
(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, ?raπs-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy- 1 ,3- 20 benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, frans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- 25 trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-{2-{2-Oxopyrro I idin-1 -yl)ethy I )-4- (2, 3-di hydro- be nzofuran-5-y I)- 1 -(N, N-d i(N-butyl)am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; 30 trans, trans-2-{2-(2-Oxopyrro I id in- 1 -y I) ethyl)-4-(2, 3-di hydro- be nzofuran-5-y I)- 1 -[(N-4-hepty l-N-(4-f I uoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid ; fraπs; frat7S-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(2,3-dihydro- 35 benzofuran-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; ?raπs, rrat7s-2-(2-(3,3-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)- yrrolidine-3-carboxylic acid; trans, rraπs-2-(2-(3,3-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- 5 benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/7S, /τat7S-2-(2-(3,3-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- ι o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, ?raπs-2-(2-(4,4-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- be nzodioxoi-5-y I)- 1 -(N,N-di( N-b uty l)am inocarbony I methy I) - pyrrolidine-3-carboxylic acid; 15 trans, trans-2-(2- (4,4- Di methy l-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-(4,4-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3- 20 benzodioxol-5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; raπs, frat7s-2-(2-(1 -propanesultamyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N, N-dibutylamiπocarbonylmethyl)-pyrrolidine-3-carboxylic 25 acid;
?raA7s, fra/7s-2-(2-(1 -propanesultamyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[(N-4-heptyl-N-(4-fl uoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; 30 trans, frans-2- (2-(1 -propanesultamy I) ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1 -propanesultamy I) ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3- 35 carboxylic acid; fΛa/7s, ?rat7s-2-(2-(1 -propanesultamyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidiπe-3-carboxylic acid; frans, fra/7S-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy- 1 ,3- 5 benzodioxol-5-y I)- 1 -(N,N-di(n-buty I) aminocarbonyl methy I)- pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( -propanesultamyl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethylj-pyrrolidine-3-carboxylic i o acid; trans, tranε-2- (2- (l -propanesultamyl)ethy I) -4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; 15 trans, trans-2- (2- (1 -pro panes ulta my I) ethyl ) -4- (2, 3-di hydro- be nzofuran-5-y I)- 1 -(N, N-d i(n-buty I) am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; trans, frat7s-2-(2-(1 -propanesultamyl)ethy I )-4- (2 , 3-di hyd ro- benzofuran-5-yl)- 1 -[(N-4-heptyl-N-(4-fl uoro-3- 20 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, rrat7s-2-(2-(1 -propanesultamyl)ethyl)-4- (2, 3-di hyd robe nzofu ran -5-y I)- 1 -[(N-butyl-N- (4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- 25 carboxylic acid; trans, rraπs-2-(2-( 1 -pyrazo ly I) ethyl)-4-( 1 ,3-benzodioxoi-5-yl)-1 -[(N- 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; tra t7s, frans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[(N- 3o butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, rat?s-2-(2-(1 -pyrazo ly I) ethyl) -4- (1 ,3-benzodioxol-5-yl)- 1 -(N- butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; 35 frat7s, rat7S-2-(2-( 1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonyimethyl]- pyrrolidine-3-carboxylic acid; f raπs, ?ra/7S-2-(2-(1 -pyrazoly I) ethyl) -4- (7- met hoxy- 1 ,3-benzodioxol- 5-yl)-1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, ra t?s-2-(2-(1 -pyrazoly I) ethyl) -4- (7- met hoxy- 1 ,3-benzodioxol- 5 5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; rrans, rrat7S-2-(2-(1 -pyrazolyl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol- 5-yl)- 1 -[(N-butyl-N-(4- ι o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, frat7S-2-(2-( 1 -py razolyl)ethy l)-4- (2, 3-di hydro-be nzofuran-5-y I)- 1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 15 trans, trans-2-{2-{ \ -pyrazolyl)ethy l)-4- (2, 3-di hydro-be nzofu ran -5-y I)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans, frans-2-(2-(1 -pyrazolyl)ethyl)-4-(2, 3-di hyd ro-benzofu ran-5-yl)- 20 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, fra/7S-2-(2-(2-oxazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N ,N- di(n-b uty l)aminocarbonyl methy l)-pyrrolidine-3-carboxy lie acid; /-a/7s, rrat7S-2-(2-(Oxazol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -[(N- 25 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, fra/7S-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-y I)- 1 -[(N- butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; 30 rans, f/-aπs-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[(N- butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, frat7s-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-y I)- 1 -[(N- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- 35 pyrrolidine-3-carboxylic acid; O 99/06397
trans, ?ra/7s-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol- 5-y I)- 1 -(N, N-d i( n-b uty I )am inocarbony I methy l)-pyrro I idine-3- carboxylic acid; trans, trans-2- (2- (Oxazol-2-y I )ethy I )-4- (7- met hoxy- 1 ,3-benzodioxol- 5-yl)- 1 -[(N-4-heptyl-N-(4-fl uoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/7S,frans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- 5-yl)- 1 -[(N-butyl-N-(4- d i methy lam i nob uty l)ami no) carbony I methy l]-pyrro lid ine-3- carboxylic acid; fraπs, ?raπs-2- (2- (5-Methy I oxazol-2-y I) ethyl)-4-( 1 ,3-benzodioxol-5- y I)- 1 -(N, N-d i( n-b uty I) am inocarbony I methy I ) -pyrrol idine-3- carboxylic acid; trans, trans-2- (2- (5-Methyloxazol-2-y I) ethyl)-4-( 1 ,3-benzodioxol-5- yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frat7S, frat7S-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5- yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; fraπs, ra/7S-2-(2-(2,5-Dioxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3-benzodioxol- 5-y I)- 1 -(N, N-d i(n-buty I )am inocarbony I methy l)-pyrro lid ine-3- carboxylic acid; Tra /7s, iTa/7S-2-(2-(2,5-Dioxopyrro lid in- 1 -y I) ethyl) -4- (1 ,3-benzodioxol- 5-yl)- 1 -[(N-4-heptyl-N-(4-fl uoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,rrat)s-2-(2-(2,5-Dioxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3-benzodioxol- 5-y I)- 1 -[( N-b uty l-N- (3- hydroxy propy I) ami no) carbony I methy I]- pyrrolidine-3-carboxylic acid; trans, trans-2-{2-(2, 5- Dioxopyrro lid in-1 -y I) ethyl)-4-(1 ,3-benzodioxol- 5-y I)- 1 -[( N-b uty l-N- (pro poxy) ami no) carbony I methy l]-pyrro lid ine- 3-carboxylic acid; fra/7s, fraπs-2-(2-(2,5-Dioxopyrrolidin- 1 -yl)ethyl)-4-(1 ,3-benzodioxol- 5-yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; ra/7s, fra/7S-2-(2-(2,5-Dioxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; ?rat7S, fraA7S-2-(2-(2,5-Dioxopyrrolidin- 1 -yl)ethyl)-4-(7-methoxy-1 ,3- 5 benzodioxol-5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-y I)- 1 -[(N-
4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]- ι o pyrrolidine-3-carboxylic acid; trans, <τa/7S-2-(2-(Pyridin-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-y I)- 1 -[( N- butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3- carboxylic acid; trans, fraπs-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[(N- 15 butyl-N-(propoxy)amino)carbonyimethyl]-pyrrolidine-3-carboxylic acid; trans, raπs-2-(2-(Pyridin-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-y I)- 1 -[(N- b uty l-N- (4-di methy I ami nob uty I) ami no) carbony I methy I]- pyrrolidine-3-carboxylic acid; 20 fraπs, ?raπs-2- (2- (Pyr id in-2-y I) ethyl) -4- (7- methoxy-1 ,3-benzodioxol-
5-y I)- 1 -(N, N-d i(n-butyl)am inocarbony I methy l)-pyrro I idine-3- carboxylic acid; fraπs, rraπs-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)- 1 -[(N-4-heptyl-N-(4-fluoro-3- 25 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid ; frat7S, fra/7s-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-
5-yl)- 1 -[(N-butyl-N-(4- dimethylaminobutyl)amino) carbony I methy l]-pyrrol idine-3- 30 carboxylic acid; trans, fraπs-2-(2-(Pyrimidi n-2-yl)ethyl)-4-( 1 ,3-benzodioxo l-5-yl)- 1 -
( N , N-di(n-buty I) am inocarbony I methy l)-pyrro I id ine-3-carboxy lie acid; rra/7S, frans-2-(2-( Pyrimidin-2-yl)ethyl)-4-( 1 , 3-benzodioxo l-5-yl)- 1 - 35 [(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]- pyrrolidine-3-carboxylic acid; rraπs, ?raπs-2-(2-(Pyrimidin-2-y I) ethyl) -4- (1 ,3-benzodioxol-5-yl)-1-
[( N-buty l-N- (4-di methy lam inobutyl)ami no) carbony I methy I]- pyrrolidine-3-carboxylic acid; trans, fraπs-2- (2-(1 ,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol-5- y I)- 1-(N, N-d i (n-buty I) am inocarbony I methy l)-pyrrolidine-3- carboxylic acid; trans, fra/7S-2-(2-(1 ,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol- 5- yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methy lphenyl)ami no) carbony I methy l]-pyrrolidine-3-carboxy lie acid; and trans, trans-2-{2-(i ,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol-5- y I)- 1-[( N-buty l-N-(4 dimethylaminobutyl)amino) carbony Imethyl]- pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N- di(n-b uty l)am inocarbony I methy l)-pyrrolidine-3-carboxy lie acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(N,N-di(n-b uty l)aminocarbonyl methy l)-pyrrolidine-3-carboxy lie acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3- be nzodioxol-5-y I)- 1-(N, N-d i (n-buty I) am inocarbony I methy I) - pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-'((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-
1-(N,N-di(n-b uty I) am inocarbony I methy l)-pyrrolidine-3-carboxy lie acid; (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-
(N,N-di(n-butyl)am inocarbony lmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt.
Most preferred compounds of the invention are selected from the group consisting of:
?rans,fra/7s-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 - (N,N-di (n-buty l)am inocarbony I methy l)-pyrrol id ine-3-carboxy lie acid; frat7s, ?ra 7s-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonyimethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-{2-{J ,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 5 -1 -[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] am inocarbony I methy l]-pyrrolidine-3-carboxy lie acid; trans, trans-2-{2-{ ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- benzod ioxol-5-y I) -1 -(N, N-d i (n-buty I) am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; i o trans, fraπs-2-((2-Methoxyphe noxy) -methy I) -4- (1 ,3-benzodioxol-5-yl)-
1 -( N, N-d i (n-b uty I) am inocarbony I methy I) -pyrrol id ine-3-carboxy lie acid; fra/7s, fra/7s-2-(2-(2-Oxopyrrolidiπ- 1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- 15 carboxylic acid; trans, trans-2-(2-C\ ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)- 1 -(N-4-heptyl-N-(4-fluoro-3- methy Ipheny I) jam inocarbony I methy l)-pyrro lid ine-3-carboxy lie acid; 20 fraA7s, fra/7s-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5- y I)- 1 -(N, N-d i (n-buty l)aminocarbony I methy l)-pyrrol idine-3- carboxylic acid; fraA7s, fra/7s-2-(2,2,-Di methy l-2-(1 , 3-dioxolan-2-yl)ethyl)-4-(7- methoxy-1 ,3-benzodioxol-5-yl)-1 -(N,N-di(n- 25 butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra/7s,frat7s-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, fra/7s-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1 ,3- 30 benzodioxol-5-yl)-1 -(N, N-di (n-buty l)aminocarbony I methy I)- pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-y I)- 1 -(N , N- di (n-b uty I) aminocarbonyl methy l)-pyrrolidine-3-carboxy lie acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- 35 y I)- 1 -(N, N-d i (n-buty I) aminocarbonyl methy I ) -pyrrol id i ne-3- carboxylic acid; (2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5- y I)- 1 -(N,N-di(n-b uty l)am inocarbony I methy l)-py rrolidi ne-3- carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-py rrolidi ne-3-carboxy lie acid; fra/7s, fra/7S-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N ,N- di (n-buty l)aminocarbony I methy l)-py rrolidi ne-3-carboxy lie acid; (2R, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[((N-p ropy l-N-pentanesu If onyl)ami no) ethyl]-py rrolidi ne-3- carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(N, N-d i (n-b uty I) am inocarbony I methy I) -pyrro I idine-3 -carboxy lie acid; (2S,3 R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3- be nzod ioxol-5-y I)- 1 -(N,N-di (n-buty I) am inocarbony I methy I) - pyrrolidine-3-carboxylic acid ;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-beπzodioxol-5-yl)-
1 -(N, N-d i (n-b uty I) am inocarbony I methy l)-pyrrolidine-3-carboxy lie acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 - ( N , N-d i (n-buty I) am inocarbony I methy I) -pyrro I id in e-3-carboxy lie acid;
or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of the invention are shown in Schemes l-XV.
Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -CO2H. A β-ketoester J_, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3_ is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4_. Reduction of 4. (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5_ as a mixture of cis-cis, trans, trans and cis, trans products. Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans, trans and cis, trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans, trans isomer and then carried on as described below. The pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(0)- or Rβ-S(0)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(0)- or R6-S(0)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, Cl, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 6_ which is still a mixture of trans, trans and cis, trans isomers. Hydrolysis of the ester 6_ (for example, using a base such a sodium hydroxide in EtOH/H2θ) selectively hydrolyzes the trans, trans ester to give a mixture of Z and 8_, which are readily separated.
Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1 , m is 0, Z is -CH2- and W is -CO2H. A substituted benzyl chloride 9_ is reacted with a lithio dithiane 1_ in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct U.. The anion of compound J_L is formed using a base such as n-butyllithium and then reacted with R1 -CH2-X' wherein X' is a WO 99/06397 " 4 ? " PCT/US98/15479
leaving group such as a halide or sulfonate to give compound J_2. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound j_3. Reaction of ketone J_3 with benzyl amine and formaldehyde gives the keto piperidine compound 1_4. 5 Treatment of compound 4 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles 1_5. Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile J_6. Hydrolysis of the nitrile using i o hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester J_7 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound J_8. Compound 1 8 is further elaborated by the procedures described in Scheme I for
15 compound 5. to give the final product compound J_9.
Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -CO2H. β-Keto ester 2_0 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an α-haloester 2J_ (where J is lower
20 alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert- butoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 2£. Treating compound 2_2 with R3-NH2 and heating in acetic acid gives the cyclic compound 2_3. The double
25 bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 2j4. Epimerization with sodium ethoxide in ethanol to give the desired trans, trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans, trans
30 carboxylic acid 2_5.
Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1 , Z is -CH2- and W is -CO2H. The trans,trans compound Z, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is
35 activated (for example, by making the acid chloride using thionyl chloride) to give compound 5_2, where L is a leaving group (in the case of an acid chloride, L is Cl). Compound 5_2 is treated with diazomethane to give the diazo ketone 5J3. Rearrangement of compound 5_3 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 5_4 or an ester which may be
5 hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process.
A preferred embodiment is shown in Schemes V and VI. A benzoyi acetate 2_6 is reacted with a nitro vinyl benzodioxolyl compound 2J_ using 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to i o give compound 2J3. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 2_9. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 3_0 as a mixture of cis-cis, trans, trans and cis, trans isomers. Chromatography separates
15 out the cis-cis isomer, leaving a mixture of the trans, trans and cis, trans isomers (31).
Scheme VI illustrates the further elaboration of the trans, trans isomer. The mixture (3 1) of trans, trans and cis, trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in
2o acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 3_2, still as a mixture of trans, trans and cis, trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans, trans compound but leaves the ethyl ester of the cis, trans compound untouched, thus allowing separation of the
25 trans, trans carboxylic acid 3_3 from the cis, trans ester 3_4.
Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 3_5 is reacted with lithio dithiane 3_6 to give the alkylated compound 3_Z. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium
30 diisopropylamide gives compound 3J3. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 3_9 with benzylamine and formaldehyde gives the keto piperidine 4_0. Treatment of compound 4_0 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture
35 of isomers 4±. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 4_2. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 4_3. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 4_4. Compound 4_4 is further elaborated by the procedures described in Scheme V for compound 3J. resulting in the formation of the N-derivatized carboxylic acid 4 >.
5 A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 46, (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl α-bromoacetate 4_7 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48.. i o Treating compound 4j£ with ethoxypropylamine and heating in acetic acid gives the cyclic compound 4_9. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 5_0. Epimerization with sodium ethoxide in ethanol to give the desired trans, trans configuration is followed by sodium hydroxide
15 hydrolysis of the ester to afford the desired trans, trans carboxylic acid 51.
Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid. Compound 5_5, which can be prepared by the procedures described in Scheme IV, is converted (for
20 example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 5_6. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 5_7. Nitrile 5_7 under standard tetrazole forming conditions (sodium azide
25 and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 5_8. Alternatively nitrile 5_Z is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF,
30 DMSO, or dimethylacetamide to give amidoxime 5_9. The amidoxime 5J3 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium
35 carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in cyclization to compound 6_0. Alternatively reacting the amidoxime 5_9 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61. Scheme X illustrates the preparation of compounds in which R3 is an acyimethylene group. A carboxylic acid 6_2 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N- dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the α-chloroketone 63. Pyrrolidine ester 5. where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the α-chloroketone 6.3 to provide alkylated pyrrolidine 6_4. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 6_5.
Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5., prepared in Scheme I, is reacted with a difunctionalized compound X-R8-X where R8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6_6. Treatment of 6_6 with an amine (R20NH2) affords secondary amine 6_7. This amine (67) can be reacted with an activated acyl compound (for example, R4-C(0)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 6_8- Alternatively amine 6_7 can be reacted with an activated sulfonyl compound (for example, R8-S(0)2-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 6_9_. Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters such as Zl to provide pyrrolidines such as compound 7_2 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 5_2 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62. 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 7_3 is reacted with acrylate 7_4 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 7_5 as a mixture of isomers. This method can be modified to provide the N- acetamido derivatives directly by reacting 7_3 and 7_4 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 7_6.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 8J , which can be further elaborated on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester J_7 (for example, prepared by the procedure described in Scheme V) is Boc- nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyi pyrrolidine carboxylic acid 7_8. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 7_9_. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 8_0. Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 8_1 The use of (-)-cinchonine will give the opposite enantiomer.
Scheme XIV describes another procedure for preparation of pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc, Perkin Trans. 1 , 5: 1091-97 (1991 ). Thus, the azomethine ylide precursor 8_2 (where R55 is hydrogen or methyl) is condensed with a substituted acrylate 8_3 (wherein R2 is as described herein and R56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 8_4. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85. which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 8j6. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 8_Z
A preferred process is shown in Scheme XV. Nitro vinyl compound 5 (8_8) is reacted with beta-keto ester 8_9 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a i o temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 9_Q. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day
15 of compound 9_0 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium
20 on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91 a or a mixture of nitrone 91 a and imine 91 b. The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like,
25 and the hydrogenation is continued to give pyrrolidine compound 9_2 as the c/s,c/s-isomer. Epimerization at C-3 is effected by treatment of compound 9_2 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the
3o like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -20° C to about 120° C to give the trans, trans compound 9_3. Compound 9.3 itself can optionally be resolved into enantiomers prior to reacting with X-R3. The substantially pure
35 (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound 9_3 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 9_3 with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+)-isomer of 9_3 selectively crystallizes as the salt, leaving the (-)-isomer of 9_3 in solution. Alternatively, the substantially pure (i.e., 5 at least 95% of the desired isomer) optically active (-)-isomer of compound 9_3 can be selectively crystallized by reaction of a mixture of the
(+)-isomer and the (-)-isomer of 9_3 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired i o (-t-)-isomer of compound 9J3 in solution.
Compound 93 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like
15 in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 9_4. The ester can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide
20 and the like in a solvent such as ethanol-water or THF-ethanol and the like.
A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic β-ketoesters (Scheme XVI) may be prepared by copper-catalyzed addition of a
25 Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding β-ketoester, for example by activation using
30 carbonyldiimidazole and condensation with magnesio-ethoxymalonate. Alternatively, olefinic β-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired β-ketoester. N-alkyl,0-alkyl bromohydroxamates are prepared according to
35 Scheme XVII. N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.
The β-ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH. A mixture of isomers are generated, in which the trans- trans is generally preferred.
Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can be further enriched through recrystallization. The salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid. Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product. Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4- heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-(Ω- hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product. For one particular class of electrophile, N-(Ω-hydroxyalkyl)-N- alkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, followed by displacement with halogen (for example, using lithium bromide) provides the corresponding halide. Displacement of halide with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.
Scheme
Figure imgf000058_0001
[H]
Figure imgf000058_0002
Mixture of
Figure imgf000058_0003
Cis-Cis
Trans-Trans Cis-Trans
R2
Figure imgf000058_0004
Mixture of Trans-Trans
Cis-Trans
Figure imgf000058_0005
Cis-Trans Scheme II
Figure imgf000059_0001
11 ~ 10
Figure imgf000059_0002
MER
Figure imgf000059_0003
18 19 Scheme III
Figure imgf000060_0001
2ft
22
Figure imgf000060_0002
C02H Trans-Trans
Scheme IV
Figure imgf000061_0001
52
CH2N2
Figure imgf000061_0002
0^*CHN2
Figure imgf000061_0003
53
54
Scheme V
Figure imgf000062_0001
Trans-Trans v^ Chromatographic separation Cis-Trans
Figure imgf000062_0002
Cis-Cis + Mixture of Trans-Trans and Cis-Trans
31
Scheme VI
Figure imgf000063_0001
Trans-Trans Cis-Trans
33 34
Scheme VII
Figure imgf000064_0001
4. 41
Scheme VII cont.
Figure imgf000065_0001
Scheme VIII
Figure imgf000066_0001
Trans-Trans Scheme IX
Figure imgf000067_0001
(CH2)m
Figure imgf000067_0002
I C02H CONH2
55 5£
Figure imgf000067_0003
52
Figure imgf000067_0004
go 61 Scheme X
Figure imgf000068_0001
Figure imgf000068_0002
65
54
Scheme XI
Figure imgf000069_0001
66
Figure imgf000069_0002
63 67
Figure imgf000069_0003
Scheme XII
Figure imgf000070_0001
2Q 71 22
Figure imgf000070_0002
73
74
Figure imgf000070_0003
25 76 Scheme XIII
Figure imgf000071_0001
1. (+)-cinchonine
2. recrystallizθ frorr
EtOAc/hexane
3. Na2C03
Figure imgf000071_0002
Bu2NC(0)CH2Br EtNiPr2, CH3CN
Figure imgf000071_0003
Scheme XIV
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000072_0003
86 82
Scheme XV
Figure imgf000073_0001
SS 52
Figure imgf000073_0002
90
Figure imgf000073_0003
92 93
Figure imgf000073_0004
25 94 SCHEME XVI
Figure imgf000074_0001
SCHEME XVII
O
NaH H2 O TFA BrCHaCOBr
BocHN' →~ BocN' ' Br
R-X Pd-C I
R
R
SCHEME XVIII
Figure imgf000074_0002
SCHEME XIX
recrystaliization neutralization
Figure imgf000075_0002
Figure imgf000075_0001
(racemic)
Figure imgf000075_0003
(single enantiomer)
1. EDAC,
Figure imgf000075_0004
(siπgle enantiomer)
Figure imgf000075_0005
Figure imgf000075_0006
(racemic) (single enantiomer) SCHEMEXX
Figure imgf000076_0001
SCHEME XXI
Figure imgf000076_0002
Compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000077_0001
( I I I )
wherein n is 0 or 1 ; m is 0 to 6; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHFh7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2R i 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6,
Figure imgf000077_0002
Figure imgf000078_0001
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonyl alky I, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, R b is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-, and
R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000079_0001
( IV) (V)
wherein n is 0 or 1 ; m is 0 to 6;
W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN, (e) -C(0)NHR-i 7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy,
(k) sulfonamido,
(I) -C(0)NHS(0)2R i 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino,
(m) -S(0)2NHC(0)Rι6,
Figure imgf000079_0002
Figure imgf000080_0001
N-° s=o
-^
(s)
Figure imgf000080_0002
R i and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N"Rcc" wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-| and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1 ;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof. Particularly preferred intermediates are compounds of formula
(III), (IV) and (V) wherein n and m are both 0;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi,
(v) phenyl,
(vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4- methoxyphenyl,
4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4- methylphenyl,
4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- methoxyphenyl,
3-fluoro-4-ethoxy phenyl, 2-fluorophenyl, 4-methoxy methoxyphenyl ,
4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyi)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl,
1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000081_0001
(V I ) wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene;
Q is a leaving group; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi 7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2R i6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6,
Figure imgf000082_0001
Figure imgf000083_0001
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl , dialkylaminocarbonylalkyl , aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000083_0002
(V I I ) (VI II)
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene;
Q is a leaving group;
W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHR-|7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2R i 6 where R-|6 is loweralkyl, haloalkyi, phenyl or dialkylamino,
(m) -S(0)2NHC(0)R 6,
Figure imgf000084_0001
N-°s s=o
-^
(s)
Figure imgf000085_0001
Ri and R2 are independently selected from hydrd'gen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-, and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein m is zero or 1 ; R5b is alkylene;
Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof. Particularly preferred intermediates are compounds of formula
(VI), (VII) and (VIII) wherein n and m are both 0; R5b is alkylene;
Q is a leaving group; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl,
4-fluorophenyl, 3-fluorophenyI, 4-ethoxyphenyl, 4-ethylphenyl, 4- methylphenyl,
4-trifIuoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- methoxyphenyl,
3-fluoro-4-ethoxy phenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent -ϊs selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl ,
1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
Figure imgf000086_0001
( IX)
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene; R 20a 's hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi , cycloalkylalkyl, aryl or arylalkyi; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl, (g) dialkylaminocarbonyl,
(h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0)2NHC(0)Rι6)
Figure imgf000087_0001
Figure imgf000088_0001
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(R bb)N"Rcc" wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-| and R2 is other than hydrogen; or a salt thereof; or a compound of the formula:
Figure imgf000088_0002
(X) (XI)
wherein n is 0 or 1 ; m is 0 to 6;
R5b is alkylene;
R 0a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy,
(j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2R i 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0) NHC(0)Ri6,
Figure imgf000089_0001
Figure imgf000090_0001
alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-, and
R2 is other than hydrogen; or a salt thereof. Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1 ;
R5b is alkylene;
R20a 's hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyI, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyI)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept. The following abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1 ,8-diazabicyclo[5.4.0]undec-7-ene, EDCI for 1-(3- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et3N for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran.
Example 1 trans.trans- 2-(4-MethoxyDhenylj-4-(t .3-benzodioxol-5-vπ-1 -
(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Example A Ethyl 2-(4-methoxybenzovπ-4-nitromethyl-3-(1.3-benzodioxole-5-vπbutyrate To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2- nitrovinyl)-1 ,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 ml_ of toluene and heated to 80 °C was added 1 ,8-diazabicyclo[5,4,0] undec-7- ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved. The solution was stirred without heating for 30 minutes (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography (5% ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 ml_) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI solution. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g. of recovered ethyl (4-methoxybenzoyl)acetate.
Example 1 B
Ethyl 2-f4-methoxyphenvπ-4-(1.3-benzodioxol-5-vπ-4.5-dihvdro-3H-pyrrole-3- carboxylate The compound resulting from Example 1 A (21 g) in 500 ml_ of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
Example 1 C
Ethyl 2-/4-methoxyphenyl-4-(1.3-benzodioxol-5-vO-Pyrrolidine-3-carpoxylate) as a mixture of cis-cis: trans.trans: and c/s.frans-isomers The compound resulting from Example 1 B (1 1.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 ml_ of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1 :2 concentrated HCI in ethanol at such a rate that the color was kept at light yellow-green. After the yellow color persisted without additional HCI, the solution was stirred an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% fraπs, frans-compound and 34% c/s, fraπs-compound. Further elution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis, c/s-compound.
Example 1 D
5 iVaπs. frans-2-(4-Methoxyphenyl -(1.3-benzodioxol-5-yπ-1-
(propylaminocarbonylmethv0-pyrro!idine-3-carboxylic acid The mixture of 64% trans, trans- and 34% cis, frans-py rrolidines (the mixture resulting from Example 1 C) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl i o bromoacetamide (3.42 g, 19.0 mmol), prepared by-the method of Weaver, W.E. and Whaley, W.M., J. Amer. Chem. Soc, 6_9_: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and
15 concentrated in vacuo to give 7.16 g of product as a mixture of trans, trans- and cis, trans- ethyl esters.
This mixture was dissolved in a solution of 50 mL of ethanol and 15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and
20 60 mL of water added. The mixture was extracted with ether to remove the unreacted cis, trans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran,
25 drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound, m.p. 151-153 °C. 1 H NMR (CD3OD, 300 MHz) δ 0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J = 7 Hz, 2H), 2.84 ( d, J = 16 Hz, 1 H), 2.95-3.20 (m, 4H), 3.20 (d, J = 16 Hz, 1 H), 3.34-3.42 (m, 1 H), 3.58-3.66 (m, 1 H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz,
30 1 H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1 H), 6.86 (dd, J= 8 Hz, J = 1 Hz, 1H),
6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1 H), 7.40 (d, J = 9 Hz, 2H).
Example 2 frans. raπ3-2-(4-Methoxyphenvπ-4-(1.3-benzodioxol-5-vπ-1 -(aminocarbonylmethvπ- 35 pyrrolidine-3-carboxylic acid
Using the method described in Example 1 D, 300 mg of the mixture of 64% trans, trans- and 34% c/s, fraπs-pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrile to give 291 mg of a mixture of trans, trans- and cis, trans- N-alkylated esters. A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis, trans- ethyl ester. The isolation and purification procedures described in Example 1 D were used to give 134 mg of the title compound, m.p. 246-248 °C. 1 H NMR (DMSO-d6, 300 MHz) δ 2.61 (dt J = 16 Hz, 1 H), 2.71 (t, J = 9 Hz, 1 H), 2.90 (t, J = 9 Hz, 1 H), 2.98 (d, J = 16 Hz, 1 H),3.25-3.35 (m, 1 H), 3.45-3.55 (m, 1 H), 3,71 (s, 3H), 3.75 (d, J =
10 Hz, 1 H), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J = 8 Hz, 2H), 7.10 (s, 1 H), 7.17 (s, 1 H), 7.34 (s, 1 H), 7.38 (d, J = 8 Hz, 2H).
Example 3 fraπs.l*rans-2-(4-Methoxyphenvn-4-f 1.3-benzodioxol-5-vn-1 -(4-fluorobeπzvn- pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans, trans- and 34% cis, trans- pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans, trans- and c/s, fraπs-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 1 H NMR (CDCI3, 300 MHz) δ 2.74 (t, J = 9 Hz, 1 H), 2.95 (t, J = 7 Hz, 1 H), 2.98 (d, J
= 14, 1 H), 3.07 (dd, J = 9 Hz, 1 Hz, 1 H), 3.42-3.53 (m, 1 H), 3.70 (d, J = 9 Hz, 1 H), 3.78 (d, J = 14, 1 H), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, 1 H), 6.77 (dd, J = 8 Hz, 1 Hz, 1 H), 6.91 (d, J = 9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20 - 7.25 (M, 1 H), 7.44 (d, J = 9 Hz, 2H).
Example 4 fraπs. fraπs-2-f4-Methoχyphenyl -(1 ,3-benzodioxol-5-yl)-1-(2-ethoxyethyO- pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg. of the mixture of 64% trans, trans- and 34% cis, fraπs-pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1 .5 mL acetonitrile for 3 hours (bath temperature at 95 °C) to give 346 mg of a mixture of trans, trans- and c s, fraπs-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 140 mg of the title compound, m.p. 88 - 90 °C. 1 H NMR (CDCI3. 300 MHz) δ 1.25 (t, J = 7 Hz, 3H), 2.21- 2.32 (m, 1 H), 2.70-2.80 (m, 1 H), 2.85-2,94 (m, 2H), 3.38-3.55 (m, 6H), 3.67 (d, J = 10 Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1 H), 6.84 (m, 1 H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J = 1 Hz, 1 H), 7.33 (d, J = 9 Hz, 2H).
Example 5 - trans.frans-2-(4-Methoxyphenvπ-4-f 1.3-benzodioxol-5-vn-1 -(2-Dropoxyethvπ- pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 520 mg of the mixture resulting from Example 1 C, 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans, trans- and c/s, frans-esters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mg of the title compound as an amorphous powder. 1 H NMR (CDCI3. 300 MHz) δ 0.87 (t, J = 7 Hz, 3H), 1 .53 (sextet, J = 7 Hz, 2H),
2.28-2.41 (m, 1H), 2.71-2.83 (m. 1 H), 2.92-3.08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 (m, 1 H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H), 7.07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H).
Example 6 frans.fraπs-2-(4-Methoxyphenyl -H .3-benzodioxol-5-yl;-1-f2-(2- methoxyethoxy)ethyπ-pyrrolidine-3-carboxylic acid
Example 6A
Ethyl fraπs.frans-2-(4-methoxyphenvπ-4-π .3-benzodioxol-5-ylι Pyrrolidine-3- carboxylate To the pure cis, c/s-compound resulting from Example 1 C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21 % sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutralized with HCI in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).
Example 6B rrat7s.frans-2-f4-Methoxyphenvπ-4-(1.3-benzodioxol-5-yl;-1-[2-ι2- methoxyethoxy)ethyl)-pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, -250 mg of the compound resulting from Example 6A, 150 mg of 2-(2- methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the frans, fraπs-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 1 H NMR (CD3OD, 300 MHz) δ 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1 H), 5.94 (s, 2H), 6.79 (d, J = 8 Hz, 1 H), 6.89 (dd, J = 8 Hz, 1 Hz, 1 H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J = 1 Hz, 1 H), 7.49 (d, J = 9 Hz, 2H).
Example 7 frans. rat7S-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yπ-1 - 2-(2-pyridyl)ethyl]- pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2- methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 202 mg of the title compound as the dihydrate. m.p. 77-80 °C. 1 H NMR (CD3OD, 300 MHz) δ 2.8 - 3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s,
3H), 3.99 (d, J = 10 Hz, 1 H), 5.92 (d, J = 1 Hz, 2H), 6.72 (d, J = 8 Hz, 1 H), fi 80 (rid. J = 8 Hz. 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1 H), 7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, 1 H).
Example 8 5 fraπs, frans-2-(4-MethoxyphenylM-(1 ,3-benzodioxol-5-vO-1 -(morpholin-4- ylcarbonyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1 -morpholinocarbonyl chloride. The mixture i o was stirred 3 hours at room temperature. Toluene- was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 288 mg of the title compound, m.p. 244-246 °C. H NMR (DMSO- 15 d6, 300 MHz) δ 2.96 (dd, J = 12, Hz, 13 Hz, 1 H), 3.03-3.13 (m, 2H), 3.20- 3.30 (m, 2H), 3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J = 10 Hz, 1 H), 5.99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz, 2H), 7.07 (s, 1 H), 7.25 (d, J = 9 Hz, 2H).
20 Example 9 frans.fraπs-2-(4-Methoxyphenyl)-4-(1.3-benzodioxole-5-yl')-1 -(butylaminocarbonyπ- pyrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl
25 isocyanate. After 40 minutes at room temperature, toluene was added, ' and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 232 mg of the title compound, m.p. 220-221 °C. 1 H NMR (DMSO- d6, 300 MHz) δ 0.78 (t, J = 7 Hz, 3H), 1.10 (sextet, J = 7 Hz, 2H), 1.22
30 (quintet, J = 7 Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, 1 H), 4.93 (d, J = 9 Hz, 1 H), 5.80 (t, broad, J = 7 Hz, 1 H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz, 2H), 7.00 (d, J = 1 Hz, 1 H), 7.12 (d, J = 9 Hz, 2H). Example 10 fraπs.fraπs-2-(4-Methoxyphenyl -π .3-benzodioxol-5-vπ-1 -(4- ' methoxyphenylaminocarbonyl)-3-pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (300 mg) was treated with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example 1 D to give 279 mg of the title compound, m.p. 185-187 °C. 1 H NMR (CDCI3, 300 MHz) δ 3.23 (dd, J = 12 Hz, 13 Hz, 1 H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1 H), 5.06 (d, J = 10 Hz, 1 H), 5.90 (s, 1 H), 5.95 (s, 1 H)r 6.72 (d, J = 9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H).
Example 1 1 fraπs.frat7S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yπ-1-acetylpyrrolidine-3- carboxylic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1 D to give 21 1 mg of the title compound, m.p. 248-250 °C. Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d5, 300 MHz) δ 1.55 and 2.00 (s, 3H), 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, 1 H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1 H), 4.95 and 5.04 (d, J = 10Hz, 1 H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz, 2H), 7.18 and 7.32 (d, J = 9 Hz, 2H).
Example 12 frans.frans-2-(4-Methoxyphenvn-4-(1 .3-benzodioxol-5-vn-1 -(2-furovn-pyrrolidine-3- carboxyiic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example 1 D to give 269 mg of the title compound as an amorphous powder. 1 H NMR (DMSO-dβ, 300 MHz) δ 3.06 (dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 4.25 (m, 1 H), 5.19 ( d, J = 10 Hz, 1 H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1 H).
5
Example 13 frans. frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-yl )-1- (phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl i o isocyanate and the procedures described in Example 9, the title compound was prepared, m.p. 209-21 1 °C. 1 H NMR (DMSO-d6, 300 MHz) δ 3.03 (dd, 1 H), 3.55 (m, 1 H), 3.70 (m, 1 H), 3.72 (s, 3H), 4.15 (m, 1 H), 5.13 (d, 1 H), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, 1 H).
15
Example 14 fraπs.fraπs-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yO-1- (allylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound 20 was prepared, m.p. 138-140 °C. 1 H NMR (CDCI3, 300 MHz) δ 2.84 (d, 1 H), 2.90-3.10 (dt, 2H), 3.28 (d, 1 H), 3.35 (dd, 1 H), 3.62 (m, 1 H), 3.72- 3.97 (m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, 1 H), 5.97 (s, 2H), 6.74- 6.97 (m, 5H), 7.38 (d, 2H).
25 Example 15 fraπs.rrans-2-(4-Methoxyphenyπ-4-(1.3-benzodioxol-5-vπ-1-fn- butylaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 105-107 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.90 (t, 3H), 30 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1 H), 2.87-3.35 (m, 6H), 3.62 (m, 1 H),
3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H).
Example 16 rraπs.fraπs-2-(4-Methoχyphenvπ-4-f 1.3-benzodioxol-5-vπ-1 -(N-m-propyπ-N- 35 methylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) δ 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd, 1 H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1 H), 3.40 (d, 1H), 3.60 (m, 1 H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1 H), 6.86 (m, 2H),
7.03 (m, 1 H), 7.32 (d, 2H).
Example 17 fraπs.fraπs-2-f4-Methoxyphenyπ-4-(1.3-benzodioxol-5-yl;-1-(pyrrolidin-1 - ylcarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 1.40- 1.70 (m, 6H), 2.80 (d, 1 H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1 H), 6.80-6.90 (m, 3H),
7.04 (d, 1 H), 7.30 (d, 2H).
Example 18 frat7S,fraπ5-2-(4-Methoxyphenvπ-4-f1.3-benzodioxol-5-yπ-1- (isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 175-177 °C. 1 H NMR (CD3OD, 300 MHz) δ 0.87 (dd, 6H), 1.75 (septet, 1 H), 2.85 (d, 1 H), 2.90-3.10 (m, 4H), 3.23 (d, 1 H), 3.40
(m, 1 H), 3.58-3.67 (m, 1 H), 3.78 (s, 3H), 3.89 (d, 1 H), 5.92 (s, 2H), 6.76 (d, 1 H), 6.86 (dd, 1 H), 6.91 (d, 2H), 7.02 (d, 1 H), 7.40 (d, 2H).
Example 19 frans, fraπ5-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-v0-1-
(cvclopentylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 137-139 °C. 1 H NMR (CDCI3. 300 MHz) δ 1 .34 (m, 2H), 1.62 (m, 4H), 1 .90 (m, 2H), 2.76 (d, 1 H), 2.90 (t, 1 H), 3.04 (dd, 1 H), 3.22 (d, 1 H), 3.28 (dd, 1 H), 3.40 (m, 1 H), 3.80 (s, 3H), 4.15. (m, 1 H), 5.97
(d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H). Example 20 fraπs. fra/7S-2-(4-Methoxyphenyl -(1.3-benzodioxol-5-yu-1 -(morpholin-4- ylaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 2.82 (d, 1 H), 3.00 (m, 2H), 3.24 (m, 1 H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1 H), 6.84 (d, 3H), 7.00 (s, 1 H), 7.28 (d, 2H).
Example 21 frans. frans-2-(4-Methoxyphenyl -(1 ,3-benzodioxol-5-yO-1 -(2-phenoxyethyl)- pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1H NMR (CD3OD, 300 MHz) δ 2.82 (m, 1 H), 2.96 (dd, 1 H), 3.13 (m, 1 H), 3.32 (m, 1 H), 3.51 -3.70 (m, 2H), 3.77
(s, 3H), 4.00 (d, 1 H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1 H), 6.80-6.95 (m, 6H), 7.03 (d, 1 H), 7.22 (dd, 2H), 7.39 (d, 2H).
Example 22 fraπs.fraπs-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y0-1 -(2- methoxyethylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 107-109 °C. 1 H NMR (CD3OD, 300 MHz) δ 2.82 (d, 1 H), 2.97 (q, 2H), 3.21 (d, 1 H), 3.38 (m, 1 H), 3.32 (s, 3H), 3.44 (m, 4H), 3.62 (m, 1 H), 3.79 (s, 3H), 3.86 (d, 1 H), 5.93 (s, 2H), 6.76 (d, 1 H), 6.85
(dd, 1 H), 6.91 (d, 2H), 7.01 (d, 1 H), 7.38 (d, 2H).
Example 23 frans.frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1-(2-butoxyethyπ- pyrrolidine-3-carboxylic acid
Using the procedures described in Example 4 the title compound was prepared, m.p. 53-55 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.88 (t, J=7Hz, 3H), 1 .32 (sextet, J=7Hz, 2H), 1 .50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz, 6Hz, 1 H), 2.92 (q, J=10Hz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=10Hz, 1 H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.83
(d, J=9Hz, 2H), 6.82-6.87 (m, 1 H), 7.06 (d, J=2Hz, 1H), 7.32 (d, J=9Hz, 2H). MS m/e 442 (M+H)+. Example 24 frans. frans-2-(1.3-Benzodioxol-5-vO-4-(4-methoχyphenyr)-1- (propylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4- methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2- nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound, m.p. 97- 99 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 (d, J=16Hz, 1 H), 2.74 (t, J=10Hz-r 1 H), 2.80-3.10 (m, 4H), 3.26-3.38 (m, 1H), 3.53 (m, 1 H), 3.73 (s, 3H), 3.80 (d, J=10Hz, 2H), 7.80 (t, J=6Hz, 1 H). MS (DCI/NH3) m/e 441 (M+H)+.
Example 25 frans.rrans-2-(1.3-Benzodioxol-5-yn-4-(4-methoxyphenyn-1 -(2-propoxyethyn- pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4- methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2- nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound, m.p. 67- 69 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.89 (t, J=7Hz, 3H), 1 .56 (sextet, J=7Hz, 2H), 2.33 (m, 1 H), 2.78-3.00 ( , 3H), 3.32 (t, J=7Hz, 2H), 3.45- 3.57 (m, 4H), 3.73 (m, 1 H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d, J=8Hz, 1 H), 6.85 (d, J=8Hz, 3H), 6.98 (s, 1 H), 7.37 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 428 (M+H)+.
Example 26 frans.frans-2-(1.3-Benzodioxol-5-vπ-4-(4-methoχyphenvπ-1 -[2-(2- methoxyethoxy)ethyl)l-pyrrolidine-3-carboxylic acid Using the procedures . described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2- methoxyethoxy)ethytbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 85-86 °C. 1 H NMR (CD3OD, 300 MHz) δ 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=10Hz, 1 H), 6.02 (s, 2H), 6.91 (d, J=8Hz, 1 H), 6.95 (d, J=9Hz, 2H), .7.06 (dd, J=8Hz, 1 H), 7.12 (dd, J=1 Hz,
1 H), 7.37 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 444 (M+H)+. Example 27 frans.frans-2-(1.3-Benzodioxol-5-yl)-4-(4-methoχyphenyπ-1-(butoxyethyl)-
Pyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2- ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 54-56 °C. 1 H NMR (CDCI3. 300 MHz) δ 0.89 (t, J- 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m, 1 H), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3-.56 (m, 4H), 3.68 (d,
J=10Hz, 1 H), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1 Hz, 2H), 6.72 (d, J=8Hz, 1 H), 6.74 (dd, J=9Hz, 3H), 6.96 (s, 1 H), 7.36 (d, J=9Hz, 2H).
Example 28 fran5.fraπs-2-(4-MethoxyphenyO-4-(1 ,4-benzodioxan-6-yO-1 -
(propylaminocarbonylmethylι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting 6- (2-nitrovinyl)- 1 ,4-benzodioxane for 5-(2-nitrovinyl)- 1 ,3-benzodioxole afforded the title compound, m.p. 80-81 °C. H NMR (CDCI3, 300 MHz) δ 0.89 (t, J-7Hz, 3H), 1 .49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, 1 H), 2.92 (t, J=10Hz, 1 H), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, 1 H), 3.52-3.62 (m, 1 H), 3.80 (s, 3H), 3.80 (t, J=10Hz, 1 H), 4.27 (s, 4H), 6.74-6.93 (m, 5H), 7.29 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 455 (M+H)+.
Example 29 frans.frans-2-(4-Methoxyphenyl)-4-(1.4-benzodioxan-6-yπ-1-(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , substituting 6-(2- nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, m.p. 74-76 °C. Rotational isomers are seen in the NMR. 1 H NMR (CDCI3, 300 MHz) δ 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1 H), 2.85 (2s, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, 1 H), 3.75 (d, 1 H), 3.78 (s, 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H). MS (DCI/NH3) m/e 469 (M+H)+. Example 30 frans.fraπs-2-t4-Methoχyphenylι-4-f1.3-benzodioxol-5-vn-1-fN-methyl-N- butylaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. Rotational isomers are seen in the NMR. 1H NMR (CD3OD, 300 MHz) δ 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, 1H), 3.60 (m, 1H), 3.80 (s, 3H), 3.85 (m, 1H), 5.91 (s, 2H), 6.74 (d, 1H), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.35 (dd, 2H).
Example 31 frans.frans-2-(4-Methoxy-2-methoxvmethoxvphenvn-4-n.3-benzodioxol-5-vl.-1-.N- methyl-N-butylaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(1.3-benzodioxol-5-y0-pyrrolidine-
3-carboxylate) Using the procedures described in Examples 1A and 1B and substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2- methoxymethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-4,5-dihydro-3H- pyrrole-3-carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in 20 mL of methanol, treated with 500 mg of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
Example 31 B frans. raπs-2-(4-Methoxy-2-methoxymethoxyphenvπ-4-(1.3-benzodioxol-5-vn-1 -(N- methyl-N-butylaminocarbonylmethylι-pyrrolidine-3-carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting trans, trans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example 1 D substituting N-methyl-N-butyl bromoacetamide for N- propyl bromoacetamide to give the title compound (75 mg, 62%). m.p. 65-67 °C. Rotational isomers are seen in the NMR. 1 H NMR (CDCI3. 300 MHz) δ 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40- 1.48 (m, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43- 3.65 (m, 2H), 3.78 (s, 3H), 4.30 (t, J=7Hz, 1 H), 5.09 (q, J=7Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J=3Hz, 1 H), 6.68 (s, 1 H), 6.72 (s, 1 H), 6.85 (2t, J=1 Hz, 1 H), 7.04 (t, J=1 Hz, 1H), 7.42 (dd, J=3Hz, 1 H).
Example 32 frans.frans-2-(4-Methoχyphenyπ-4-(1.3-benzodioxol-5-vπ-1-(3-ethoxypropyπ- pyrrolidin-5-one-3-carboxylic acid
Example 32A Ethyl 2-(4-methoxybenzoylι-3-carbornethoxy-1 ,3-benzodioxole-5-propionate To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1 ,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 L of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.
Example 32B Ethyl 1 -(3-ethoxypropylV2-(4-methoxyphenvn-4-H .3-benzodioxol-5-v0-4.5-dihvdro- 5-QXO-1 H-pyrrole-3-carboxylate
A mixture of the compound resulting from Example 32 A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 °C. After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 L). The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg (42%) of the title compound. Example 32C Ethvl 1-f3-ethoxypropvlV2-(4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pvrrolidin-5- one-3-carboxylate The compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
Example 32D frans.frans-2-f4-Methoxyphenyπ-4-f1.3-benzodioxol-5-yπ-1-(3-ethoxypropyπ- pyrrolidin-5-one-3-carboxylic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 % sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue which was washed with ether. The aqueous layer was neutralized with 3 M HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, 64%). m.p. 134-140 °C. 1 H NMR (DMSO-d6, 300 MHz) δ 1.04 (t, J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 (m, 1 H), 2.93 (dd, J=9Hz, 1 H), 3.25 (t, J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1 H), 3.78 (s, 3H), 3.88 (d, J=10Hz, 1 H), 4.72 (d, J=10Hz, 1 H), 6.02 (s, 2H), 6.74 (dd, J=8Hz, 1 Hz, 1 H), 6.87 (d, J=8Hz, 2H), 6.98 (d, J=8Hz, 2H), 7.38 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 33 frans.fraπs-2-(4-Methoχyphenvπ-4-(1.3-benzodioxol-5-vπ-1-(3-methoxybenzyπ- pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, 65%). m.p. 150-152 °C. 1 H NMR (CD3OD ,
300 MHz) δ 2.96 (dd, J=8Hz, 10Hz, 1 H), 3.72 (s, 3H), 3.80 (s, 3H), 4.06 (d, J-I OHz, 1 H), 1.58 (d,
Figure imgf000106_0001
1 H). 4.92 (q, J=16Hz, 2H), 5.92 (s, 2H), 6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), 6.94 (d, J=8Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI/NH3) m/e 475 (M+H)+.
Example 34 frans.frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-yn-1-(N.N- diisoamylaminocarbonylmethyl»-pyrrolidine-3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI3, 300 MHz) δ 0.70 - 0.90 (m, 12H), 1.10-1.60 (m, 10H), 2.75 (d, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=10Hz, 1H), 3.40 - 3.52 (m, 2H), 3.55 - 3.62 (m, 1H), 3.75 (d, J=12 Hz, 1 H), 3.79 (s, 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Example 35 frat7g,frans-2-(4-Methς>xyphenyl)-4-(1 ,3-benzς>diQXQl-5-yl)-1-(N,N- dipentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, J=13Hz, 1 H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d, J=13Hz, 1 H), 3.52-3,60 (m, 1 H), 3.70 ( J=10Hz, 1 H), 3.75 (s, 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 36 frans.frans-2-(4-Methoxyphenvπ-4-(1.3-benzodioxol-5-vn-1-(N.N-di(2- methoxyethvπaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 °C. 1 H NMR (CDCI3, 300 MHz) δ 2.82 (d,
J=13, 1H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H), 3.73 (d, J=10Hz, 1 H), 3.79 (s, 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Example 37 frans.frans-2-f4-Methoxyphenyn-4-(1.3-benzodioxol-5-vn-1-f2-hexynvn-Dyrrolidinq-
3-carboxylic acid Using the procedures described in Example 4, 200 mg. of the pure trans, trans isomer, the compound resulting from Example 6A was reacted with 109 mg of 1-bromo-2-hexyne, prepared by the method described in Perkin I, , 2004 (1987), for 1 hour at 55 °C, to give 226 mg of the intermediate ester. The ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. 1H NMR (CDCI3, 300 MHz) δ 1.00^t, J=7Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 H), 3.07 (dd, J=18Hz, 2Hz, 1 H), 3.15 (dd, J=9Hz, 2Hz, 1 H), 3.26 (t, J=9Hz, 1 H), 3.36 (dd, J = 18 Hz, 2Hz, 1 H), 3.47-3.55 (m, 1 H), 3.79 (s, 3H), 3.88 (d, J=9Hz, 1 H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.22 (d, J=9Hz, 2H).
Example 39 frans.frans-2-(4-MethoxyPhenvn-4-(1.3-benzodioxol-5-vn-1-(N-cvclopropylmethyl- N-propylaminocarbonylmethyl)-pyrrplidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) δ -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32- 0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 (d, J=13Hz, 1 H), 2.85-3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, 1H), 3.65-3.73 (2 doublets, J=10Hz, 2Hz, 1 H), 3.78 (s, 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).
Example 39 frans.rrans-2-(4-Methoxyphenvπ-4-(1.3-benzodioxol-5-yπ-1 -(N-methyl-N- pentylaminocarbonylmethvn-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1 . Rotational isomers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 1 .00-1.08 (m), 1 .13-1 .32 (m), 1.35-1 ,50 (m), 2.72-2.82 (2 doublets, J=13Hz, 1 H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52- 3.62 (rn, ". ! !), 3.72 (2 doublets, 1 H), 3.75 and 3.76 (2 singlets, 3H), 5.92 (2 singlets, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Example 40 fraπs.frans-2-(4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1 -(N.N- diisobutylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.54 (d, J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (m, 1 H), 1.90- 2.02 (m, 1 H), 2.67 (d, J=13Hz, 1H), 2.70 (d, J=13Hz, 1 H), 2.84 (dd,
J=6Hz, 15Hz, 1 H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9Hz, 15Hz, 1 H), 3.35 (dd, J=2Hz, 10Hz, 1 H), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, J=9Hz, 1 H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.31 (d, J=9Hz, 2H).
Example 41 frans.frans-2- 4-Methoxyphenvn-4-f1.3-benzodioxol-5-ylι-1-fN-methyl-N-ι2- propynyl)aminocarbonylmethyπ-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (CDCI3) 300 MHz) δ 2.09 and 2.32 (2 triplets, J=2Hz, 1 H), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, 1 H), 3.78 (s, 3H), 4.03 (d, J=13Hz, 1 H), 4.00-4.30 (m, 3H), 5.93 (s, 2H), 6.72 (2 doublets, J=8Hz, 1 H), 6.80-6.90 (m, 3H), 7.02 and 7.11 (2 doublets, J = 2Hz, 1 H), 7.30 (2 doublets, J=9Hz, 2H).
Example 42 frans.f-ans-2-f4-Methoχyphenvπ-4-(1.3-benzodioxol-5-vπ-1-(N-methyl-N-(n- hexyl)aminocarbony!methy0-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. H NMR (CDCI3, 300 MHz) δ 0.85 (2 triplets, J=7Hz, 3H), 1 .00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=13Hz, 1 H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, 1 H), 3.72 (2 doublets, 1 H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1 H), 7.30 (d, J=9Hz, 1 H). Example 43 frans.fraπs-2-r4-Methoxyphenyl.-4-f1.3-benzodioxol-5-ylι-1-tΑ .Λ/-cy/Yn- butvnaminocarbonylmethyl -o\/rro\ d\r\e-3-caτbox \\c acid The title compound was prepared using the procedures described in Example 1. m.p. 123-125 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.79 (t,
J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J=13Hz, 1 H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13Hz, 1 H), 3.52-3.62 (m, 1 H), 3.75 (d, J=10 Hz, 1 H), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 (d, J=8Hz, 1 H), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 511 (M+H)+. Anal calcd for C29H38N2O6: C, 68.21 ; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Example 44 frans.fraπs-2-f4-Methoxyphenvπ-4-f1.3-benzodioxol-5-vπ-1 -fN.N- diethylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
The title compound was prepared using the procedures described in Example 1. m.p. 132-134 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.98 (t, J=7Hz, 3H), 1.06 (t, J=7Hz, 3H), 2.78 (d, J=13 Hz, 1 H), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1 H), 3.76 (d, J=12 Hz, 1 H), 3.79 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.90 (m, 3H), 7.02 (d,
J=2Hz, 1H), 7.32 (d, J=9Hz, 2H).
Example 45 frans.frans-2-(4-Methoxyphenyπ-4-(1.3-benzodioxol-5-yπ-1-(N-methyl-N- phenylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD3OD, 300 MHz) δ 2.75- 2.85 (m, 2H), 3.05-3.13 (m, 1 H), 3.18 (s, 3H), 3.40-3.58 (m, 2H), 3.78 (s, 3H), 3.88 (d, J=12Hz, 1 H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1 H), 6.75- 6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).
Example 46 rrans.frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1 -(N-methyl-N- cyclohexylaminocarbonylmethvn-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the
NMR. 1 l-ι NMR (OD3OD. 300 MHz, δ 1.00-1.85 (m, 10H), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, J=12Hz, 1 H), 2.96-3.22 (m, 3H), 3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=10Hz, 1 H), 3.77 and 3.78 (2 singlets, 3H), 5.92 (s, 2H), 6.72 (2 doublets, J=8Hz, 1 H), 6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2Hz, 1 H), 7.30-7.40 (2 doublets, J=9Hz, 5 2H).
Example 47 frans.frans-2-(4-Methoxyphenvπ-4-(1.3-benzodioxol-5-yπ-1-(N.N-dim- propyl)aminocarbonylmethylVpyrroHdine-3-carboxylic acid i o The title compound was prepared using the -procedures described in Example 1. m.p. 170-172 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.69 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1 H), 3.72 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, 1 H), 6.80-6.90 (m, 3H), 15 7.02 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Example 48 fraπs.fraπs-2-f4-MethoxyphenylV4-(1.3-benzodioxol-5-vπ-1 -(N-methyl-N- isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 20 The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1H NMR (CD3OD, 300 MHz) δ 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (m, 1 H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=10Hz, 1H), 25 5.93 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (2 doublets, J=2Hz, 1 H), 7.80-7.90 (2 doublets, J=9Hz, 2H).
Example 49 Alternate Preoration of 30 Ethyl 2-(4-methoxybenzovπ-4-nitromethyl-3-(1.3-benzodioxole-5-yl')butyrate
Example 49A E-2-(3.4-Methylenedioxyphenyl)-1-nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol 35 (120 mL) at 10 °C was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 L while maintaining the temperature between 10-15 °C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below 5 °C, until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then-recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1 H NMR (300MHz, CDCI3) δ 7.94 (1 H, d, J=13.5Hz), 7.47 (1 H, d, J=13.5Hz), 7.09 (1 H, dd, J=7.5&2Hz), 7.01 (1 H, d, J=2Hz), 6.87 (1 H, d, J=7.5Hz), 6.06 (2H, s). MS (DCI/NH3) m/e 194 (M+H)+, 21 1 (M+H+NH3)+.
Example 49B Ethyl 2-(4-methoxyphenvhoxo-4-nitro-3-(3.4-methylenedioxyphenylιbutyrate To a stirred solution of the nitrostyrene resulting from Example
49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl)acetate (1 1.5 g, 51.7 mmol) in THF (50 mL) followed by 1 ,8-diazabicyclo[5,4,0]undec-7- ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with 20% ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents were removed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR. 1 H NMR (300 MHz, CDCI3,) δ 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1 H, dd, J=9Hz,3Hz), 6.73 (1 H, d, J=9Hz), 6.65 (1 H, d, J=3Hz), 5.95 (2H, s), 5.89 (1 H, d, J=4Hz), 5.88 (1 H, d,
J=4Hz), 4.90-4.60 (3H, m), 4.39 (1 H, m), 4.18 (2H, q, J=7Hz), 3.94 (2H, m), 3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) m/e 416 (M+H)+, 433 (M+H+NH3)+.
Example 50 ffans.frans-2-r4-Methoxyphenyn-4-(1.3-benzodioxol-5-yl,-1-ft- butyloxycarbonylmethyl.-pyrrolidine-3-carboxylic acid To a stirred solution of the compound resulting from Example 1 C (100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively diisopropylethylamine (70 μL, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 μL, 0.29 mmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester. To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 μL), and then extracted with ethyl acetate (2x). The combined organic extracts were dried (Na2Sθ4), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid. 1 H NMR (300 MHz, CDCI3) δ 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90
(1 H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1 H, d, J=8Hz), 5.96 (2H, s), 3.96 (1H, d, J=9Hz), 3.81 (3H, s), 3.58 (1H, ddd, J=12, 10Hz,3Hz), 3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=17Hz), 3.08 (1H, t, J=10Hz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=17Hz). MS (DCI/NH3) m/e 456 (M+H)+.
Anal calc for C29H29NO7 • 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
Example 51 frans.frans-2-(4-Methoxyρhenyl)-4-f1-naρhthvn-1-(N-methyl-N-
Dropylιaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene-1 -carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) δ 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75
(1 H, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (1 H, m), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, s), 3.65 (1H, m), 3.49 (1 H, d, J=14Hz), 3.40-2.93 (5H, m), 2.91 , 2.83 (3H, s), 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH3) m/e 461
(M+H)+. Anal calcd for C29H29NO7 • 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: C, 70.95; H, 7.00; N, 5.46.
Example 52 frans.rrans-2-(4-Methoxyphenyl.-4-(2.3-dihvdrobenzofuran-5-vn-1-rN-methyl-N- propylιaminocarbonvlmethyn-pyrrolidine-3-carboxylic acid
Example 52A
2.3-Dihvdrobenzofuran-5-carboxaldehyde To a stirred solution of α,α-dichloromethyl methyl ether (2.15 g,
19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2CI2 (5 L) maintaining the temperature at or below -35 °C. The mixture was warmed to 0 °C, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid, b.p. 119-121 °C at 0.3 mm Hg.
Example 52B fraπs.frans-2-f4-Methoxyphenyπ-4-f2.3-dihvdrobenzofuran-5-yπ-1-(N-methyl-N- propyl,aminocarbonylmethyn-pyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) δ 7.33 (1 H, d, J=8Hz), 7.28 (1 H, m), 7.19 (1 H, m), 6.87 (1 H, d, J=8Hz), 6.73 (1 H, d, J=8Hz), 4.56 (1 H, t, J=8Hz),
3.83 (1 H, d, J=10Hz), 3.80 (3H, s), 3.63 (1 H, m), 3.4-3.0 (9H, m), 2.87,
2.84 (3H, s), 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS (DCI/NH3) m/e 453 (M+H)+. Anal calc for C26H32N2O5 • 0.25 H20: C , 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80. Example 53 frans.rran5-2.4-Bisf4-methoxyphenyh-1-(N-methyl-N-propyπaminocarbonylmethvπ- pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) δ 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m), 3.83 (1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1 H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1 H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H20: C , 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31 ; N, 6.00.
Example 54 trans. frans-2-»4-Methoxyphenvπ-4-(3.4-dimethoxyphenvπ-1-fN-methyl-N- propylιaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) δ 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1 H, m), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86
(3H, s), 3.83 (1 H, m), 3.79 (3H, s), 3.64 (1 H, m), 3.50-2.95 (6H, m), 2.87 (1 H, m), 2.85, 2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 471 (M+H)+. Anal calc for C26H34N2O6 • 0.5 H20: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
Example 55 rans.fran5-2-f4-Methoxyphenyn-4-f3-methoxyphenyn-1-(N-methyl-N- propyπaminocarbonylmethylVpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) δ 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t, J=7.5 Hz), 7.05 (2H, m), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1 H, m), 3.83 (1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1 H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1 H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
Example 56 fraπs.frans-2-(4-Methoχyphenyl')-4-f2-naphthyl>-1-(N-methyl-N-
DrθDylteminocarbonylmethvπ-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) δ 7.82 (4H, m), 7.69 (1 H, m>, 7.47 (2H, m), 7.37
(2H. dd, J=7.5&2 Hz), 6.85 (2H. dd. J=7.5&2 Hz), 3.90 (1H, d. J=8 Hz), 3.78 (3H, s), 3.57 (1 H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1 H, m),
1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 461 (M+H)+. Anal calc for C28H32N2O4 - 0.5 H20: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.1 1 ; N, 6.01.
Example 57 frans. frans-2-(4-Methoxyphenylι-4-M .3-benzodioxol-5-yl I -f2-(ethylsulfinvπethyl'>- pyrrolidine-3-carboxylic acid To the compound resulting from Example 1 C (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of Kl and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg (75%) of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH2CI2 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room temperature. A 10% solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and 10% MeOH in C H2CI2 to afford the sulfoxide (62 mg, 65%).
The ethyl ester was hydrolyzed by the procedure described in FYΛmnl 1 D to afford the title compound as a diastereomeric mixture. m.p. 61 -63 °C. MS (DCI/NH3) m/e 446 (M+H)+. 1 H NMR (CDCI3, 300 MHz) δ 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02- 3.08 (m, 1 H), 3.32, 3.36 (d, J=3Hz, 1 H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, J=7.5Hz, 1 H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 3.84- 3.89 (m, 3H), 7.02 (d, J=6Hz, 1 H), 7.30, 7.34 (d, J=7.5Hz, 2H).
Example 58
Figure imgf000117_0001
(isopropylsulfonylamino thylVpyrrolidine-3-carboxylic acid To 2-bromoethylamine hydrobromide (1 mnrfδl) suspended in anhydrous CH3CN was added 1 equivalent of Et3N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et3N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 mmol) in 3 mL of CH3CN. The mixture was warmed at 50-60 °C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1 D to afford the title compound (133 mg, 88%). m.p. 94-96 °C. 1H NMR (CD3OD, 300 MHz) δ 1.26 (d, J=6Hz, 6H), 1.97 (s, 1 H), 2.38 (m, 1 H), 2.77 (m, 1 H), 2.88 (t, J=9Hz, 1 H), 3.04 (m, 1 H), 3.14 (t, J=7.5Hz. 2H), 3.35 ( , 2H), 3.46 (m, 1 H), 3.58 (m, 1 H), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, J=9Hz, 1 H), 6.86 (dd, J=9Hz,3Hz, 1 H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1 H), 7.36 (d, J=9Hz, 2H). MS (DCI/NH3) m/e (M+H)+.
Example 59 frans.frans-2-(4-Methoxyphenyπ-4-M .3-benzodioxol-5-vπ-1-(2-(isobutoxyιethyπ- pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1 D from the compound resulting from Example 1 C and 2- (isobutoxy) ethyl bromide, m.p. 68-70 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.88 (d, J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1 H), 2.22 (m, 2H), 2.72-2.79 (m, 1 H), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 6.85 (dd, J=9Hz, 7.5 Hz, 3H). 7.08 (s, 1 H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e
442 (M+H)+.
Example 60 fraπs.frans-2-f4-Methoxyphenvπ-4-f1.3-benzodioxol-5-vπ-1 -fbutylsulfonyl)-
Pyrrolidine-3-carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1 C dissolved in 10 mL of THF was added 1-butanesulfonyI chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mg (90%) of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid, m.p. 67-69 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J=9Hz, 1 H), 3.49 (t, J=12Hz, 1 H), 3.65 (dd, J=12Hz, 1 H), 3.82 (s, 3H), 4.32 (dd, J=12Hz, 1 H), 5.17 (d, J=9Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 462 (M+H)+.
Example 61 frar7S.?rans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -,2-(N-methyl-N- isopropylcarbonylamino')ethvπ-pyrrolidine-3-carboxylic acid Example 61 A frans.frans-2-f4-Methoxyphenyn-4-M .3-benzodioxol-5-vn-1-(2-bromoethyl,- pyrrolidine-3-carboxylic acid ethyl ester To the mixture of cis.trans and trans, trans pyrrolidines resulting from Example 1 C (400 mg) dissolved in 9 mL of 1 ,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide. The resultant mixture was heated at 100 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated under reduced pressure. The crude product was purified- by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.
Example 61 B frans.fraπs-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -(2-fmethylaminolethyl,- pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 61 A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.
Example 61 C fraπs.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-yn-1-r2-rN-methyl-N- isobutyrylaminoιethyπ-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (-150 mg) dissolved in 5 mL of 1 ,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours. The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1 :1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1 :1 EtOAc- hexanes going to EtOAc and finally using 10% MeOH-EtOAc. The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 H3PO4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2S04. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) of the major rotamer δ 1.06 (d, 3H. J=10Hz), 1.12 (d, 3H. J=10Hz), 2.15 (m, 1 H), 2.5-3-.0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, 1 H, J=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1 H, J=2Hz), 7.29 (m, 1 H). MS (DCI/NH3) m/z 469 (M+H)+. Analysis calcd for C26H32N2O6 • 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71 ; N, 5.24.
Example 62 rraπs.frans-2-f4-Methoxyphenvπ-4-(1.3-benzodioxol-5-vπ-1-ι2-(N-methyl-N- propionylamino)ethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61 C. 1 H NMR (CDCI3, 300 MHz) of the major rotamer δ 1.13 (t, 3H, J=8Hz), 2.19 (m, 1 H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1 H, J=8Hz), 6.75-6.9 (m, 4H). 7.00 (bd s, 1 H), 7.29 (bd s, 1 H). MS (DCI/NH3) m/z 455 (M+H)+. Analysis calcd for C25H30N2O6 • 1.0 H20: C, 63.55; H, 6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73.
Example 63 fraπs.rrans-2-f4-Methoxyphenyn-4-f1.3-benzodioxol-5-vπ-1 -(N-methyl-N- benzylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI3. 300 MHz) of the major rotamer δ 2.79 (s, 3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, 1 H), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 (m, 4H), 7.00 (m, 1 H), 7.15-7.35 (m, 7H). MS (FAB/NBA) m/z 503 (M+H)+. Anal calcd for
C29H30N2O6 - 0.5 H 0: C, 68.36; H,5.74; N, 5.50. Found: C.68.41 ; H, 5.74; N, 5.36 . Example 64 rans.frans-2-ι4-MethoxyDhenyl)-4-f1.3-benzodioxol-5-vπ-1-fN-ethyl-N- butylaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) of the major rotamer δ 0.88 (t, 3H, J=7Hz), 1.06 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11 H), 3.79 (s,3H), 3.80 (m, 1 H), 5.92 (bd s, 2H), 6.75 (d, 1 H, J=8Hz), 6.85 (d, 1H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (s, 1 H), 7.33 (d, 1 H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+. Anal calcd for C27H34N2O6 • 0.5 HOAc: C, 65.61 ; H.7.08; N, 5.46. Found: C.65.51 ; H, 6.70; N, 5.66.
Example 65 rrans.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-yl;-1-ιN-methyl-N-(2.2- dimethylpropynaminocarbonylmethyn-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer δ 0.90 (s, 9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1 H), 3.80 (s, 3H), 3.82 (m, 1 H), 5.94 (bd s, 2H), 6.74 (d, 1 H, J=8Hz), 6.86 (d, 2H, J=8Hz), 6.87 (m, 1 H), 7.03 (d, 1 H, J=2Hz), 7.33 (d, 2H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+.
Example 66 trans. frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-ylV1-(2-(N-methyl-N- butylsulfonylaminoιethyπ-pyrrolidine-3-carboxylic acid
To the compound resulting from Example 61 B (60 mg, 0.13 mmol) dissolved in 5 mL of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1 .1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 :1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound, m.p. 64-66 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1 H), 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, 1 H), 3.25-3.34 (m, 1 H),
3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, 1 H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 6.82 (dd, J=7.5Hz,3Hz, 1 H), 6.86 (d, J=9Hz, 2H), 7.02 (d, J=3Hz, 1 H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 519 (M+H)+.
Example 67 s frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-yl)-1-.2-(N-methyl-N- propylsulfonylaminotethyn-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesuIfonyl chloride for 1- butanesulfonyl chloride, m.p. 69-70 °C. 1 H NMR (CDCI3. 300 MHz) δ 1.02 0 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2 26 (m, 1H), 2.72 (s, 3H), 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47-3.58 (m, 2H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J=7.5Hz, 1 H), 6.84 (d,d, J=7.5Hz, 3Hz, 1H), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, 1H), 7.43 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 505 (M+H)+. 5
Example 69 fraπs.fraπs-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1-f2- (propylsulfonvπethyl -pyrrolidine-3-carboxylic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of 0 anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 °C for 1 hours. To this mixture was added the compound resulting from Example 61 A (180 mg, 0.38 mmol) in 2 mL THF. Heating was continued at 60-70 °C for an additional 2 hours, and then the volatiles were removed under 5 reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to give 170 mg (95%).
To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of 0 acetone and 5 mL of H2O was added a solution of osmium tetroxide (10 mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2Sθ4 and concentrated in vacuo. Flash 5 chromatography afforded 177 mg (98%) of the ethyl ester which was hydrolyzed by the procedures described in Example 1 D to afford the title compound. m.p. 73-75 °C. 1H NMR (CDCI3, 300 MHz) δ 1.04 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 (m, 1 H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1 H), 3.53-3.60 (m, 1H), 3.68 (d, J=9Hz, 1 H),. 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 (d, J=9Hz, 2H), 6.99 (d, J=3Hz, 1 H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 476 (M+H)+.
Example 69 frans.frans-2-f4-Methoxyphenvπ-4-f1.3-benzodioxol-5-vπ-1-N-(frans-5-methylhex- 2-envn-pyrrolidine-3-carboxylic acid
Example 69A frang-5-Methylhex-2-enoiQ dd ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 °C. Diisopropyl(ethoxycarbonyimethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C. Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na2S04, and evaporated to give a colorless oil which was purified by flash chromatography on silica gel eluting with hexanes. The title compound was isolated as a colorless oil (2.1 g).
Example 69B rrans-5-Methylhex-2-en-1 -ol The compound resulting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride
(1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature. Diethyl ether (50 mL) was added, the solids removed by filtration and washed with additional ether (2 x 25 mL). The filtrate was extracted with ether (2 x 25 mL). The ether extractions a d washings were combined, dried, and evaported to give a colorless oil which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C frans-1 -Bromo-5-rnethylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C for two hours. The solution was poured onto ice, the-layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).
Example 69P rraπs.fraπs-2-f4-Methoxyphenvπ-4-f1.3-benzodioxol-5-yl,-1-N-ffrat7S-5-methylhex-
2-envπ-pyrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1 D but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. 1 H NMR (CDCI3, 300 MHz) δ 0.84 (d, 6H, J=8Hz), 1.57 (heptet, 1 H, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,14Hz), 2.86 (t, 1 H, J=10Hz), 2.96 (dd, 1 H, J=8Hz,10Hz), 3.20 (dd, 1 H, J= 5Hz,14Hz), 3.29 (dd, 1 H, J=3Hz,10Hz), 3.50 (m, 1 H), 3.70 (d, 1 H, J=10Hz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1 H, J=8Hz), 6.83 (d, 3H, J=9Hz), 7.05 (s, 1 H), 7.32 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C26H31 NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
Example 70 frans.frans-2-f4-Methoxyphenvπ-4-(1.3-benzodioxol-5-vn-1-N-(frans-3.5- dimethylhex-2-envπ-Pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olefins. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desire fracticr.c were !yophi!ize o give , the product (and its diastereomer) as a white solid. 1 H NMR of the major (trans) isomer: (CDCI3. 300 MHz) δ 0.83 (d, 6H, J=8Hz), 1.56 (s,3H), 1.74 (m, 1 H), 1.92 (d, 2H, J=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H), 3.78 (s, 3H), 3.9-4.0 (m, 1 H), 5.22 (m, 1 H), 5.90 (d, 2H, J=12Hz). 6.63 (m, 1 H), 6.78 (m, 3H), 6.95 (s, 1 H), 7.45 (d, 3H, J=8Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for
C27H33NO5 • 1.0 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10; N, 2.34.
Example 71 fraπs.fraπs-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -(4- heptylcarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 71 A 1 -Chioro-3-propyl-2-hexanone To 2-propylpentanoic acid (156.6 μl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 μL, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 μL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 μL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
Example 71 B fraπs. fraπs-Ethyl 2-(4-methoxyphenyl )-4-M .3-benzodioxol-5-yh- 1 -> 4- heptylcarbonylmethyl ι-pyrrolidine-3-carboxylate
To the compound resulting from Example 71 A (1.00 mmol, maximum theoretical yield) was added a solution of the trans, trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 % solution in toluene), diisopropylethylamine (700 μL, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole %), and the reaction mixture was stirred 18 hours 5 under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole %) and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1 :9 ethyl o acetate-hexane to give 237 mg (46%) of the title -compound as a yellow oil .
Example 71 C trans. trans-2-( 4- Methoxyp hen yh-4-M .3-benzodioxol-5-v0-1 -(4- 5 heptylcarbonylmethvn-pyrrolidine-3-carboxylic a£id
To the compound resulting from Example 71 B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium 0 hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid 5 to cloudiness and then 10% aqueous citric acid was added to adjust the pH to -5. This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel 0 eluted with 1 :1 ethyl acetate-hexane to give 86 mg (39%) of the title compound as an off white powder. 1 H NMR (CDCI3, 300 MHz) δ 0.73-0.97 (m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1 H), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.75 (d, 1 H), 6.86 (d, 2H), 6.92 (d, 1 H), 7.12 (s, 1 H), 7.32 (d, 2H). MS 5 (FAB) m/e 482 (M+H)+. Anal calcd for C28H35NO6: C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41 ; N, 2.73. Example 72 frans.frans-2-f4-Methoxvphenyn-4-n .3-benzodioxol-5-yn-1-fvalerylmethyn- pyrrolidine-3-carboxylic acid
Example 72A 1-Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
Example 72B fraπs. fraπs-Ethyl 2-(4-methoxyphenyl ,-4-M .3-benzodioxole-5-vn-1 (valerylmethvn-pyrrolidine-3-carboxylate Substituting the compound resulting from Example 72A for 1- chloro-3-propyl-2-hexanone and using the procedure described in Example 71 B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil.
Example 72C frans. frar7s-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1 - (valerylmethvh-pyrrolidine-3-carboxylic acid
By substituting the compound resulting from Example 72B for frans. frans-Ethyl 2-(4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(4- heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the procedure described in Example 71 C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg (46%) was obtained as an off white powder. 1 H NMR (CDCI3, 300 MHz) δ 0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31- 3.49 (m, 2H), 3.56 (m, 1H), 3.77, 3.79 (d,s, 4H), 5.94 (s, 2H), 6.75 (d, 1 H), 6.81-6.93 (m, 3H), 7.09 (d, 1H), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+. Anal, calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C. 67.95; H. 6.64; N, 3.05. Exam ie 7 rrans.frans-2-f4-Methoxyphenyl,-4-n.3-benzodioxol-5-vn-1-.N-f3.4- dimethoxybenzvπ-N-methylaminocarbonylmethvπpyrrolidine-S-carboxylic acid
Example 73A trans.trans- and c/s.fraπs-2-(4-Methoxyphenyn-4-f 1 ,3-benzodioxol-5- yl )-1 -f(3.4-dimethoxybenzyl )aminocarbonylmethyl )pyrrolidine-3- carboxylic acid ethyl ester Using the procedure of Example 1 D, paragraph 1 , substituting 3,4- dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
Example 73B trans.trans- and c;s.fraπs-2-(4-Methoxyphenyl ι-4-M .3-benzodioxol-5- yπ-1 -(N-ι 3.4-dimethoxybenzyn-N- methylaminocarbonylmethyl )pyrrolidine-3-carboxylic acid ethyl ester
The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 μL, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et2θ) indicated incomplete reaction. An additional portion of methyl iodide (28 μL, 64 mg, 0.45 mmol) and dry 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2(1 H)pyrimidinone (50 μL, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na2Sθ4) . filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et2θ gave the title compounds as an inseparable mixture in 43% yield. 1 H NMR (CDCI3, 300 MHz) δ 2.79 (s) and 2.81 (s), for the N-CH3 signals. MS m/z 591 (M+H)+. Example 73C rrans. frans-2-(4-MethoxyDhenyl l-4-f 1 .3-benzodioxol-5-yl ,- 1 -( N-(3.4- dimethoxybenzvn-N-methylaminocarbonylmethyl ιpyrrolidine-3- carboxvlic acid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 °C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H2O. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL H2O and 15 mL Et2θ. The aqueous phase was extracted with 5 mL Et2θ, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2S04), then filtered and concentrated in vacuo to give 40 mg (42%) of the title compound as a white foam. 1 H NMR
(CD3OD, 300 MHz, two rotameric forms) δ 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1 H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1 H), 6.67- 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31H35N2O8 (M+H)+: 563.2393. Found: 563.2385.
Example 74 frans.frans-2-(4-Methoxyphenvπ-4- 1.3-beπzodioxol-5-yn-1-fN-f3.4- dimethoxybenzyl)aminocarbonylmethyπpyrrolidine-3-carboxylic acid
The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 2.85 (d, J=16Hz, 1H), 2.92 (br t, J=9Hz, 1H), 2.98 (br t, J=10Hz, 1 H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 H), 3.67 (s, 3H), 3.78 (s,
3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1 H), 4.21 (d, J=15Hz, 1 H), 4.41 (d, J = 15Hz, 1 H), 5.91 (s, 2H), 6.67 (d, J=8Hz, 1 H), 6.75-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS calcd for C30H32N2O8 (M+H)+: 549.2237. Found: 549.2224. Examole 75 f2R.3R.4R 2-,4-MethoxyphenylV4-f1.3-benzodioxol-5-yl,-1-lMR,-1-(N.N- dipropylaminocarbonylV1-butvnpyrrolidine-3-carboxylic acid
Ex m le 5A frang,frang-2-(4-Methoxyphgnyl)-4-(1 ,3-benzQdioχpl-5-yl)-H(1 RM
(benzyloxycarbonynbutvnpyrrolidine-3-carboxylic acid ethyl ester
The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34
(1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H2θ , and ammonium carbonate (34 mg, 0.35 mmol) and (2S)-benzyl 2- bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na2C03 and 25 mL of CH2CI2. The aqueous phase was extracted with 2 x 10 mL C^C^, and the combined organic phases were washed with 15 mL brine, dried (Na2S04), then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3: 1 CH2Cl2-hexane to produce 106 mg (68%) of the title compound as a waxy solid. 1 H NMR indicated the presence of two diastereomeric products.
Example 75B fraπs.frans-2-(4-Methoxyphenvπ-4-(1.3-benzodioxol-5-yn-1 -((1 RV1 -(N.N- dipropylaminocarbonylι-1 -butvπpyrrolidine-3-carboxylic acid ethyl ester The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to give 81.4 mg (96%) of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 °C, then 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2Cθ3. The organic phase was washed with 10 mL of brine, dried (Na2S0 ), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1 :2 Et2θ-hexane. 5 Further purification of overlap fractions by preparative TLC eluting with 1 :2 Et∑O-hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%) of a more polar product.
Example 75C o , 2R.3R.4R ,-2-(4-Methoxyphenyn-4-(1 .3-benzodioxol-5-yn-1 -(( 1 R ,-1 -
(N.N-dipropylaminocarbonyπ-1 -butyπpyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield. [α]o = - 5 52° (c=0.235, CH3OH). 1H NMR (CD3OD, 300 MHz) δ 0.55 (t, J=7Hz, 3H), 0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25- 1.68 (br m, 4H), 1.90-2.07 (br m, 1 H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (m, overlapping with CD2HOD signal), 3.40-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1 H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 0 (d, J=8 Hz, 1 H), 6.79 (dd, J=1.5,8 Hz, 1 H), 6.92-6.98 (br m, 3H), 7.29-7.39
(m, 2H). MS m z 525 (M+H)A
Example 76 (2S.3S.4SV2-(4-Methoxyphenvn-4-n ,3-benzodioxol-5-vn-1 -> ( 1 R - 5 (N.N-diproDylaminocarbonyπ-1 -butvhpyrrolidine-3-carboxylic acid
The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [CC]D = +58° (c=0.37, CH3OH). 1H NMR (CD3OD, 300 MHz) δ 0.57 (br t, J=7Hz, 3H), 0 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 (br m, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71 -6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 (M+H)+. Example 77 ι2S.3S.4SV2-f4-Methoxyphenyl,-4-f1.3-benzodioxol-5-yl,-1->(1SV1-fN.N- dipropvlaminocarbonyn-1 -butyl )pyrrolidine-3-carboxylic acid
s Example 77A frans. fraπs-2- -Methoxyphenyl )-4-M .3-benzodioxol-5-yn-1 -f(1 S )-1 - fN.N-dipropylaminocarbonyn-1 -butynpyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, o made by standard procedure) was dissolved in 2 ΓDL THF under an argon atmosphere, diisopropylethylamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 °C. Trifluoromethanesulfonic anhydride (95 μL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and 5 at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 μL, 75 mg, 0.58 mmol) in 3 mL of CH2CI2 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature. TLC 0 (Et2θ-hexane 1 :2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na2Cθ3. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2Sθ4), filtered 5 and concentrated in vacuo to a yellowish oil. Purification by flash chromatography on silica gel eluting with 1 :2 Et2θ-hexane gave 19.9 mg (7%) of a less polar product and 20.1 mg (7%) of a more polar product. 1 H NMR spectra and MS were the same as those of Example 76B.
0 Example 77B ι2S.3S.4S)-2-(4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1 -fn S 1-fN.N- dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product 5 from Example 73B, to provide the title compound in 100% yield. 1 H NMR (CD3OD, 300 MHz) and MS identical to those of Example 75C. Exgmple 78 (2R.3R,4R)-2-f4-Methpxyphenγl)-4-(1 ,3-beηzς>diθxpl-5-yl -1-((lS)-1-(N,N- dipropvlaminocarbonvn-1 -butvnpvrrolidine-3-carboxvlic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. H NMR (CD3OD, 300 MHz) and MS identical to those of Example 76.
Example 79 frans.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-vn-1-/r/V./V-rJ/Yn- butyl)aminocarbonylmethyl)-3-(5-tetτazoM)ovπo\\d r\e Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound, m.p. 194-196 °C.
Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature. Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3- carbonitrile compound.
To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL ) was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid to get 532 mg (62%) of the title compound, m.p. 165-167 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 0.87 (t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, 1 H), 3.90 (t, J=9Hz, 1 H), 4.37 (d, J=9Hz, 1 H), 5.86 (s, 2H), 6.62 (d, J=8Hz, 1 H), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, 1 H), 7.1 1 (d, J=9Hz, 2H).
Example 90 frans.fraπs-2-(4-Fluorophenvn-4-n .3-benzodioxol-5-vn-1-<Λ ./V-fi/rn- άι;fv/)a /πocarbσn t77ef/7v/)pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3-benzodioxoIe using the procedures described in Examples 1 and .43. 1H NMR (CDCI3, 300 MHz) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d, J=13 Hz, 1 H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1 H), 3.32-3.45 (m, 3H), 3.55-3.65 (m, 1 H), 3.86 (d, J=10Hz, 1 H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8 Hz, 1 H), 6.86 (d, J= 8 Hz, 1 H), 6.95-7.07 (m, 3H), 7.32- 7.45 (m, 2H).
Example 81 fraπs.frans-2-(4-Methoxyphenvπ-4-π .3-benzodioxol-5-vn-1-fN.N-di(n- butvflaminocarbonylmethvOpyrrolidine-3-carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C. After cooling to room temperature, 250 mg (0.678 mmol) of ethyl frans,frans-2-(4-methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 °C for 30 minutes. The product was chromatographed on silica gel, eluting with 1 :1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester. The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. 1 H NMR (CDCI3, 300 MHz) δ rotational isomers - 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1 .5 (m, 8H), 2.65-3.20 (m, 6H) 3.43-3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, J=15Hz, 1 H), 4.49 (dd, J=12Hz, 6Hz) and 5.23 (dd, J=12Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d,
J=9Hz, 2H), 7.22 (d, J=9Hz, 2H). Example 82 rrans.rrans-2-(4-Methoxyphenyn-4-n .3-benzodioxol-5-vn-1 -fN-n-butvn-N-m- propvnaminocarbonvlmethvnpvrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C. 1 H NMR (CDCI3, 300 MHz) rotational isomers δ 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.23- 3.61 (m, 5H), 3.71 and 3.75 (two doublets, J=10Hz, 1 H), 3.78 (s, 3H), 5.92-5.96 (m, 2H), 6.72 (d, J=8Hz, 1 H), 6.83-6.89 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.81 (d, J=9Hz, 2H).
Example 83 fraπs.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -f2-fN.N-di(n- propyπaminocarbonvπethyl]pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg, 0.677 mmol),
205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydrolyzed to the title compound by the method of Example 1 D in 83% yield. 1H NMR (CDCI3, 300 MHz) δ 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H), 3.14-3.21 (m, 2H), 3.31 -3.38 (m, 1 H), 3.51-3.61 (m, 1 H), 3.73 (d, J=12H, 1 H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, 1 H). 6.79-6.85 (m, 3H), 7.04 (d, J=2Hz, 1H)< 7.32 (d, J=9Hz, 2H). Example 84 frans.fraπs-2-(4-Methoxyphenyn-4-π .3-benzodioxol-5-yl,-1-fN.N-dirn- butvnaminocarbonyl.pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyi chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1 H NMR (CDCI3, 300 MHz) δ 0.86 (t, J=7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.1 1 (t, J=12Hz. 1 H), 3.30- 3.41 (m, 2H), 3.59-3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, 1 H), 5.81 (d, J=9Hz, 1 H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9Hz. 2H).
Example 85 frans.fraπs-2-f4-Methoxyphenyπ-4-M .3-benzodioxol-5-yπ-1-t'/V.A/-fJ/Yn- ■3ufy/)at77/-7σcarDoπy/mef/7y/)pyrrolidine-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of
MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 °C to yield 627.5 mg of the title compound.
Example 86 frans.fraπs-2-ι4-Methoxyphenyπ-4-(1.3-benzodioxol-5-yl)-1 -[2-fN.N-dim- butvnamino ethyl]pyrrolidine-3-carpoxylic acid A solution of the bromoethyl compound resulting from Example
61 A (150 mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 °C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2Sθ4 and concentrated. More toluene was added, and the solution was again concentrated to get rid "of excess dibutylamine. The residue was dissolved in warrfi heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg (87%) of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1 D to give the title compound as a white powder. 1 H NMR (CD3OD, 300 MHz) δ 0.89 (t, J=7Hz, 6H), 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1 H), 2.80-3.08 (m, 8H), 3.14-3.25 (m, 1 H), 3.31 -3.38 (m, 1 H), 3.59-3.60 (m, 1 H), 3.74 (s, 3H), 3.75 (d, J=10Hz, 1 H), 5.89 (s, 2H), 6.71 (d, J=9Hz, 1 H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 (d, J=10Hz, 2H), 6.96 (d, J=2Hz, 1 H), 7.37 (d, J=10Hz, 2H).
Example 87 frans.frans-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1-(2-rN-fN.N-dim- butvnaminocarbonvn-N-methylamino1ethyl)pyrrolidine-3-carboxylic acid Dibutyl carbamoyi chloride (135 mg) was added to the compound resulting from Example 61 B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2Sθ4 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate. The ester was hydrolyzed by the method of Example 1 D to afford
141 mg of the title compound. 1 H NMR (CD3OD, 300 MHz) δ 0.92 (t, J=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s. 3H), 2.65-2.76 (m, 1 H), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1 H), 3.62-3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, J=12 Hz, 1 H), 5.93 (s, 2H), 6.75 (d, J=9Hz, 1 H), 6.87 (dd, J=9Hz, 2Hz, 1 H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1 H), 7.40 (d,
J=10Hz, 2H).
Example 88 frans.frans-2-f4-Methoxyphenyn-4-M .3-benzodioxol-5-vn-1-(N.N-difn- butyl)aminocarbonylmethylιPyrrolidine-3-fN-methanesulfonylιcarboxamide
Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours. After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%) of the title compound, m.p. 170-173 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1 .05-1.51 (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50 (m, 3H), 3.70-3.78 (m, 1 H), 3.80 (s, 3H), 3.87 (d, J=10Hz, 1 H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, J=9Hz, 1 H), 6.84 (dd, J=9Hz, 2Hz, 1 H), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2Hz, 1 H), 7.34 (d. J=10Hz, 2H).
Example 89 frans.frans-2-(4-MethoxvphenvlV4-f1.3-benzodioxol-5-vn-1-fN.N-di.n- butvπaminocarboπylmethylιpyrrolidine-3- N-benzenesulfonvπcarboxamide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 °C for a sample recrystallized from acetonitrile. 1 H NMR (CDCI3, 300 MHz) δ
0.81 (t, J=7 Hz, 3H), 0.89 (t. J=7Hz, 3H), 1.02-1.50 (m, 8H). 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1 H), 3.65 (d. J=10Hz, 1 H), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J=10Hz, 2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7Hz, 1 H), 8.95 (d, J=7Hz, 2H).
Example 90 frans. frans-2-f4-Methoxyphenvπ-4-M .3-benzodioxol-5-vπ-1-rN.N-di(n-butvπ aminosulfonylmethyl]-pyrrolidine-3-carboxylic acid Chloromethyl sulfenyl chloride, prepared by the method of
Brintzinger et. al., Chem. Ber. 8 5_: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide to give chloromethyl sulfenyl chloride by the method of E. Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans, trans-2-{4- Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[N, N-di(n- butyl)aminosulfenylmethyl]-pyrroiidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 3_2: 5043-5045 (1991 ) to give the title compound after hydrolysis of the ethyl ester. Example 91 frans./rans-2-(4^Methoxyphenyn-4-f1.3-benzodioxol-5-yn-1-ffN.N-dim- butvπaminocarbonyl-1 -f/?S>-ethyl]pyrrolidine-3-carboxylic acid
Example 91 A i± Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH2CI2, the solution was cooled to 0 °C under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na2Cθ3 solution, then the organic phase was washed sequentially with 25 mL of 1 M aqueous NaHSθ4 and 25 mL brine, dried (Na2Sθ4), filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 %) of the crude bromoamide as a colorless oil. 1H NMR (CDCI3, 300 MHz) δ 0.93 (t, J=7Hz) and 0.97 (t, J=7.5Hz, 6H total), 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1 H), 1.82 (d, J=6Hz, 3H), 3.04-3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J=7H, 1 H). MS (DCI/NH3) m/e 264 and 266 (M+H)+.
Example 91 B trans.trans- and c/s.frans-2- 4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-ι (N.N- dim-butvπamino^carbonyl-1-ff?SVethyliPyrrolidine-3-carboxylic acid ethyl ester A solution of the resultant mixture of trans.trans and cis.trans compounds from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example 91 A (183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C under a N2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et2θ and 10 mL of 1 M aqueous Na2C03 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude). The product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 4 diastereomers. 1H NMR (CDCI3, 300 MHz) δ 0.66-1.55 (several m, 19H), 2.63- 3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 (m, 2.6H), 4.38 (d, J=10.5Hz, 0.2H) and 4.58 (d, J=10.5Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m, 2H). MS (DCI/NH3) m/e 553 (M+H)+.
Example 91 C frans. fran5-2-f4-Methoxyphenyn-4-n.3-benzodioxol-5-ylV1-f.N.N- dibutylamino)carbonyl-1-(f?S)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield. 1H NMR (CD3OD, 300 MHz) δ 0.70-1.05 (several m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.03 Jm, 3.5H), 3.20-3.65 (br m,
4.6H plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J=8Hz, 0.6H), 4.06 (t, J=7.5Hz, 0.4H), 4.25 (d, J=8Hz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d, J=2.5Hz) and 6.75 (d, J=3Hz, 1H total), 6.78-6.85 (m, 1 H), 6.91-7.00 (m, 3H), 7.30- 7.38 (m, 2H). MS (DCI/NH3) m/e 525 (M+H)+. Anal calcd for C30H40N2O6 O.5H2O: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
Example 92 fraπs.fraπs-2-(Pentyl -4-( 1.3-benzodioxol-5-yB-1 -(N.N-dim- butyl,aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
Example 92A Methyl 2-(4-hexenoylt-4-nitro-3-(1.3-benzodioxole-5-yl)butyrate A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1 ,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 μL, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1 :3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture of diastereomers in a 1 :1 ratio. 1H NMR (CDCI3, 300 MHz) δ 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1 H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J =8Hz, 0.5H), 4.10-4.20 (m, 1 H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 (m, 1 H), 6.68 (br s, 1 H), 6.75 (d, 7.5Hz, 1 H). MS (DCI/NH3) m/e 381 (M+NH4)+. Anal calcd for Cι8H2i N07: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71 ; N, 3.72. Example 92B Methyl frans.fraπs-2-fpentyl.-4-f1.3-benzodioxol-5-ynpyrrolidine-3-carboxylate The procedures of Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example 1 B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated N HCθ3 diluted with 10 mL water and 30 mL of CH2CI2. The aqueous phase was extracted (2 x 30 mL CH2CI2), then the combined organic phases were washed with 20 mL brine, dried over Na2Sθ4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH2CI2 gave 336 mg (57%) the title compound as a yellow oil. 1H NMR (CDCI3, 300 MHz) δ 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1 H), 3.34-3.45 (m, 2H), 3.53 (q, J=9Hz, 1H), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H). MS
(DCI/NH3) m/e 320 (M+H)+. Anal calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.
Example 92C frans.frans-2-fPentvn-4-f1.3-benzodioxol-5-yl,-1-(N.N-difn- butvπaminocarbonylmethyflpyrrolidine-3-carboxylic acid The procedures of Example 1 B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam. H NMR (CDCI3, 300 MHz) δ 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43- 1.78 (br m, 6H), 2.76 (t, J=7Hz, 1 H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=14Hz, 1 H), 5.98 (AB, 2H), 6.70 (d, J=7Hz, 1 H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCI/NH3) m/e 475 (M+H)+. Anal calcd for C27H42N2O5 O.5H2O: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68. Example 93 fraπs.frans-2-fPentyl>-4-f1.3-benzodioxol-5-vn-1-r2-fN-propyl-N- propylsulfonylamino,ethyljpyrrolidine-3-carboxylic acid
Example 93A
Methyl frans.fraπs-2-(pentvn-4-f1.3-benzodioxol-5-vn-1-f2-bromoethyl)PyrrolidinQ-
3-carboχyiate The procedure of Example 61 A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example 1C, to provide the title compound as a yellow oil. 1H NMR (CDCI3, 300 MHz) δ 0.89 (br t, J=7Hz. 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 (m, 2H), 2.76- 2.91 (m, 2H), 3.10-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69- 6.77 (m, 2H), 6.90-6.94 (m, 1H). MS (DCI/NH3) m/e 426, 428 (M+H)+.
Example 93B
Methyl frans.frans-2-(Pentvn-4-(1.3-benzodioxol-5-yn-1-[2-fN-propyl-N- propylsulfonylamino)ethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 μmol) in 1 mL EtOH was treated with propylamine (60 μL, 0.73 mmol). The solution was warmed to 80 °C for 4 hours.
The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M. aqueous Na2Cθ3. The organic phase was washed with 15 mL brine, then dried over Na2S04, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 μL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 μL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 x 3 mL CH2CI2. The combined organic extracts were washed with 2 mL brine, then dried over Na2S04, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg (53%) of the title compound as a waxy solid. Rf = 0.17 (20%EtOAc-hexane). MS (DCI/NH3) m/e 511 (M+H)+. Examplg 93C rrans. rans-2-fPentyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-propyl-N- propylsurfonylamino thyl]pyrrolidine-3-carboxylic acid The procedure of Example 71 C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71 B, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14 (5%MeOH-CH2CI2). 1H NMR (CDCI3, 300 MHz) δ 0.88 (br t) and 0.92 (t, J=7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H), 3.05 (br t, J=9Hz, 1H), 3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J=8Hz, 1H), 6.77 (dd, J=1.5,8Hz, 1H), 6.89 (d, J=;L5Hz, 1H). MS (DCI/NH3) m/e 497 (M+H)+.
Example 94 trans. trans-2-( Propyl -f 1.3-benzodioxol-5-yl;-1 -f N.N-di - butyltaminocarbonylmethvπpyπOlidine-3-carboxylic acid
Example 94A Ethyl 2-(4-butanovn-4-nitro-3-( 1.3-benzodioxole-5-ynbutyrate The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, 80%), Rf = 0.28 (25%EtOAc-hexane). 1H NMR (CDCI3, 300 MHz) δ 0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 (t, J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 (t, J=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m, 1 H), 2.60 (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-4.20 (br m,
1 H), 4.23 (q, J=7Hz, 1H), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m, 3H). MS (DCI/NH3) m/e 369 (M+NH4)+. Anal calcd for C 7H2ιN0 : C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.
Example 94B
Ethyl trans. frans-2-. propyn-4-f1.3-benzodioxol-5-vnpyrrolidine-3-carboxylate The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MS (DCI/NH3) m/e 306 (M+H)+. Example 94C
Figure imgf000144_0001
frans.frans-g-fPropvn^-n .S-benzodioxol-S-vlVI-.fN.N-dim- butylιaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid The procedure of Example 92C was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. 1H NMR (CDCI3, 300 MHz) δ 0.89 (t, J=7.5Hz), 0.92 (t, J=7.5Hz), and 0.97 (t, J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 (t, J=7.5Hz, 1H), 3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1 H), 3.78 (d, J=15Hz, 1 H), 5.92 (q, J=1 Hz, 2H), 6.70 (d, J=8Hz, 1 H), 6.79 (dd, J=1Hz,8Hz, 1 H), 6.90 (d, J=1 Hz, H). MS (DCI/NH3) m/e 447 (M+H)+. Anal calcd for C25H38N2O5O.5 H20: O.65.91 ; H, 8.63; N, 6.15.
Found: C, 65.91; H, 8.68; N, 5.94.
Example 95 (2R.3R.4S.-r-»-.-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-ftert- butyloxycarbonyl-aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Example 95A fraπs.fraπs-2-(4-Methoxyphenyl -π .3-benzodioxol-5-ylV1 -( tert- butyloxycarbonylaminocarbonylmethyllpyrrolidine-3-carboxylic acid The resulting mixture of 64% trans, trans- and cis, trans- pyrrolidines resulting from Example 1 C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1 :1 ) indicated that all of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. 1 H NMR (CDCL3, 300 MHz) δ 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.1 1 -1.62 (several br m, 9H), 3.05 (br m, 1 H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7 Hz, 1 H), 4.14-4.28 (br m, 1 H), 4.89-5.24 (br m, 1 H), 5.94 (d, J=3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH3) m/e 470 (M+H)+. To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1 .06 g, 25.17 mmol) in 60 mL of water. The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH -7) with 1 U hydrochloric acid, then to pH 4 with 10 % citric acid and extracted with 5 % ethanol in methylene chloride (3 x 100 mL). The combined organic layers dried (Na2Sθ4), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 o %. ). 1H NMR (CDCI3, 300 MHz) δ 1.16 (v br s, 9H), 3.11 (br m, 1 H), 3.50- 3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, 1 H), 4.96 (br m, 1 H), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 95B f2R.3R.4S,-(+,-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-(tert- butyloxycarbonylaminocarbonylmethvB-pyrrolidine-3-carboxylic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam. This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1 H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate. The pure (2R,3R,4S)-(+)- enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether. The aqueous layer was further extracted twice with 100 mL of ether. The combined ether layers were washed with brine, dried (Na2Sθ4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 % of theoretical 50 % maximum; >99.5 ee). 1 H NMR (CDCI3, 300 MHz) δ 1.05-1.50 (br m, 9H), 3.12 (br m, 1 H), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, 1 H), 4.96 (br m, 1 H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J=9 Hz, 2H), 7.19. (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+. Example 95C (2R.3R.4S)-f-i-l-Ethvl 2-f4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pyrrolidine-3- carboxvlate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 °C. with stirring for 18 hours at which point all of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer _was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 69%). 1 H NMR (CDCI3, 300MHz) δ 1.1 1 (t, J=7 Hz, 3H), 2.18 (v br s, 1 H), 2.93 (t, J= 9 Hz, 1 H), 3.19,3.22 (dd, J=7 Hz, 1 H), 3.50-3.69 (m, 2H), 3.80 (s, 3H),
4.07 (q, J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1 H), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH3) m/e 370 (M+H)+.
Example 95D
»2R.3R.4S,-l+,-2-f4-Methoχyphenvn-4-f1.3-benzodioxol-5-vn-1 -(tert- butyloxycarbonyl-aminocarbonylmethylι-pyrrolidine-3-carboxylic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 μL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 °C. for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1 :3 ethyl acetate- hexane to give pure ester as a colorless oil. 1 H NMR (CDCI3, 300MHz) δ 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1 .52
(m, 8H), 2.78 (d, J=14 Hz, 1 H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 (d, J=9 Hz, 1 H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 (d, J=9 Hz, 1 H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1 H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 539 (M+H)+. To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40 °C. over 2.5 hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous hydrochloric acid until cloudy, and the pH was then adjusted to -4-5 with 10% aqueous citric acid. This mixture was extracted with 1 :19 ethanol-methylene chloride (3 x 50 mL). The combined extracts were dried (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 83%). 1H NMR (CDCI3, 300MHz) δ 0.80 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3JH), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz. 1 H), 6.87 (br d, J=8 Hz, 3H), 7.05 ( br s, 1 H), 7.33 (v br s, 2H). MS (DCI/NH3) m/e 511 (M+H)+. [αp = +74.42°. Anal calcd for C29H38N2θ6 0.5 H20: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.
Example 95E
Alternate Preparation of (2R.3R.4SVιH-V2-(4-Methoχyphenvn-4-(1.3-benzodioxol-5- vπ-1-(tert-butyloxycarbonylaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid The product of Example 95A (2.858 g) was suspended in 10 mL of
EtOAc. 0.7833 g of R (+) alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 167°. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-168°. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-110°. (HPLC of this showed 20%of the desired enantiomer and 80% of the unwanted enantiomer.)
The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
Example 96 fraπs.fraπs-2-f4-Methoxvphenvn-4-π .3-benzodioxol-5-yl.-1-r2-fN-propyl-N- butvrvlamino.ethvllDvrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C. The product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 (s, 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J=8Hz). 6.84 (m. 1 H), 6.85 (d, 2H, J=8Hz), 7.04 *(d, 1 H, J=1 Hz), 7.40
(d, 2H, J=8Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 LO TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.
Example 97 rrat7s.frans-2-f4-Methoxyphenvn-4-(1.3-benzodioxol-5-yl,-1-r2-fN-propyl-N-
(ethylaminocarbonynamino)ethvnpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl isocyanate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.80 (t, J=8Hz) and 1 .05 (t, J=8Hz) and 1.20 (m) and 1.42 (m) total of 8H for the four peaks, 2.35 (br s, 1 H), 2.70 (m, 1 H), 3.0 (m, 3H), 3.2 (m, 3H), 3.25 (dq, 1 H, J=1 ,8Hz), 3.42 (m, 1 H), 3.6 (m, 1 H), 3.75 (m, 1 H), 3.78 (s, 3H), 4.8 (br s, 1 H), 5.95 (s, 2H), 6.74 (d, 1 H, J=8Hz), 6.85 (m, 3H), 7.00 (s, 1 H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 498 (M+H)A Anal calcd for C27H35N3O6 • 0.75 H20: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.
Example 98 rrat7S. rans-2->4-Methoxyphenvn-4-n .3-benzodioxol-5-yli-1-[2-rN-butyl-N- butyrylaminQ)ethyl]pyrroiidiπe-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :4 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (m, 3H). 0.90 (t, 3H, J=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 511 (M+H)+. HRMS calcd for C29H38N2O6: 511.2808. Found: 51 1 .2809
Example 99 frans.frans-2-(4-Methoxyphenvπ-4-M .3-benzodioxol-5-vπ-1-[2-(N-propyl-N- ethoxycarbonylaminθ)ethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether- hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, J=8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1 H), 2.75 (m, 1 H), 2.88 (br q, 2H, J=8Hz), 3.08 (br m, 2H), 3.27 (br m, 2H), 3.44 (m. 1 H), 3.54 (dt, 1 H, J=1 ,8Hz), 3.63 (d, 1 H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.81 (dd, 1 H, J=1 ,8Hz), 6.85 (d, 2H, J=8Hz), 7.00 (s, 1 H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C27H34N2O7 • 0.5 H20: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71 ; N, 5.30. Example 100 frans.fra/7S-2-f4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-methyl-N-f2- ethylbutyrylιaminθ)ethyl]pyrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N- methylmorpholine (50 μL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 M H3PO4, and brine, dried with Na2Sθ4, and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1 :3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61 C. The crude product was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300
MHz) (mixture of rotamers) δ 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (m, 2H). 1.25-1.75 (m, 5H), 2.16 (m, 1 H), 2.32 (m, 1 H), 2.45 (m, 1 H), 2.70 (m, 1 H), 2.86, 2.94 (s, total 3H), 2.95 (m. 1 H), 3.35 (m, 1 H), 3.52 (m, 2H), 3.65 (m, 1 H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), 6.73 (m, 1 H), 6.84 (m, 3H), 6.97 (m, 1 H), 7.30 (m, 2H). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 • 0.25 H20: C, 67.11 ; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-ylV1-r2-(N-methyl-N-(2- propytvaleryl)aminotethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2- ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.79 (t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10 (m, 4H), 1.2-1.5 (m, 4H), 2.55 (m, 1 H), 2.96 (s, 3H), 3.15 (br m, 1 H), 3.32 (br m, 1 H), 3.56 (m, 2H), 3.68 (m, 1 H) 3.68 (s, 3H), 3.70 (m, 1 H), 3.80 (m, 2H), 4.65 (br d, 1 H), 5.92 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85
(d, 2H, J=8Hz), 7.05 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 525 (M+H)+. Anal calcd for C30H40N2O6 1.25 TFA: C, 58.51 ; H, 6.23; N, 4.20. Found: C, 58.52; H, 6.28; N, 4.33.
Example 102 rrans.frat7S-2-f4-Methoxvphenyn-4-n .3-benzodioxol-5-vn-1-r2-fN-propyl-N-.tert- butyloxycarbonylmethyl.amino.ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and t-butyl bromoacetate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether- hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1 H), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1 H, J=2,8Hz), 3.50 (dt, 1H, J=2,8Hz), 3.62 (d, 1 H, J=8Hz), 3.78 (s. 3H), 5.95 (s, 2H),
6.72 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1 H), 7.16 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 541 (M+H)+. Anal calcd for C30H40N2O7 • 1.0 H20: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.
Example 103 frans.fraπs-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-[2-(N-propyl-N-(n- propylaminocarbonylmethyl)aminθιethyl1pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.78 (t, 3H, J=8Hz), 0.88 (t, 3H, J=8Hz), 1.45 (m, 2H), 1.48 (m, 3H, J=8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1 H), 3.04 (m, 1 H), 3.15 (m, 3H), 3.28 (t, 1 H, J=8Hz), 3.45 (t, 1 H, J=8Hz), 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75 (m, 1 H), 3.80 (s, 3H), 4.25 (d, 1 H, J=8Hz), 5.95 (s, 2H), 6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1 ,8Hz), 6.88 (d, 2H, J=8Hz), 7.04 (d, 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 526 (M+H)A Anal calcd for C29H39N3O6 ■ 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63. Examole 104 frans.frar;s-2-(4-Methoxvphenvn-4-M.3-benzodioxol-5-vn-1-f2-fN-propyl-N-f4- methoxvphenoxvcarbonvnamino)ethvnpvrrolidine-3-carboxylic acid The title compound was prepared by the methods described in
Example 61 , but substituting propylamine for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a whjje solid. 1 H NMR
(CD3OD, 300 MHz) mixture of rotamers δ 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, total of 1 H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 (m, total of 1 H), 5.95 (s) and 5.98 (s, total of 2H), 6.63(m, 1 H), 6.72 (d, 1 H, J=8Hz), 6.81 (m, 2H), 6.93 (m, 5H), 7.40 (m, 2H). MS (DCI/NH3) m/e 577 (M+H)+. Anal calcd for
C32H36N2θ8 - 1.0 H20: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.
Example 105 rans.fraπs-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-r2-fN-propyl-N-(4- methoxybenzovnamino ethyHpyrrolidine-3-carboxylic acid
The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.78 (m) and 0.98 (t, J=8Hz) total of 3H, 1.47 (m) and 1 .52 (q, J=8Hz) total of 2H, 2.25 (br s, 1 H), 2.78 (br s, 1 H), 2.90 (br t, 2H), 3.12- 3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1 H, J=8Hz),
6.83 (m, 5H), 6.94 (m, 1 H), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 • 0.75 H20: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59. Example 106 frar7S.frans-2-(4-Methoxyphenyn-4-M .3-benzodioxol-5-yl,-1-f2-(N-propyl-N- benzoylamino.ethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzoyi chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) mixture of rotamers δ 0.65 and 0.9 (m, total of 3H) , 1.4 and 1.55 (m, total of 2H), 2.05 and 2.15 (m, total of 1 H), 2.6 - 3.6 (m, 8H), 5.92 (s, 2H), 6.70(d, 1 H, J=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH3) m/e 531 (M+H)+. Anal calcd for C31H34N2O6 • 0.3 H20: C, 69.46; H, 6.51 ; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.
Example 1Q7 fraπs.frans-2-,4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -r2-(N-propyl-N- benzyloxycarbonylaminoιethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac μC 18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.8 (m, 3H) 1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m,
1 H), 2.93 (m, 1H), 3.15 (m, 2H), 3.32 (m. 3H), 3.52 (m, 2H), 3.66 (m, 1 H), 3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s. 2H), 6.72(d, 1H, J=8Hz), 6.82 (m, 3H), 7.0 (br d, 1 H, J= 15Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 - 1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found: C, 60.66; H, 5.34; N, 4.28.
Example 108 frans.frans-2-f4-MethoxyphenylV4-(1.3-benzodioxol-5-vn-1-f2-(N-propyl-N-(4- methoxybenzyloxycarbonvnamino^ethvnpyrrolidine-3-carboxylic acid The title compound is prepared by the methods described in
Example 61 , substituting propylamine for methylamine in Example 61 B and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61C.
Example 1Q9 frans.frans-2-(4-Methoxyphenvn-4-n .3-benzodioxol-5-yn-1-f2-fN-butyl-N- ethoxycarbonylaminotethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, 1 H), 5.94 (s, 2H), 6.76 (d, 1 H, J=8Hz), 6.92 (d, 2H,
J=8Hz), 7.03 (br s, 1 H), 7.17 (br s, 1 H), 7.7 (br s, 2H). MS (FAB) m/e 513 (M+H)+. Anal calcd for C28H36N2O7 • 0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Found: C, 60.99; H, 6.80; N, 4.93.
Example 110 fraπs.fraπs-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-r2-(N-butyl-N- propoxycarbonylamino ethyl]pyrrolidine-3-carboxylic aci ' The title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether- hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (br s, 1 H), 0.85 (t, 3H, J=8Hz), 0.92 (br s, 1 H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, 1 H), 2.15 (br s, 1 H), 2.72 (m, 1 H), 2.87 (m, 1 H),
3.1-3.45 (m, 5H), 3.55 (m, 1 H), 3.64 (d, 1 H, J=8Hz), 3.79 (s, 3H), 3.88 (br s, 1 H), 3.97 (br s, 1 H), 5.95 (s, 2H), 6.73(d, 1 H, J=8Hz), 6.85 (m, 3H, 7.0 (s, 1 H), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for C29H38N2O7 • 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21. Example 111 frans.frar>s-2-(4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1-f2-.N-propyl-N- propoxvcarbonylamino)ethvπpvrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether- hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m,_3H), 1.62 (m, 1 H), 2.15
(br s, 1 H), 2.68-3.45 (m, 8H), 3.54 (m, 1 H), 3.66 (m, 1 H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.82 (m, 1 H), 6.84 (d, 2H, J=8Hz), 7.00 (br s, 1 H), 7.33 (m, 2H). MS (DCI/NH3) m/e 513 (M+H)+. Anal calcd for C28H36N2O7 0.15 H20: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.
Example 112 fraπs.frans-1-fN.N-Di(n-butylιaminocarbonylmethylV2.4-dif1.3-benzodioxol-5- yl)Pyrrolidine-3-carboxylic acid Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. 42, 20 (1967) starting with 3,4- methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid, m.p. 58-60 °C. 1H NMR (CDCI3. 300 MHz) δ 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J=13Hz, 1H), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62 (m, 1H), 3.78 (d, J=9Hz, 1H), 5.95 (s, 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, J=1 Hz, 1 H), 7.01 (d, H=1Hz, 1H). MS (DCI/NH3) m/e 525 (M+H)+.
Example 113 fraπs.frans-1-(2-fN-m-Butvn-N-propylsulfonylamino)ethvn-2-f4-methoxyphenyn-4- (1 r3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 64-65 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.83 (t, J=7Hz, 3H), 0.98 (t, J=7Hz, 3H), 1.12-1.25 (m, 2H), 1.32-1 .41 (m, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.59 (m, 1H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.83 (dd, J=8Hz, 1 Hz, 1 H), 6.88 (d, J=9Hz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e
547 (M+H)+.
Example 114 fraπs.fraπs-1-fN.N-Di(n-butynaminocarbonylmethyl>-2-(4-methoχyphenvn-4-M .3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid, m.p. 74 76 °C. 1 H NMR
(CDCI3, 300 MHz) δ 0.80 (t, J=6Hz, 3H), 0.88 (t, J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21 -1.48 (m, 6H), 2.75 (d, J=12Hz, 1 H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, 1 H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, J=9Hz, 1H), 6.85 (d, J=9Hz, 2H), 6.91 (d,d, J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 525 (M+H)+.
Example 115 frans.frans-1-f2-fN-Propyl-N-propylsulfonylamino^ethyn-2-f4-methoxyphenvn-4- (1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73 °C. 1 H NMR (CDCI3. 300 MHz) δ 0.79 (t, J=8Hz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (m, 1 H), 2.69-3.32 (m, 9H), 3.42 (dd, J=3Hz, 12Hz, 1 H), 3.52-3.58 (m, 1H), 3.64 (d, J=12Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=11 Hz, 1 H), 6.83 (dd, J=1 Hz, 1 1 Hz, 1 H), 6.87 (d,
J=1 1 Hz, 2H), 7.0 (d, J=2Hz, 1 H), 7.32 (d, J=11 Hz, 2H). MS (DCI/NH3) m/e
533 (M+H)+.
Example 116 trans, frans-1 -(2-fN-Butyl-N-butylsulfonylamino ethvn-2-(4-methoχyphenvn-4-π .3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 62-63 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=6Hz, 3H), 0.91 )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1 .33- 1.42 (m, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (m, 1 H), 2.70-3.28 (m, 9H), 3.41 (d, J=8Hz, 1 H), 3.52-3.58 (m, 1 H), 3.65 (d, J=8Hz, 1 H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz, 2H), 7.01 (s, 1 H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+.
Example 117 frans.frans-l-^-fN.N-Difn-butvnaminocarbonylmethyn^-^- methoxymethoxyphenvn-4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4- methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid, m.p. 48-49 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.81 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1 .44 (quintet, J=7Hz, 2H), 2.75 (d, J=12Hz, 1 H), 2.94-3.10 (m, 4H), 3.25-3.35 (m, 1 H), 3.40 (d, J=12Hz, 1 H), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, 1 H), 3.77 (d, J=9Hz, 1 H), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, 1 H), 6.86
(dd, J=1Hz, 8Hz, 1H), 7.0 (d, J=8Hz, 2H), 7.04 (d, J=1 Hz, 1 H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 541 (M+H)+.
Example 118 fraπs.frans-1-f2-fN.N-Dim-butyl aminocarbonylmethvn-2-(4-hydroxyphenvn-4-(1.3- benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid hydrochloride salt The compound resulting from Example 1 16 was treated with concentrated HCI in 1 :1 THF-isopropanol to give the title compound as a white solid, m.p. 211-212 °C. 1 H NMR (CD3OD. 300 MHz) δ 0.90 (t, J=8Hz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1 H), 3.14- 3.35 (t, J=9Hz, 1H), 3.90 (bs, 3H), 4.17 (d, J=15Hz, 1 H), 5.96 (s, 2H), 6.82-6.93 (m, 4H), 7.03 (d, J=1 Hz, 1 H), 7.42 (bs, 2H). MS (DCI/NH3) m/e
497 (M+H)+.
Example 119 frans.frans-1-(2-lN-lsobutyl-N-propylsulfonylamino)ethvn-2-(4-methoxyphenvn-4-
( .3-benzodioxol-5-ynpyrrolidine-3-carboxyric acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 73-74 °C. H NMR (CDCI3, 300 MHz) δ 0.80 (d, J=6Hz, 6H), 0.98 (t, J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1 H), 1.74
(sextet, J=8Hz, 2H), 2.23-2:34 (m, 1 H), 2.68-2.98 (m, 7H), 3.08-3.18 (m, 1 H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.86 (d, J=8Hz, 2H), 6.98 (d, J=1 Hz, 1 H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 547
(M+H)+.
Example 120 frans.frar>s-1-f2-(N-Benzenesulfonyl-N-propylamino^ethyn-2-(4-methoxyphenvn-4- (1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 89-91 °C. 1 H -NMR (CDCI3, 300 MHz) δ 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (m, 1 H), 2.62-
2.72 (m, 1 H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1 H), 3.38 (dd, J=3Hz, 9Hz, 1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H),
6.73 (d, J=8Hz, 1 H), 6.84 (dd, J=1 Hz, 8Hz, 1 H), 6.85 (d, J=9Hz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.28 (d, J=9Hz, 2H), 7.39-7.54 (m, 3H), 7.70 (d, J=7Hz,
2H). MS (DCI/NH3) m/e 567 (M+H)+.
Example 121 trans.trans-1 -(2-(N-(4-Methoxybenzenesulfonvn-N-propylamino ethylι-2-(4- methoxyphenyl ;-4-(1.3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 96-97 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H), 2.62- 2.71 (m, 1 H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz, 1 H), 3.48-3.56 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s, 3H), 3.86 (s, 3H),
5.95 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.81-6.89 (m, 5H), 7.01 (d, J=1 Hz, 1 H), 7.28 (d, J=8Hz, 2H), 7.62 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 597 (M+H)+.
Example 122 raπs.frans-1 -fN.N-Dim-butynaminocarbonylmethyn-2-(2-methoxyethoxy-4- methoxyphenvn-4-(1.3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2- methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid, m.p. 63-65 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.84 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, 1 H), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, 1 H), 5.92 (s, 2H), 6.40 (d, J=2Hz, 1 H), 6.52 (dd, J=2Hz, 9Hz, 1 H), 6.70 (d, J=8Hz, 1 H), 6.83
(dd, J=1 Hz, 8Hz, 1 H), 5.98 (d, J=2Hz, 1 H), 7.53 (d, J=9Hz, 1 H). MS (DCI/NH3) m/e 585 (M+H)+.
Example 123 frans.frans-1-f2-fN-Propyl-N-l2.4-dimethylbenzenesurfonynamino.ethvn-2-(4- methoxyphenyn-4-f1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-90 °C. 1 H NMR (CDC13, 300 MHz) δ 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H), 2.32 (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1 H), 2.78 (t, J=9Hz, 1 H), 2.89 (dd,
J=8Hz, 1 H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 ( , 3H), 3.46-3.55 (m, 1 H), 3.60 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 9Hz, 1H), 6.86 (d, J=9Hz, 2H), 6.97 (d, J=1 Hz, 1 H), 7.03 (bs, 2H), 7.29 (d, J=9Hz, 1 H). MS (DCI/NH3) m/e 595 (M+H)+.
Example 124 frans.frans-1-l2-fN-Propyl-N-(3-chlcropropylsulfonvnaminoiethvn-2-(4- methoxyphenyn-4-M .3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 75-76 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70- 2.80 (m, 1 H), 2.85-3.10 (m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9Hz, 1 H), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.86 (d, J=8Hz, 2H), 7.00 (s, 1 H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+.
Example 125 trans, trans- l-^-fN-Propyl-N-^-methoxyethylsulfonvnamino^ethvn^-.4- methoxyphenvn-4-(1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, trans,trans-' -{2-
(N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid, m.p. 62-64 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, 1 H), 2.72-2.79 (m, 1 H), 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s. 3H). 3.43 (dd. J=3Hz, 9Hz, 1H), 3.53-3.58 (m, 1H), 3.65 (d, J=9Hz, 1 H), 3.69 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (dd, J=1 Hz, 8Hz, 1H), 6.87 (d, J=8Hz. 2H), 7.02 (d. J=1 Hz, 1 H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 549 (M+H)+.
Example 126 fraπs.frans-1 -f2-fN-Propyl-N-f2-ethoxyethylsulfonvnamino^ethyn-2-f4- methoxyphenyn-4-f1.3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 58-60 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 1.18 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24- 2.33 (m, 1 H), 2.70-2.80 (m, 1 H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.46 (q, J=7Hz, 2H), 3.52- 3.58 (m, 1 H), 3.65 (d J=9Hz, 1 H), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.83 (dd, J=1 Hz, 7Hz, 1 H), 6.87 (d, J=8Hz,
2H), 7.00 (d, J=1 Hz, 1 H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 563
(M+H)+.
Example 127 frans.frans-1-f2-fN-Propyl-N-(5-dimethylamino-1-naphthylsulfonyl')amino^ethvn-2-
(4-methoxyphenvn-4-(1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid, m.p. 102-104 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.62 (t, J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H), 2.78 (t, J=9Hz, 1H), 2.88 (s, 6H), 2.72-2.89 (m, 1 H), 3.05-3.12 (m, 2H),
3.26-3.45 (m, 3H), 3.45-3.52 (m, 1 H), 3.58 (d, J=9Hz, 1 H), 6.97 (d, J=1 Hz, 1 H), 7.13 (d, J=7Hz, 1 H), 7.26 (d, J=8Hz, 1 H), 7.42-7.50 (m, 2H), 8.08 (dd, J=1 Hz, 7Hz, 1 H), 8.20 (d, J=8Hz, 1 H), 8.48 (d, J=8Hz, 1 H). MS (DCI/NH3) m/e 660 (M+H)+. Example 128 trans, trans- 1 -(2-( N-Propyl-N-(ethylsulfonyl laminoiethyl ι-2-(4-methoxyphenyn-4- M .3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 70-72 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H), 1.43 (q, J=8Hz, 2H), 2.22-2.30 (m, 1 H), 2.71 -2.80 (m, 1 H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H), 3.43 (dd, J=3Hz, 9Hz, 1 H), 3.53-3.60 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.82 (dd, J=1 Hz, 7Hz, 1 H), 6.88 (d, J=8Hz, 2H), 7.00 (d, J=1 Hz, 1 H),. 7.32 (d, J=8Hz, 2W). MS (DCI/NH3) m/e
519 (M+H)+.
Example 129 trans, frans- 1-r2-fN-Propyl-N-(4-methylbenzenesulfonyl,aminolethvn-2-(4- ' methoxyphenvn-4-f1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 78-79 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H), 2.40 (s, 3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd, J=3Hz, 9Hz, 1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s, 3H),
5.95 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz, 2H), 7.00 (s, 1 H), 7.21 (d, J=8Hz, 2H), 7.29 (d, J=8Hz, 2H), 7.57 (d, J=8Hz, 2H).
MS (DCI/NH3) m/e 581 (M+H)+.
Example 130 frans. rans-1-fN.N-Difn-butvnaminocarbonylmethyn-2-f3-pyridvn-4-f1.3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid, m.p. 167-168 °C. 1H NMR (CDCI3. 300 MHz) δ 0.82 (t, J-7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, 6H), 3.34-3.43 (m, 2H), 3.57 (dd, J=3Hz, 9Hz, 1 H), 3.75-3.83 (m, 1 H), 4.08 (d, J=9Hz, 1 H), 5.93 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.90 (dd, J=2Hz, 8Hz, 1 H), 7.03 (d, J=2Hz, 1 H), 7.38 (dd, J=4Hz, 8Hz, 1 H), 8.04 (d, J=8Hz, 1 H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCI/NH3) m/e 482 (M+H)+. Examole 131 frans.frans-1-f2-fN-Propvl-N-fn-butvlsulfonvnamino.ethvn-2-f4-methoxvphenyn.4- f 1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 65-66 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.31-1.46 (m, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (m, 1 H), 2.70-3.08 (m, 7H), 3.12-3.23 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.52-3.58 (m, 1 H), 3.64 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1H), 6.83- (dd, J=1 Hz, 7Hz, 1 H), 6.86 (d. J=8Hz, 2H), 7.00 (d, J=1Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 132 frans.frans-1-f2-fN-Propyl-N-f4-chlorobenzenesulfonynaminθ)ethyn-2-f4- methoxyphenyl)-4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 105-106 °C. 1 H NMR (CDCI3. 300 MHz) δ 0.72 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (m, 1 H), 2.78-2.86 (m, 1 H), 2.96-3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, J=5Hz, 9Hz, 1 H), 3.62-3.68 (m, 1 H), 3.80 (s, 3H), 3.94 (d, J=9Hz, 1 H), 5.92 (s, 2H), 6.75 (d, J=8Hz, 1 H), 6.84 (dd, J=2Hz, 8Hz, 1 H), 6.94 (d, J=8Hz, 2H), 6.98 (d, J=2Hz, 1H), 7.36 (d, J=8Hz, 1 H), 7.49 (d, J=8Hz, 1 H), 7.68 (d, J=8Hz, 1H). MS (DCI/NH3) m e 601 (M+H)+.
Example 133 frans.frans-1-(2-(N-Propyl-N-(benzylsulfonvnamino ethyl;-2-f4-methoχyphenvn-4- (1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-89 °C. H NMR (CDCI3, 300 MHz) δ 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, 1 H), 2.56- 2.67 (m, 1 H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 7Hz, 1 H), 6.86 (d, J=8Hz, 2H), 6.97 (d, J=1 Hz, 1 H), 7.27-7.35 (m, 7H). MS (DCI/NH3) m/e 581 (M+H)+. Examcle 134 frans.frans-1-(2-fN-Propyl-N-f4-fluorobenzenesulfonynamino)ethvn-2-(4- methoxyphenyn-4-f1.3-benzodioxol-5-vnpvrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 91-93 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1 H), 2.56- 2.67 (m, 1 H), 2.78-2.87 (m, 2H), 2.97 (septet, J=8Hz, 2H), 3.1 1 -3.16 (m, 2H), 3.33 (dd, J=2Hz, 9Hz, 1 H), 3.43-3.50 (m. 1 H), 3.57 (d, J=9Hz, 1 H), 3.78 (s, 3H), 7.08 (t, J=8Hz, 2H), 7.24 (d, J=8Hz, 2H), 7.69 (dd, J=5Hz. 8Hz, 2H). MS (DCI/NH3) m/e 585 (M+H)+.
Example 135 frans.fran5-1-(N-Methyl-N-prppylaminocarbonylmethyl)-2-(4-methoχyphenyl)-4-f4- benzofuranyl;pyrrolidine-3-carboxylic acid
Example 135A Benzofuran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 eq) in DMF (60 mL) at 0 °C was added a solution of 3- bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgS04, filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, 74%). b.p. 160-163 °C at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yield a colorless liquid (8.13 g, 70%). b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether (80 mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 °C. After stirring for 15 minutes, e solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated. The organic solution was dried over MgSθ4 and concentated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 g), both as colorless oils.
Example 135B frans.frans-1 -fN-Methyl-N-propylaminocarbonylmethyl)-2-f4-methoxyphenyl)-4-f4- benzofuranylιPyrrolidine-3-carboxylic acid
The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49A for piperonal. 1H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.59 (1 H, t, J=3Hz), 7.4-7.2 (6H, m), 6.8 (2H, d, J=8Hz), 4.03 (1 H, m), 3.94 (1 H, dd. J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (1 H, dd, J=8Hz, 7
3Hz), 3.42 (1 H, dd, J=11 Hz, 5Hz), 3.40-2.90 (5H, m), 2.82 (2.81 ) (3H, s), 1.50 (2H, septet. J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH3) m/e
451 (M+H)+. Anal.calc. for C26H30N2O5 • AcOH: C, 65.87; H, 6.71 ; N ,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s
Example 136 frans.frans-1-fN-Methyl-N-propylaminocarbonylmethyn-2-f4-methoxyphenyn-4-f6- benzofuranyl.Pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal. H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.65 (1 H, bd), 7.60 (1 H, d, J=2Hz), 7.55 (1 H, d, J=8Hz), 7.35 (3H, m), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1 H, dd, J=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 (M+H)+. Anal.calc. for C26H30N2O5 • 0.5 H 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71 ; N, 6.07. Example 137 frans.frans-1-fN-Methvl-N-propylaminocarbonylmethvn-2-f4-methoxvphenyn-4-fβ- benzo-2.3-dihvdrofuranvnpyrrolidine-3-carboxylic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H2 in AcOH, followed by preparative hplc) of the compound resulting from Example 136 1H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1 H, m), 7.82 (3H, m). 5.40 (1 H, dd, J=11 Hz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1 H, m), 4.10 (1H, m), 3.88 (1 H, m), 3.79 (3H, s), 3.60 (1 H, m), 3.35 (1 H, m), 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) m/e 453 (M+H)+. Anal.calc. for C26H32N2O5 - 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.
Example 138 frans.frans-1-(N.N-Difn-butvnaminocarbonylmethvn-2-(4-methoχyphenvn-4-f4- benzofuranynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR (300 MHz, CDCI3) δ 7.62 (1 H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 (3H, m), 7.26 (1 H, d, J=2Hz), 7.23 (1H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8, 6Hz,4Hz). 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.67 (1H, dd, J=10Hz, 3Hz), 3.44 (2H. m). 3.35-3.15 (3H, m). 3.00 (2H, m). 2.84 (1 H. d, J=14Hz), 1.43
(3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
Example 139 frans.frans-1-fN.N-Di(n-butynaminocarbonylmethyn-2-f4-methoxyphenvn-4-f4- benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 135A substituted 4- bromophenol for 3-bromophenol, in Example 49A for piperonal and subsiiiuiiiiy .N-dibu yl brcmoacetami *1 fnr N-methyl-N-propyl bromoacetamide. "> H NMR (300 MHz, CDCI3) δ 7.64 (1H, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, m), 7.33 (2H, d, J=8Hz), 6.85 (2H, d. J=8Hz), 6.73 (1H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=1 1 Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=10Hz, 3Hz), 3.44 (2H, m). 3.30 (1 H, m), 3.20-2.95 (5H, m). 2.82 (1 H, d. J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz). 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N. 5.29.
Example 14Q frans.frans-1-fN.N-Difn-butyl.aminocarbonylmethvn-2-f4-methoχyphenvn-4-f6- benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting N.N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR (300 MHz, CDCI3) δ 7.63 (1 H, bd), 7.59 (1 H, d, J=2Hz), 7.53 (1 H, d, J=8Hz), 7.36 (3H, m), 6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=11 Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, s), 3.53 (1 H, dd, J=10Hz, 3Hz), 3.44 (2H, m), 3.30 (1 H, m), 3.20-2.95 (5H, m), 2.80 (1 H, d, J=14Hz), 1.43 (3H, m),
1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5 - 0.75 H20: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.1 1 ; H, 7.33; N, 5.32.
Example 141 frans.frans-1 -fN.N-Difn-butvnaminocarbonylmethvn-2-(4-methoχyphenvn-4-(6- benzo-2.3-dihvdrofuranvnpyrrplidine-3-carboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, followed by preparative hp!c). H NMR (300 MHz, CDCI3) δ 7.40 (2H, d, J=8Hz), 7.16 (1 H, d, J=8Hz), 6.97 (1 H, dd, J=8Hz, 2Hz), 6.89 (3H, m), 5.90 (1 H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58 (2H, m), 3.40 (1 H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1 .29 (3H, m), 1.08 (2H, m), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 509 (M+H)+. Anal.calc. for C30H40N2O5 - 0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60. Examole 142 frans.frans-1-fN-Methyl-N-propylaminocarbonylmethylι-2-(4-methoχyphenyn-4-f5- indanvnpyrrolidine-3-carboxylic acid
Example 142A lndane-5-carboxaldehvde lndane-5-carboxaldehyde was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5-carboxakJehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5- carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystallized from hot acetonitrile to yield the 5-aldimine as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether. The organic solution was dried over MgSθ4, filtered, and concentated in vacuo. Vacuum distillation of the residue afforded indane-5- carboxaldehyde (1.54 g, 88%) as a colorless liquid, b.p. 88-90 °C at 0.9 mm Hg.
Example 142B frans.frans-1-fN-Methyl-N-propylaminocarbonylmethyn-2-f4-methoxyphenyn-4-f5- indanvnpyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.25-7.1 (5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1 H, d, J=8Hz), 3.75 (3H, s), 3.50- 2.90 (6H, m), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e
451 (M+H)+, 473 (M+Na)+. Anal.calc. for C27H34N2O4 - 2.5 H20 : C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53. Examole 143 trans, trans- 1 -f N-Methyl-N-propylaminocarbonylmethyn-2-f 4-methoxyphenvn-4-f R. indolynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51 : 5106 (1986), for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) (minor rotamer) δ 8.43 (1 H, brs)t 7.57 (1 H, d, J=8Hz), 7.43 (1H, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (1 H, d, J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1 H, m), 3.93 (1 H, dd, J=6Hz, 3Hz), 3.80 (1 H, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86
(2.82) (3H, s), 1.47 (2H, septet, J=7Hz), 0.83 (0.73), (3H, t, J=7Hz). MS (DCI/NH3) m/e 450 (M+H)+. Anal.calc. for C26H31 N3O4 • 0.75 H20: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
Example 144 frans.frans-1-fN-Methyl-N-propylaminocarbonylmethvn-2-(4-methoxyphenvn-4- f3.4-difluorophenynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.60-7.3
(4H, m), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1 H, m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 447 (M+H)+. Anal.calc. for C24H28F2N2O4 • 1.80 H20: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
Example 145 frans.frans-1 -fN-Methyl-N-propylaminocarbonylmethyn-2-(4-methoxyphenyn-4-
(phenvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in
Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) δ 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, J=8Hz), 3.90 (1 H, m), 3.79 (3H, s), 3.70- 2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH3) m/e 41 1 (M+H)+. Anal.calc. for C24H30N2O4 • 2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29. Example 146 frans.frans-1-fN-Methyl-N-propylaminocarbonylmethyl»-2-f4-methoxyphenvn-4-(4- hydroxyphenynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) δ 7.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89 (2H, d, J=8Hz), 3.81 (3H, s), 3.65 (1 H, d, J=8Hz), 3.70-3.00 (8H, m), 2.92 (2.83) (3H, s), 1.50 (2H, septet, J=7Hz), 0.87 (0.77). (3H, t, J=7Hz). MS
(DCI/NH3) m/e 427 (M+H)+. Anal.calc. for C24H30N2O5 - 1.00 H20: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
Example 147 frans.frans-1-fN-Methyl-N-propylaminocarbonylmethvn-2-(4-methoxyphenvn-4- f2.4-dimethoxyphenvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) δ 7.61 (1 H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 (1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 (3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/NH3) m/e 471 (M+H)+. Anal.calc. for C26H34N2O6 • 0.75 H20: C, 64.51 ; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
Example 148 frans.fraπs-1 -(N.N-Difn-butynaminocarbonylmethyl.-2-f4-methoxyphenyn-4-f5- benzo-2.3-dihvdrofuranvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5- carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) δ 7.31 (2H, d, J=8Hz), 7.27 (1 H, d, J=2Hz), 7.18 (1 H, dd, J=7Hz, 3Hz), 6.86 (2H, d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, s), 3.62 (1 H, m), 3.50-3.25 (4H, m), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, m),
2.79 (1 H, d, J=14Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 509 (M+H)+. Anal.calc. for C30H40N2O5 • 0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21 ; H, 7.92; N, 5.36.
Example 149 frans.frans-1 -fN.N-Difn-butynaminocarbonylmethyn-2-f4-methoxyphenvn-4-f4- methoxyphenvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) δ 7.38 (2Η, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1 H, m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (1 H, d, J=14Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal.calc. for C29H40N2O5: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
frans.frans-1 -fN.N-Di(n-butynaminocarbonylmethyn-2-f4-methoxyphenvn-4-f3.4- difluorophenynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in
Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) δ 7.35 (1 H, m), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78 (3H, s), 3.79 (1H, m), 3.62 (1 H, m), 3.50-3.30 (3H, m), 3.23 (1 H, m), 3.15-2.90 (4H, m), 2.78 (1 H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 503 (M+H)+. Anal.calc. for C28H36F2N2θ4- • 1 H20: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
Example 151 frans.frans-1 -(N.N-Di(n-butvnaminocarbonylmethvn-2-f4-methoxyphenvn-4-(2.4- dimethoxyphenynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. "Η NMR (300 MHz, CDCI3) δ 7.37 (2H, d,
J=8Hz), 7.20 (1 H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), 6.49 (1H, dd, J=6Hz, 2Hz), 5.35 (1 H, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 527 (M+H)+. Anal.calc. for C30H42N2O6 • 1 .30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
Example 152 frans.frans-1 -fN.N-Difn-butynaminocarbonylmethyn-2-phenyl-4-f1.3-benzodioxol-5- ynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in
Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B. 1H NMR (300 MHz, CDCI3) δ 7.50-7.25 (5H, m), 7.04 (1H, d, J=3Hz), 6.87 (1 H, dd, J=7Hz, 3Hz), 6.74 (1 H, d, J=8Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.85 (1 H, d, J=8Hz), 3.64 (1 H, m), 3.42 (3H, m), 3.27 (2H, m), 3.20-2.90 (5H, m), 2.81 (1 H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 481 (M+H)+. Anal.calc. for C28H36N2O5: C, 69.98; H, 7.55; N, 5.83. Found: C, 69.69; H, 7.63; N, 5.71.
Example 153 frans.frans-1 -fN.N-Difn-butvnaminocarbonylmethvn-2-phenyl-4-f5-benzo-2.3- dihvdrofuranvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) δ 7.53 (2H, m), 7.40 (4H, m), 7.13 (1H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1 H, d, J=10Hz), 4.56 (2H, t, J=8Hz), 4.18 (1H, d, J=14Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (1 H, d, J=14Hz), 3.35 (1 H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 479 (M+H)+. Anal.calc. for C29H38N2O4 - 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57. Example 154 frans.frans-1-fN.N-Difn-butyl)aminocarbonylmethyn-2-f4-t-butylphenvn-4-f5-ben?o- 2.3-dihydrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967) starting from 4-t- butylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5- carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) δ 7.60-7.30 (6H, ), 6.90 (1H, m), 4.50 (2H, m), 3.95 (1H, m), 3.85-2.95 (11H, m), 2.90 (1 H, d, J=14Hz), 1..58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) m/e 535 (M+H)+. Anal.calc. for C33H46N2O4 • 0.25 H20: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
Example 155 frans.fraπs-2-fN.N-Difn-butylιaminocarbonylmethvn-2-f4-methoxyphenvn-4-f4- fluorophenvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) δ 7.50 (1 H, m), 7.42 (1 H, dd,
J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1 H, d, J=8Hz), 3.83 (1 H, m), 3.8 (3H, s), 3.67 (1 H, m), 3.47 (3H, m), 3.30-2.90 (5H, m), 2.82 (1 H, d, J=14Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal.calc. for C28H37FN2O4: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.
Example 156 fraπs.frans-1-f N.N-Difn-butvnaminocarbonylmethyn-2-f3-furvn-4-(1.3-benzodioxol- 5-ynpyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting β-oxo-3-furanpropionate in Example 49B. 1 H NMR (300 MHz, CDCI3) δ 7.41 (2H, m), 6.97 (1H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, s), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, m), 3.70-3.25 (5H, m), 3.20-2.90 (4H, m), 2.85 (1 H, d, J=14Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, m). MS (DCI/NH3) m/e 471 (M+H)+. Anal.calc. for C26H34N2O6: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Example 157 frans.frans-1-fN.N-Difn-butvnaminocarbonylmethyn-2-fisopropyn-4-f1.3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B. 1 H NMR (300 MHz, CDCI3) δ 6.85 (1 H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=8Hz), 5.92 (2H, s), 3.75 (1 H, d, J=14Hz), 3.66 (1H, q,
J=7Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H,m), 2.83 (1 H, t, J=7Hz), 1.88 (1 H, m), 1.55 (4H, m), 1.32 (4H, m), 0.92 (12H, m). MS (DCI/NH3) m/e
447 (M+H)+. Anal.calc. for C25H38N2O5 - 0.50 H20: C, 65.91 ; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.
Example 158 frans.frans-1-fN.N-Di(n-butylιaminocarbonylmethyn-2-f4-t-butylphenyn-4-f1.3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4- t-butylacetophenone), in Example 49B. 1H NMR (300 MHz, CDCI3) δ 7.32
(4H, d, J=3Hz), 7.04 (1H, d, J=2Hz), 6.87 (1 H, dd, J=8Hz, 3Hz), 6.74 (1H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=14Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1 H, d, J=14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS (DCI/NH3) m/e 537 (M+H)+. Anal.calc. for C32H44N2O5: C, 71.61 ; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
Example 159 frans.frans-1-fN.N-Difn-butvnaminocarbonylmethvn-2-f4-t-butylPhenvn-4-f5-benzo- 2.3-dihvdrofuranvnpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) δ 7.30 (1 H, s), 7.13 (1 H, dd, J=7Hz, 2Hz), 6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 (2H, m), 3.3 (5H, m), 2.41 (1 H, m), 1.65 (4H, m), 1.44 (4H, m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH3) m/e 445 (M+H)+. Anal.calc. for C26H40N2O4 • 1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Example 16Q frans.frans-1-fN.N-Difn-butyl.aminocarbonylmethvn-2-fanti-4-methoxycyclohexyn-
4-(1.3-benzodioxQl-5-yi)pyrrQiidine-3-carbQχyiic acid
Example 16QA syn and anti Ethyl 4-methoxycyclohexanoylacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature. At the same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 °C. The mixture was cooled to room temperature, and the imidazoie-acid mixture added to it. The reaction stirred overnight at room temerature. The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with 5% potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with 20% ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyciohexyl β-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl β-keto ester (914 mg) as a colorless oil and the cis 4- methoxycyciohexyl β keto ester (1.07 g) as a colorless oil.
Example 160B frans.frans-1-fN.N-Difn-butvnaminocarbonylmethvn-2-fanti-4-methoxycvclohexyn- 4-f 1 ■3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid
The title compound was prepared by the procedures described in Fxamples 1 and 49 substituting the anti-compound resulting from Example 160A in Example 49B. 1H NMR (300 MHz, CDCI3) δ 6.84 (1 H, d, J=2Hz), 6.76 (1H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1 H, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal.calc. for C29H44N2O6 - 0.50 H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.
Example 161 frans.frans-1-fN. N-Difn-butvnaminocarbonylmethyn-2-fsyn-4-methoxycvclohexyn- 4-(1 ,3-benzQdipxQl-5-yl)pyrrQlidine-3-car-TOxylic cid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A in Example 49B. 1H NMR (300 MHz, CDCI3) δ 6.84 (1 H, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.65 (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1 H, m), 2.10 (2H, m), 1.83 (2H, m), 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal.calc. for C29H44N2O6 • 0.30 H20: C, 66.72; H, 8.61 ; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.
Example 162 frans.frans-1-(N.N-Difn-butvnaminocarbonylmethvn-2.4-di(5-benzo-2.3- dihydrofuranynpyrrolidine-3-carboxylic acid
Example 162A
5-Acetyl-2.3-dihvdrobenzofuran To a 0 °C solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 °C. The solution was stirred 15 minutes at 0 °C, and then a solution of 2,3-dihydrofuran (2.00 L, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 °C. The dark red solution was stirred 1 hour at 2 °C and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Example 162B frans.frans-1-fN.N-Difn-butvnaminocarbonvlmethyn-2.4-dif5-benzo-2.3- dihvdrofuranvnpvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162 A in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) δ 7.43 (1 H, s), 7.38 (1H, s), 7.06 (2H, m), 6.75 (1 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, m), 3.82 (2H, m), 3.57 (1 H, d, J=14Hz), 3.38 (1H, m), 3.30-3.05 (6H, m), 2.95 (2H, q, J=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) m/e 521 (M+H)+. Anal.calc. for C31H40N2O5 - 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.
Example 163 frans.frans-1-fN.N-Difn-butynaminocarbonylmethyn-2-f3-furyn-4-f5-benzo-2.3- dihydrofuranynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl β-oxo-3-furanpropionate in
Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. "Η NMR (300 MHz, CDCI3) δ 7.42 (1 H, m), 7.38 (1 H, m), 7.13 (1H, s), 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, m), 4.57 (2H, t, J=7Hz), 3.95 (1 H, d, J=8Hz), 3.63 (1 H, m), 3.55 (1 H, d, J=14), 3.50-3.25 (4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, m), 2.87 (1 H, d,
J=14Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH3) m/e 469 (M+H)+. Anal.calc. for C-27H36N2O5 - 0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82. Example 164 frans.frans-1-fN.N-Difn-butylιaminocarbonylmethvn-2-f4-methoxyphenyn-4-f3- fluorophenynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. "< H NMR (300 MHz, CDCI3) δ 7.30 (2H, d, J=8Hz), 7.22 (2H, m), 6.91 (1 H, m), 6.86 (2H, d, J=8Hz), 3.79 (1 H, m), 3.78 (3H, s), 3.68 (1 H, m), 3.55-3.37 (3H, m), 3.29 (1 H, m), 3.15-2.90 (5H, m), 2.78 (1 H, d, J=14Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCIZNH3) m/e 485 (M+H)+. Anal.calc. for C28H37FN2O4 • 0.25 H20: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.
Example 165 frans.frans-1-fN.N-Difn-butvnaminocarbonylmethvn-2-f4-methoχyphenvn-4-f3- pyπdyl)pyrr iidipe-3-caι >Qχylic acid
The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al., Can. J. Chem. 63: 2354 (1985). 1 H NMR (300 MHz, CDCI3) δ 8.82 (1 H, bs), 8.73 (1 H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (1 H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=10Hz), 6.90 (2H, d, J=10Hz), 4.39 (1H, d, J=12Hz), 3.95 (1H, m), 3.80 (3H, s), 3.79 (1 H, m), 3.68 (1 H, d, J=18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) m/e 468 (M+H)+. Anal.calc. for C27H37N3O4 - 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
Example 166 frans.frans-1-fN.N-Di(n-butylιaminocarbonylmethvn-2-f2-fluorophenvn-4-(1.3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B. 1H NMR (300 MHz, CDCI3) δ 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25 (1 H, m), 7.13 (1 H, dt, J=7Hz, 3H∑), 7.02 (2H, m), 6.88 (1 H, dd, J=7Hz,
3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 4.25 (1 H, d, J=9Hz), 3.68 (1 H, m), 3.42 (3H, m), 3.39 (1 H, m), 3.20-2.95 (4H, m), 2.91 (1 H, d, J=14Hz), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal.calc. for C28H35 N2O5 • 0.25 H20: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51 ; H, 6.67; N, 5.18.
Example 167 frans.frans-1-fN.N-Difn-butvnaminocarbonylmethyn-2-f3-fluorophenyn-4-f1.3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-fluorobenzoylacetate in
Example 49B. 1H NMR (300 MHz, CDCI3) δ 7.38 (1 H, m), 7.18 (1H, d, J=7Hz), 7.15 (1H, m), 7.00 (1 H, d, J=2Hz), 6.95 (1H, m), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (1 H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.94 (1H, d, J=14Hz), 3.63 (1 H, m), 3.42 (3H, m), 3.35-2.95 (5H, m), 2.87 (1 H, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal.calc. for C28H35FN2O5: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
Example 168 frans.frans-1-f4-N.N-Difn-butvnaminophenvn-2-f4-methoxyphenvn-4-(1.3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid 4-Nitro-1 -fluorobenzene, ethyl trans, frans-2-(4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl trans, rans-2-(4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)-1 -(4-nitrophenyl)-py rrolidi ne-3-carboxylate. The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N- dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1 D affords the title compound. Example 169 frans.frans-1-f2-N.N-Dibutvlaminopvrimidin-4-yn-2-f4-methoxyphenyn-4-f1.3- benzodioxol-5-vnpvrrolidine-3-carboxylic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4- dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans, rans-2-(4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-y I )-py rrolidi ne-3-carboxy late (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example 1D to the title compound.
Examples 170-266 Using the procedures described in Examples 1 , 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.
Ex. No. Name
1 70 frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -
(isopropylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
1 71 frans,fraπs-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(ethylaminocarbonyimethyl)- pyrrolidine-3-carboxylic acid;
172 frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(1 - methylpropylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
1 73 fraπs,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(phenylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid;
1 74 frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(piperidinylcarbonylmethyl)- pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(1 - (propylaminocarbonyl)ethyl)-pyrrolidine-3- carboxylic acid; frans,fraπs-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(α- (propylaminocarbonyl)benzyl)-pyrrolidine-3- carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(bis- (propylaminocarbonyl)methyl)-pyrrolidine-3- carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-
(propylaminocarbonyl)ethyl)-pyrrolidine-3- carboxylic acid; fraπs,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(propylaminosu If onyl methyl)- pyrrolidine-3-carboxylic acid; fraπs, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-phenethyl)-py rrolidi ne-3- carboxylic acid; frans,fra/7S-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(pentanoylmethyl)- pyrrolidine-3-carboxylic acid; frans, frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(ben zoylmethyl)-py rrolidi ne-
3-carboxylic acid; fraπs, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(hexyl)-pyrrolidine-3- carboxylic acid; fraπs, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodi oxol-5-y I)- 1 -(2-hexynyl)-py rrolidi ne-3- carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(propoxy methy lcarbonyl- pyrrolidine-3-carboxylic acid; fraπs,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(phenylacetyl)-pyrrolidine-3- carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(anilinylcarbonyl)- pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-acetylaminoethyl)- pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-( 1 3- benzodioxol-5-yl)-1 -(2-phenoxyethy l)-py rrolidi ne-
3-carboxylic acid; fraπs,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxo!-5-yl)-1 -(2-benzodioxanylmethyl)- pyrrolidine-3-carboxylic acid; fraπs,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-tetrahydrofuranylmethyl)- pyrrolidine-3-carboxylic acid; fraπs,fraπs-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-
(propylaminocarbonylamino)ethenyl)-py rrolidi ne-3- carboxylic acid; frans, frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(2-
(propylaminocarbonylamino)ethyl)-pyrrolidine-3- carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(3-oxohex-1 -enyl)- pyrrolidine-3-carboxylic acid; trans, frans-2-(2,4-Dimethoxyphenyl)-4-( 1 , 3- benzodioxol-5-yl)-1 -(propylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, frans-2-(2-Carboxy-4-methoxypheny!)-4- ( 1 ,3-benzodioxol-5-yl)- 1 - (propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, frans-2-(2-Aminocarbonyl-4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; frans,fra/7S-2-(2-Methanesulfonamido-4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, frans-2-(2-Aminocarbonylmethoxy-4- methoxyphenyl)-4-(1 ,3-benzodioxol-E yl)-1 - (propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, frans-2-(2-Methoxyethoxy-4- methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, frans-2-(2-Carboxymethoxy-4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonyl methy l)-pyrrol idine-3- carboxylic acid; frans, frans-2-(4-Methoxy-2- tetrazolylmethoxyphenyl)-4-( 1 ,3-benzodioxol-5- yl)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, trans-2- (2- Allyloxy-4-methoxyphenyl)-4- ( 1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonyl methy l)-pyrrolidine-3- carboxylic acid; trans, trans 2,4-Bis(4-methoxyphenyl)-1 -
( pro pylaminocarbony I methy l)-py rrolidi ne-3- carboxylic acid; trans, trans 2,4-Bis( 1 ,3-benzodioxol-5-yl)-1 - (propylaminocarbonyl methy l)-py rrolidi ne-3- carboxylic acid; 206 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)- 1 -(N-methyI-N- propyl aminocarbonyl methyl )-pyrrolidine-3- carboxylic acid;
207 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxole-5-yl)-1 -(N-methyl-N- butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
208 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-methyl-N-(4- methoxyphenyl) aminocarbonyl )-3-py rrolidi ne-3- carboxylic acid;
209 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-y I)- 1 -( N-methyl- N- phenyl aminocarbonyl )-py rrolidi ne-3-carboxy lie acid;
21 0 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-methyl-N- allylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
21 1 trans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-methyl-N-(n- butyl)aminocarbonylmethy l)-py rrolidi ne-3- carboxylic acid;
212 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-methyl-N- isobutyl aminocarbonyl methy l)-py rrolidi ne-3- carboxylic acid;
21 3 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-methyl- N- cyclopentylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
214 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N -methy l-N-(2- methoxyethyl)aminocarbonyl)-py rrolidi ne-3- carboxylic acid; 215 trans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1-(N-methyl-N- butoxyethylaminocarbonyl)-pyrrolidine-3- carboxylic acid;
216 trans, frans-2-(1, 3-Benzodioxol-5-yl)-4-(4- methoxyphenyl)-1-(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
217 frans,frans-2-(4-Methoxyphenyl)-4-(1,4- benzodioxan-6-yl)-1-(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
218 frans,frans-2-(4-Methoxyphenyl)-4-(1,3- benzodioxol -5-y I)- 1-( N-methyl- N- isopropylaminocarbony I methyl )-py rrolidi ne-3- carboxylic acid;
219 frans,frans-2-(4-Methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1-(N-methyl-N- ethylaminocarbo ny I methyl)-py rrolidi ne-3- carboxylic acid;
220 frans,frans-2-(4-Methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1-(N-methyl-N-(1- methylpropyl)aminocarbonylmethyl)-py rrolidi ne-3- carboxylic acid;
221 frans,frans-2-(4-Methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1 -(N-methyl- N- phenylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
222 trans, frans-2-(4-Methoxyphenyl)-4-(1 , 3- benzodioxol-5-yl)-1-(1-(N-methyl-N- propylaminocarbonyi)ethyl)-pyrrolidine-3- carboxylic acid;
223 trans, frans-2-(4-Methoxyphenyl)-4-(1 , 3- benzodioxol-5-yl)-1-(α-(N-methyl-N- propyiaminocarbonyl)benzyl)-pyrrolidine-3- carboxylic acid; 224 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- propylaminocarbonylmethyl)-pyrrolidine-3~ carboxylic acid;
225 trans, frans-2-(4-Methoxyphenyl)-4-( 1 , 3- benzodioxole-5-yl)-1 -(N-ethyl-N- butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
226 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N-(4- methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3- carboxylic acid;
227 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- phenylaminocarbonyl)-py rrolidi ne-3-carboxy lie acid;
228 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- allylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
229 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- isobutyl aminocarbonyl methy I )-py rrolidi ne-3- carboxylic acid;
230 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- cyclopentylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
231 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- methoxyethylaminocarbonyl)-py rrolidi ne-3- carboxylic acid;
232 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- butoxyethylaminocarbonyl)-pyrrolidine-3- carboxylic acid; 233 trans, frans-2-( 1 ,3-Benzodioxol-5-yl)-4-(4- methoxyphenyl)-1 -(N-ethyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
234 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,4- benzodioxan-6-yl)-1 -(N-ethyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
235 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- isopropylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
236 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N,N- diethylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
237 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N-( 1 - m ethyl p ropy I) aminocarbonylmethyl)-py rrolidi ne-3- carboxylic acid;
238 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)- 1 -(N -ethyl- N- phenylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
239 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)- 1 -( 1 -(N-ethyl-N- propyl aminocarbonyl) ethyl)-py rrolidi ne-3- carboxylic acid;
240 frans, rans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)- 1 -(α-(N-ethyl-N- propylaminocarbonyl)benzyl)-py rrolidi ne-3- carboxylic acid;
241 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- b enzodioxol-5-y I)- 1 -( N-methyl- N- isobutylaminocarbonylmethyl)-py rrolidi ne-3- carboxylic acid; 242 frans, frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(N-methyl- N- cyclohexylaminocarbonylmethyl)-pyrrolidine-3- carboxyiic acid;
243 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N,N- dipropylaminocarbonylmethyl)-pyrroIidine-3- carboxylic acid;
244 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(isobutyloxyethyL)- pyrrolidine-3-carboxylic acid;
245 frans, rans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(butylsulfonyl)-pyrrolidine-3- carboxylic acid;
246 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -
(isopropylsulfonylaminoethyl)-pyrrolidine-3- carboxylic acid;
247 frans, rans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)- 1 -
(ethoxymethyl carbony I methyl )-py rrolidi ne-3- carboxylic acid;
248 frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(2-ethylbutyryl methyl )- pyrrolidine-3-carboxylic acid;
249 frans,frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)-1 -(N-methyl-N-(3,4- dimethoxybenzyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid;
250 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -[(1 R)-1 -(N-methyl-N- propylaminocarbonyl)butyl]-pyrrolidine-3- carboxylic acid;
251 frans, frans-2-(4-Methoxyphenyl)-4-(1 ,3- benzodioxol-5-yl)- 1 -[(1 S)-1 -(N-methyl-N- propylaminocarbonyl)b uty l]-py rrolidi ne-3- carboxylic acid; 252 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(3-isopropoxypropyl)- pyrrolidine-3-carboxylic acid;
253 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(5-methylhexyl)-pyrrolidine- 3-carboxylic acid;
254 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(5-methyl-2-hexenyl)- pyrrolidine-3-carboxylic acid;
255 frans,frans-2-(4-Methoxyphenyl)-4-( 1 - benzodioxol-5-yl)- 1 -(5-methyl-4-hexenyl)- pyrrolidine-3-carboxylic acid;
256 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(3,5-dimethyl-2-hexenyl)- pyrrolidine-3-carboxylic acid;
257 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(2-(N-methyl-N- isobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid;
258 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yI)-1 -(N-methyl-N-(2,2- di methy Ipropyl) aminocarbonyl methy l)-py rrolidi ne- 3-carboxylic acid;
259 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-1 -(N-ethyl-N- buty I am inocarbony I methy I) -py rrolidi ne-3- carboxylic acid;
260 frans, frans-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-y I)- 1 -( N-methyl- N- benzylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
262 trans, frans-2-(4- Methoxypheny l)-4-(5-i ndanyl)- 1 - ( N-methyl- N-p ropy laminocarbony I methyl )- pyrrolidine-3-carboxylic acid; 262 trans, frans-2-(4-Methoxyphenyl)-4-(2, 3- dihydrobenzofuran-5-yl)-1 -(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
263 trans, frans-2-(4-Methoxyphenyl)-4-( 1 - methylindol-5-yl)- 1 -(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
264 trans, frans-2-(4-Methoxyphenyl)-4-(2-naphthyl)- l -(N-methyl-N-propylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid;
265 frans,frans-2-(4-Methoxyphenyl)-4-( 1 ,2- dimethoxy-4- phenyl)- 1 -( N-methyl- N - propylaminocarbonyl methyl) -pyrrol idine-3- carboxylic acid;
266 trans, trans -2-(4-Methoxyphenyl)-4-( 1 -methoxy-3- phenyl)-1 -(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid;
Examples 267-288 Following the procedures described in Example 1 and Scheme II, the following compounds can be prepared.
267 frans,frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(propylaminocarbonylmethyl)- piperidine-4-carboxylic acid;
268 trans, frans-3-(4-Methoxyphenyl)-5-( 1 , 3- benzodioxol-5-yl)-1 -(aminocarbonylmethyl)- piperidine-4-carboxylic acid;
269 frans,frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(4-fluorobenzyl)-piperidine- 4-carboxylic acid;
270 frans,frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(2-ethoxyethyl)-piperidine-4- carboxylic acid; 271 fraπs,fraπs-3-(4-Methoxyphenyl)-5-(1,3- benzodioxol-5-yl)-1-(2-propoxyethyl)-piperidine- 4-carboxylic acid;
272 fraπs,frans-3-(4-Methoxyphenyl)-5-(1 ,3- benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethy!]- piperidine-4-carboxylic acid;
273 frans,frans-3-(4-Methoxyphenyl)-5-(1,3- benzodioxol-5-yl)-1-[2-(2-pyridyl)ethyl]- piperidine-4-carboxylic acid;
274 frans, rans-3-(4-Methoxyphenyl)-5-(1 ^3- benzodioxol-5-yl)-1-(morpholin-4-ylcarbonyl)- piperidine-4-carboxylic acid;
275 frans,frans-3-(4-Methoxyphenyl)-5-(1,3- benzodioxole-5-yl)-1-(butylaminocarbonyl)- piperidine-4-carboxyiic acid;
276 frans,frans-3-(4-Methoxyphenyl)-5-(1,3- benzodioxol-5-yl)-1-(4- methoxyphenylaminocarbonyl)-3-piperidine-4- carboxylic acid;
277 frans, rans-3-(4-Methoxyphenyl)-5-(1 ,3- benzodioxol-5-yl)-1 -acetyl pipe ridine-3-carboxylic acid;
278 frans,frans-3-(4-Methoxyphenyl)-5-(1,3- benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3- carboxylic acid;
279 frans,frans-3-(4-Methoxyphenyl)-5-(1 ,3- benzodioxol-5-yl)-1-(phenylaminocarbonyl)- piperidine-4-carboxylic acid;
280 frans,frans-3-(4-Methoxyphenyl)-5-(1 ,3- benzodioxol-5-yl)-1-(allylaminocarbonylmethyl)- piperidine-4-carboxylic acid;
281 frans,frans-3-(4-Methoxyphenyl)-5-(1,3- benzodioxol-5-yl)-1-(n- butylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 282 frans, frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(N-n-butyl-N- methylaminocarbonylmethyl)-piperidine-4- carboxylic acid;
283 frans, rans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(py rrolidi n- 1 - ylcarbonylmethyl)-piperidine-4-carboxylic acid;
284 frans, rans-3-(4-Methoxyphenyl)-5-(1 ,3- benzodioxol-5-yl)-1 -
(isobutylam inocarbony lmethyl)-pipe riα+ne-4- carboxylic acid;
285 frans,frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)- 1 -
(cyclopentylaminocarbonyl methyl )-piperidine-4- carboxylic acid;
286 frans,frans-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)- 1 -(morpholin-4- ylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
287 trans, frans-3-(4-Methoxyphenyl)-5-( 1 , 3- benzodioxol-5-yl)-1 -(2-phenoxyethyl)-piperidine- 4-carboxylic acid;
288 frans,fraπs-3-(4-Methoxyphenyl)-5-( 1 ,3- benzodioxol-5-yl)-1 -(methoxyethylaminocarbonyl)- piperidine-4-carboxylic acid.
Example 289 trans. trans- 2-f4-Methoxyphenyh-4-f 1 .3-benzodioxol-5-yl )-1 - f4- dibutylaminophenyπ-pyrrolidine-3-carboxylic acid 4-Nitro-fluorobenzene, ethyl trans, fraπs-2-(4-methoxypheny l)-4-
(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di- isopropyl ethylamine are heated in dioxane to give ethyl trans, trans-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(4-nitrophenyl)- pyrrolidine-3-carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch (J. Am Chem. Soc, 93, 2897, 1971) to give the corresponding N,N- dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
Example 290 frans. frans-2-f4-Methoxvphenyn-4-( 1 .3-benzodioxol-5-yl )-1 -f 2- dibutvlamino-Dvrimidine-4-yn-pyrrolidine-3-carboxylic acid 2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4- dichloropyrimidine according to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans, rans-2-(4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrroJjdine-3-carboxylate
(example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
Example 291 frans.frans-2-f4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1-(N-butyl-N- phenylaminocarbonylmethyn-Pyrrolidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. 1H NMR (CD3OD) : δ 0.87 (t,3H,J=8); 1.2-1.35 (m,2H); 1.35-1.5 (m,2H); 2.78 (m, 2H); 3.10 (t,1 H, J=9); 3.26 (d, 1 H,J=15);
3.44 (dd,1 H,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,1 H); 3.78 (s,3H); 5.93 (s,2H); 6.7-6.9 (m,4H); 7.0-7.2 (m,5H); 7.4 (m,3H). MS (DCI/NH3): m/e
531 (M+H)+. Anal calcd for C31 H34N206: C, 70.17; H, 6.46; N, 5.28. Found: C.70.36; H, 6.52; N, 4.99.
Example 292
Sodium frans.frans-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -W./V-o,/7n- bυtyDaminocarbonylmeth )-pyrrolidinβ-3-carboxylate
Example 292A
Ethyl 3-(4-methoxyphenyl ι-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 35- L reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oil and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 5 minutes, allowed to settle and 28 L of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 10° C and stirring continued for 16 hours. A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous sodium chloride . The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Example 292B 3.4-Methylenedioxy-1 -(2-nitroethenyh-benzene
In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to -5° C and the reaction solution cooled to a temperature of +3.5° C. A 21° C solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1 ° C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 21 ° C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper).
The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Example 292C
Ethyl 2-f4-methoxybenzoyl ι-3-f 1 .3-benzodioxol-5-vh-4-nitro- butanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1 -(2-nitroethenyl)-benzene and 24 L ethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl 3-(4- methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1 ,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Example 292D Ethyl 2-(4-methoxyphenyl .-4-f 1 .3-benzodioxol-5-vπ-4.5-dihvdro-3H- pyrrol-3-carboxylate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi # 28 (300 g). The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm miliipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (0° C). The solids were dried in vacuo at 50° C to a constant weight of 193.4 g (21% yield, melting point 80-81° C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Example 292E Ethyl 2-f4-methoxyphenyl t-4-f 1 .3-benzodioxol-5-yl >-pyrrolidine 3- carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4- methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H - pyrrole-3-carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCI was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHCθ3 was added. The reaction mixture was concentrated and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHCθ3 and once with 2.5 L of 23% aq.
NaCl, the dried over 190g MgS04, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
Example 292F
Ethyl 2-f4-methoxypheny^-4-f 1 .3-benzodioxol-5-vh-1 -fN.N-difn- butyπaminocarbonylmethyl i pyrrolidine 3-carboxylate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4- methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg, 6.02 mol). The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 78° C for 17 hrs. After the disappearance of starting material , the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (0° C). Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCl nad dried over 0.399 kg MgSθ4 and filtered. Concentration as above provided 3.112 kg (96 % yield) of the title compound as a dark oil.
Example 292G frans. rans-2-f4-Methoxvphenvl )-4-f 1 .3-benzodioxol-5-vl )-Dvrrolidina
3-carboxylate and preparation of trans. trans 2-f4-methoχyphenyl)-4-
(3.4-dioxyphenyh-pyrrolidine-3-carboxylic acid ethyl ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)- 4-(3,4-methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol). 16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 79° C for 1 hr. The mixture was cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 15° C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether. The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M HCI was added to the aqueous layer. The aqueous layer was extracted with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCl, dried with 0.298 kg MgS04 , filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain 1 .102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 65° C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 10° C and filtered. The crystals were washed with 2 L ether (0° C) and dried to constant weight in vacuo at 50° C to give 0.846 kg (43% yield, melting point 1 19-120) of crude product, which was further purified by normal phase silica gel chromatography.
Example 292H Sodium frans. frans-2-f 4-methoxyphenvπ-4-( 1 .3-benzodioxol-5-yl >- 1 - ( N . N-dif n-butvnaminocarbonylmethvπ pyrrolidine 3-carboxylate Into a 20-L flask was charged trans, trans 2-(4-methoxyphenyl)-
4-(3,4-methyledioxyphenyl)-1 -(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3-carboxyιιc aciα (0.92 / *y, ι -o ι » mθι /-V OUIU II UI I <-» > 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the title compound.
Example 293 frans-frans-2-f4-Methoχyphenyl ,-4-f 1 .3-benzodioxol-5-yl ,-1 - decahvdroisoquinolin-2- carbonylmethvH-pyrrαJidine-3-carboxylic acJ L
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS (DCI/NH3) m/z 521. Anal calcd for C30H36N2O6 • 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 .
Example 294 frans-frans-2-f4-Methoxyphenyn-4-f 1 .3-benzodioxol-5-vn- 1 -r3.3- dimethylpiperidinyl- carbonylmethvπ-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. δ 0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, 1 H, J=8), 6.90 (dd, 1 H, J=1 ,8), 7.01 (d, 2H, J=9), 7.03 (s, 1 H), 7.47 (d, 2H, J=9). MS (DCI/NH3) m z 495. Anal calcd for C28H34N2O6 . 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 .
Example 295 frans-frans-2-f 4-Methoxyphenyl ι-4-f 1 .S-benzodioxol-δ-vn- l -^-f N- Dropyl-N-iso-butoxycarbonylamino thyll-pyrroridine-S-carboxylic acid The title compound was prepared by the methods detailed in
Example 61 , but substituting propylamine for methylamine in Example 61 B and isobutyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m, 1 H), 2.72 (m, 1 H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1 H), 3.55 (m, 1 H), 3.62 (m, 1H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J= 8Hz), 6.82 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 527 (M+H)+. Anal calcd for C29H38N2O6 • 0.5 H20: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
Example 296 frans-frans-2-f 4-Methoxyphenyn-4-f 1 .3-benzodioxol-5-yn-1 -f 1 .2.3.4- tetrahydroisoquinolin-2- carbonylmethyn-pyrrolidine-3-carboxylic add, The title compound was prepared using the-procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. δ 2.97 (m, 2H), 4.68 (s, 3H), 5.97 (s, 2H), 6.83 (d, 1H, J=8), 6.9-7.0 (m, 3H), 7.03 (d, 1 H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NH3) m/z 515.
Example 297 frans-frans-2-f4-Methoxyphenyn-4-f 1 .3-benzodioxol-5-yn-1 -r2-fN- propyl-N-dimethylaminocarbonylamino;ethvπ-pyrrolidine-3-carboxylic cid The title compound was prepared by the methods detailed in
Example 61 , but substituting propylamine for methylamine in Example 61 B and dimethylcarbamyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H), 3.1-3.45 (m, 4H), 3.70 (m, 1 H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J= 8Hz), 6.87 (m, 3H), 7.05 (s, 1 H), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 498 (M+H)+. Anal calcd for C27H35N3O6 • 1.25 TFA: C, 55.35; H, 5.71 ; N, 6.56. Found: C, 55.41 ; H, 5.71 ; N, 6.41.
Example 298 trans, frans-2- (4-Methoxyphenvn-4-( 1 .3-benzodioxol-5-vn- 1 -f 2-f N- p ropyl-N-f4-nitrobenzenesulf on vnamino .ethyl ι-pyrro idine-3- carboxylic acid
Using the procedures described in Eampie 66, the title compound v αc prepared θ? a yellow solid, m.p. 85-87°C. "I H NMR (CDCI3, 300 MHz) δ 0.77 (t, J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (m, 1H), 2.57-2.66 (m, 1H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, 1H), 3.49-3.57 (m, 1H), 3.59 (d, J=9Hz, 1H), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=1Hz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 (d, J=1Hz, 1H), 7.27 (d, J=9Hz, 2H), 7.82 (d, J=9Hz, 2H), 8.23 (d, J=9Hz,2H). MS (DCI/NH3) m/e 612 (M+H)+-
Example 299 frans. frans-2-f 4-Meth ox vpheny -4- (1.3-benzodioxol-5-vn-1-f2-fN- propyl-N-n-pentanesulfonylaminolethyn-pyrrolidlne-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p.59-61 °C 1H NMR (CDCI3, 300MHz) δ 0.79 (t, J=7.5Hz, 3H), 0.90 (t, J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (m,
1H), 3.63 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1H), 6.83 (dd, J=1Hz,J=7.5Hz, 1H), 6.87(d, J=8Hz, 2H), 7.00 (d, J=1Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+-
Example 300 f rans.trans-2-l 4- Met ho xyph en y\) -4- (1.3-benzodioxol-5-ylι- 1 -(2-(N- propyl-N-f4-trifluoromethoxybenzenesulfonyl)amino)ethyn- pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.122-124°C. 1H NMR (CD3OD, 300MHz) δθ.75 (t, J=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J=10Hz, 1H), 3.81 (d, J=9Hz, 2H), 3.86 (s, 3H), 3.92 (t, J=9Hz, 1H), 4.63 (d, J=10Hz, 1H), 5.97 (s, 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 1H), 7.06-7.08 (m, 3H), 7.46 (d, J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, J=9Hz, 2H). MS (DCI/NH3), m/e
651 (M+H)+. Example 301 frans. frans-2-f 4-Methoxyphenyl )-4-f 1 .3-benzodioxol-5-vn- 1 -f2-f N- propyl-N-f2-methyl-2-Dropenesulfonvnamino)ethvn-pyrrolidine-3- carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 69-71 °C. H NMR (CDCI3, 300MHz) δ 0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 (s, 3H), 2.25-2.35 (m, 1 H), 2.68-2.77 (m, 1 H), 2.85-3.28 (m, 7H), 3.40 (d, J=9Hz, 1 H), 3.52- 3.68 (m, 2H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 4.92 (s, 1 H), 5.07 (s, 1 H), 5.97 (s, 2H), 6.74 (d, J=7Hz, 1 H), 6.82-6.89 (m,3H), 7.01 (s,1 H), 7.33 (d,
J=9Hz, 2H). MS (DCI/NH3), m/e 545 (M+H)+.
Example 302 trans-trans-2-(4-WΛ ethoxyphenyl .-4-f 1 .3-benzodioxol-5-vn- 1 -\2- ethyl pi peridinyl-carbonylmethvn-Pyrrolidine-3-carboxylic acid .
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. δ 0.75 (t, 3H, J=7), 1.4-1.7 (m, 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1 H, J=8), 6.91 (d, 1 H, J=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCI/NH3) m/z 495. Anal calcd for C28H34N2O6 . 1.6 TFA: C, 55.35; H, 5.30; N, 4.14. Found: C, 55.26; H, 5.37; N, 4.01 .
Example 303 frans. frans-2-f 4-Methoxyphenyl ι-4-( 1 .3-benzodioxol-5-vn- 1 -(2-(N- propyl-N-f2-methylpropanesulfonynamino')ethyn-pyrrolidine-3- carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73°C. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7.5Hz, 3H),1.04 (d, J=6Hz, 6H), 1 .44(q, J=7.5Hz, 2H), 2.15-2.33 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, 1 H), 3.23-
3.45 (m, 1 H), 3.43 (d, J=1 1 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J=9Hz, 1 H), 6.83 (dd, J=1 Hz,J=9Hz, 1 H), 6.87(d, J=9Hz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=9Hz, 2H). MS
(DCI/NH3) m/e 547 M+H)+. Example 304 frans. frans-2-f4-Methoxyphenyn-4-( 1 .3-benzodioxol-5-yn- 1 -(2-f N- proρyl-N-heptanesulfonylamino ιethyl ι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound s was prepared as a white solid. m.p.58-59°C. 1 H NMR (CDCI3, 300MHz) δ 0.80(t, J=7.5Hz, 3H), 0;88 (t, J=7Hz, 3H), 1.23-1.36 (m, 8H), 1 .94 (q, J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (m, 1 H), 2.70-3.09(m, 7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,J=9Hz, 1 H), 3.52-3.58(m,1 H), 3.65(d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, J=7Hz, 1 H), 6.83 o (dd, J=1 Hz, J=7Hz, 1 H), 6.87(d, J=9Hz, 2H), 7.01 (d; J=1 Hz, 1 H), 7.32(d,
J=9Hz, 2H). MS (DCI/NH3) m/e 589 M+H)+.
Example 305 frans-frans-2-f 4-Methoxvphenvn-4-f 1 .3-benzodioxol-5-vn- 1 -r2-f N- 5 ethyl-N-ethoxycarbonylamino^ethvn-Pyrrolidine-3-carboxylic acid
Prepared by the methods detailed in Example 61 , but substituting ethylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH3C N 0 in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid. H NMR (CDCI3, 300 MHz) δ 0.90 (t, 3H, J=7), 1.22 (m, 3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J=7Hz), 3.5 (br s, 1 H), 5.97 (dd, 2H, J=1 ,7Hz), 6.72 (d, 1 H, J= 8Hz), 6.84 (m, 3H), 7.00 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 485 (M+H)+. 5 Anal calcd for C26H32N2O7 ■ 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01 ; H, 5.36; N, 4.56.
Example 306 frans. frans-2-(4-Methoxyphenvn-4-f 1 .3-benzodioxol-5-yn- 1 -(2-(N- 0 Dropyl-N-hexanesulfonylamino^ethyl ;-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60°C. 1 H NMR (CDCI3, 300MHz) δ 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, J=7.5Hz, 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1 H), 2.72-3.08(m, 5 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1 H), 3.55-3.62(m, 1 H), 3.65 (d, J=10Hz, 1 H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1 H), 6.82(d, J=7.5Hz,1 H), 6.87(d, J=9Hz, 2H), 7.01 (s,1 H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 (M+H)+.
Example 307 frans-frans-2-f4-Ethylphenyn-4-f 1 .3-benzodioxol-5-yn-1 -fN.N-difn- butvπaminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI3, 300 MHz) δ 7.31 (2H, d, J=8Hz), 7.16 (2H, d, J=8Hz), 7.03 (1 H, d, J=3Hz), 6.86 (1 H, dd, J=8&3Hz), 6.73 (1H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1 H, m), 3.53-3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (1 H, d, J=14Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, m), 1.40- 1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH3) 509 (MH+) Anal.calc. for C30H40N2O5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25 .
Example 308 frans-frans-2-(4-Methoxyphenvn-4-( 1 .3-benzodioxol-5-vn- 1 -r2-(N- propyl-N-(2-chloroethoxy')carbonylamino)ethyπ-pyrrolidine-3- carboxylic acid Prepared by the methods detailed in Example 61 , but substituting propylamine for methylamine in Example 61 B and 2-chloroethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1 :1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.80 (t, 3H, J=7), 1.22 (m, 3H), 2.15 (m, 1 H), 2.75 (m, 1 H), 2.85 (m, 1 H), 3.1 (m, 2H), 3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1 H), 4.30 (m, 1 H), 5.98 (s, 2H), 6.72 (m, 1 H), 6.82 (m, 3H), 7.00 (m, 1 H), 7.30(m, 2H). MS (DCI/NH3) m/e 533 (M+H)+. Anal calcd for C27H33N2O7CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10. Examole 309 frans-frans-2-f2-Methoxyethvn-4-f 1 .3-benzodioxol-5-vn- 1 -rN . N-dif n- butyl ιaminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1 , substituting ethyl 5-nτethoxy-3-oxopentanoate for ethyl 4- methoxybenzoylacetate in Example 1A. The title compound is a yellow foam. "Η NMR (CDCI3, 300 MHz) δ 0.91 (t, J=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1 H), 3.30 (s) and 3.20-3.68 (br m, 11H total), 3.72-4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J=8.5Hz, 1 H), 6.82 (dd, J=1.5, 8.5Hz, 1 H), 6.91 (d, J=1.5Hz, 1 H); MS (FAB) m/e 463 (M+H)+.
Anal calcd for C25H38N2O5 H2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
Example 310 frans. frans-2-f 4-Methoxyphenyl ,-4-( 1 .3-benzodioxol-5-yn- 1 -(2-f N- ethyl-N-n-pentanesulfonylamino ethvn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58°C. H NMR (CDCI3, 300MHz) δ 0.89(t, J=7Hz, 3H), 1 .06(t, J=7.5Hz, 3H), 1 .26-1.37(m, 4H), 1 .72(quintet, J=7.5Hz, 2H), 2.22-2.32(m,1 H), 2.71 -2.96(m,5H), 3.08-3.30(m,4H),
3.95(d, J=9Hz, 1 H), 3.53-3.60(m, 1 H), 3.67(d, J=9Hz,1 H), 3.80(s, 1 H), 5.97(s, 2H), 6.73(d, J=9Hz, 1 H), 6.82(d, J=9Hz,1 H), 6.88(d, J=9Hz, 2H),7.02(s,1 H), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 (M+H)+.
Example 311 fraπs-frans-2-f4-Methoxyphenyn-4-f 1 .3-benzodioxol-5-vn-1 -*N. N- dicvclohexylamino carbonylmethyl1-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) δ 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1 H, J=8), 6.86 (dd, 1 H, J=2,8), 6.95 (d, 2H, J=9), 7.04 (d, 1 H, J=2), 7.38 (d, 2H, J=9). MS (DCI/NH3) m/z 563. Anal calcd for C33H42N2O6 . 0.5 H20: C, 69.33; H, 7.58; N, 4.90 . Found: C, 69.42; H, 7.29; N, 4.78. Example 312 frans-frans-2-f4-Methoxyphenyn-4-( 1 .3-benzodioxol-5-yn-1 -r2-f N- proDyl-N-tert-butoxycarbonylamino )ethvn-pyrrolidine-3-carboxylic add, The title compound was prepared using the procedures described in example 61 , substituting propylamine for aqueous methylamine in Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61 C. NMR (CD3OD, 300 MHz) suggests presence of rotamers δ 0.81 (t, 3H, J=7), 1.2-1.5 (m, 1 1 H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1 ,2), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2,8), 6.92 (d, 2HrJ=9), 6.99 (bd s, 1 H), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 527. Anal calcd for C29H38N2O7 : C, 66.14; H, 7.27; N, 5.32 . Found: C, 66..05; H, 7.36; N, 5.15.
Example 313 frans-frans-2-f4-Methoxy-3-fluorophenvn-4-f 1 .3-benzodioxol-5-yn-
1 -rN .N-difn-butyl )aminocarbonylmethvn-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. m.p. 142-143 °C. NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1 .03-1.50 (m, 8H), 2.82 (d, J=13Hz,
1 H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1 H), 3.55-3.65 (m, 1 H), 3.82 (d, J=10Hz, 1 H), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8Hz, 1 H), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, 1 H), 7.06 (m, 2H). Anal calcd for C29H37N2O6F : C, 65.89; H, 7.06; N, 5.30 . Found: C, 65.82; H, 7.13; N, 5.29.
Example 314 frans. frans-2-fPropyn-4-( 1.3-benzodioxol-5-vn- 1 -f2-fN-propvl- pentanesulfonylamino thyljPyrrolidine-3-carboxylic acid
Example 314A Propyl pentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL CH2CI2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH2CI2 under a nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then at 25 °C for 4 h. The soiuiiυπ was partitioned between 20 rr.L of 1.0 M ?πβnnς NaHS04 and 25 mL CH2CI2- The organic phase was washed sequentially with 25 mL H2O and 25 mL brine, then dried (Na2S04), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H), 1.28- 1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q,
J=6Hz, 2H), 4.10-4.23 (br m, 1 H); MS (DCI/NH3) m/e 211 (M+NH4)+.
Example 3149B Ethyl fraπs.frans-4-f 1 ■3-benzpdioxol-5-vn-1-f2-bromoethvn-2-propylpyrrolidine-3- carboxylate
The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 94B for the pyrrolidine mixture.
Example 314C Ethylfrar?g.frar?g-2-(Propyl)-4-(1.3-benzpdicxoi-5-yl)-1-(2-(N-prppyi- pentanesuifQnyiaminp)ethyi)pyrrQiidine-3-cart?pχyiate
A solution of the compound of Example 314A (6.6 mg, 34 μmol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 μmol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 μmol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 °C overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHC03, 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 mL brine, dried by passing through a plug of Na2Sθ4, and the filtrate concentrated in vacuo to an oil. The crude product was purified by preparative TLC (silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg (73%) of the title compound as a wax.
Example 314D frans.frans-4-f1.3-benzodioxol-5-vn-2-fPropyn-1 -f2-fN-propvl- pentanesulfonylamino thvnpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C. 1H NMR (CDCI3, 300 MHz) δ 0.88-1.00 (m, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J=8Hz, 1 H), 6.79 (m, 1 H), 6.93 (br s, 1 H); HRMS (FAB) calcd for C25H41 N2O6S (M+H)+ 497.2685, found 497.2679.
Example 315 frans. frans-2-f4-Methoxyphenyh-4-f 1 .3-benzodioxol-5-vn-1 -f 2-f N-
Dropyl-N-dimethylsulfamoylamino')ethvn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61°C. 1 H NMR (CDC13, 300MHz) δ 0.79 (t, J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1 H), 2.65(s, 6H), 2.70-2.79(m, 1 H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d,
J=9Hz, 1 H),3.55 (t, J=9Hz,1 H), 3.65(d, J=9Hz,1 H), 3.81 (s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1 H), 6.83(d, J=9Hz, 1 H), 6.88(d, J=9Hz, 2H), 7.02(s, 1 H), 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 (M+H)+.
Example 316 frans-frans-2-f4-Methoxphenyn-4-f 1 .3-benzodioxol-5-vn- 1 -f2-(N- propyl-N-f4-methoxyphenyllsulfonylamino^propyll-pyrrolidine-3- carboxylic acid
Example 316A
Ethyl trans-trans and cis-trans 2-(4-Methoxyphenvh-4-f 1 .3-benzodiox- 5-y ι -1 -f3-bromopropyn Pyrrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4- methoxyphenyl)-4-( 1 ,3-benzodiox-5-yl) -pyrrolidine-3-carboxylate (4.00 g; prepared according to example 1C), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2S04) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 (98%) of the title compound. Example 316B Ethyl trans-trans and cis-trans 2-f4-Methoxyphenyl )-4-f 1 ,3-benzodiox- 5-vh -1 -(3-propylaminopropyn pyrrolidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at 80° for 2 hrs. with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried (Na2S04). The soilution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without purification.
Example 316C frans-frans-2-f4-Methoxphenvn-4-( 1 .3-benzodioxol-5-vn- 1 - 2-(N- propyl-N-r4-methoxyphenyllsulfonylamino)propyπ-pyrrolidine-3- carboxylic acid
Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1D. NMR
(CDCI3, 300 MHz) δ 0.83 (t, J=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 (m, 2H), 2.00-2.11 (m, 1 H), 2.40-2.51 (m, 1 H), 2.69-2.78 (m, 1 H), 2.84-3.03 (m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 3H), 6.93 (d, J=8Hz, 2H), 7.02 (d, J=2Hz, 1H), 7.29 (d, J=8Hz, 2H), 7.69 (d, J=8Hz, 2H). Anal calcd for C32H38N2O8S : C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.
Example 317 frans-frans-2-f4-M ethoχphenvn-4-f 1 .3-benzodioxol-5-yn- 1 -r2-(N- proDyl-N-propylsulfonylamino^propyn-pyrrolidine-3-carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 316B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resuling product was chromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1D. NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60 (m, 2H), 1.65-1.85 (m, 4H), 2.04-2.16 (m, 1H), 2.42-2.57 (m, 1H), 2.72- 3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C28H38N2O7S: C, 61.52; H, 7.01; N, 5.12. Found: C, 61.32; H, 7.01; N, 5.01.
Example 318 frans. frans-2-f 3-Fluoro-4-methoxyphenyl )-4-f1.3-benzodioxol-5- yl)1-f2-fN-propyl-N-pentanesulfonylamino1>ethyn-pyrrolidine-3- carboxylic acid
Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68°C. 1H NMR (CDCI3, 300MHz) δ 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m, 4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, 1H), 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd,
J=3Hz,J=9Hz,1H), 3.53-3.60(m, 1H), 3.66(d, J=10Hz, 1H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(dd, J=1Hz,J=8Hz,1 H), 6.92(t, J=8Hz,1H), 6.97(d, J=1Hz, 1H), 7.12(d, J=8Hz, 1H), 7.18(dd, J=1Hz,J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+.
Example 319 frans-frans-2-f4-Pyridinyn-4-(1.3-benzodioxol-5-yn-1-rN.N-difn- butynaminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am. Chem. Soc. 1993, 115, 11705) in place of ethyl (4- methoxybenzoyl)acetate. m.p. 131-132 °C. NMR (CDCI3, 300 MHz) δ 0.82 (t, J+7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.9 f(d, J=13Hz, 1H), 3.00-3.25 (m, 4H), 3.32 (m, 1H), 3.39 (d, J=13Hz, 1H), 3.45-3.52 (m, 1H), 3.67-3.78 (m, 1H), 4.10 (d, J=9Hz, 1H), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H), 7.02 (d, J=2Hz, 1H), 7.45 (d, J=8Hz, 2H), 8.50 (d, J=8Hz, 2H). Anal calcd for C27H35N3O5 : C, 67.34; H, 7.33; N, 8.73. Found: C, 67.39; H, 7.45; N, 8.61. Example 320 frans-frans-2-f4-Methoxyphenvn-4-f 1 .3-benzodioxol-5-yn- 1 -f2-f N- propyl-N-diethylaminocarbonylamino^ethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 61 , substituting propylamine for aqueous methylamine in Example 61 B and diethylcarbamyl chloride for isobutyryl chloride in Example 61 C. NMR (CD3OD, 300 MHz) δ 0.74 (t, 3H, J=7), 1.09 (t, 6H, J=7), 1.33 (m, 2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1 H), 5.93 (s, 2H), 6.86 (d, 1H, J=8), 7.06 (dd, 1H, J=2,8), 6.94 (e\ 2H, J=9), 7.04 (d, 1H,
J=2), 7.40 (d, 2H, J=9). MS (DCI/NH3) m/z 526. Anal calcd for C29H39N3O6 . 0.1 TFA: C, 65.31 ; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43; N, 8.14.
Example 321 frans-frans-2-f4-Methoxyphenvn-4-f 1 .3-benzodioxol-5-yn- 1 -'3.5- dimethylpiperidinyl- carbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows mixture of isomers. δ 0.88 (d, 3H, J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1 H,
J=8), 6.89 (dd, 1H, J=1 ,8), 7.00 d, 2H, J=9), 7.03 (m, 1 H), 7.47 (d, 2H, J=9). MS (DCI/NH3) m/z 495.
Example 322 frans-frans-2-f 4-Methoxyphenyh-4-f 1 .3-benzodioxol-5-yn-1 -rN.N- difs-butyl)aminocarbonylmethyl*|-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) suggests a mixture of isomers. δ 0.83 (t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, 1 H, J=8), 6.86 (d, 1H, J=8), 6.94 (d, 2H, J=9), 7.03 (d, 1 H, J=2),
7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 511. Example 323 frans-frans-2-f 4-Methoxvphenyn-4-f 1 .3-benzodioxol-5-vn- 1 -rN-f 9-
Methylphenyh-N-butylamino carbonylmethyll-Pyrrolidine-3-carhoxylir: acid. The title compound was prepared using the procedures described in example 1. MS (DCI/NH3) m/z 545. Anal calcd for C32H36N2O6 . 0.9 H20: C, 68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.
Example 324 frans-frans-2-f4-Methoxyphenvn-4-( 1 .3-benz-odioxol-5-vn- 1 -fN-f 3-
Methylphenyn-N-butylamino carbonylmethvn-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) d 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H), 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1 H, J=10), 3.3 (m, 1 H), 3.44 (dd, 1 H, J=5,10), 3.53 (m, 1 H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m, 1 H), 5.93 (s, 2H), 6.74 (d, 1 H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1 H, J=2), 7.09 (d, 2H, J=9), 7.18 (d, 1 H, J=7), 7.27 (t, 1 H, J=7). MS (DCI/NH3) m/z 545. Anal calcd for C32H36N2O6 . 0.8 H20: C, 68.75; H, 6.78; N, 5.01 . Found: C, 68.70; H, 6.67; N, 4.85.
Example 325 frans.frans-4-(1.3-Benzodioxol-5-vn-2-fbenzyloxymethvn-1 -ffN.N- dibutylaminocarbonylmethvnpyrrolidine-3-carboxylic acid
Example 325A Ethyl frans.frans-4-f1.3-Benzodioxol-5-vn-2-fbenzyloxymethvn-1-(fN.N-difn- butvnaminocarbonvimethvnpyrrolidine-3-carboxylate The procedures of Example 1 A-1 D were followed, substituting ethyl 4- benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; 1H NMR (CDCI3, 300 MHz) δ 0.88 (t, J=7Hz, 6H), 1.17 (t. J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, J=8Hz, 1 H), 2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64- 3.75 (m, 2H), 3.92 (d, J-14Hz, 1 H), 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (m, 2H), 6.69 (d, J=9Hz, 1H), 6.77 (dd, J=1.5, 9Hz, 1 H), 6.91 (d, J=1.5Hz, 1 H); MS (DCI/NH3) m/e 553 (M+H)+. Example 325B frans.frans-4-f1.3-BenzodioxoI-5-vn-2-fbenzyloxymethyn-1-(fN.N-di(n- butynaminocarbonylmethylιPvrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71 C, as a colorless glass. TLC (5% Me0H-CH2CI ) Rf 0.13; 1H NMR (CDCI3, 300 MHz) δ 0.86 (t, J=7Hz), and 0.90 (t, J=7Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 1 H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, 1 H), 6.84 (dd, J=1 ,8Hz, 1 H), 6.93 (d, J=1 Hz, 1H), 7.28-7.39 (m, 5H); MS (DCI/NH3) m/e 524 (M+H)+.
Example 326 frans.frans-4-(1.3-Benzodioxol-5-vn-2-(hvdroxymethyn-1-ffN.N-difn- butynaminocarbonylmethynpyrroIidine-3-carboxylic acid
Example 326A
Ethylfrans.frans-4-f1.3-Benzodioxol-5-vn-2-fhydroxymethvn-1-f(N.N-difn- butynaminocarbonylmethvnpyrrolidine-3-carboxylate The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg of 20% Pd(OH)2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Example 326B frans.fraπs-4-f1.3-Benzodioxol-5-vn-2-(hvdroxymethvn-1-ffN.N- difbutynaminocarbonylmethvnpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C.
Example 327 frans.frans--4-f1.3-Benzodioxol-5-yn-2-fN-methylpropenamid-3-yn-1 -ffN.N-di(n- butynaminocarbonylmethvnpyrrolidine-3-carboxylic acid Example 327A Ethvl trans.trans-'Λ-n .3-Benzodioxol-5-yn-2-fformvn-1 -f f N.N-difn- butynaminocarbonylmethylιpyrrolidine-3-carboxylate The title compound is made by selective oxidation (e.g. using the Swern oxidation with DMSO, oxalyl chloride, ethyldiisopropyiamine or using the Dess- Martin periodinane) of the compound of Example 326A.
Example 327B Ethyl frans.frans-4-f1.3-Benzodioxol-5-yn-2-fO-tert-butylpropenoat-3-vn-1-ffN.N- difn-butynaminocarbonylmethynpyrrolidine-3-carboxylate
The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH2CI2 solution.
Example 327C Ethyl frans. frans--4-f1.3-Benzodioxol-5-vn-2-fpropenoic acid-3-yl;-1-(N.N-di(n- butvnaminocarbonylmethynpyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH2CI2 (1 :1 ).
Example 327P
Ethyl frans.frans-4-f1.3-Benzodioxol-5-ylι-2-fN-methylpropenamid-3-yn-1 -(N.N- difn-butynaminocarbonylmethynpyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327C with methylamine hydrochloride in the presence of a carbodiimide (e.g. N- ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC).
Example 327E frans.frans--4-(1.3-Benzodioxol-5-vn-2-fN-methylpropenamid-3-vn-1 -fN.N-di(n- butyliaminocarbonylmethvnpyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71 C.
Example 328 frans.frans-4-(1 ■3-Benzodioxol-5-vn-2-f1 -hydroxy-2-propen-3-vn-1 -(N.N-di(n- butynaminocarbonylmethvnpyrrolidine-3-carboxylic acid Example 328A Ethyl frans.frans--4-f 1.3-Benzodioxol-5-yn-2-(1-hydroxy-2-propen-3-vn-1 -fN.N-di(n- butynaminocarbonylmethvnpyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327C 5 with borane methyl sulfide complex.
Example 328B frans.frans--4-f1.3-Benzodioxol-5-yn-2-f1-hvdrox-2-propen-3-yn-1-(N.N-difn- butynaminocarbonylmethynpyrrolidine-3-carboxylic acid i o The title compound is produced by condensing the compound of Example
328A with lithium hydroxide according to the procedure of Example 71 C.
Example 329 frans.frans-4-f1.3-Benzodioxol-5-yn-2-fN-benzylaminomethyn-1 -fN.N-difn- 15 butyl,aminocarbonylmethynpyrrolidine-3-carboxylic acid
Example 329A Ethyl frans.frans--4-f 1.3-Benzodioxol-5-vn-2-fN-benzylaminomethvn-1 -f N.N-difn- butynaminocarbonylmethvnpyrrolidine-3-carboxylate 20 The title compound is produced by condensing the compound of Example
327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 329B frans.frans--4-f 1.3-Benzodioxol-5-yl)-2-fN-benzylaminomethyn-1 -fN.N-difn- 25 butynaminocarbonylmethynpyrrolidine-3-carboxylic acid
The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71 C.
Example 330 30 frans.frans--4-f1.3-Benzodioxol-5-yn-2-fN-acetyl-N-benzylaminomethyn-1 -fN.N- difn-butylιaminocarbonylmethynpyrrolidine-3-carboxylic acid
Example 33QA Ethyl trans. rans--4-f 1.3-Benzodioxol-5-yn-2-fN-acetyl-N-benzylaminomethvn-1 - 35 (N.N-difn-butvnaminocarbonylmethynpyrrolidine-3-carboxylate
The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine. Example 33QB frans.frans-4-f1.3-Benzodioxol-5-ylι-2-fN-acetyl-N-benzylaminomethyn-1-fN.N- difn-butylιaminocarbonylmethylιpyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71 C.
Example 331 frans.frans-4-f 1.3-Benzodioxol-5-yn-2-fethvnvn-1-fN.N-difn- butvnaminocarbonylmethynpyrrolidine-3-carboxylic acid
Example 331 A Ethyl frans. frans-4-f1.3-Benzodioxol-5-vn-2-fethvnvn-1-fN.N-difn- butynaminocarbonylmethylιpyrrolidine-3-carboxylate
The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.
Example 331 B frans.frans-4-f1.3-Benzodioxol-5-vn-2-fethynyn-1 -fN.N-difn- butyl)aminocarbonylmethynpyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 71 C.
Example 332 frans.frans--4-(1.3-Benzodioxol-5-vn-2-f1-pentvnvn-1-(N.N-di(n- butynaminocarbonylmethvnpyrrolidine-3-carboxylic acid
Example 332A Ethyl frans.frans--4-(1.3-Benzodioxol-5-vn-2-fpentvnvn-1 -fN.N-difn- butynaminocarbonylmethynpyrrolidine-3-carboxylate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. (J. Org. Chem. 1989, 54(15), 3618-24). Example 332B frans.frans--4-(1.3-Benzodioxol-5-vn-2-f1-pentynvn-1-(N.N-di(n- butyl)aminocarbonylmethynpyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of 5 Example 332A with lithium hydroxide according to the procedure of Example 71C.
Example 333 ( rat?g-fraπg-2-(4-Methpxphenyl)-4-( 1 ,3-bepzodiθxcl-5-yl)- 1 -f2-(216- ι o dioxopiperidinyh ethyl)-pyrrolidine-3-carboxylic acid
The compound of example 61 A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of 15 example 1 D.
Example 334 frans-frans-2-f4-Methoxyphenvn-4-( 1 .3-benzodioxol-5-yn- 1 -'N .N- diphenylaminocarbonylmethyn-pyrrolidine-3-carboxylic acid. 20 The title compound was prepared according to the procedures described in Example 1. 1H NMR (300 MHz, CD3OD) δ 2.83 (dd, 1 , J = 8.1 , 9.7), 2.99 (d, 1 , J = 15.4), 3.19 (t, 1 , J = 9.5), 3.49 (d, 1 , J = 15.3), 3.51 (dd, 1 , J = 4.6, 9.5), 3.57 (m, 1 ), 3.79 (s, 3), 3.85 (d, 1 , J = 9.5), 5.90 (s, 2), 6.71 (d, 1 , J = 8.0), 6.84 (m, 3), 7.04 (d, 1 , J = 1.6), 7.14-7.16 (m, 6), 25 7.19-7.34 (m, 6); MS (DCI/NH3) m/z 551 ; Anal Calcd for
C33H3oN2θ6-0.65H2θ.0.35C2H5θCOCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
Example 335 30 frans-frans-2-f4-Methoxyphenvn-4-f 1 .3-benzodioxol-5-yl )-1 -'N . N- diisopropylaminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD3OD) δ 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J = 6.4), 1.30 (d, 6, J = 6.8), 2.85 (d, 1 , J = 12.5), 3.04 (dd, 1 , 35 J = 8.1 , 9.8), 3.14 (t, 1 , J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1 ), 5.92 (s, 2), 6.75 (d, 1 , J = 8.1 ), 6.85 (dd, 1 , J = 1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1 , J = 1.7), 7.35 (m, 2). MS (DCI/NH3) m/z 483. Anal Calcd for C27H34N2O6 • 0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336 trans. frans-2-(3-Fluoro-4-methoxyphenyl »-4-f 1 .3-benzodioxol-5-yn-
1 -(2-N-propyl-N-butanesulfonylamino)ethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66°C. 1 H NMR (CDCI3, 300MHz) δ 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34-
1.52(m, 4H), 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1 H), 2.72-2.94(m, 5H), 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1 H), 3.53- 3.60(m, ι H), 3.67(d, J=9Hz, 1 H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1 H), 6.82(d, J=8Hz, 1 H), 6.92(t, J=9Hz, 1 H), 6.97(s, 1 H), 7.12(d, J=9Hz, 1 H), 7.18(d, J=12Hz, 1H). MS (DCI/NH3) m/e 565 (M+H)+.
Example 337 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared.
Figure imgf000216_0001
Table 1
R
Figure imgf000216_0002
Table 1 cont.
Figure imgf000217_0001
7. 8.
Figure imgf000217_0002
10. 11. 12.
Figure imgf000217_0003
14. 15.
13.
Figure imgf000217_0004
16. 17. 18.
Figure imgf000217_0005
19. 20. 21. Table 1 cont.
R R R
Figure imgf000218_0001
22. 23. 24.
Figure imgf000218_0002
25. 26. 27.
Figure imgf000218_0003
28. 29. 30.
Figure imgf000218_0004
31. 32. 33.
Figure imgf000218_0005
34. 35. 36.
Figure imgf000218_0006
37. 38. 39. Table 1 cont.
Figure imgf000219_0001
40. 41. 42.
Figure imgf000219_0002
43. 44. 45.
Figure imgf000219_0003
58. 59- 60- Table 1 cont.
R R R
Figure imgf000220_0001
61. 62.
63.
CTϊN^ PC^ [Jγ^
64. 65. 66.
Figure imgf000220_0002
67. 68. 69.
Figure imgf000220_0003
70. 71. 72.
Figure imgf000220_0004
73. 74. 75.
Figure imgf000220_0005
Table 1 cont.
R R R
Figure imgf000221_0001
79. 80. 81.
Figure imgf000221_0002
82. 83- 84.
Figure imgf000221_0003
88. 89. 90.
Figure imgf000221_0004
91. 92- 93-
Figure imgf000221_0005
94. 95. 96. Table 1 cont.
R R
Figure imgf000222_0001
97. 99.
98.
Figure imgf000222_0002
103. 105.
Figure imgf000222_0003
106. 107. 108.
Figure imgf000222_0004
109 110. 111.
Figure imgf000222_0005
112. 113. 114.
Figure imgf000222_0006
116. 117. Table 1 cont.
Figure imgf000223_0001
118. 119. 120.
Figure imgf000223_0002
124. 125. 126.
Figure imgf000223_0003
133. 134. 135. Table 1 cont.
R R R
Figure imgf000224_0001
136. 137. 138.
Figure imgf000224_0002
139. 1 40 141.
Figure imgf000224_0003
145. 146. 147.
Figure imgf000224_0004
148. 149. 150.
Figure imgf000224_0005
Table 1 cont.
R R
Figure imgf000225_0001
154.
155. 156.
Figure imgf000225_0002
160. 161. 162.
Figure imgf000225_0003
163. 164. 165.
Figure imgf000225_0004
166.
167. 168. Table 1 cont.
Figure imgf000226_0001
169. 170 171.
Figure imgf000226_0002
172. 173' 174.
Figure imgf000226_0003
175. 176. 177
Figure imgf000226_0004
178. 179. 180.
Figure imgf000226_0005
187. 188 189. Table 1 cont. R R R
Figure imgf000227_0001
190. 191. 192.
Figure imgf000227_0002
193. 194. 195.
Figure imgf000227_0003
199. 200. 201.
Figure imgf000227_0004
206.
207. Table 1 cont.
R R
Figure imgf000228_0001
208. 209. 210.
Figure imgf000228_0002
211. 212. 213.
Figure imgf000228_0003
214. 215. 216.
Figure imgf000228_0004
217. 218. 219.
Figure imgf000228_0005
220. 221. 222. Table 1 cont.
R R R
Figure imgf000229_0001
223. 224. 225.
Figure imgf000229_0002
229. 230. 231.
Figure imgf000229_0003
232. 233.
234.
Figure imgf000229_0004
235. 236. 237. Table 1 cont.
R R R
Figure imgf000230_0001
247. 248. 249.
Figure imgf000230_0002
250. 251.
252. Table 1 cont.
R R R
Figure imgf000231_0001
-.JO. 254.
255.
Figure imgf000231_0002
259. 260. 261.
Figure imgf000231_0003
262. 263. 264.
Figure imgf000231_0004
267.
265. 266. Table 1 cont.
R R R
Figure imgf000232_0001
Table 1 cont.
R R
Figure imgf000233_0001
289. 290. 291.
Figure imgf000233_0002
292.
293. 294.
Figure imgf000233_0003
Table 1 cont.
R R R
Figure imgf000234_0001
298. 299. 300.
Figure imgf000234_0002
301. 302.
303.
Figure imgf000234_0003
304.
305. 306.
Figure imgf000234_0004
307. 308. 309.
Figure imgf000234_0005
310. 311. 312. Table 1 cont.
R
Figure imgf000235_0001
313. 314. 315.
Figure imgf000235_0002
316. 317. 318.
Figure imgf000235_0003
325. 326. 327. Table 1 cont.
Figure imgf000236_0001
328. 329. 330.
Figure imgf000236_0002
331. 332. 333.
Figure imgf000236_0003
340. 341 - 342. Table 1 cont.
R R
Figure imgf000237_0001
343. 344. 345.
Figure imgf000237_0002
346. 347. 348.
Figure imgf000237_0003
Figure imgf000238_0001
361. 362.
363.
Figure imgf000238_0002
364. 365. 366.
Figure imgf000238_0003
Table 1 cont.
R R R
Figure imgf000239_0001
376. 377. 378.
Figure imgf000239_0002
379. 380. 381.
Figure imgf000239_0003
382, 383. 384
Figure imgf000239_0004
385. 386. 387 Table 1 cont.
R R R
Figure imgf000240_0001
394.
395. 396.
Figure imgf000240_0002
397.
398. 399.
Figure imgf000240_0003
401. 402. Table 1 cont.
R
Figure imgf000241_0001
406. 407. 408.
Figure imgf000241_0002
Table 1 cont.
Figure imgf000242_0001
Ns n CnOnOπEt
Figure imgf000242_0002
418. 419. 420.
Figure imgf000242_0003
421. 422. 423.
Figure imgf000242_0004
430. 431. 432. Table 1 cont.
R R R
Figure imgf000243_0001
442. 443. 444.
Figure imgf000243_0002
Table 1 cont.
R R R
Figure imgf000244_0001
451.
452. 453.
Figure imgf000244_0002
454. 455. 456.
Figure imgf000244_0003
460. 461. 462. Table 1 cont.
R R R
Mβ0Λ .*k Mθ0Λ γ βo-COy
463. 464. 465.
Figure imgf000245_0001
467.
466. 468.
Figure imgf000245_0002
Table 1 cont.
Figure imgf000246_0001
490. 491. 492. Table 1 cont.
R R R
Figure imgf000247_0001
502. 503. 504.
Figure imgf000247_0002
Table 1 cont.
R R R
Figure imgf000248_0001
508. 509. 510.
Figure imgf000248_0002
511. 512. 513.
Figure imgf000248_0003
514. 515. 516.
Figure imgf000248_0004
517. 518. 519.
Figure imgf000248_0005
520. 521.
522. Table 1 cont.
R R R
Figure imgf000249_0001
529. 530. 531.
Figure imgf000249_0002
532. 533. 534.
Figure imgf000249_0003
535. 536. 537. Table 1 cont.
R R R
Figure imgf000250_0001
540. 542. 543.
Figure imgf000250_0002
544. 545. 546.
Figure imgf000250_0003
»
551- 552. Table 1 cont.
Figure imgf000251_0001
559. 560. 561.
Figure imgf000251_0002
565. 566. 567. Table 1 cont.
R
Figure imgf000252_0001
568. 569. 570.
Figure imgf000252_0002
571. 572. 573.
Figure imgf000252_0003
574. 575. 576.
Figure imgf000252_0004
578. 579.
577.
Figure imgf000252_0005
583. 584. 585. Table 1 cont.
R R R
Figure imgf000253_0001
592. 593. 594.
Figure imgf000253_0002
595. 596. 597.
Figure imgf000253_0003
598. 599. 60°-
Figure imgf000253_0004
601. 602. 603- Table 1 cont.
Figure imgf000254_0001
613. 614. 615.
Figure imgf000254_0002
Table 1 cont.
R R R
Figure imgf000255_0001
634. 635. 636.
Figure imgf000255_0002
Table 1 cont.
R R R
Figure imgf000256_0001
640. 641. 642.
Figure imgf000256_0002
649. 650. 651.
Figure imgf000256_0003
. . 654.
Figure imgf000257_0001
Figure imgf000257_0002
Figure imgf000257_0003
Table 1 cont.
Figure imgf000258_0001
670. . 672.
Figure imgf000258_0002
676. 677. 678.
Figure imgf000258_0003
682. 683. 684. Table 1 cont.
R R R
Figure imgf000259_0001
Table 1 cont.
R R
Figure imgf000260_0001
709. 710. 711.
Figure imgf000260_0002
712. 713. 714.
Figure imgf000260_0003
715. Example 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.
Table 2A
Figure imgf000261_0001
Figure imgf000261_0002
Figure imgf000261_0003
Table 2A cont,
Figure imgf000262_0001
Table 2A cont.
Figure imgf000263_0001
Table 2A cont.
Figure imgf000264_0001
Table 2A cont.
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000266_0002
Figure imgf000266_0003
Table 2A cont.
Figure imgf000267_0001
Table 2A cont.
Figure imgf000268_0001
Figure imgf000268_0002
Table 2A cont.
Figure imgf000269_0001
Table 2A cont.
Figure imgf000270_0001
118. 119. 120. Table 2A cont.
Figure imgf000271_0001
Figure imgf000271_0002
Table 2A cont.
Figure imgf000272_0001
.
Figure imgf000272_0002
137.
Figure imgf000272_0003
Table 2A cont.
Figure imgf000273_0001
Figure imgf000273_0002
154. 155. Table 2A cont.
Figure imgf000274_0001
Figure imgf000274_0002
Table 2A cont.
Figure imgf000275_0001
Figure imgf000275_0002
Table 2A cont.
Figure imgf000276_0001
Figure imgf000276_0002
190. 191. 192. Table 2A cont.
Figure imgf000277_0001
193. 194. 195.
Figure imgf000277_0002
Figure imgf000277_0003
Table 2A cont.
Figure imgf000278_0001
Table 2A cont.
Figure imgf000279_0001
223. 224. 225.
Figure imgf000279_0002
Table 2A cont.
Figure imgf000280_0001
Table 2A cont.
241. 242. 243.
Figure imgf000281_0002
Table 2A cont.
Figure imgf000282_0001
253. 254. 255.
Figure imgf000282_0002
262. 264.
263.
Figure imgf000282_0003
Table 2A cont.
Figure imgf000283_0001
8. 269. 270.
Figure imgf000283_0002
274. 275. 276.
Figure imgf000283_0003
277. 278. 279.
Table 2A cont.
Figure imgf000284_0001
283. 284. 285.
Figure imgf000284_0002
289. 290. 291.
Figure imgf000284_0003
Table 2A cont.
Figure imgf000285_0001
Table 2A cont.
Figure imgf000286_0001
Table 2A cont.
Figure imgf000287_0001
Figure imgf000288_0001
337.
338. 339.
Figure imgf000288_0002
Table 2A cont.
Figure imgf000289_0001
Table 2A cont.
Figure imgf000290_0001
367. 368. 369.
Figure imgf000290_0002
373. 374. 375. Table 2A cont.
Figure imgf000291_0001
377. 378. 6.
Figure imgf000291_0002
382. 383. 384.
Figure imgf000291_0003
Table 2A cont.
Figure imgf000292_0001
390.
388. 389.
Figure imgf000292_0002
Table 2A cont.
Figure imgf000293_0001
Figure imgf000294_0001
Table 2A cont.
Figure imgf000295_0001
Table 2A cont.
Figure imgf000296_0001
448. 450.
449.
Figure imgf000296_0002
454. 455. 456. Table 2A cont.
Figure imgf000297_0001
457. 458. 459.
Figure imgf000297_0002
465.
463. 464.
Table 2B
R
Figure imgf000298_0001
13. 14- 5-
Figure imgf000298_0002
16. 17 18.
Figure imgf000298_0003
19 20. 21.
Figure imgf000299_0001
Figure imgf000299_0002
Table 2B cont.
Figure imgf000300_0001
43. 44. 45.
Figure imgf000300_0002
46. 47. 48.
Figure imgf000300_0003
52. 53. 54.
Figure imgf000300_0004
Table 2B cont.
R R
Figure imgf000301_0001
65. 66.
Figure imgf000301_0002
67. 68. 69.
Figure imgf000301_0003
76. 77. 78. Table 2B cont.
R
Figure imgf000302_0001
79. 80. 81.
Figure imgf000302_0002
82.
83. 84.
Figure imgf000302_0003
85. 86. 87.
Figure imgf000302_0004
91. 92. 93.
Figure imgf000302_0005
97. 98.
99. Table 2B cont.
Figure imgf000303_0001
103. 104. 105.
Figure imgf000303_0002
109. 110. 111.
Figure imgf000303_0003
112. 113. 114.
Figure imgf000303_0004
115. 116. 117. Table 2B cont.
R R R
Figure imgf000304_0001
. 122.
123.
Figure imgf000304_0002
124. 125. 126.
Figure imgf000304_0003
Table 2B cont.
R R R
Figure imgf000305_0001
133. 134. 135.
Figure imgf000305_0002
136. 137. 138.
Figure imgf000305_0003
139. 140. 141.
Figure imgf000305_0004
146. 147.
145. Table 2B cont.
Figure imgf000306_0001
148. 149.
150.
Figure imgf000306_0002
151. 152. 153.
Figure imgf000306_0003
54- 155. 156.
Figure imgf000306_0004
157. 158_ 159.
Figure imgf000306_0005
Table 2B cont.
R
Figure imgf000307_0001
163. 164. 165.
Figure imgf000307_0003
NCxχx Y"
Figure imgf000307_0002
166. 167.
168.
NCtχv N rx Ύ-* NCXXV
170.
169. 171.
Figure imgf000307_0004
175. 176. 177. Table 2B cont.
R R R
Figure imgf000308_0001
178. 179.
180.
Figure imgf000308_0002
183.
181. 182.
Figure imgf000308_0003
192. Table 2B cont.
R
Figure imgf000309_0001
205. 206. 207. Table 2B cont.
Figure imgf000310_0001
208. 209. 210.
Figure imgf000310_0002
211.
212. 213.
Figure imgf000310_0003
214. 215. 216.
Figure imgf000310_0004
220. 221. 222. Table 2B cont.
R R R
Figure imgf000311_0001
223. 224. 225.
Figure imgf000311_0002
226. 227. 228.
Figure imgf000311_0003
229. 230. 231.
Figure imgf000311_0004
232. 233. 234.
Figure imgf000311_0005
Table 2B cont.
Figure imgf000312_0001
241. 242. 243.
Figure imgf000312_0002
246.
244. 245.
Figure imgf000312_0003
249.
247. 248
Figure imgf000312_0004
Table 2B cont.
R R R
Figure imgf000313_0001
257. 258.
256.
Figure imgf000313_0002
261. 259. 260.
Figure imgf000313_0003
262. 263. 264.
Figure imgf000313_0004
265. 266. 2 7- Table 2B cont.
Figure imgf000314_0001
277. 278.
279.
Figure imgf000314_0002
Table 2B cont.
R
Figure imgf000315_0001
292. 293. 294.
Figure imgf000315_0002
295. 296. 297. Table 2B cont.
R R R
Figure imgf000316_0001
298. 299. 300.
Figure imgf000316_0002
301. 302. 303.
Figure imgf000316_0003
307. 308. 309.
Figure imgf000316_0004
310. 311. 312. Table 2B cont.
R R R
Figure imgf000317_0001
Table 2B cont.
Figure imgf000318_0001
337. 338. 339.
Figure imgf000318_0002
Table 2B cont.
Figure imgf000319_0001
Table 2B cont.
Figure imgf000320_0001
364. 365. 366.
Figure imgf000320_0002
367. 368. 369.
Figure imgf000320_0003
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000322_0002
Figure imgf000322_0003
Table 2B cont.
R R R
Figure imgf000323_0001
418. 419. 420.
Figure imgf000323_0002
424. 425. Λ rtC Table 2B cont.
Figure imgf000324_0001
427. 428. 429.
Figure imgf000324_0002
430. 431. 432.
Figure imgf000324_0003
433. 434. 435
Figure imgf000324_0004
442- 443. 444. Table 2B cont.
R R R
Figure imgf000325_0001
445. 446. 447.
Figure imgf000325_0002
448. 449. 450.
Figure imgf000325_0003
451. 452. 453.
Figure imgf000325_0004
454. 455. 456.
Figure imgf000325_0005
457. 458. 459. Table 2B cont.
Figure imgf000326_0001
460. 461. 462.
Figure imgf000326_0002
463. 464. 465.
Figure imgf000326_0003
472. 73- 474. Table 2B cont.
R R R
Figure imgf000327_0001
475. 476. 477.
Figure imgf000327_0002
481. 482. 483.
Figure imgf000327_0003
484. 485. 486.
αχ ιirYV -g Xrf*
Figure imgf000327_0004
487. 488. 489. Table 2B cont.
R
Figure imgf000328_0001
490. 491. 492.
Figure imgf000328_0002
Table 2B cont.
R R R
Figure imgf000329_0001
508. 509. 510.
Figure imgf000329_0002
511. 512. 513.
Figure imgf000329_0003
514. 515, 516.
Figure imgf000329_0004
517. 518. 519.
Figure imgf000329_0005
Table 2B cont.
Figure imgf000330_0001
526. 527. 528.
Figure imgf000330_0002
530. 531.
529.
Figure imgf000330_0003
.
536. 537. Table 2B cont.
R R R
Figure imgf000331_0001
538. 539. 54°-
Figure imgf000331_0002
550. 551. 552- Tabie 2B cont.
Figure imgf000332_0001
553. 554. 555.
Figure imgf000332_0002
556. ggy 558.
Figure imgf000332_0003
ώ , clχχY
Figure imgf000332_0004
565. 566. 567. Table 2B cont.
R R R
Figure imgf000333_0001
.
569. 570.
Figure imgf000333_0002
571. 572. 573.
Figure imgf000333_0003
574. 575. 576.
Figure imgf000333_0004
577. 578. 579.
Figure imgf000333_0005
580. 581. 582. Table 2B cont.
R R R
Figure imgf000334_0001
583. 584. 585.
Figure imgf000334_0002
Tabie 2B cont.
R R R
Figure imgf000335_0001
598. 599. 600.
Figure imgf000335_0002
601. 602. 603.
Figure imgf000335_0003
. 608. o oYy.
Figure imgf000335_0004
Table 2B cont.
Figure imgf000336_0001
Figure imgf000336_0002
Figure imgf000336_0003
624.
622. 623.
Figure imgf000336_0004
627.
625. 626. Table 2B cont.
R
Figure imgf000337_0001
628. 629. 630.
Figure imgf000337_0002
631. 632.
Example 339 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared. Table 3A
Figure imgf000338_0001
Figure imgf000338_0002
Figure imgf000338_0003
Table 3A cont.
Figure imgf000339_0001
Figure imgf000339_0002
Figure imgf000339_0003
21.
19. 20.
Figure imgf000340_0001
Figure imgf000340_0002
Figure imgf000341_0001
Figure imgf000341_0002
Table 3B cont.
R R R
Figure imgf000342_0001
43. 44. 45.
Figure imgf000342_0002
6- 47. 48.
Figure imgf000342_0003
49- 50. 51.
Figure imgf000342_0004
Table 3B cont.
R
Figure imgf000343_0001
65. 66.
Figure imgf000343_0002
. 68. 69.
Figure imgf000343_0003
76. 77. 78. Table 3B cont.
Figure imgf000344_0001
79. 80. 81.
Figure imgf000344_0002
82.
83. 84.
Figure imgf000344_0003
85. 86. 87.
Figure imgf000344_0004
89. 88. 90.
Figure imgf000344_0005
91. 92. 93.
Figure imgf000344_0006
94. 95. 96.
Figure imgf000344_0007
97. 98.
99. Table 3B cont.
R R R
Figure imgf000345_0001
103. 104. 105.
Figure imgf000345_0002
106. 107. 108.
Figure imgf000345_0003
109. 110. 111.
Figure imgf000345_0004
Table 3B cont.
R R R
Figure imgf000346_0001
127. 128. 129.
Figure imgf000346_0002
130. 131. 132. Table 3B cont.
R R R
Figure imgf000347_0001
133. 134. 135.
Figure imgf000347_0002
136. 137. 138.
Figure imgf000347_0003
139. 140. 141.
Figure imgf000347_0004
144.
142. 143.
Figure imgf000347_0005
Table 3B cont.
Figure imgf000348_0001
148. 149.
150.
Figure imgf000348_0002
151. 152. 153.
Figure imgf000348_0003
154- 155. 156.
Figure imgf000348_0004
Table 3B cont.
R R R
Figure imgf000349_0001
163. 164. 165.
Figure imgf000349_0002
NχχN
Figure imgf000349_0003
166. 167,
168.
Figure imgf000349_0004
169. .
171.
Figure imgf000349_0005
175. 176. 177. Table 3B cont.
R
Figure imgf000350_0001
178. 179. 180.
Figure imgf000350_0002
183.
181. 182.
Figure imgf000350_0003
187.
188. 189.
Figure imgf000350_0004
192. Table 3B cont.
R
Figure imgf000351_0001
193.
194. 195.
Figure imgf000351_0002
205. 206. 207. Table 3B cont.
R
Figure imgf000352_0001
208. 209. 210.
Figure imgf000352_0002
214. 215. 216.
Figure imgf000352_0003
217. 218 219.
Figure imgf000352_0004
220. 221. 222. Table 3B cont.
R
Figure imgf000353_0001
223. 224. 225.
Figure imgf000353_0002
. 227. 228.
Figure imgf000353_0003
229. 230. 231.
Figure imgf000353_0004
232. 233. 234.
Figure imgf000353_0005
Table 3B cont.
R R
Figure imgf000354_0001
241. 242. 243.
Figure imgf000354_0002
244. 245. 246.
• rAVYo *
Figure imgf000354_0003
247. 248. 249.
Figure imgf000354_0004
Table 3B cont.
R R
Figure imgf000355_0001
259. 260. 261.
Figure imgf000355_0002
262. 263. 264.
Figure imgf000355_0003
.
266. 267. Table 3B cont.
R R
Figure imgf000356_0001
271. 272. 273.
Figure imgf000356_0002
277. 278.
279.
Figure imgf000356_0003
Figure imgf000357_0001
Figure imgf000357_0002
Figure imgf000357_0003
Figure imgf000358_0001
Figure imgf000358_0002
Figure imgf000358_0003
Table 3B cont.
R R
Figure imgf000359_0001
313. 314. 315.
Figure imgf000359_0002
Table 3B cont.
Figure imgf000360_0001
337. 338. 339.
Figure imgf000360_0002
Table 3B cont.
R R R
Figure imgf000361_0001
Table 3B cont.
Figure imgf000362_0001
.
362. 363.
Figure imgf000362_0002
364. 365. 366.
Figure imgf000362_0003
367. 368. 369.
Figure imgf000362_0004
371. 372.
370.
Figure imgf000363_0001
Table 3B cont.
R R R
Figure imgf000364_0001
Xbγ 0 CX J A- o c k
394. 395. o yo.
Figure imgf000364_0002
Figure imgf000365_0001
Figure imgf000365_0002
Figure imgf000365_0003
Figure imgf000366_0001
Table 3B cont.
R R R
Figure imgf000367_0001
445. 446. 447.
Figure imgf000367_0002
. 449. 450.
Figure imgf000367_0003
451. 452. 453.
Figure imgf000367_0004
. 455. 456.
Figure imgf000367_0005
457. 458. 459 Table 3B cont.
R R R
Figure imgf000368_0001
460. 461. 462.
Figure imgf000368_0002
463. 464. 465
Figure imgf000368_0003
472. 473- 474. Tabie 3B cont.
R R R
Figure imgf000369_0001
475. 476. 477.
Figure imgf000369_0002
. 479. 480.
Figure imgf000369_0003
481. 482. 483.
Figure imgf000369_0004
484. 485. 486.
Figure imgf000369_0005
487. 488. 489. Table 3B cont.
R R
Figure imgf000370_0001
490. 491. 492.
Figure imgf000370_0002
505. 506. Table 3B cont.
R R R
Figure imgf000371_0001
508. 509. 510.
Figure imgf000371_0002
511. 512. 513.
Figure imgf000371_0003
Table 3B cont.
R
Figure imgf000372_0001
529. 530. 531.
Figure imgf000372_0002
Table 3B cont
R R R
Figure imgf000373_0001
538. 539. 540.
Figure imgf000373_0002
550. 551. 552. Table 3B cont.
R R R
Figure imgf000374_0001
553. 554' 555.
Figure imgf000374_0002
556. 557. 558.
Figure imgf000374_0003
565. 566. 567. Table 3B cont.
R R R
Figure imgf000375_0001
571. 572. 573.
Figure imgf000375_0002
. 575. 576.
Figure imgf000375_0003
577. 578. 579.
Figure imgf000375_0004
580. 581. 582. Table 3B cont.
R R R
Figure imgf000376_0001
583. 584. 585.
Figure imgf000376_0002
593. 594.
592.
Figure imgf000376_0003
595. 596. 597. Table 3B cont.
Figure imgf000377_0001
598. 599. 600.
Figure imgf000377_0002
601. 602. 603.
Figure imgf000377_0003
Table 3B cont.
Figure imgf000378_0001
622. 623.
Figure imgf000378_0002
625. 626. 627. Table 3B cont.
Figure imgf000379_0001
628. 629. 630.
Figure imgf000379_0002
631. 632.
Example 340 frans.frans-4-(1.3-Benzodioxol-5-vπ-2-(4-methoxyphenvπ-1-fN-f3-methylbut-1 -vπ- N-phenyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. *« H NMR (300 MHz, CD3OD) δ 0.85 (d, J=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (m, 1 H), 3.43-3.85 (m, 9H), 3.88s (3), 5.95 (s, 2H), 6.80 (d, J=7 Hz, 1 H), 6.86 (dd, J=9 Hz, 1 H), 6.89-7.00 (m, 2H), 6.97 (d, J=1 Hz, 1 H), 7.04 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.40-7.47 (m, 3H). MS (Cl.) m/e C (53.12, 53.1 1), H (4.63, 4.80), N (3.33, 3.28). Example 341 trans. trans-A-l 1.3-Benzodioxol-5-yl.-2-/4-methoxγphenvn-1-(N- butyl-N- -methylDhenylaminocarbonylmethyh-pyrrolidine-3- carbQxylic aςij Using the procedures described in Example 1, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20- 1.47 (m, 4H), 2.37 (s, 3H), 2.83 (q, J=7 Hz, 2H), 3.06-3.25 (m, 2H), 3.40- 3.50 (m, 1H), 3.51-3.63 (m, 3H), 3.80 (s, 3H), 3.87 (d, J=9 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=8 Hz, 1H), 6.80-6.86 (m, 3H), 6.89 (d, J=8 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 7.12 (d. J=8 Hz, 2H), 7.19 (d,
Figure imgf000380_0001
Hz, 2H). MS (DCl) m/e 545 (M+H)+. Analysis calcd for C32H36N2O6: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03.
Example 342 frans.fraπs-4-f1.3-Benzodioxol-5-vn-2-(4-proDoxyDhenvn-1-(N.N- di(n-butyl;aminoιcarbonvhmethvπ-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) δ 7.30 (2H, d, J=9), 7.03 (1H, d, J=2), 6.83 (3H, m), 6.72 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 3.88 (2H, t, J=7), 3.73 (1H, d, J=12), 3.58 (1H, m), 3.53-3.20 (4H, m),
3.10-2.90 (4H, m), 2.72 (1H, d, J=15), 1.79 (2H, q, J=8), 1.50-1.05 (8H, m), 1.02 (3H, t, J=7), 0.87 (3H, t, J=7), 0.80 (3H, t, J=7). MS (DCI/NH3) m/e 539 (M+H)+. Anal calcd for C31H42N2O6 • 0.5H2O: C, 67.98; H ,7.91; N, 5.11. Found: C68.24; H, 7.70; N, 5.03.
Example 343 trans. fraπs-4-M .3-Benzodioxol-5-yl;-2-(4-propylphenvπ-1-(N.N-di(n- butyπaminocarbonylmethvπDyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) δ 7.31 (2H, d, J=9), 7.13 (2H, d, J=9), 7.03 (1H, d, J=2), 6.84 (1H, dd, J=6, 2), 6.73 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 3.76 (1H, d, J=10), 3.60 (1H, m), 3.55-3.20 (4H, m), 3.13-2.88 (4H, m), 2.75 (1H, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q, J=8), 1.50-1.00 (8H, m), 0.92 (3H, t, J=7), 0.85 (3H, t, J=7), 0.78 (3H, t, J=7). MS (DCI/NH3) m/e 523 (MH+). Anal calcd for C31H42N2O5-0.25 H2O : C, 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18. Example 344 fraπs-frans-2-(4-Methoxyphenylι-4-H.3-benzodioxol-5-ylι-1-r3-(N- Dropyl-N-t>Dentanesulfonylaminθ)propyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 316, the title compound was prepared. 1H NMR (300MHz, CDCI3) δ 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.3-1.4 (m, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (m, 4H), 2.05-2.15 (m, 1H), 2.43-2.56 (m, 1H), 2.72-3.1 (m, 7H), 3.27- 3.4 (m, 2H), 3.5-3.6 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.8-6.9 (m, 1H), 6.85 (d, J= 9Hz, 2H), 7.02 (cf, J=2Hz, 1H), 7.80 (d,
J=9Hz, 2H).
Example 345 trans. frans-4-M .2-Dihvdrobenzofuran-5-ylι-2-(4-ethylphenyn-1- fN.N-difn-butynaminocarbonylmethvn-Dyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) δ 7.40 (3H, m), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 3), 6.72 (1H, d, J=9), 5.28 (1H, d, J=12), 4.55 (2H, t, J=9), 4.15 (1H, d, J=18), 4.03 (2H, m), 3.75 (2H, m), 3.40 (2H, m), 3.20 (2H, t, J=9), 3.15 (1H, m), 3.10-2.90 (2H, m), 2.63 (2H, q, J=9), 1.47 (2H, m), 1.31 (4H, m), 1.12 (3H, t, J=8), 1.10 (2H,m), 0.92 (3H, t, J=9), 0.80 (3H, t, J=9). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N2O4 • 1.0 TFA: C ,63.86 ; H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.
Example 346 frans.fraπs-4-π.3-Benzodioxol-5-yn-2-(4-methoxyDhenylι-1-frfN-f3- Dentvπ-N-phenylaminoιcarbonvπmethvπDyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.93 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H), 1.33 (m, 4H), 2.72 (d, J=15.2 Hz, 1H), 2.81 (m, 1H),
3.11-3.23 (m, 2H), 3.45-3.57 (m, 2H), 3.79 (s, 3H), 3.83 (d, J=9.8 Hz, 1H), 4.54 (m, 1H), 5.92 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.83 (m, 3H), 6.98 (bs, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.07 (2), 7.37 (m, 3H). MS (DCl) m/e 545 (M+H+). Anal calcd for C32H33N2O6 • 0.35H2O: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94. Example 347 frans. frans-4-H .3-Benzodioxol-5-yl 2-(4-m ethoxyphenyh-l -(Xi N- butyπ-N-(3-trifluoromethylphenvhamino ιcarbonvπmethvhpyrrolidine-
3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (t, J=6.6 Hz, 3H), 1.17- 1.45 (m, 4H), 2.65 (d, J=16.5 Hz, 1H), 2.72 (m, 1 H), 3.10 (t, J=9.5 Hz, 1 H), 3.21-3.27 (m. 1 H), 3.40 (dd, J=4.1 , 9.9 Hz, 1 H), 3.54 (m, 1 H), 3.61- 3.74 (m, 3H), 3.77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m, 3H), 7.33 (d, J=7.5 Hz. 1 H), 7.40 (s, 1H), 7.58 (t,
Figure imgf000382_0001
1 H), 7.69 (d, J=7.5
Hz, 1H). MS (DCl) m/e 599 (M+H+). Anal calcd for C32H33F3N2O6: C, 64.21 ; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57.
Example 348 trans. frans-4-M .3-Benzodioxol-5-yl .-2-ι/4-methoxyphenvn- 1 -(N- p ropy l-N- -morpholinylcarbonyπaminocarbonylmethyπ-py rrolidi ne-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.78 (t, J=7 Hz, 3H), 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (m, 1 H), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (m,
5H), 3.05 (3.70, J=m Hz, 11 H), 3.76 (s, 3H), 5.88 (s, 2H), 6.67 (d, J=8 Hz, 1 H), 6.80 (dd, J=7 Hz, 1 H), 6.83-6.90 (m, 2H), 6.98 (d, J=2 Hz, 1 H), 7.32- 7.39 (m, 2H). MS m/e calc'd for (M+H) C29H39N3O7: (M+H) 540.2710,.
Found (M+H) 540.2713.
Example 349 trans. frans-4-( 1 ■3-Benzodioxol-5-vπ -2-(4-methoxyphenvπ- 1 -(c/s-
2.6-di methyl pi peridin- 1 -yhcarbonyl methyl ; -pyrrolidine-3-carbox vii c acid Using the procedures described in Example 1 , the title compound was prepared. i H NMR (300 MHz, CD3OD) δ 0.94 (d, J=7 Hz, 3H), 1.15d (7, 3H), 1.10-1.70 (m, 6H), 1.70-1.90 (m, 1 H), 2.9. (d, J=13 Hz, 1 H), 3.00-3.20 (m, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 (s, 3H). 3.80-4.00 (m, 1 H), 4.10-4.65 (m, 2H), 5.95 (s, 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (m, 2H). MS m/e calc'd for (M+H)+ C28H35 2O6: (M+H) 495.2495. Found (M+H) 495.2493. Example 350 trans. fraπs-2-(4-Methoxymethoxyphenvπ-4-(1.3-benzodioxol-5-vh- 1-f2-(N-propyl-N-n-pentanesulfonylamino)ethyllpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p.57-59 °C. 1H NMR (CDCI3, 300 MHz) δ 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.28-1.36
(m, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 (t, J=7Hz, 2H), 2.20-2.32 (m, 1H), 2.72-3.10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.48
(s, 3H), 3.52-3.59 (m, 1H), 3.68 (d, J=9Hz, 1H), 5.15 (s, 2H), 5.94 (s,2H), 6.73 (d. J=8Hz, 1H), 6.82 (dd, J=1Hz, J=8Hz, 1H), 6.98-7.02 (m, 3H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 591 (M+H)+.
Example 351 frans.frar>s-4-M.3-Benzodioxol-5-vn-2-(4-methoxyphenyn-1-(ffN-(2- butvh-N-phenylaminoιcarbonyhmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.79-0.89 (m, 6H), 1.14-1.21 (m, 1H), 1.25-1.40 (m, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 (t, J=9.0
Hz, 1H), 3.05-3.13 (m, 2H), 3.37-3.49 (m, 2H), 3.70 (s, 3H), 3.80 (d, J=9.8 Hz, 1H), 4.53 (m, 1H), 5.83 (m, 2H), 6.65 (d, J=8.1 Hz, 1H), 6.72 (- 6.76, J=m Hz, 3H), 6.87 (m, 2H), 6.95 (d, J=1.7 Hz, 1H), 7.03 (m, 2H), 7.29 (m, 3H). MS (DCl) m/e 531 (M+H+). Anal calcd for C31H34N2O6 • 0.4H2O: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.
Example 352 frans.fraπs-4-π .3- Benzodioxol-5-vh-2-(4-methoxyphenyπ-1-(((N-t 2- propyπ-N-phenylaminoιcarbonvOmethvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.99 (d, J=6.8 Hz, 6H), 2.71 (d, J=15.6 Hz, 1H), 2.84 (m, 1H), 3.13-3.18 (m, 2H), 3.45-3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, 1H), 4.80 (m, 1H), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.13 (m, 2H), 7.38 (m, 3H). MS (DCl) m/e 517 (M+H+). Anal calcd for C30H32N2O6 • 0.4H2O • O.O8CH3CO2C2H5: C, 68.65; H, 6.28; N, 5.28. Found: C, 68.64; H, 6.35; N. 5.14.
Example 353 trans. frar? s-4-(4-Propoxyphenyn-2-(4-methoxyphenyn-1 -(N. N-di(n- butynaminocarbonylmethvn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H (300MHz. CDCI3 ) δ 7.42 (2H. d, J=10Hz), 7.38 (2H, d, J=10Hz), 6.92 (2H. d, J=10Hz). 6.88 (2H, d, J=10Hz), 5.13 (1 H, bd. J=12Hz), 4.02 (2H. m), 3.90 (2H, t, J=8Hz), 3.80 (3~H, s), 3.71 (3H, m).
3.40 (2H, m), 3.19 (1 H, m), 3.10-2.90 (2H, m), 1.80 (2H, m), 1.48 (2H. m), 1.29 (4H, m), 1.13 (2H, m), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz). MS (DCI/NH3) m/e 525 (MH+). Anal calcd for C31 H44N205- 1 TFA : C, 62.06 H 7.10; N, 4.39 . Found: C, 62.43; H, 7.28; N, 4.39.
Example 354 trans, fraπs-4-f 1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyl ι- 1 - (f 1 .2.3.4-tetrahydroquinolin-1 -yl , carbon vnmethvnpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 1.88 (quintet, J=6.5 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.87 (t, J=8.6 Hz, 1 H), 3.14 (m, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1 H), 3.53-3.70 (m, 3H), 3.72-3.78 (m, 1 H), 3.77 (s, 3H), 3.86 (d, J=9.6 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J=8.1 Hz, 1 H), 6.83 (m, 3H),
6.98 (d, J=1.1 Hz, 1 H), 7.02-7.23 (m, 6H). MS (DCl) m/e 515 (M+H+). Anal calcd for C30H30N2O6 • O.3H2O • 0.15 CH3CO2C2H5: C, 68.93; H, 6.01 ; N, 5.25. Found: C, 68.91 ; H, 5.86; N, 5.19.
Example 355 trans. t rans-2-(3.4-Dimethoxyphenvn-4-M .3-benzodioxol-5-yl .-1 -
(N.N-di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid, m.p. 64-65 °C. 1 H NMR (CDCI3, 300MHz) δ 0.79 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H),1.07 (sextet,
• l=7H7. 2H). 1.20-1.35 (m. 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, J=13.5Hz, 1H), 2.94-3.17 (m, 4H), 3.22-3.42 (m, 1 H), 3.40-3.48 (m, 3H), 3.58-3.65 (m, 1 H), 3.82 (s, 3H), 3.85 (s, 4H),5.92 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.81 (d, J=8Hz, 1H), 6.86-6.96 (m, 3H), 7.07 (d, J=3Hz, 1H). MS (DCI/NH3) m/e 541 (M+H)+.
Example 356 trans. frans-2-(3.4-Dimethoxyphenvn-4-(,1 .3-benzodioxol -5-yl)-1 -f2-
(N-prQpyl-N-r?-pentanesulf<?pylamino)ethyllpyrrQlidine-3-carbQxylic dd Using the procedures described in Example X , the title compound was prepared and isolated as a white solid, m.p. 75-86 °C H NMR (CD3OD, 300 MHz) δ 0.75 (t, J=7Hz, 3H), 0.82 (t, J=7Hz, 3H), 1.32-1.43
(m, 6H), 1.65-1.77 (m, 2H), 3.0-3.09 (m, 4H), 3.23-3.27 (m, 2H), 3.44 (t, J=6Hz, 1 H), 3.47-3.56 (m, 2H), 3.78 (d, J=9Hz, 1 H), 3.83-3.93 (m, 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J=13Hz, 1H), 5.97 (s. 2H), 6.82 (d,
J=7Hz, 1 H), 6.93 (d, J=7Hz, 1 H), 7.06 (d, J=7Hz, 1 H), 7.08 (d, J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, 1 H), 7.27 (d, J=3Hz, 1 H). MS (DCI/NH3) m/e 591
(M+H)+.
Example 357 trans. frans-2-(3.4-Dimethoxyphenvπ-4-M .3-benzodioxol-5-yh-1 -r2- (N-propyl-N-/ hexanesulfonylamino ιethyl]pyrrolidine-3-carboxylic acid Using the procedures described In Example 1 , the title compound was prepared and isolated as a white solid, m.p. 65-66 °C H NMR (CDCI3, 300 MHz) δ 0.80 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.23-1.48
(m, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (m, 1 H), 2.73-3.10 (m, 7H), 3.19-3.32 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1 H), 3.53-3.59 (m, 1 H), 3.68 (d, J=9Hz, 1H),3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.79-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, 1 H). MS
(DCI/NH3) m/e 605 (M+H)+. Example 358 frans. frans-2-(4-Methoχyphenvπ-4-( 1 .3-benzodioxol-5-vh- 1 -r2- (phthalimido thyll-pyrrolidine-3-carboxylic acid The compound of Example 1 C (250 mg), N-bromoethylphthalimide (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitrile and heated for 2.5 hours at 95 °C Toluene was added, and the mixture was washed with KHCO3 solution. The solution was dried (Na2Sθ4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 mg of an intermediate ethyl ester which was hydrolyzed by the method of Example 1 D to give 130 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) δ 3.12-3.26 (m, 2H), 3.60-3.75 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.55 (m, 1H), 4.69 (d, J=9Hz, 1 H), 4.76- 4.88 (m, 1 H), 5.96 (s, 2H), 6.55 (d, J=8Hz, 1H), 6.60-6.70 (m, 3H), 6.79 (d, J=8Hz, 1 H), 7.05-7.45 (m, 5H), 7.75 (d, J=7Hz, 1 H).
Example 359 frans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxyphenyl . -1 -1 1 (N-f 2- pentvn-N-phenylamino^carbonvnmethvnpyrrolidine-S-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.86-0.98 (m, 6H), 1.17-1.22 (m, 1H), 1.23-1.41 (m, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1 H), 2.83 (m, 1H), 3.10-3.21 (m, 2H), 3.45-3.60 (m, 2H), 3.79 (s, 3H), 3.86 (m, 1H), 4.74 (m, 1 H), 5.91 (m, 2H), 6.73 (dd, J=1.1 , 7.7 Hz, 3H), 6.82 (m, 2H), 7.04- 7.14 (m, 3H), 7.36 (m, 3H). MS (DCl) m/e 545 (M+H+). Anal calcd for
C32H36N2O6 • 0.25 CH3CO2C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C, 70.03; H, 6.54; N, 4.78.
Example 360 trans. frans-4-M .3-Benzodioxol-5-yl ;-2-(4-methoxyphenvπ- 1 -(N- butyl-N-(2-naphthyl ;aminocarbonylmethyl j-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.83 (t, J=7 Hz, 3H), 1.23- 1.39 (m, 4H), 1 .40-1.55 (m, 3H), 2.60-2.72 (m, 2H), 3.00-3.80 (m, 5H),
3.66 (s, 3H), 5.87 (s, 2H), 6.39 (d, J=9 Hz, 2H), 6.74-6.85 (m, 3H), 7.17 (d, J=2 Hz. 1 H), 7.40 (dd, J=8 Hz, 1H). 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1 H). 7.90-8.00 (m, 2H). MS (DCl) m/e 581 (M+H)+. Analysis calcd for C35H36N2O6 • 0.3 H2O: C, 71.73; H, 6.29; N, 4.78. Found: C, 71.74; H, 6.26; N, 4.72.
Example 361 trans. trans-2-( 4-Propoxyphenyl -4-(1.3-benzodioxol-5-yn-1 -r2-(N- propyl-N-n-pentanesulfonylaminoιethyl"|pyrrolidine-3-carboxy ic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 53-54 °C H NMR (CDCI3, 300MHz) δ 0.79 (t, J=7Hz, 3H), 0.89 (t,
Figure imgf000387_0001
3H), 1.03 (t,
J=7Hz, 3H), 1.24-1.34 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (m, 2H), 1.80 (sextet, 2H), 2.23-2.33 (m, 1H), 2.72-2.93 (m, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (m, 2H), 3.42 (d, J=9Hz, 1H), 3.54-3.62 (m, 1H). 3.67 (d, J=9Hz, 1H), 4.90 (t, J=7Hz, 2H), 5.95 (s, 2H), 6.73 (d,
J=8Hz, 1H), 6.85 (d, J=8Hz, 2H), 7.02 (s, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m e 589 (M+H)+.
Example 362 frans. frans-4-M .3-Benzodioxol-5-vn-2-(4-methoxyphenvπ-1 -ff 2- methylindolin-1 -yl ιcarbonvnmethyl .pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ mixture of indole C2 diastereomers, 0.95 (m, 1.5 (CH3 )), 1.05 (d, 6.3H, 1.5 (CH3)), 2.62 (m, 1 H), 3.01 (m, 2H), 3.14-3.25 (m, 1 H), 3.37-3.52 (m, 1.5H), 3.56-3.80 (m,
2H), 3.65 (s, 1.5 (CH3O)), 3.76 (s, 1.5 (CH3O)), 3.93 (m, 0.5H), 4.05-4.13
(m, 0.5H,), 4.42 (m, 0.5H), 4.65-4.74 (m, 1H), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 0.5H), 6.75 (m, 0.5H), 6.85 (m, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.00-7.06 (m, 2H), 7.14 (t, J=7.7 Hz, 1 H), 7.21 (t, J=6.6 Hz, 1 H), 7.38 (m, 2H), 7.99 (m, 1 H). MS (DCl) m/e 515 (M+H+). Anal calcd for C30H30N2O6 •
0.35H2O • 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07. Example 363 trans. frans-4-M .3-Benzodioxol-5-vn-2-f4-methoχyphenvh-1 -(2- hydroxy-3-propylhex-1 -vhpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 1.06 (m, 6H), 1.26-1.60 (m, 9H), 3.16 (dd, J=10.9, 12.6 Hz, 1H), 3.18 (d, J=11 Hz, 1H), 3.44 (d, J=2.0 Hz, 1 H), 3.61 (t, J=1 1 Hz, 1 H), 3.73 (t, J=11.0 Hz, 1 H), 3.85 (m, 1H), 3.96-4.17 (m, 2H), 4.02 (s, 1.5 (CH3O diastereomer)), 4.03 (s, 1.5 (CH3O diastereomer)), 6.15 (s, 2H), 7.01 (d, J=8.1 Hz, 0.5H), 7.00 (d, J=8.1 Hz, 0.5H), 7.10 (m, 1H), 7.23 (m, 3H), 7.77 (m, 2H). MS (DCl.) m/e 484
(M+H+). Anal calcd for C28H37NO6 • 0.33 H3PO4: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.
Example 364 frans. frans-4-M .3-Benzodioxol-5-yn-2-, 4-methoxvphenvl , - 1 -f , (N-(4- heptvh-N-f3.4-dimethoxybenzyπamino)carbonyhmethyπpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 81 :1 mixture of rotamers, 0.61 (t, J=7.1 Hz, 1.5H), 0.72 (7.3, 1.5H), 0.76 (t, J=7.1 , 1.5, 0.83, t, 7.3 Hz,
1.5H), 1.05-1.60 (m, 8H), 2.84-3.10 (m, J=2.5, 3.18, t, 9.7 Hz, 0.5H), 3.41-3.52 (m, 2H), 3.47-3.69 (m, 2H), 3.66 (s, 1.5H), 3.73 (s, 1.5H), 3.77 (s, 1.5H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.86 (d, J=9.8 Hz, 0.5H), 4.19 (d, J=17.7 Hz, 0.5H), 4.29 (d, J=15.2 Hz, 0.5H), 4.40-4.49 (m, 0.5H), 4.47 (d, J=15.3 Hz, 0.5H), 4.60 (d, J=17.6 Hz, 0.5H), 5.93 (m, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.5H), 6.52 (d, J=2.0 Hz, 0.5H), 6.74 (m, 2.5H), 6.80 (s, 1 H), 6.83- 6.88 (m, 1 H), 6.92 (rn, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1 H), 7.19 (m, 1 H), 7.36 (m, 1 H). MS (DCl) m/e 647 (M+H+). Anal calcd for C37H46N2O8: C, 68.71 ; H, 7.17; N, 4.33. Found: C, 68.41 ; H, 7.26; N, 4.1 1.
Example 365 fraπs. frans-4-f 1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyn-1 - ( (indolin- 1 -vhcarbonynmethyl .pyrrolidine-S-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ2.97 (dd, J=8.1 , 9.5 Hz, 1 H), 3.10 (t, J=8.1 Hz, 2H), 3.16-3.22 (m, 2H), 3.51-3.68 (m, 3H), 3.73 (m, 3H), 3.83-4.05 (m, 3H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1 H), 6.86 (m, 3H), 6.99 (dt, J=1.1 , 7.4 Hz, 1 H), 7.08 (d, J=0.7 Hz, 1 H), 7.1 1 (m, 1 H), 7.18 (d, J=7.1 Hz, 1 H), 7.38 (d, J=8.5 Hz, 2H), 8.02 (8.1 , 1 H). MS (Cl.) m/e 501 (M+H+). Anal calcd for C29H28N2O6 • 0.5 H2O • 0.15 CH3CO2C2H5: C, 68.01 ; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.
Example 366 trans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxyphenvn-1 -(N- butyl-N-(2-chlorophenyl ιaminocarbonylmethyhpyrrolidine-3- carboxvlic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δθ.89 (dt, J=7 Hz, 3H), 1.23- 1.51 (m, 4H), 2.52-4.00 (m, 8H), 3.78 (d, J=6 Hz, 3H), 5.92 (d, J=6 Hz, 2H), 6.70-6.87 (m, 4H), 7.02-7.21 (m, 4H), 7.27-7.52 (m, 3H). MS (DCl) m/e 565 (M+H)+. Analysis calcd for C31 H32N2O6CI • O.6H2O: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.
Example 367 frans. frans-2-(4-Methoχphenyh-4-( 1 .3-benzodioxol-5-vh-1 -
(3.4.5-trimethoxybenzvπpyrrolidine-3-carboxylic acid The compound resulting from Example 1C (0.25 g) was reacted with 0.169 g of 3,4,5-trimethoxybenzyl chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature. The resulting ester was isolated and then hydrolyzed by the method of Example 1 D to give 0.193 g of the title compound, m.p. 108-110 °C 1 H NMR (300 MHz, CDCI3) δ2.75 (t, J=9Hz, 1 H), 2.95-3.05 (m, 2H), 3.20 (d, J=11 Hz, 1 H), 3.45-3.55 (m, 1 H), 3.7-3.8 (m, 2H), 3.84 (s, 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 (s, 2H), 6.70 (d, J=8Hz, 1 H), 6.30-6.35 (m, 1 H), 6.90 (d, J=9Hz, 2H), 7.13 (d, J=2Hz, 1 H), 7.43 (d, J=9Hz, 2H). Example 368 frans. frans-4-M .3-Benzodioxol-5-yπ-2-(4-methoxyphenvπ- 1 -( N- butyl-N-(3-chlorophenyhaminocarbonylmethvπ-pyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.89 (t, J=7 Hz, 3H), 1.20- 1.42 (m, 4H). 3.42-3.87 (m, 9H), 3.9 (s, 3H), 5.96 (s, 2H), 6.75 (7.10, J=m Hz. 7H), 7.33-7.50 (m, 4H). MS (Cl.) m/e 565(M+H). Analysis calcd for C31 H33N2O6CM .OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41 ; H, 4.99; N, 4.08.
Example 369 frans. frans-2-(4-Methoxphenvn-4-M .3-benzodioxol-5-vn-1 -f2-fdi-n- butylamino*)pyrimidin-4-yπpyrrolidine-3-carboxylic acid The compound resulting from Example 1 C (0.25 g) was reacted with 0.1 1 g of 2,4-dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-methoxphenyl)-4-(1 ,3- benzodioxol-5-yl)- 1 -(2-chloro-4-pyrimidyl)-py rrolidi ne-3- carboxylate. This compound was reacted with 1 mL of dibutylamine in 2 mL of toluene at 125 °C for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example 1 D to give 0.142 g of the title comopund as a white powder. 1 H NMR (300 MHz, CDCI3) δ0.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H). 3.05 (m, 1 H), 3.3-3.5 (br, 2H), 3.55-3.67 (m, 2H), 3.75 (s, 3H), 4.6 (br, 1 H), 5.2 (br, 1 H), 5.45 (br, 1 H), 5.87 (s, 2H), 6.3 (br, 1 H), 6.67 (d, J=8Hz, 1 H), 6.7-6.85 (m, 4H), 7.10 (d, J=9Hz, 2H).
Example 370 trans. trans-Λ-i .3-Benzodioxol-5-vh-2-(4-methoxyphenyn- 1 -(^N-(2- methylbut-2-yl ;-N-phenylamino^carbonvnmethyl ,pvrrolidine-3- carboxvlic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.90 (t, J=7.5 Hz, 3H), 1.12 (s, 3H), 1.14 (s, 3H), 2.06 (q, J=7.5 Hz, 2H), 2.73 (d, J=15.3 Hz, 1 H), 2.91
(t, J=9.5 Hz, 1 H), 3.1 1 (d, J=15.6 Hz, 1 H), 3.21 (t, J=8.8 Hz, 1 H), 3.50- 3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J=10.2 Hz, 1 H), 5.91 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (m, 3H), 6.93 (m, 1 H), 6.98 (m, 1 H), 7.03 (d. J=1.7 Hz, 1 H), 7.17 (m, 2H), 7.36 (m, 3H). MS (DCl) m/e 545 (M+H+). Anal calcd for C32H36 2O6: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 4.97.
Example 371 frans. frans-2-(4-Ethylphenyn-4-f5-indanyn-1 -(N.N-di(n- butyπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example "1 , the title compound was prepared. 1 H (300MHz, CDCI3) δ 7.25 (3H, m), 7.21 (1 H, d, 3Hz),
7.17 (3H, m), 3.80 (1 H, d, 10Hz), 3.65 (1 H, ddd, 6, 5, 3Hz), 3.4 (4H, m), 3.10 (2H, m). 2.98 (2H, m), 2.88 (5H, m), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, m), 1.42 (2H, m), 1.32 (1 H, m), 1.21 (3H, t, 7Hz), 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCl, NH3) m/e 505 (M+H+). Anal calcd for C32H44N2O3: C, 76.15; H, 8.79; N 5.55. Found: C, 75.96; H, 8.75; N, 5.36.
Example 372 trans, rans-2-f 3.4-Difluorophenvn-4-f 1 .3-benzodioxol-5-vn-1 -(N .N- di(n-butyhaminocarbonylmethyn-pyrrolidine-3-carboxylic add
Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid, m.p. 62-63 °C "Η NMR (CDCI3, 300 MHz), δ 0.83 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.13 (sextet, J=7Hz, 2H), 1.20-1.32 (m,3H), 1.36-1.49 (m,3H), 2.85-2.93
(m,2H), 2.98-3.23 (m, 4H), 3.36-3.45 (m, 3H), 3.58-3.66 (m 1H), 3.94 (d, J=8Hz, 1 H), 5.93 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 6.84 (dd, J=1Hz, J=7.5Hz, 1 H), 6.98 (d, J=7.5Hz, 1 H), 7.08-7.15 (m, 2H), 7.22-7.28 (m, 1H). MS (CDI/NH3) m/e517 (M+H)+.
Example 373 frans. frans-2-f 3.4-Dif luorophenyl ;-4-(1 .3-benzodioxol-5-yn- 1 -r2-(N- propyl-N-n-pentanesulfonylamino thvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid, m.p. 71-72 °C 1 H NMR (CDCI3, 300 MHz) δ 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.25-1.38 (m, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (m, 1H), 2.72-2.95 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.34 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1 H), 3.53-3.60 (m, 1H), 3.71 (d, J=9Hz, 1 H), 5.96 (s, 2H), 6.75 (d, J=9Hz, 1 H), 3.82 (dd„ J=2Hz, J=9Hz, 1H), 5.96 (d, J=2Hz, 5 1H), 7.09-7.18 (m, 2H), 7.23-7.34 (m, 1H). MS (CDI/NH3) m/e567
(M+H)+.
Example 374 frans.frans-4-f 1 .3-Benzodioxol-5-vn-2-(ethoxymethyn-1 -f( (N.N-di(n- •10 butynaminocarbonylmethyn-pyrrolldine-3--carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.53. H NMR (CDCI3, 300 MHz, rotameric forms) δ 0.70 (t, J=7Hz), 0.80 (t, J=7Hz) and 0.96-1.04 (m, 6H total), 1.04-1.75 (m, 11 H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 15 2.80-3.08 (m, 2H total), 3.10-3.82 (br m, 12H), 4.03 (m) and 4.22-4.45 (br m, 2H total), 5.90 (s) and 5.91 (s, 2H total), 6.65-6.84 (m) and 6.93 (m) and 6.99 (m, 3H total). MS (FAB) m/e 463 (M+H)+. Anal calcd for C25H38N2θ6 - 1.5 H2O: C, 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62. 20
Example 375 frans. frans-4-M .3-Benzodioxol-5-vn-2-fn-butvn- 1 -(,N . N- diι n-butynaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound 25 was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2Cl2)
Rf = 0.37. H NMR (CDCI3, 300 MHz, rotameric forms) o 0.71 (t, J=7Hz) and 0.77-1.05 (m, 9H total), 1.05-1.20 (m, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (m, 1 H), 2.87-3.00 (m, 1 H), 3.05-3.60 (m, 5H), 3.60-3.80 (br m, 2H), 3.88-4.05 (br m, 1H), 4.28 (br d, J=15Hz, 1 H total), 5.90 (s) and 30 5.92 (s, 2H total), 6.67-6.82 (m, 3H total). MS (FAB) m/e 461 (M+H)+.
Anal calcd for C26H40N2O5 • 1.75 H2O: C, 63.45; H, 8.90; N, 5.69. Found: C, 63.18; H, 8.22; N, 5.60. Example 376 frans. frans-4-M .3-Benzodioxol-5-yl ι-2-(2-methylbutyn-1 -f N. N-di(n- butyπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as a colorless glass. TLC (10% MeOH- CH2CI2) Rf = 0.49. 1 H NMR (CDCI3, 300 MHz, rotameric forms and mixture of diastereomers) δ 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, 1H), 2.87-3.01 (br m, 1H), 3.06- 3.82 (br m, 7H), 3.90-4.40 (br m, 2H), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+.
Exam le 377, trans. frans-4-M .3-Benzodioxol-5-yl ,-2-(3-methylbutyn-1 -(N.N-di n- butyl ιaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.41. H NMR (CDCI3, 300 MHz, rotameric forms) δ 0.73 (t, J=7Hz) and 0.77-1.05 (m, 12H total), 1.07-1.75 (m, approx. 14H plus H2O), 2.48-2.63 (m, 1 H), 2.87-3.05 (m,
1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, J=15Hz, 1H), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (m, 3H total). MS
(FAB) m/e 475 (M+H)+.
Example 378 frans.frans-2-(4-Methoxyphenyn-4-π .3-benzodioxol-5-vn-1 -r2-(N- propyl-N-ffN-methyl-N-propylamino ιsulfonvhamino^ethyllpyrrolidine-
3-carboxyiic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 58-59 °C. 1H NMR (CDCI3, 300MHz) δ 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (m, 4H), 2.22-2.30 (m, 1 H), 2.62 (s, 3H), 2.68-2.78 (m, 1 H), 2.84-3.03 (m, 5H), 3.08-3.31 (m, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (m, 1 H), 3.63 (d, J=9Hz, 1 H),3.79 (s, 3H), 5.95 (s, 2H), 3.73 (d, J=8Hz, 1 H), 6.83 (dd, J=2Hz, J=8Hz, 1 H), 3.87 (d, J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 576 (M+H)+. Example 379 frans. frans-2.4-Di(3.4-difluorophenvn- 1 -(N.N-difn- butyπaminocarbonylmethyl ι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300MHz, CDCI3 ) δ 7.35 (2H, m), 7.18 (4H, m), 4.87 (1 H, d, J=12), 4.00-3.60 (5H, m), 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 1.29 (4H, m), 1.15 (2H, m), 0.91 (3H, t, J=9), 0.83 (3H, t, J=9). MS (DCI/NH3) m/e 509 (M+H+). Anal calcd for C27H32F4N2θ3- 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.
Example 380 frar7g.frang-4-(3,4-Pimgthylphgnyl)-2-(4-metho)c;yphenyn-i-(N,N-di(n- butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ 7.43 (2H, d, J=9), 7.25 (1 H, bs), 7.18 (1 H, dd, J=8, 3), 7.1 1 (1 H, d, J=9), 6.90 (2H, d, J=10), 5.48 (1 H, d, J=12), 4.26 (1 H, d, J=18), 4.16 (2H, m), 3.83 (2H, m), 3.81 (3H, s), 3.56 (1 H, bd, J=18), 3.37 (1H, m), 3.20 (1 H, m), 2.96 (2H, m), 2.24 (3H, s), 2.22 (3H, s), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 495 (M+H+). Anal calcd for C30H42N2O4- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.
Example 381 trans, frans-2.4-Dif 3-fluoro-4-methoxyρhenyπ- 1 -(N .N-di(n- butvnaminocarbonv methvn-pyrrolidine-3-carboxyrιc acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300MHz, CDCI3 ) δ 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (1 H, m), 4.26 (1 H, m), 4.16 (2H, m), 3.83 (2H, m), 3.87 (6H, s), 3.56 (1 H, m), 3.37 (1 H, m), 3.20 (1 H, m), 2.96 (2H, m), 1 .47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 533 (M+H+). Anal calcd for C29H3βF2N2θ5- 0.75 H2O: C,
63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99. Example 382 frans. frans-4-M .3-Benzodioxol-5-yn-2-(4-methoxyphenyl ι- 1 -f((N-f 2- pentyl ι.N-f3-methylphenyl ιamino jcarbonvπmethyπpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.90 (m, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.13-1.37 (m, 4H), 2.30 (s, 3H), 2.34 (s (CH3 rotamer)), 2.73- 2.91 (m, 2H), 3.17-3.26 (m, 2H), 3.32-3.62 (m, 2H), 3.77-4.08 (m, 1 H), 3.80 (s, 3H), 4.71 (m, 1 H), 5.92 (m, 2H), 6.61 -6.84 (m, 6H), 7.04-7.16 (m, 3H), 7.23-7.29 (m, 2H). MS (DCl) m/e 559 (MXH+). Anal calcd for C33H38N2O6 • 0.35 H2O • 0.05 CH3CO2C2H5: C 70.03; H, 6.92; N, 4.92. Found: C, 70.08; H, 6.82; N, 4.95.
Example 383 trans. trans-4-( 1 .3-Benzodioxol-5-vn-2-.4-methoxyphenvn- 1 -(N- butyl-N-M -naphthvnaminocarbonylmethvnpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20- 1.40 (m, 2H), 1.40-1.60 (m, 2H), 2.42-2.80 (m, 2H), 2.85-4.00 (m, 6H),
3.77 (d, J=1.5 Hz, 3H), 4.05-4.20 (m, 1 H), 5.94 (d, J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1 H), 6.70-6.85 (m, 4H), 6.95-7.02 (m, 2H), 7.17 (dd, 8H, 1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m, 4H), 7.87-8.00 (m, 2H). MS (E.S.I.) m/e (M+H) 581. Analysis calcd for C35H36N2O6 • 1.4 H2O: C, 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.
Example 384 frans. frans-2-f4-Methoxyphenyn-4-M .3-benzodioxol-5-vn-1 -r2-( N- phenyl-N-n-hexanesulfonylamino)ethyl1pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid, m.p. 67-68 °C 1 H NMR (CD3OD, 300 MHz) δ 0.88 (t, J=7Hz, 3H), 1.25-1.40 (m, 6H), 1.73
(quintet, J=7Hz, 2H), 2.13-2.23 (m, 1 H), 2.64-2.88 (m, 3H), 3.02 (sextet, J=8Hz, 2H), 3.44-3.53 (m, 2H), 3.58 (d, J=9Hz, 1 H), 3.56-3.75 (m, 1H), 3.78 (s, 3H), 3.88-3.98 (m, 1 H), 5.93 (s, 2H), 6.72 (d, J=9Hz, 1 H), 5.78- 5.84 (m, 3H), 6.96 (d, J=2Hz, 1 H), 7.20 (d, J=9Hz, 2H), 7.27-7.36 (m, 5H). MS (DCI/NH3) m/e 609 (M+H)+.
Example 385 frans. frans-4-(1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyn- 1 -r2- methyl- 1 .2.3.4-tetrahydroquinolin-1 -yncarbonylmethyhpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 1.03 (m, 3H), 1.10-1.45 (m, 1 H), 2.10-2.85 (m, 4H), 2.90-4.00 (m, 7H), 3.76 (s i .5H), 3.77 (s, 1.5H, isomer), 5.90 (m, 2H), 6.70-7.40 (m, 11H). MS (DCl) m/e 529 (M+H)+. Analysis calcd for C31 H32N2O6 • 0.3 H2O: C, 69.73; H, 6.15; N, 5.25. Found: C, 69.74; H, 6.10; N, 5.01.
Example 386 trans. frans-4-f 1 .3-Benzodioxol-5-vπ-2-(4-methoxyphenvπ- 1 -(3- butyl-hept-2-en-1 -vπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.86 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.20-1.41 (m, 8H), 1.95-2.06 (m, 4H), 3.24 (d. J=11.0
Hz, 1 H), 3.51 -3.59 (m, 3H), 3.60-3.71 (m, 1 H), 3.77-3.84 (m, 1 H), 3.81 (s, 3H), 4.45 (d, J=1 1.0 Hz, 1H), 5.52 (t, J=7.4 Hz, 1 H), 5.93 (s, 2H), 6.77 (d, J=8.1 Hz, 1H), 6.87 (dd, J=1.8, 8.1 Hz, 1H), 6.99 (m, 3H), 7.46 (m, 2H). MS (DCl) m/e 494 (M+H+). Anal calcd for C30H39NO5: C, 72.99; H, 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.
Example 387 trans. frans-2-(3-Fluoro-4-methoxyphenyn-4-( 1 .3-benzodioxol-5-yl)- 1 -'2-(N -propyl-N-r-hexanesulf on ylaminotethyllpy rrolidi ne-3- carboxylic acid
Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 63-65 °C. 1 H NMR (CDCI3, 300MHz) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=6Hz, 3H), 1 .23-1.47 (m,
6H), 1.44 (sextet, J=7Hz, 2H), 1 .71 (quintet, J=6Hz, 2H), 2.24-2.34 (m, 1 H), 2.70-2.93 (m, 5H), 2.96-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd,
J-?Hτ. .l=9Hz. 1 H). 3.52-3.59 (m, 1 H), 3.66 (d, J=9Hz, 1 H), 3.87 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.42 (t, J=8Hz, 1H),
6.96 (s, 1H), 7.12 (d, J=9Hz, 1H), 7.17 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+.
5 Example 388 f rans.frans-4-M.3-Benzodioxol-5-vh-2-(4-methoxyphenvn-1-ff 3- pyridvπmethvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 2.87 (m, 2H), 3.04 (dd, J=3.2, 0 9.7 Hz, 1H), 3.21 (d, J=13.7 Hz, 1H), 3.51 (m, 1H)T3.76-3.85 (m, 2H), 3.79 (s, 3H), 5.90 (m, 2H), 6.71 (m, 1H), 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, 1H), 8.39 (m, 1H), 8.46 (dd, J=1.4 Hz, 1H). Anal calcd for C25H24N2O5 • 0.70 H2O • 0.05 CH3CO2C2H5: C, 67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90. 5
Example 389 frans. frans- 2 -fn-Hexyn-4-M.3-benzodioxol-5-vh-1-fN.N-di(n- butylιaminocarbonylmethvn-pyrrolidine-3-carboxylic acicj
Using the procedures described in Example 1, the title compound 0 was prepared. 1H NMR (CDCI3, 300 MHz) δ 0.82-1.00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H), 1.70-1.90 (br m, 2H), 3.10-3.46 (m, 6H), 3.65 (t, J=10.8 Hz, 1H), 3.76 (t, J=11.0 Hz, 1H), 3.92-4.06 (m, 2H), 4.14- 4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS(DCI/NH3) m/e 489 (M+H)+. Anal calcd E for C-28H44N2O5 • 0.9 TFA: C, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N, 4.61.
Example 390 frans. frans-4-M.3-Benzodioxol-5-yh-2-f4-methoxyphenyl;-1-fffN-f 2- 0 pentvn-N-(4-fluoro-3- methylphenvnamino^carbonvπmethvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.92 (m, 3H), 0.97 (t, J=7.1 Hz, 3H), 1.13-1.40 (m, 4H), 2.22 (m, 3H), 2.58-2.74 (m, 1H), 2.78-2.87 5 (m, 1H), 3.09-3.25 (m, 2H), 3.39-3.60 (m, 2H), 3.70-3.90 (m, 1H), 3.80 (s, 3H), 4.70 (m, 1H), 5.93 (m, 2H), 6.70-6.76 (m, 1H), 6.75 (dd, J=1.4, 8.1 Hz, 1 H), 6.80-6.94 (m, 4H), 6.96-7.13 (m, 4H). MS (DCl.) m/e 577 (M+H+). Anal calcd for C33H37 N2O6 • 0.25 H2O: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21 ; H, 6.46; N, 4.74.
s Example 391 fraπs. frans-4-( 1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyn-1 -((2- pyridyl)methyl)pyrrQlidine-3-carbQxylic add Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 2.97 (dd, J=7.9, 9.7 Hz, 1 H), 0 3.04 (t, J=9.6 Hz, 1H), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 (d, J=14.0 Hz, 1 H),
3.59 (m, 1H), 3.78 (s, 3H), 3.96 (d, J=9.9 Hz, 1 H), 3.97 (d, J=13.6 Hz, 1 H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1 H), 6.83 (dd, J=1.7, 7.9 Hz, 1 H), 6.92 (m, 2H), 6.96 (d, J=1.8 Hz, 1 H), 7.28 (m, 1H), 7.44 (m, 2H), 7.53 (d, J=8.1 Hz, 1 H), 7.80 (dt, J=1.8, 7.7 Hz, 1 H), 8.42 (m, 1H). MS (DCl) m/e 433 (M+H+). 5 Anal calcd for C25H24N2O5 • 0.35 H2O: C, 68.43; H, 5.67; N, 6.38. Found: C, 68.44; H, 5.61 ; N, 6.24.
Example 392 trans. frans-2-(3-PhenylpropyO-4-( 1 .3-benzodioxol-5-vO-1 -(N.N- 0 di(n-butyπaminocarbonylmethvB-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H NMR (CDCI3, 300 MHz) δ 0.89-0.97 (m, 6H), 1.22-1.36 (m, 4H), 1.41 -1.55 (m, 4H), 1.63-1.95 (m, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (m, 7H), 3.53-3.60 (m, 2H), 3.65-3.76 (m, 1 H), 3.82-3.90 5 (m, 1 H), 3.96-4.10 (m, 1 H), 5.92 (s, 2H), 6.71 (d, J=8.1 Hz, 1H), 6.77 (dd, J=8.1 , 1.5 Hz, 1 H), 6.86(d, J=1.2 Hz, 1 H), 7.10-7.28 (m, 5H). MS(DCI/NH3) m/e 523 (M+H)+. Anal calcd for C31 H42N2O5 • 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.
0 Example 393 frans-frans-2-f 4- Methoxy-3-f luo rophenyl ; -4- (7-methoxy- 1 .3- benzodioxol-5-ylb 1 -(N . N-di(n-butvπaminocarbonylmethvπ- pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound 5 was prepared and isolated as a white solid, m.p. 115-117 °C. "Η NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.85 (d, J=13Hz, 1 H), 2.90-3.17 (m, 5H), 3.20-3.35 (m, 1 H), 3.35- 3.50 (m, 3H), 3.55-3.65 (m, 1 H), 3.84 (d, J=10Hz, 1 H), 3.87 (s, 3H), 3.92 (s, 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, 1 H), 6.90 (t, J=8Hz, 1 H), 7.05-7.20 (m, 2H).
5
Example 394 frans-f rans-2-(1.4-Benzodioxan-6-yπ-4-(7-methoxy-1 .3-benzodioxol-
5-vπ- 1 -(N. N-di(n-butvπaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid ^ i o Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid, m.p. 107-110 °C H NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50
(m, 8H), 2.75 (d, J=13Hz, 1 H), 2.90-3.12 (m, 4H), 3.32-3.60 (m, 5H), 3.69 (d, J= 8Hz, 1 H), 3.90 (s, 3H), 4.23 (s, 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 15 (s, 1 H), 6.70 (s, 1H), 6.78-6.93 (m ,3H).
Example 395 trans. frans-4-(1 .3-Benzodioxol-5-yl ι-2-(4-methoxyphenyl ;- 1 -(3- butyl-2-fluoro-hept-2-en- 1 -vhpyrrolidine-3-carboxylic acid 20 Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.84 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H), 1.16-1.37 (m, 8H), 1.83 (t, J=8.5 Hz, 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, J=9.3 Hz, 1 H), 3.32-3.42 (m, 2H), 3.50 (m, 1H), 3.71 (d, J=9.2 Hz, 1 H), 3.78 (s, 3H), 5.91 (m, 2H), 6.72 (d, J=7.8 25 Hz, 1 H), 6.83 (dd, J=1.7, 8.1 Hz, 1H), 6.90 (m, 2H), 7.02 (d, J=1.7 Hz, 1 H), 7.34 (m, 2H). MS (DCl) m/e 512 (M+H+). Anal calcd for C30H38FNO5: C, 70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.
Example 396 30 frans.frans-2-(3-Fluoro-4-ethoxyphenvn-4-( 1 .3-benzodioxol-5-vn-1 -
*2-(N-propy!-N-n-pentanesulfonylamino ,ethvnpyrro!idine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 65-66 °C 1 H NMR 35 (CDCI3, 300 MHz) δ 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.26-1.36
(m, 4H), 1.41 -1.52 (m, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (m, 1 H), 2.69-2.96 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.37 (m, 2H), 3.43 (d, J=9Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J=9Hz, 1H), 4.08 (q, J=7Hz, 2H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (s, 1H), 7.07 (d, J=8Hz, 1H), 7.15 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+.
Example 397 frans. frans-2-(4-Methoxy-3-fluorophenyl ι-4-(7-methoxy-1 .3-
Figure imgf000400_0001
propylaminoι arbonylmethvπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared and isolated as a white solid, m.p. 118-120 °C "Η NMR (300 MHz, CDCI3) δ 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (m, 8H),
2.80-3.50 (m, 9H), 3.55-3.65 (m, 1H), 3.82 (d, J= 10Hz, 1H), 3.85 (s, 3H), 3.92 (s, 3H), 5.96 (s, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.90 (t, J=8Hz, 1H),
7.08-7.22 (m, 2H).
Example 398 frans. fraπs-4-( 1 .3-benzodioxol-5-yl 1-2- (4-methoχyphenvh-1 -(N- but yl-N-(4-chlo rophenyh aminocarbonyl methvhp yrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20- 1.50 (m, 4H), 2.66-4.00 (m, 9H), 3.81 (s, 3H), 5.95 (s, 2H), 6.77 (d, J=7 Hz, 1H), 6.85 (d, J=8 Hz, 3H), 7.05 (m, 5H), 7.33-7.42 (m, 2H). MS (Cl,) m/e 565 (M+H). Analysis calcd for C31 H33N2O6CI • 0.25 H3PO4: C 63.16; H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53.
Example 399 frans. frans-4-( 1 .3-Benzodioxol-5-vn-2-(4-methoxyphenvn- 1 -(4- methyl- 1 .2.3.4-tetrahydroαuinolin-1 -yl )Carbonylmethyl .pyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 1.27 (d, J=7 Hz, 1.5H), 1.28 (d, 7H, 1.5-diastereomer), 1.39-1.55 (m, 1 H), 2.02-2.15 (m, 1 H), 2.60-
3.25 (m, 5H), 3.33-4.00 (m, 5H), 3.78 s, 3H), 5.92 (ϋ, J=3 Hz, 2! !), £.73 (dd, J=8 Hz, 1H), 6.75-6.90 (m, 3H), 6.91-7.35 (m, 7H). MS (DCl) m/e 529 (M+H)+. Analysis calcd for C31H32N2O6: C, 70.44; H, 6.10; N, 5.30. Found: C, 70.16; H, 6.04; N, 5.04.
Example 400 frans. fraπs-2-(3-Fluoro-4-methoxyphenyll-4-(1.3-benzodioxol-5-ylι-
1-r2-(N-propyl-N-(2-(piperidin-1- vnethanesulfonylamino thyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p.95-96 °C "Η NMR
(CDCI3, 300MHz) δ 0.82 (t, J=7Hz, 3H), 1.43-1.55 (m, 4H), 1.63-1.72 (m,
4H), 2.29-2.38 (m, 1H), 2.64-2.78 (m, 5H), 2.87 (t, J=8Hz, 1H), 2.95-3.04 (m, 5H), 3.20-3.30 (m, 1H), 3.32-3.43 (m, 4H), 3.54-3.63 (m, 1H), 3.78 (d, J=8Hz, 1H), 3.87 (s, 3H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.88 (t, J=8Hz, 1H), 6.94 (d, J=2Hz, 1H), 7.08-7.20
(m, 2H). MS (DCI/NH3) m/e 620 (M+H)+.
Example 401 trans. trans- 2 -(n-Heptvh-4-M .3-benzodioxol-5-yh-1 -(N.N-di(n- butyl )aminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3, 300 MHz) δ 0.83-0.98 (s, 9H), 1.18-1.40 (m, 14H), 1.44-1.60 (m, 4H), 1.72-1.96 (br m, 2H), 3.12-3.45 (m, 6H), 3.65 (t, J = 10.5 Hz, 1H), 3.76 (t, J = 11.2 1H), 3.90-4.06 (m, 2H), 4.13- 4.33 (m, 2H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 7.8, 1.7
Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS(DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N2O5 • 0.75 TFA: C, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.
Example 402 frans.frans-4-(1.3-Benzodioxol-5-vn-2-(4-methoxyphenvh-1-(3- methyl-1 ^.S^-tetrahvdroαuinolin-l-vπcarbonylmethvhpyrrolidine-S- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) δ 0.99 (d, 1.5H), 1.03 (d, J=6
Hz, 1.5H, second diastereomer), 2.60-4.00m (12), 3.78 (s, 1.5H), 3.79 (s, 1.5H, second diastereomer), 5.92 (s, 1H), 5.93 (s, 1H, diastereomer), 6.65-7.40 (m, 11H). MS (DCl) m/e 529 (M+H)+. Analysis calcd for C31H32N206- O.8H2O: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 6.10; N, 5.30.
Example 4Q3 frang,frang-4-(1,3-BgnzQdiQxol-5-yl)-2-(4-met <->xyp epyl)-l-(N- butyl-N-(4-fluorophenyhaminocarbonylmethvhpyrrolidine-3- carboxylic acid Using the procedures described in ExampleX, the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.2-1.47 (m, 4H), 2.7 (d, J=12 Hz, 1H), 2.80 (t, J=9 Hz, 1H), 3.09 (t, J=9 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.47 (m, 1H), 3.49-3.65 (m, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 (s, 3H), 5.94 (s, 2H), 6.72-6.86 (m, 4H), 7.00-7.15 (m, 7H). MS (DCl) m/e 549 (M+H)+. Analysis calcd for C31H33N2O6F • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.
Example 404 trans, frans-1 -(N-Butyl-N-(3-methylphenvπaminocarbonylmethvh-2- (4-methoxyphenvπ-4-(5-benzofuranvπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3) δ 7.66 (1H, bs), 7.60 (1H, d, J=3Hz), 7.45 (2H, s), 7.15 (4H, m), 6.75 (5H, m), 3.96 (1H, d, =10Hz), 3.78 (3H, s), 3.74 (1H, m), 3.59 (3H, m), 3.21 (1H, t, J=9Hz), 3.19 (1H, d, J=16Hz), 2.92 (1H, t, J=9Hz), 2.70 (1H, d, J=16Hz), 2.29 (3H, s),
1.41 (2H, m), 1.24 (2H, m), 0.85 (3H, t, J=7Hz). MS (DCl, NH3) m/e 541
(M+H+). Anal, calcd for C33H34N2O • 1 H2O: C, 71.21; H, 6.52; N 5.03. Found: C, 71.31; H, 6.30; N, 4.98.
Example 405 frans. frans-1 -(N-Butyl-N-(3-methylPhenyl,aminocarbonylmethvn-2- (4-fluorophenvπ-4-(5-benzofuranvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz. CDCI3) δ 7.67 (1H, bs), 7.60 (1H, d, J=3Hz), 7.45 (2H, m). 7.18 (3H, m), 7.12 (1H. d, J=7Hz), 6.93 (2H, m),
C.7C (1H, d, J-3H.Z), 6.™ (?H. bd).4.02 (1H, m), 3.77 (1H, m), 3.59 (3H, m), 3.29 (1 H, m), 3.19 (1 H, m), 2.94 (1 H, m), 2.71 (1 H, m), 2.30 (3H, s), 1.45 (2H, m), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, =7Hz). MS (DCl, NH3) m/e 529 (M+H+). Anal, calcd for C33H34N2O5 • 0.2 HOAc: C,
71.98; H, 6.30; N 5.18. Found : C, 71.68; H, 5.89; N, 5.25.
Example 406 frans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxvphenvn- 1 -(( N . N- (di-(3-methylphenyl ιamino)carbonyl , methyl ιpyrrolidine-3-carboxylic acid Using the procedures described in Example A the title compound was prepared. H NMR (300 MHz, CD3OD) δ 2.27 (s, 6H), 2.81 (dd, J=8.1 , 9.5 Hz, 1 H), 2.98 (d, J=15.3 Hz, 1 H), 3.20 (t, J=16.6 Hz, 1 H), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, J=9.5 Hz, 1 H), 5.91 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.85 (m, 3H), 6.95 (m, 4H), 7.05 (d, J=1.7 Hz, 1 H), 7.06-7.24 (m, 6H). MS (DCl) m e 579 (M+H+). Anal calcd for C35H34N2O6 • 0.15 H2O • 0.20 CH3CO2C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81 ; H, 5.79; N, 4.51.
Example 407 frans. frans-4-( 1 .2-Dihvdrobenzof uran-5-yl )-2-(4-methoχyphenvπ- 1 -
(((N-butyl-N-(3-methylphenyl ιamino /carbon vπmethvπpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H (300MHz, CDCI3 ) δ 7.73 (2H, m), 7.40-7.10 (4H, m), 6.92 (2H, m), 6.72 (2H, d, J=9), 6.63 (1 H, m), 5.40 (1 H, m), 4.55 (2H, t,
J=9), 4.30-4.10 (3H, m), 3.84 (3H, s), 3.82 (1 H, m), 3.65 (1 H, m), 3.39 (1 H, m), 3.21 (2H, t, J=9), 3.10-2.90 (2H, m), 2.26 (3H, s), 1.55 (2H, m), 1.45 (2H, m), 0.92 (3H, t, J=9). MS (DCI/NH3) m/e 543 (M+H+). Anal calcd for C33H38N2O5 • 0.65 H2O: C, 71.50; H, 7.15; N, 5.05 . Found: C, 71.47; H, 6.96; N, 4.83. Examole 408 trans. frans-2-(3-Fluoro-4-methoxyphenyh-4-( 1 .3-benzodioxol-5-yl ι-
1 -f2-(N-propyl-N-r2-(N.N- dimethylamino')1ethanesulfonylaminθ)ethyπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 81-82 °C "Η NMR (CDCI3, 300 MHz) δ 0.80 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15-
2.24 (m, 1H), 2.36 (s, 6H), 2.66-2.76 (m, 1H), 2.83-3.04 (m, 6H), 3.18- 3.41 (m, 5H), 3.55-3.63 (m, 1H), 3.72 (d, J=8Hz, 1Η), 3.85 (s, 3H), 5.90 (d, J=6Hz, 2H), 6.67 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.84 (t, J=8Hz, 1 H), 7.94 (d, J=2Hz, 1H), 7.09 (d, J=8Hz, 1H), 7.20 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 580 (M+H)+.
Example 409 frans. frans-1 -(N .N-Dibutylaminocarbonylmethyl ι-2-(4-fluorophenyn- 4-(5-benzofuranyl ι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 7.88 (1 H, bs), 7.80 (2H, m), 7.61 (1 H, d, J=3Hz), 7.55 (1H, bd, J=8Hz), 7.46 (1 H, d, J=8Hz), 7.07 (2H, t, J=8Hz), 6.76 (1 H, d, J=3Hz), 5.53 (1 H, bd, J=11 Hz), 4.18 (2H, m), 3.91 (3H, m), 3.55 (1 H, d, J=16Hz), 3.30 (3H, m), 3.12 (1 H, dd, J=10&9Hz), 2.95 (1 H, m), 1.51 (2H, m), 1.31 (4H, m), 1.12 (2H, m), 0.92 (3H, m), 0.83 (3H, t, J=7Hz). MS m/e (DCl, NH3) 595 (M+H+).
Example 410 trans. trans-A-{ \ .2-Dihvdrobenzofuran-5-vn-2-(4-ethylphenvπ-1 -(( (N- butyl-N-(3-methylphenvπamino carbonvπ methyl) pyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.35 (2H, m), 7.20-7.00 (7H, m). 6.70 (2H, d, J=9). 5.38 (1 H. m). 4.55 (2H. t, J=9). 4.05 (1 H, m), 3.64 (2H, m), 3.45 (1 H, m), 3.21 (2H, t. J=9), 2.95 (1 H, m), 2.75 (1 H, m), 2.63 (2H, q. J=8), 2.38 (2H, m), 2.27 (3H. s), 1.43 (2H, m), 1.30 (2H, m), 1.22 (3H, t, J=9), 0.89 (3H, t, J=9). MS (DCI/NH3) m/e 541 (M+H+). Anal calcd for C34H40N2O4 • 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11 ; H, 7.06; N, 4.80.
Example 411 frans. frans-4-(1 .2-Dihvdrobenzof uran-5-yH-2-(4-f luorophenvh- 1 -
(N.N-di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ 7.40 (2H, m), 7.28 (1H, bs), 7.18 (1H, dd, J=8, 3), 7.00 (2H, t, J=9), 6.72 (1 H, J, J=9), 4.53 (2H, t, J=9), 3.92 (1H, m), 3.65 (1H, m), 3.42 (3H, m), 3.19 (2H, t, J=9), 3.15-
2.90 (6H, m), 1.43 (3H, m), 1.25 (3H, m), 1.10 (2H, m), 0.90 (3H, t, J=8), 0.83 (3H, t, J=8). MS (DCI/NH3) m/e 497 (M+H+). Anal calcd for C29H37FN2O4 • 0.25 H2O: C, 69.51 ; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.
Example 412 frans. frans-4-(1 .2-Dihvdrobenzof uran-5-vH-2-(4-f luorophenvlM - (((N-butyl-N-O-methylphenvnamino .carbonvnmethvnpyrrolidine-S- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.28 (1 H, bs), 7.25-7.00 (5H, m), 6.91 (2H, m), 6.72 (3H, d, J=9), 4.54 (2H, t, J=9), 4.00 (1 H, m), 3.60 (3H, m), 3.45 (1 H, m), 3.19 (2H, t, J=9), 3.11 (2H, m), 2.84 (1 H, m), 2.67 (1 H, bd, J=18), 2.26 (3H,s), 1.42 (2H, m), 1.25 (2H, m), 0.88 (3H, t, J=8). MS (DCI/NH3) m/e 531 (M+H+). Anal calcd for C32H35FN2O4 • 0.25 H2O: C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03.
Example 413 frans.frans-4-(lndan-5-vn-2-(4-methoxyphenyl /-1 -(N. N-di(n- butyl .aminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.32 (3H, m), 7.18 (2H, m), 6.85 (2H, d, J=9), 3.83 (1 H, m), 3.79 (3H, s), 3.67 (1 H. m), 3.50-3.20 (4H, m), 3.20-2.92 (4H, m), 2.87 (5H, m), 2.79 (1 H, bd, J=15), 2.06 (2H, m), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.88 (3H, t, J=8), 0.82 (3H, t, J=8). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N2O4: C, 73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.
Example 414 frans.frans-2-(4-Methoxvphenvn-4-(3.4-difluorophenyn-1 -r(N-butyl-
N-(3-methylphenvnamino ιcarbonylmethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1H NMR (300MHz, CDCI3) δ 0.86 (t, J=7Hz, 3H), 1.10-1.35 (m, 2H), 1.35-1.52 (m, 2H), 2.29 (s, 3H), 2.63 (d, J=13Hz, 1 H), 2.76 (t, J=7Hz, 1H), 3.06-3.20 (m, 2H), 3.42-3.53 (m, 1H), 3.50-3.64 (m, 3H), 3.80 (s, 3H), 3.86 (d, J=9Hz, 1H), 6.66-6.82 (m, 4H), 7.02-7.22 (m, 6H), 7.30-7.40 (m, 1H).
Example 415 frans. frans-1 -(N-Butyl-N-(3-chlorophenyl jaminocarbonylmethyl )-2- (4-fluorophenvπ-4-(5-benzofuranyπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 7.64 (1H, d, J=2Hz), 7.61 (1 H, d, J=3Hz), 7.47 (1 H, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1 H, dt,
J=8&2Hz), 7.21 (1 H, d, J=8Hz), 7.19 (2H, m), 7.00 (1 H, bs), 6.94 (2H, t, J=8Hz), 6.83 (1 H, bd, =8Hz), 6.74 (1H, dd, J=2&1Hz), 3.96 (1H, d, =10Hz), 3.75 (1H, ddd, 6, 5&3Hz), 3.59 (3H, m), 3.23 (1 H, t, J=10Hz), 3.18 (1H, d, J=16Hz), 2.92 (1H, dd, =10&9Hz), 2.69 (1H, d, J=16Hz), 1.41 (2H, m), 1.23 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCl, NH3) 549, 551
(M+H+). Anal, calcd for C31 H30CIFN2O: C, 67.82; H, 5.51; N, 5.10. Found: C, 67.43; H, 5.33; N, 4.78.
Example 416 frans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxyphenvn-1 -((( N- propyl-N-(4-phenoxybenzyl )amino^carbonvπ methy hpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ (rotamer) 7.40-7.20 (5H, m), 7.13 (2H, m), 6.98 (2H, m), 6.93-6.60 (7H, m), 5.93 (1H, d, J=2), 5.88
(5.85) (1 H, α, J=2), 4.90 (4.GG) (11 !, d, J=15), 4.10 (4.25) (1 H. H. -1=15). 3.77 (3.73) (3H, s), 3.72 (1 H, m), 3.60 (1H, m), 3.53-3.20 (3H, m), 3.15- 2.75 (4H, m), 1.60-1.20 (2H, m), 0.83 (0.64) (3H, t, J=8). MS (DCI/NH3) m/e 623 (M+H+). Anal calcd for C37H38N2O7 -0.25 H2O: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.
Example 417 frans. frans-4-(1 .2-Dihvdrobenzofuran-5-yn-2-(4-ethylphenvn-1 -(((N-
(2-pentyl)-N-(4-fiUQro-3- methylphenyl ιamino^carbonvnmethynpyrrolidine-3-carboxylic acid Using the procedures described in Example A the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.30 (1 H, bs), 7.20-7.00 (5H, m), 6.87 (1H, m), 6.73 (2H, d, J=9), 6.57 (1 H, m), 4.81 (1 H, m), 4.55 (2H, t, J=9), 3.92 (1 H, bd, J=11), 3.60 (1 H, m), 3.43 (1H, m), 3.18 (2H, t, J=9), 3.17 (1 H, m), 3.06 (1 H, dd, J=15, 6), 2.88 (1 H, dd, J=11 , 9), 2.61 (2H, q, J=8), 2.59 (1 H, m), 2.18 (3H, m), 1.40-1.10 (4H ,m), 1.22 (3H, t, J=9), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 573 (M+H+). Anal calcd for C35H41 FN2O4 • 0.75 H2O: C, 71.71; H, 7.31 ; N, 4.78. Found: C, 71.56; H, 7.33; N, 4.56.
Example 418 frans. frans-2-(4-Methoxphenyl -4-( 1 .3-benzodioxol-5-vn- 1 -f2-(N- propyl-N-'2-pyrimidinyl]amino ethvπpyrrolidine-3-carboxylic acid
Ethyl 2-(4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N- propylamino)propyl]pyrrolidine-3-carboxylate, prepared by the procedures of Example 61 B (300 mg), 138 mg of 2-bromopyrimidine, and 150 mg of diisopropylethylamine were heated at 95 °C for 15 hours in 2 mL of acetonitrile. The resulting intermediate trans-trans ethyl ester was isolated by chromatography on silica gel eluting with 5-10% ETOAc in CH2CI2 and hydrolyzed with NaOH in ethanol/water to give 95 mg of the title compound. 1 H NMR (300 MHz, CDCI3) δ 0.82 (t, J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (m, 1 H), 2.75-2.97 (m, 3H), 3.40-3.55 (m ,4H), 3.60-3.70 (m, 3H), 3.75 (s, 3H), 5.95 (s, 2H), 6.34 (t, J=4Hz, 1 H), 6.65 (d, J=8Hz, 1H), 6.75-6.82 (m, 1 H), 6.78 (d, J=9Hz, 2H), 6.96 (d, J=2Hz, 1H), 7.27 (d, J=9Hz, 2H), 8.20 (d, J=4Hz, 2H). Example 419 trans. frans-4-( 1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyn-1 -(3- butyl-2-chloro-hept-2-en-1 -ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. μ NMR (300 MHz, CD3OD) δ 0.84 (t, J=6.8 Hz, 3H), 0.88 (t, J=6.7 Hz, 3H), 1.19-1.39 (m, 8H), 2.05-2.09 (m, 2H), 2.17-2.23 (m, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1 H), 2.95 (t, J=9.2 Hz, 1 H), 3.32-3.37 (m, 2H), 3.49 (m, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.77 (s, 3H), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 1H), 6.85 (dd, J=1.9, 8.1 Hz, 1H), 6.89 (m, 2H), 7.08 (d, J=1.5 Hz, 1H), 7.36 ( , 2H). MS (DCl) m/e 528 (M+H+). Anal calcd for
C30H38CINO5 • 0.25 H2O: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.
Example 420 frans. frans-4-(1 .2-Dihydrobenzofuran-5-yn-2-(4-methoxyphenvn-1 -
(((N-(2-pentyD-N-(4-fluorς>-3- methylρhenvnaminθ)Carbonvnmethyl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.28 (1H, bs), 7.15 (3H, m), 6.90 (1 H. m), 6.77 (2H, dd, J=9, 3), 6.71 (2H, d, J=9), 6.56 (1H, m), 4.80
(1 H, m), 4.53 (2H, t, J=9), 3.92 (1 H, m), 3.79 (3H, s), 3.60 (1H, m), 3.45 (1 H, m), 3.19 (2H, t, J=9), 3.18 (1 H, m), 3.03 (1H, dd, J=15, 6), 2.85 (1 H, m), 2.55 (1H, m), 2.18 (3H, m), 1.40-1.05 (4H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C34H39FN2O5 • 0.35 H2O: C, 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.
Example 421 frans. frans-4-( 1 .2-Dihydrobenzofuran-5-yn-2-(4-methoχyphenvn-1 - ((ι N-butyl-N-(3-chlorophenvnaminθ )Carbonyl )methvnpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.29 (1 H, d, J=3), 7.25-7.05 (5H, m), 6.98 (1 H, bs), 6.80 (2H, m), 6.72 (2H, d, J=9), 4.53 (2H, t, J=9), 3.85 (1 H, d, J=10). 3.79 (3H, s), 3.58 (3H, m), 3.42 (1H, dd, J=10, 6), 3.18 (4H, m), 2.87 (1H, m), 2.66 (1 H, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 (3H, t, J=9). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C32H35CIN2O5 • 0.25 H2O: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21 ; N, 4.55.
Example 422 frans. frans-4-(1 .3-Benzodioxol-5-yn-2-(5-ethylfuran-2-vn-1 -(N.N- di(n-butvnaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ 7.77 (1H, bs), 7.11 (1H, d, J=3), 7.02 (1 H, dd, J=9, 3), 6.82 (1 H, d, J=9), 6.52 1 H, d, J=4), 6.08 (1 H, d, J=4), 5.98 (2H, s), 5.80 (1H, d, J=6), 4.70 (1H, bd, J=15), 4.37 (2H, m),
3.70 (2H, m), 3.39 (2H, m), 3.20 (1 H, m), 3.10-2.82 (2H, m), 2.76 (2H, q, J=8), 1.45 (2H, m), 1.32 (3H, t, J=9), 1.30-1.10 (6H, m), 0.87 (3H, t, J=9), 0.85 (3H, t, J=9). MS (DCI/NH3) m/e 499 (M+H+). Anal calcd for
C28H38N206 • 1.75 HCI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51 ; H, 6.96; N, 4.88.
Example 423 frans. frans-4-( 1 .2-Dihydrobenzofuran-5-yn-2-(4-fluorophenvn-1 -
(((N-(2-pentvn-N-(4-fluoro-3- methylphenyπaminθ)Carbonvπmethyl ιpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.30-7.10 (4H, m), 6.92 (3H, m), 6.73 (2H, d, J=9), 6.59 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J=9), 4.00 (1 H, bd, J=10), 3.62 (1H, m), 3.45 (1 H, m), 3.22 (1 H, m), 3.21 (2H, t, J=9), 3.02 (1H, dd, J=15, 6), 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 (3H, bs), 1.40-1.30 (3H, m), 1.15 (1H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C33H36F2N2O4: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.
Example 424 frans. frans-4-(1 .2-Dihvdrobenzof uran-5-ylb2-(4-f luorophenyn-1 - (((N-butyl-N-(3-chlorophenvπamino'>carbonyπmethyl ιpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ 7.30 (2H, m), 7.25-7.10 (4H, m), 6.95 (3μ, m), 6.82 (1 H, bd, J=9), 6.73 (1H, d, J=9), 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (3H, m), 3.43 (1H, dd, J=9, 6), 3.21 (2H. t, J=9), 3.16 (2H, m), 2.87 (1H, m), 2.69 (1H, m), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=9). MS (DCI/NH3) m/e 551 (M+H+). Anal calcd for C31 H32CIFN2O4 • 0.25 H2O: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.
Example 425 frans.frans-4-(1 .2-Dihydrobenzofuran-5-vn-2-(3-ethylphenvn-1 -(((N- butyl-N-(3-chlorophenvnamino)carbonvnmethynpyrrolidine-3- carboxyϋc add Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ 7.30 (1H, m), 7.21 (1H, d, J=9), 7.15 (2H, m), 7.09 (4H, bs), 6.96 (1H, bs), 6.80 (1H, bd, J=9), 6.73 (1H, d, J=9), 4.54 (2H, t, J=9), 3.89 (1H, bd, J=1 1), 3.60 (3H, m), 3.43
(1H, m), 3.22 (2H, t, J=9), 3.18 (2H, m), 2.92 (1H, m), 2.72 (1H, m), 2.62 (2H, q, J=8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, J=9), 0.87 (3H, t, J=9). MS (DCI/NH3) m/e 561 (M+H+). Anal calcd for C33H37CIN2O4 • 0.25 H2O: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.
Example 426 frans. frans-1 -(N-Butyl-N-(3-chlorophenyncarboxamidomethyπ-2-(4- methoxyphenyn-4-(5-benzofuranyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 7.67 (1 H, bs), 7.60 (1H, d, J=3Hz), 7.48 (1 H, d, J=8Hz), 7.42 (1H, dd, J=8&3Hz). 7.29 (1H, dt, J=8&3Hz), 7.21 (1H, d, J=8Hz). 7.14 (2H, m), 6.99 (1H, bs), 6.76 (4H, m), 3.88 (1 H, d, J=10Hz), 3.75 (1 H, ddd, J=6, 5&3Hz), 3.59 (2H, m), 3.53 (1 H, dd, J=10&3Hz), 3.22 (1 H, t, J=9Hz), 3.19 (1 H, m), 2.96( 1H, m), 2.70 (1H, d, =16Hz), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, =7Hz). MS (DCl, NH3) m/e 563, 561 (M+H+). Anal, calcd for C32H33CIN2O5 • 0.5 H2O: C, 67.42; H, 6.01 ; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68. Example 427 frans. frans-4-( 1 .3- Benzodioxol-5-vn-2-(4-methoxyphenyl ι-1 -((( N- cyclohexyl-N-butylamino ιcarbonvπmethyl )Pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) (rotamer) δ 0.78 (0.86) (t, 3H,
J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) (d, 1 H, J=12Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) (s, 3H), 5.92 (s, 2H), 6.72 (d, 1H, J=9Hz) 6.86 (m, 3H) 7.03 (d, 1 H, J=6Hz), 7.34 (m, 2H). MS (DCI/NH3) m/e 537 (M+H)+. Anal, calc'd for C31 H40N2O6 • 1 H2O: C,"67.13; H, 7.63; N, 5.05. Found: C, 67.09; H, 7.34; N, 4.92.
Example 428 frans. rans-4-( 1 .3-Benzodioxol-5-yh-2-(4-ethylphenyn- 1 -(((N-(3- methylphenvn-N-butylamino ,carbonyl ιmethyl .pyrrolidine-3-carboxylic add Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.86 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, 3H), 2.6 (q, 2H, J=7Hz), 2.68 (d, 1 H, J=12Hz), 2.86 (t, 1 H, J=8Hz), 3.19 (q, 2H, J=7Hz), 3.44 (dd,
1 H, J= 3Hz,10Hz), 3.59 (m, 3H), 3.94 (d, 1 H, 9Hz), 5.92 (s, 2H), 6.75 (m, 3H), 6.86 (dd, 1H, J= 2Hz, 8Hz), 7.08 (m, 6H), 7.17 (t, 1H, J= 8Hz). MS (DCI/NH3) m/e 543 (M+H)+. Anal, calc'd for C33H38N2O5 • 0.60 H2O: C,
71.61; H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.
Example 429 frans. frans-4-(Benzofuran-5-yn-2-(4-ethylphenvn-1 -((( N-(3- methylphenvπ-N-butylaminθ)Carbonyπmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 0.90 (t, 3H, J=7Hz), 1.30 (t, 3H, J=7Hz), 1.31 (m, 2H), 1.43 (m, 2H), 2.27 (s, 3H), 2.73 (q, 2H, J=7Hz), 3.15 (d, 2H, J=17Hz), 3.61 (t, 2H, J= 8Hz), 3.82 (m, 2H), 4.00 (t, 1 H, 12Hz), 4.26 (m, 2H), 5.53 (br d, 1 H), 6.54 (br s, 2H), 6.76 (d, 1H, J= 2Hz), 7.14 (m, 3H), 7.28 (s, 1H), 7.40 (m, 3H), 7.48 (d, 1 H, J= 8Hz), 7.63 (d, 1 H, J=2Hz), 7.73 (s, 1H). HRMS. calc'd for C34H39N2O4 (M+H)+: 539.2910. Found: 539.2891
Example 43Q frans.frans-4-(1 .4-Benzodioxan-β-vn-2-(4-ethvlphenvn-1 -(((N-(3- methylphenyl)-N-butylaminp)carbQnyl)methyl)pyrrolidine-3-carbQxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 0.87 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.24 (m, 2H), 1.42 (m, 2H), 2.30 (s, 3H), 2.61 (q, 2H, J=7Hz), 2.67 (d, 1H, J=14Hz), 2.86 (t, 1 H, J= 8Hz), 3.18 (q, 2H, J=7Hz), 3.41 (dd, 1 H, J=4,10Hz), 3.59 (m, 3H), 3.93 (d, 1 H, J=10Hz), 4.25 (m, 4H), 6.74 (br s, 2H), 6.80 (d, 1 H, J=8Hz), 6.93 (dd, 1H, J=2Hz,8Hz), 6.99 (d, 1H, J=2Hz), 7.07 (m, 5H), 7.17 (t. 1H, J=8Hz). MS (DCI/NH3) m/e 557 (M+H)+. Anal. calc'd for C34H40N2O5 • 0.40 H2O: C, 72.42; H, 7.29; N, 4.97. Found: C,
72.49; H, 7.16; N, 4.62.
Example 431 frans. frans-2-(3-Fluoro-4-methoxyphenvn-4-( 1 .3-benzodioxol-5-yn- 1 -, 2-(N-propyl-N-2-mesitylenesulfonylamino ;ethyllpyrrolidine-3- carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 80-82 °C 1 H NMR (CDCI3, 300 MHz) δ 0.69 (t, J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09- 2.17 (m, 1H), 2.24 (s, 3H), 2.53 (s, 6H), 2.54-2.64 (m, 1H), 2.73-2.86 (m, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (m. 3H)), 3.44-3.53 (m, 1H), 3.57 (d, J=9Hz, 1 H), 3.89 (s, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.78 (dd, J=2Hz, J=8Hz, 1 H), 6.85 (s, 2H), 6.92 (d, J=8Hz, 1 H), 9.94 (d, J=2Hz, 1 H), 7.06 (d, J=8Hz, 1 H), 7.13 (dd, J=2Hz, J=12Hz, 1 H). MS (DCI/NH3) m/e 627 (M+H)+.
Example 432 trans, frans-2-f 4-Methoxyphenvπ-4-(3.4-difluorophen vh-1 - (N-butyl-
N-O-ch orophenvhamino^carbonylmethyllpyrrolidine-S-carboxylic acid Using the procedures described in Example 1 , the title compound
«as prepared. H NMR (300 MM7J nnci ) δ 0.86 (t. J=7Hz. 3H), 1.18-1.32 (m, 2H), 1.35-1.48 (m, 2H), 2.64 (d, J=13Hz, 1H), 2.71 (t, J= 7Hz, 1H), 3.08-3.18 (m, 2H), 3.42-3.48 (m, 1H), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.80 (d, J=9Hz, 1H), 6.73-6.85 (m, 3H), 6.94 (s, 1H), 7.04-7.40 (m, 7H).
Example 433 frans. frans-2-(3-Fluoro-4-methoxyphen vH-4-(1 .3-benzodioxol-5-yπ- 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino^ethyπpyrrolidine-3- carbp-xyiic add Using the procedures described in Example 1 , the title compound was prepared. H NMR (CD3OD, 300 MHz) δ 0.80 Tt. 3H, J=7), 1.47 (bd hex, 2H, J=8), 2.15 (pen, 2H, J=7), 2.32 (m, 1H), 2.7-3.2 (m, 9H), 3.46 (dd, 1H, J=4, 10), 3.57 (m, 1H), 3.64 (t, 2H, J=6), 3.67 (d, 1H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.96 (d, 1 H, J=2), 7.06 (t, 1 H, J=9), 7.18 (m, 2H). MS (DCI/NH3) m/e 585 (M+H; 35ci)+; 587 (M+H; 37C|)+. Anal calcd for C27H34N2O7CIFS: C, 55.43; H, 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.
Example 434 frans. frans-2-(3-Fluoro-4-methoxyphenvh-4-(1 .3-benzodioxol-5-vn- 1 -(2-(N-isobutyl-N-(3-chloropropanesulfonvπaminθ )ethyl ιpyrrolidine-
3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) δ 0.79 (d, 3H, J=7), 0.84 (d, 3H, J=7),1.68 (hept, 1H, J=7), 2.18 (pen, 2H, J=7), 2.8-3.4 (m, 10H), 3.5-3.8 (m, 3H), 3.65 (t, 2H, J=6), 3.90 (s, 3H), 5.94 (s, 2H), 6.77 (d, 1H, J=8), 6.87 (dd, 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.13 (t, 1H, J=9), 7.27 ( , 2H). MS (DCI/NH3) m/e 599 (M+H)+. Anal calcd for C28H36N2O7CIFS ■ 0.3
TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71 ; N, 4.01.
Example 435 frans. frans-2-Propoxymethyl-4-(1 .3-benzodioxol-5-yn-1 -(N. N-di(n- butyπaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (CDCI3, 300 MHz) δ 0.87-0.98 (m, 9H), 1.21-1.39 (m, 4H), 1.43-1.57 (m, 4H), 1.58-1.70 (m, 2H), 3.13-3.29 (m, 4H), 3.34- 3.43 (m, 3H), 3.45-3.55 (m, 3H), 3.69 (dd, J = 10.2, 4.5 Hz, 1H), 3.80- 4.20 (m, 4H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1 H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H). MS(DCl/NH3) m/e 477 (M+H)+. Anal calcd for C26H40N2O6 0.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22.
Example 436 frans. frans-2-(3-Fluoro-4-methoxvphenyl')-4-(1 .3-benzodioxol-5-vn-
1-f2-(N-propyl-N-(4-methyibutapesulfQnyl)aminc)ethynpyrrolidine-3- carboxylic add Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 65-67 °C H NMR (CDCI3, 300MHz) δ 0.82 (t, J=7Hz, 3H), 0.88 (d, J=5Hz, 6H), 1.46 (sextet,
J=7Hz, 2H), 1.56-1.64 (m, 3H), 2.24-2.33 (m, 1 H), 2.68-2.93 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52- 3.58 (, 1 H), 3.65 (d, J=12Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1 H), 7.10 (d, J=9Hz, 1 Hz) , 7.16 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+.
Example 437 frans. frans-2-(4-Methoxy-3-fluorophenvπ-4-(7-methoxy-1 .3- benzodioxol-5-yπ- 1 -f2-(N-propyl-N-(n- pentanesulfonylιaminθιethyHpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. H NMR (300MHz, CDCI3) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (m, 4H), 1.44 (sextet, J=7Hz, 2H), 1.67-1.78 (m, 2H), 2.22-2.34 (m, 1 H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.33 (m, 2H), 3.45 (dd, J=3Hz, 9Hz, 1 H), 3.47-3.56 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.88 (s, 3H), 3.94 (s, 3H), 5.95 (s, 2H), 6.55 (s. 1 H), 6.65 (s, 1 H), 6.92 (t, J=7H, 1H), 7.11 (d, J=9Hz,1H), 7.17 (d, J=12Hz, 1H). Example 438 frans. frans-2-(3-Fluoro-4-methoxyphenvn-4-(1 .3-benzodioxol-5-yn-
1 -r2-(N-propyl-N-(2.2.3.3.3- pentafluoropropoxyethanesulfonyπamino^ethyl]pyrrolidine-3- carboxylic acid
Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 63-64 °C H NMR (CDCI3, 300MHz) δ 0.82 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24-
2.33 (m, 1H), 2.70-2.82 (m, 1 H), 2.85-3.09 (m, 5H), 3.14-3.28 (m, 4H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (m, 1 H), 3.^5 (d, J=9Hz, 1H), 3.87
(s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t. J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 685 (M+H)+.
Example 439 frans. frans-2-(1 .4-Benzodioxan-6-yn-4-(7-methoxy-1 .3-benzodioxol-
5-yl)-1 -r2-(N-prcpyl-N-(π-pentapegulfonyl)aminQ)ethyπpyrroiidiPe-3- carboxylic acid Using the procedures described in Example 66, the title compound was prepared. H NMR (CDCI3) δ 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.23-1.36 (m, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (m, 2H), 2.20- 2.30 (m, 1 H), 2.30-2.95 ( , 5H), 2.95-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 (m, 1H), 3.59 (d, J=9Hz, 1 H), 3.91 (s, 3H), 4.24 (s, 4H), 5.95 (s, 2H), 6.57 (s, 1H), 6.68 (s, 1H), 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 (d, J=2Hz, 1H).
Example 440 frans. frans-4-(1 .3-Benzodioxol-5-yn-2-(4-methoxyphenvn-1 -(((N- butyl-N-(4-methoxybenzyl ιamino)carbonvnmethvnpyrrolidine-3- carboxylic a id
Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ (rotamer) 7.32 (1H, d, J=10), 7.22 (1 H, m), 7.10 (1 H, d, J=9), 7.03 (6.98) (1 H, d, J=3), 6.90-6.80 (4H, m), 6.79 (2H, d, J=9), 6.77 (1H, t, J=8), 5.85 (2H, s), 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (1H, d, J=15), 3.81 (1H, m), 3.79 (3.78) (3H, s), 3.76 (3H, s), 3.62 (1H, m), 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1 H, ), 0.83 (0.75) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7 • 0.5 H2O: C, 67.91 ; H, 6.73; N, 4.80. Found: C, 67.78; H, 6.44; N, 4.55.
Example 441 frans. frans-2-(3-Fluoro-4-methoxvphenyn-4-( 1 .3-benzodioxol-5-yn- 1 -(2-(N-isobutvl-N-(pentanesulfonylaminoϊethynpyrrolidine-3- carboxylic acid Using the procedures described in Example _66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) δ 0.76 (d, 3H, J=7), 0.84 (d, 3H, J=7), 0.92 (t, 3H, J=7), 1.36 (m, 4H),1.70 (m, 3H), 2.90 (m, 2H), 3.02 (m, 2H), 3.1-3.8 (m, 7H), 3.84 (d, 2H, J=8), 3.91 (s, 3H), 5.96 (s, 2H), 6.80 (d, 1 H, J=8), 6.88 (dd, 1 H, J=2, 8), 7.00 (d, 1H, J=2), 7.19 (t, 1 H, J=9), 7.35 (m, 2H). MS (DCI/NH3) m/e 593 (M+H)+. Anal calcd for C30H41 N2O7F • 0.5 TFA: C, 57.31 ; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95.
Example 442 frans. frans-4-(1 .3-Benzodioxol-5-yπ-2-(4-methoxyphenvn- 1 -(N- butyl-N-(3-fluorophenylamino^carbonylmethvπpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.10- 1.30 (m, 4H), 2.70-2.90 (m, 2H), 3.13 (t, J=8 Hz, 1 H), 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1 H), 6.80-7.20 (m, 9H), 7.40 (m, 1 H). MS (DCl) m/e 549 (M+H)+. Anal calcd for C31 H33N2O6F • 0.8 H2O: C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21 ; H, 5.83; N, 4.84.
Example 443 frans. frans-4-( 1 .3-Benzodioxol-5-vπ-2-(4-f I uorophenvh-l -f N-b utyl- N-(3-chlorophenylamino ι arbonylmethyl )Pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz. CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20- 1.50 (m, 4H), 2.65-2.85 (m, 2H), 3.05-3.85 (m, 7H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1 H), 6.85 (dd, J=8 Hz, 1 H), 6.90-7.10 (m, 4H), 7.10-7.25 (m, 3H), 7.33-7.45 (m, 2H). MS (DCl) m/e 553 (M+H)+. Anal calcd for C30H30N2O5FCI: C, 65.16; , 5.47; N, 5.07. Found: C, 65.37; H, 5.41 ; N, 4.98.
Example 444 frans. frans-4-(1 .3-Benzodioxol-5-vn-2-r4-methoxyphenvn-1 -(((N- butyl-N-(3.4-dimethoxybenzyl ιamino^carbonvhmethvnpyrrolidine-3- carbQxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ (rotamer) 7.33 (1H, d, J=10), 7.23 (1 H, m), 7.03 (6.97) (1 H, d, J=3), 6.90-6.60 (6H, m), 6.47 (1 H, m), 5.93 (2H, m), 4.83 (4.09) (1H, d, J=15), 4.45 (4.22) (1H, d, J=15), 3.83 (3.86) (3H, s), 3.79 (1 H, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (1H, m), 3.43 (2H, m), 3.28 (1H, m), 3.20-2.70 (4H, m), 1.43 (1 H, m), 1.23 (2H, m), 1.02 (1 H, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 605 (M+H+). Anal calcd for C34H40 2O8: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.
Example 445 frans.frans-4-(1 .3-Benzodioxol-5-vn-2-(4-methoxyDhenvn-1 -(((N- but yl-N-(2-methoxybenzvπ amino) carbonyhmethvπpyrrolidi ne-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3 ) δ (rotamer) 7.33 (1H, d, J=10), 7.11 (2H, m), 7.03 (1 H, dd, J=8, 3), 6.90-6.60 (7H, m), 5.93 (2H, m), 4.83 (4.15) (1 H, d, J=15), 4.47 (4.30) (1 H, d, J=15), 3.81 (1H, m), 3.78 (3.73) (3H, s), 3.72 (3H, s), 3.59 (1 H, m), 3.43 (2H, m), 3.30 (1 H, m), 3.20-2.70 (4H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1 H, m), 0.83 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 4.61. Example 446 frans. rans-4-(1 .3-Benzodioxol-5-yn-2-(4-methoxyphenyπ-1 -(((N- butyl-N-O-methoxybenzvπamino^carbonyhmethyhpyrro idine-S- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. μ NMR (300 MHz, CDCI3 ) δ (rotamer) 7.31 (1H, d, J=10), 7.13 (1 H, d, J=9), 7.16 (1H, dt, J=8, 3), 7.03 (1H, dd, J=10, 2), 6.90-6.60 (6H, m), 6.50 (1H, m), 5.94 (2H, m), 4.82 (4.19) (1H, d, J=15), 4.50 (4.23) (1H, d, J=15), 3.78 (3.76) (3H, s), 3.77 (1H, m), 3.75 (3.67) (3H, s), 3.59 (1H, m), 3.57-3.35 (2H, m), 3.25 (1H, m), 3.20-2.70 (4H, m), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60.
Example 447 trans. frans-2-(3-Fluoro-4-methoxyphenyn-4-M .3-benzodioxol-5-vn-
1 -(2-(N-(2-methcxyethyl)-N-(3- chloropropanesulfonyπamino)ethvnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) δ 2.15 (pen, 2H, J=7), 2.33 (m,
1 H), 2.81 (m, 2H); 2.93 (t, 1 H, J=9); 3.1-3.6 (m, 10H), 3.24 (s, 3H); 3.65 (t, 2H, J=6), 3.70 (d, 1 H, J=9), 3.87 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1 H, J=8), 6.84 (dd, 1 H, J=2, 8), 6.97 (d, 1H, J=2), 7.07 (t, 1 H, J=9), 7.17 (m, 2H). MS (DCI/NH3) m/e 601 (M+H)+. Anal calcd for C27H34N2O8CIFS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.
Example 448 frans. frans-2-(3-Fluoro-4-methoxyphenyn-4-( 1 .3-benzodioxol-5-vn- 1 -(2-(N-(2-methoxyethyl ι-N-(pentanesulfonyl)amino thynpyrrolidine- 3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) δ 0.93 (m, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.33 (m, 1 H), 2.75-3.1 (m, 7H), 3.23 (s, 3H), 3.3-3.6 (m, 6H), 3.70 (d, 1 H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1 H, J=8), 6.84 (dd, 1 H, J=2, 8), 6.97 (d, 1 H, J=2), 7.07 (t, 1 H, J=9), 7.18 (m, 2H). MS (DCI/NH3) m/e 595 (M+H)+. Anal calcd for C29H39N2O8FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21 ; H, 6.29; N, 4.29.
Example 449 frans. frans-4-(1 .3-Benzodioxol-5-yl*)-2-(4-methoxyphenyh- 1 -(((N-4- heptyl)-N-(4-flucro-3- methylphenylamino*ιcarbonvnmethyl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.89 Jm, 6H), 1.18-1.36 (m, 8H), 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t,
J=14.9 Hz, 1H), 2.82 (m, 1 H), 3.07-3.29 (m, 2H), 3.32-3.41 (m, 1 H), 3.53-3.60 (m, 1H), 3.70-3.79 (m, 1 H), 3.79 (s, 3H), 4.68 (m, 1 H), 5.92 (m, 2H), 6.69-6.90 (m, 6H), 6.93-7.07 (m, 4H). MS (DCl) m/e 605 (M+H+). Anal calcd for C35H41 FN2O6: C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31 ; H, 6.78; N, 4.35.
Example 450 frans. frans-4-(1 .3-Benzodioxol-5-vn-2-(4-methoχyphenvn-1 -(((N-(5- nonvπ-N-(4-fluoro-3- methylphenvπamino')carbonyl )methvπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.81-0.90 (m, 6H), 1.30 (m, 12H), 2.14 (s, 1.5 (CH3 rotamer)), 2.30 (s, 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz, 1 H), 2.80 (m, 1H), 3.09-3.24 (m, 2H), 3.33-3.42 (m, 1H), 3.50-3.55 (m, 1H), 3.65-3.77 (m, 1 H), 3.79 (s, 3H), 4.64 (m, 1 H), 5.93
(m, 2H), 6.70-6.84 (m, 5H), 6.91-7.13 (m, 5H). MS (DCl) m/e 633 (M+H+). Anal calcd for C37H45FN2O6: C, 70.23; H, 7.17; N, 4.43. Found: C,
70.14; H, 7.13; N, 4.19.
Example 451 frans. frans-4-(1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyh-1 -((N-(5- nonylammo ι arbonvnmethylιPyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.80 (t, J=7.0 Hz, 3H), 0.84 (t, J=7.1 Hz, 3H), 1.15-1.55 (m, 12H), 2.88 (d, J=15.9 Hz, 1 H), 3.07 (m,
2H), 3.26 (d, J=16.3 Hz, 1 H), 3.36 (dd, J=4.4, 9.8 Hz, 1 H), 3.64 (m, 1 H), 3.76 (m, 1H), 3.79 (s, 3H), 3.98 (d, J=9.5 Hz, 1H), 5.93 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.85 (dd, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 6.99 (d, J=1.7 Hz, 1H), 7.39 (m, 2H). MS (DCl) m/e 525 (M+H+). Anal calcd for C30H46N2O6 • 0.35 H2O: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11.
Example 5 trans. frans-4-M .3-Benzodioxol-5-yn-2-(4-methoxyphenyn-1 -((N- butyl-N-(2-ftuorophenyl')amino'ιcarbonylmethyl ιpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (dt, J=7 Hz, 3H), 1.15- 1.32 (m, 4H), 3.77 (d, J=2 Hz, 3H), 2.65-5.92 (m, 9H), 5.93 (d, J=4 Hz, 2H), 6.70-6.90 (m, 4H), 7.00-7.45 (m, 7H). MS (DCl) m/e 549 (M+H)+. Anal calcd for C31 H33N2O6 • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68.
Example 453 frans. frans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-vπ-1 -r2-(N- propyl-N-(2-benzothiazolyπamino)ethyl1pyrrolidine-3-carboxylic acid
The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-bromopyrimidine. η H NMR (300 MHz, CDCI3) δ 0.88 (t, J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25-
2.37 (m, 1 H), 2.85-2.97 (m, 3H), 3.28-3.36 (m, 2H), 3.50-3.58 (m, 3H), 3.60-3.65 (m, 1 H), 3.67 (d, J=9Hz, 1 H),3.71 (s, 3H), 5.87 (d, J=2Hz, 1 H),
5.91 (d, J=2Hz, 1 H), 6.57 (d, J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, 1 H), 6.76 (d, J=8 Hz, 2H), 6.91 (d, J=2Hz, 1 H), 7.01 (t, J=8Hz, 1 H), 7.22 (t, J=8Hz, 1 H), 7.29 (d, J=8Hz, 2H), 7.40 (d, J=7Hz, 1 H), 7.55 (d, J=7Hz, 1 H).
Example 454 frans. frans-2-(2-Ethoxyeth vh-4-( 1 .3-benzodioxol-5-vn- 1 -(N .N-di(n- butyh aminocarbonyl methvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) δ 0.91 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 5H), 1.46-1.60 (m. 4H), 2.03-2.12 (m, 2H), 3.07 (t, J = 8.0 Hz, 1 H), 3.07-3.34 (m, 6H), 3.43-3.52 (m, 3H), 3.59-3.74 (m, 3H), 3.80-4.01 (m, 2H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.87 (d, J = 1.7 Hz. 1H). MS(DCI/NH3) m/e 477 (M+H)+. Anal calcd for C26H40N2O6 • 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N. 5.29.
Example 455 frans. frans-2-(4-Methoxy-3-fluorophenyn-4-( 1 .3-benzodioxol-5-vn-
1 -[2-(N-propyl-N-(2-(morpholin-4- ylethyl ιSulfonylamino*)ethyl,pyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(l 3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-[2-vinylsulfonyl]amino)ethyl]pyrrolidine-3- carboxylic acid, prepared by the procedures of Example 125, was reacted with excess morpholine for 4 hours at room temperature. Chromatography on silica gel eluting with EtOAc gave a 65% yield of an intermediate ethyl ester which was hydrolyzed to the title compound with NaOH in ethanol/water. H NMR (300 MHz, CDCI3) δ 0.81 (t, J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (m, 1H), 3.62- 3.70 (m, 5H), 3.88 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.70 (dd, J=2Hz, 8Hz, 1H), 6.90 (t, J=9Hz, 1H), 6.96 (d, J=2Hz, 1H), 7.10 (d, J=8Hz,
1H), 7.18 (dd. J=2Hz, 12Hz, 1H).
Example 456 frans. frans-2-(3-Fluoro-4-methoxyphenyn-4-(1 .3-benzodioxol-5-yn- 1 -r2-fN-propyl-N-((2.2.2- trifluoroethoxyethane)sulfonynamino)ethyllpyrrolidine-3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 95-96 °C 1 H NMR (CD3OD, 300MHz) δ 0.80 (t. J=7Hz, 3H), 1.35-1.48 (m, 2H),3.07 (sextet,
J=7Hz, 2H), 3.23-3.55 (m, 8H). 3.80-3.87 (m, 2H), 3.93 (s, 3H), 3.94- 4.02 (m, 4H), 4.66 (d, J=12Hz, 1H), 5.96 (s, 2H), 6.83 (d, J=8Hz, 1H), 6.94 (d, J=8Hz, 1 H),7.06 (d, J=2Hz, 1H), 7.23 (t, J=9Hz, 1H), 7.43 (d, J=9Hz, 1H), 7.49 (dd, J=2Hz,J=12Hz, 1H). MS (DCI/NH3) m/e 635 (M+H)+. Example 457 frans. frans-4-(1 .3-Benzodioxol-5-yn-2-(4-fluorophenyn-1 -(N-butyl- N-(3-methvlPhenvnaminocarbonylmethyl ιpyrrolidine-3-carboxylic acid Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz. CD3OD) δ 0.87 (t, J=7 Hz, 3H). 1.20-
1.50 (m, 4H), 2.31 (s, 3H), 2.65-2.80 (m, 2H), 3.19 (t, J=7 Hz, 1 H), 3.25 (d, J=10 Hz, 1H), 3.35-3.65 (m, 4H), 3.79 (d, J=10 Hz, 1H), 5.93 (s, 2H), 6.74 (d, J=7 Hz, 1 H), 6.80-6.90 (m, 3H), 6.91 -7.09 (m, 3H). 7.10-7.35 (m, 4H). MS (DCl) m/e 533 (M+H)+. Anal calcd for C31 H33N2O5F: C, 69.91 ; H, 6.25; N. 5.26. Found: C, 69.56; H, 6.26; N, δ!23.
Example 458 frans. frans-2-(3-Fluoro-4-methoxyphenyn-4-( 1 .3-benzodioxol-5-yn- 1 -(2-(N-(2-methoxyethyn-N-(butanesulfonylamino)ethvnpyrrolidine- 3-carboxylic acid
Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) δ 0.94 (m, 3H), 1.23 (hex, 2H, J=8), 1.69 (m, 2H), 3.08 (m,2H), 3.20 (s, 3H), 3.3-3.5 (m, 10H), 3.77 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5.96 (s, 2H), 6.81 (d, 1H, J=8), 6.88 (dd, 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.22 (t. 1 H, J=9), 7.38 (m, 2H). MS (APCI) m/e 581 (M+H)+. Anal calcd for C28H37N2O8FS • 1.1 TFA: C, 51.37; H,
5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.
Example 459 trans. frans-2-(3-Fluoro-4-methoxyphenvn-4-M ,3-benzodiQXQl-5-vn- 1 -r2-(N-propyl-N-(2-methylpropanesulfonyhamino)ethyl]pyrrolidine-
3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 77-78 °C. 1 H NMR (CDCI3, 300MHz) δ 0.83 (t, J=7Hz, 3H),1.06 (d, J=6Hz, 6H),1.45 (q, J=7Hz,
2H), 2.20 (septet, J=6Hz, 1 H), 2.26-2.36 (m, 1 H), 2.62-2.78 (m, 3H). 2.85-2.95 (m, 2H), 2.97-3.10 (m, 2H), 3.15-3.35 ( , 2H), 3.43 (dd, J=3Hz, J=9Hz, 1 H), 3.53-3.62 ( , 1 H), 3.66 (d, J=9Hz, 1 H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.82 (dd, J=2Hz, J=8Hz, 1 H), 6.92 (t, J=8Hz, 1 H), 6.97 (d, J=2Hz, 1 H), 7.12 (d, J=9Hz, 1 H), 7.18 (dd, J=2Hz,
•l=1 ?Hz. 1H . MS (DCI/NH3) m/e 565 (M+H)+. Example 460 frans. frans-4-( 1 .3-Benzodioxol-5-yπ-2-(4-methoxyphenyπ- 1 -f ((N- butyl-N-(4-nitrobenzvπamino »carbonvhmethvπpyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. μ NMR (300 MHz, CDCI3 ) δ (rotamer) 8.1 1 (2H, m),7.32 (3H, dd, J=9, 2), 7.16 (7.07) (1H, bd, J=10), 6.98 (6.94) (1 H, d, J=2), 6.85 (2H, d, J=9), 6.83-6.70 (2H, m), 5.99 (5.97) (2H, d, J=2), 5.02 (4.18) (1 H, d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) (3 s), 3.72 (1H, d,
J=10), 3.61 (1 H. m), 3.48 (1 H, bd, J=15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (1 H. m), 3.79 (1 H, bd, J=14), 1.43 (1 H, m), 1.23 (2H, m), 1.02 (1 H, m), 0.84 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8: C, 65.18; H. 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.
Example 461 frans. frans-2-f4-Ethylphenyl ,-4-(3.4-difluorophenvn- 1 -(N. N-di(n- butyπaminocarbonylmethyl ι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) δ 0.78 (t, 3H, J=7), 0.87 (t, 3H,
J=7), 1.02 (hex, 2H, J=7), 1.22 (t, 3H, J=7), 1.27 (m, 2H), 1.45 (m, 2H, J=7), 2.63 (q, 2H, J=7), 2.77 (d, 1 H, J=14), 2.94 (dd, 1 H, J=7, 9), 3.05 (m, 3H), 3.3-3.5 m, 3H), 3.44 (d, 1 H, J=14), 3.66 (m, 1 H), 3.75 (d, 1 H, J=10), 7.20 (td, 2H, J=1 ,8). 7.22 (m, 2H), 7.32 (td, 2H, J=1,8). 7.43 (ddd. 1 H,
J=2,8,12). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H38N2O3F2 • 0.6 H2O: C, 68.11 ; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37.
Example 462 frans. fraπs-4-( 1 ■3-Benzodioxol-5-vh-2-(4-methoxyphenvn- 1 - N- but yl-N-(4-f I uoro-3-methylph en vh aminocarbonyl methy I ipy rrolidi ne-
3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20- 1.50 (m, 4H), 2.21 (d, J=2 Hz, 3H), 2.64 (d, J=14 Hz, 1 H), 2.75 (dd, J=10 Hz. 1H), 3.05 (t. J=7 Hz. 1H), 3.25 (d, J=15 Hz, 1H), 3.35-3.70 (m, 5H). 3.77 (s. 3H), 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-7.10 (m, 4H). MS (DCl) m/e 563 (M+H)+. Anal calcd for C32H35N2O6 • 0.5 H2O: C, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.
Example 463 frans.frans-4-(1 .3-Benzodioxol-5-yn-2-(4-methoxvphenyn-1 -fN- butyl-N-((3-i§Qpropyl)phenyl)amino)carbQnγlmethyl)-pyrrQlidine-3- carboxylic acid Using the procedures described in Example X, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (t, 3H), 1.17 (d, J=7 Hz, 6H), 1.20-1.50 (m, 4H), 2.63 (d, J=15 Hz, 1H), 2.75 (t, J=7 Hz, 1H), 2.85 (m, 1H), 3.00 (t, J=7 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.70 (m, 5H), 3.75 (s, 3H), 5.90 (s, 2H), 6.65-6.80 (m, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 (m, 3H), 7.20-7.35 (m, 2H). MS (DCl) m/e 573 (M+H)+. Anal calcd for
C34H40 2O6 - 0.15 H3PO4: C, 69.52; H. 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43.
Example 464 trans.trans-A-i .3-Benzodioxol-5-vπ-2-(4-methoxyphenvπ- 1 -(N- butyl-N-(3-ethylphenyπaminocarbonylmethvπpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz. CD3OD) δ 0.87 (m, J=7 Hz, 3H). 1.16 (t. J=7 Hz, 3H), 1.20-1.47 (m, 4H), 2.50 (q, J=7 Hz, 2H), 2.70-2.85 (m, 2H), 3.13 (t, J=7 Hz, 1H), 3.20-4.5 (m, 6H), 3.78 (s, 3H), 3.83 (d, J=8 Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.90 (m, 5H), 7.02-7.13 (m, 3H), 7.15-7.25 (m, 2H). MS (DCl) m/e 559 (M+H)+. Anal calcd for C33H38N2O6 • 0.3 H2O: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31 ; H, 6.63; N, 4.60. Example 465 frans. frans-4-(1 .3-Benzodioxol-5-vn-2-(4-ethylphenyn- 1 -(((N-(3- chlorophenyl ι-N-butylamino)carbonyl ιmethvπpyrrolidine-3-carboxylic add Using the procedures described in Example 1 , the title compound was prepared. μ NMR (300 MHz, CDCI3) δ 0.87 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.41 (m, 2H), 2.63 (q, 2H, J=7Hz), 2.67 (m, 1 H),
2.92 (m, 1H), 3.20 (m, 2H), 3.42 (m, 1 H), 3.60 (q, 2H, J=7Hz), 3.93 (m, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 3H), 6.95 (br s, 1H), 7.02 (s, 1 H), 7.10 (br s, 3H), 7.25 (m, 2H). MS (APCI) m?e 563 (M+H)+. Anal, calc'd for C32H35N2O5CI • 0.80 H3PO4: C, 59.92; H, 5.88; N, 4.37. Found: C, 59.90; H, 5.83; N, 4.07.
Example 466 frans. frans-4-M .4-Benzodioxan-6-yt ,-2-(4-ethylphenvn- 1 -(((N-(3- chlorophenyn-N-butylamino carbonvnmethvnpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.86 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.40 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.70 (m, 1 H),
2.95 (m, 1 H), 3.20 (m, 2H), 3.40 (m, 1 H), 3.57 (m, 3H), 3.90 (m, 1 H), 4.25 (s, 4H), 6.80 (d, 1H, J=8Hz), 6.95 (d, 1 H, J=2Hz), 6.95 (m, 2H), 7.07 (br s, 3H), 7.22 (m, 3H). MS (APCI) m/e 577. (M+H)+. Anal, calc'd for C33H37N2O5CI • 0.85 H2O: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.
Example 467 frans. frans-4-(Benzofuran-5-yn-2-(4-ethylphenyh-1 -(((N-(3- chlorophenyn-N-butylamino')carbonynmethvnpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.85 (t, 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (m, 2H), 1.40 (m, 2H), 2.60 (q, 2H, J=7Hz), 2.72 (m, 1 H),
2.93 (m, 1 H), 3.22 (m, 2H), 3.50 (m, 1 H), 3.55 (m, 2H), 3.75 (m, 1H), 3.90 (br d, 1 H), 6.75 (d, 1H, J=1 Hz), 6.80 (br d, 1H), 6.95 (br s, 1 H), 7.08 (m,
4H). 7.20 (t, 1H, J=8Hz), 7.28 (t, 1H, J=8Hz), 7.42 (m, 2H), 7.58 (d, 1H, J=1Hz), 7.63 (s, 1H). MS (APCI) m/e 559 (M+H)+. Anal, calc'd for C33H35N2O4CI • 0.45 H2O: C, 69.88; H, 6.38; N, 4.94. Found: C, 69.83; H, 6.04; N, 4.87.
Example 468 frans. frans-2-(4-Methoxy-3-fluorophenyn-4-(7-methoxv-1 .3- benzodioxol-5-yn-1 -i:2-(N-butyl-N-phenvlamino)ethyπpyrrolidine-3- carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[2-(bromoethyl]-pyrrolidine-3-carboxylate, prepared using the procedures of Example 61 A (300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. H NMR (300 MHz, CDCI3) δ 0.90 (t, J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (m, 1 H), 2.68-2.77 (m, 1 H), 2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m. 3H), 3.45-3.55 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.83 (s, 3H), 3.90 (s, 3H), 5.95 (s, 2H), 6.51 (d, J=7Hz, 2H), 6.55-6.62 (m, 2H), 6.69 (d, J=2Hz, 1 H), 6.84 (t, J=8Hz, 1H), 7.02-7.15 (m, 3H), 7.19 (dd, J=2Hz, 12Hz, 1 H).
Example 469 trans. frans-4-( 1 .4-Benzodioxan-6-yl >-2-(4-ethylphenyπ-1 -(((N .N- di(n-butyπaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.78 (t, 3H, J=7Hz), 0.88 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.78 (m, 1H), 2.9-3.2 (envelope, 4H), 3.30 (m, 1 H), 3.40 (m, 3H), 3.60 (m, 1 H), 3.80 (m. 1 H), 4.25 (s, 4H), 6.80 (d, 1H, J=8Hz), 6.90 (m, 1H), 6.98 (d, 1 H, J=2Hz), 7.17 (d, 2H, J=8Hz), 7.30
(m, 2H). MS (APCI) m/e 523 (M+H)+. Anal, calc'd for C31 H42N2O5 • 1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81 ; H, 7.55; N, 4.48. Example 470 trans, trans- 4-(1 .4-Benzodioxan-6-yl >-2-(4-methoxyphenvπ-1 -((N- butyl-N-(3-methylphenylamino)carbonyπmethvhpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 μ NMR (300 MHz, CD3OD) δ 0.87 (t, J=7.1 Hz, 3H), 1.30 (m, 2H), 1.44 (m, 2H), 2.30 (s, 3H), 2.80 (d. J=15.2 Hz, 1H), 2.85 (t, J=9.3 Hz, 1 H), 3.19 (t, J=9.3 Hz, 1 H), 3.33 (d, J=10.2 Hz, 1 H), 3.42-3.61 (m, 3H), 3.79 (s, 3H), 3.91 (d, J=9.8 Hz, 1H), 4.22 (m, 4H), 6.75-6.86 (m, 6H), 6.95 (d. J=2.0 Hz, 1H). 7.09 (d. J=8.8 Hz, 2H), 7.22" (d, J=10.2 Hz, 1 H),
7.26 (t, J=7.6 Hz, 1 H). MS (DCl) m/e 559 (M+H+). Anal calcd for C33H38N2O6 • 0.4 CH3CO2C2H5: C, 69.97; H, 6.99; N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48.
Example 471 frans.frans-4-(1 .4-Benzodioxan-6-yn-2-(4-methoxyphenyl }-1 -((N- butyl-N-(3-chlorophenylamino)carbonynmethynpyrrolidine-3- carboxyiic add Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (t. J=7.0 Hz, 3H), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d, J=14.6 Hz, 1 H), 2.86 (t, J=9.0 Hz, 1 H), 3.16 (t, J=9.5 Hz, 1 H), 3.34-3.43 (m, 2H), 3.48-3.62 (m, 3H), 3.79 (s, 3H), 3.85 (d, J=9.5 Hz, 1 H), 4.22 (m, 4H), 6.78 (d, J=8.5 Hz, 1H), 6.81- 6.86 (m, 3H), 6.93-7.09 (m, 5H), 7.33-7.38 (m, 2H). MS (DCl) m/e 579 (M+H+). Anal calcd for C32H35CIN2O6 • 1.1 CH3CO2C2H5 • 0.15 H3PO4: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.
Example 472 frans.frans-4-M .3-Benzodioxol-5-yl ;-2-(4-methoxyphenyn-1 -(4- pyridylmethyπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 2.84 (t, J=9.6 Hz, 1 H), 2.88 (dd, J=9.6, 7.3 Hz, 1H), 3.09 (dd, J=3.3, 9.6 Hz, 1H), 3.21 (d, J=14.3 Hz, 1H), 3.53 (m, 1H), 3.78 (s, 3H), 3.81 (m, 2H), 5.92 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 1H), 6.93 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 7.43 (m. 4H). 8.44 (d, J=5.2 Hz, 2H). MS (DCl) m/e 433 (M+H+). Anal calcd for C25H24N2O5 • 0.3 CH3CO2C2H5: C, 68.57; H. 5.80; N, 6.10. Found: C. 68.68; H, 5.60; N, 5.81.
Example 473 frans. frans-4-( 1 .3-Benzodioxol-5-vn-2-(4-methoxyphenyπ- 1 -((N- butyl-N-(3-f e rf-butylphenylamino)carbonvhmethvnpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.88 (t, J=7.2 Hz, 3H), 1.23 (s, 9H), 1.26-1.45 (m, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (m, 1 H), 3.13
(t, J=9.0 Hz, 1H), 3.29 (d, J=15.1 Hz, 1H), 3.50-3.66 (m, 4H), 3.77 (s. 3H), 3.84 (d, J=9.6 Hz. 1 H), 5.92 (s. 2H), 6.74 (d, J=7.7 Hz, 1 H), 6.79-6.85 (m. 4H), 6.86-6.90 (m, 1 H). 6.99 (t, J=1.8 Hz, 1 H), 7.06 (d, J=1.8 Hz, 1 H), 7.13 (m, 2H), 7.33 (t, J=7.7 Hz, 1 H), 7.42 (m, 1 H). MS (DCl) m/e 587 (M+H+). Anal calcd for C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.
Example 474 frans. frans-4-( 1 ■3-Benzodioxol-5-vn-2-(4-methoxyphenyl i- 1 -((N- butyl-N-(3-n-butylphenylamino)carbonyl ιmethvnpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.88 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 1.23-1.59 (m, 8H), 2.58 (t, J=7.6 Hz, 2H), 2.75 (d, J=15.3 Hz, 1 H), 2.80 (dd, J=8.5, 9.5 Hz, 1 H), 3.12 (t, J=9.3 Hz, 1 H), 3.29 (d, J=15.6 Hz, 1 H), 3.46 (dd, J=4.9, 9.7 Hz, 1 H), 3.52-3.64 (m, 3H), 3.78 (s, 3H), 3.83 (d, J=9.8 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.79- 6.87 (m, 4H), 7.05 (d, J=1.7 Hz, 1 H), 7.10 (d, J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 (t, J=7.6 Hz, 1 H). MS (DCl) m/e 587 (M+H+). Anal calcd for C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74. Example 475 f rans. fraπs-4-(3.4-Difluorophenyl 1-2- (4-ethylphenvh- 1 -(N-(n-buty H- N-(3-methylphenyl ιaminocarbonylmethvQpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (CD3OD, 300 MHz) δ 0.87 (t, 3H, J=7), 1.19 (t, 3H,
J=7), 1.28 (m, 2H), 1.43 (m, 2H), 2.28 (s, 3H), 2.60 (q, 2H, J=7), 2.66 (m, 2H), 3.06 (m, 1 H), 3.21 (d, 1 H, J=15), 3.42 (dd, 1 H, J=4,9), 3.58 (m, 3H), 3.71 (d, 1 H, J=9), 6.80 (s, 2H), 7.06 (s, 4H), 7.18 (m, 4H), 7.45 (m, 1 H). MS (APCI) m/e 535 (M+H)+. Anal calcd for C32H36N2O3F2 • 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.
Example 476 frans. frans-2-(4-Ethylphenyπ-4-(3.4-difluorophenvπ- 1 -(N-(n-butyl 1- N-(3-chlorophenyl ιaminocarbonylmethyl ιpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) δ 0.82 (t, 3H, J=7), 1.16 (t, 3H, J=7), 1.23 (m, 2H). 1.35 (m, 2H), 2.55 (q, 2H, J=7), 2.66 (m, 2H), 3.01 (t. 1 H, J=9), 3.16 (d, 1 H. J=15), 3.32 (dd. 1H. J=4,9), 3.56 (m, 3H), 3.67 (d, 1 H, J=9), 6.94 (d, 1 H, J=7), 7.02 (m, 5H), 7.14 (m, 2H), 7.32 (m, 3H). MS (APCI) m/e 555 (M+H)+. Anal calcd for C31 H33N2O3CIF2 • 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.
Example 477 frans. frans-4-( 1 .4-Benzodioxan-6-yl ,-2-(4-fluorophenyn-1 -(N-butyl- N-(3-chlorophenyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.10-
1.30 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (t, J=7 Hz, 1H), 3.15-3.75 (m, 6H).
4.02 (m; 4H), 6.75 (d, J=6 Hz, 1 H), 6.85 (dd, J=7 Hz, 1H), 6.90 (7.19, J=m Hz, 6H), 7.32-7.43 (m, 3H). MS (DCl) m/e 567 (M+H)+. Anal calcd for
C31 H32N2O5FCI • 1.6 H2O: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20;
H, 5.54; N, 4.42. Example 478 frans. frans-4-(Benzofuran-5-yn-2-(4-ethylphenyl )- 1 -(N . N-di(n- butyhaminocarbonylmethyl ι-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CDCI3) δ 0.78 (t. 3H. J=7Hz), 0.84 (t.
3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 1.21 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.45 (m. 2H), 2.62 (q, 2H, J=7Hz). 2.80 (d, 1 H, J=13Hz). 3.0 (m, 2H), 3.15 (m, 2H), 3.35 (m. 1 H), 3.43 (m, 2H). 3.52 (m, 1H), 4.40 (m, 2H), 6.73 (d, 1 H, J=1 Hz), 7.14 (d, 2H, J=8Hz), 7.26 (s. 1 H), 7.31 (d, 2H, J=8Hz), 7.44 (s, 2H), 7.60 (d, 1 H. J=1 Hz), 7.65 (s, 1 H). MS (APCI) m/e 505 (M+H)+. Anal, calc'd for C31 H40N2O4: C, 73.78; H, 7.99; N, 5.55. Found: C. 73.69; H,
7.97; N, 5.21.
Example 479 trans. frans-2-(4-Methoxy-3-fluorophenvh-4-(7-methoxy- 1 .3- benzodioxol-5-vn-1 -r2-(N-propyl-N-(pyrrolidine-1 - carbonylmethynamino .ethyllpyrrolidine-3-carboxylic acid
Ethyl 2-(4-methoxy-3-fluoropheny!)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)- 1 -[2-( N-propyl-aminoethyl]-pyrrolidine-3- carboxylate, prepared according to the procedures of Example 61 B (300 mg), N-bromoacetyl pyrrrolidine (132 mg) and diisopropylethylamine (154 mg) were heated for 1 hour at 50 °C in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example 1 D. H NMR (300 MHz, CDCI3) δ 0.88 (t, J=7Hz, 3H), 1.30-1.45 (m, 2H), 1.75-1.92 (m, 4H), 2.30-2.40 (m, 1 H),
2.47-2.58 (m, 2H), 2.70-3.00 (m, 5H), 3.24-3.45 (m, 6H), 3.50-3.70 (m, 2H), 3.83 (s, 3H), 3.86 (d, J=9Hz, 1 H), 3.88 (s, 3H), 5.93 (s, 2H). 6.58 (d, J=2Hz, 1 H), 6.70 (d, J=2Hz, 1 H), 6.87 (t, J=8Hz, 1H), 7.10 (d, J=9Hz, 1 H), 7.21 (dd, J=2Hz, 12Hz, 1 H).
Example 480 trans. trans-2-(4- Met hoχyphenyl ι-4-π .3-benzodioxol-5-yl >- 1 -( 2- (( N-
(perhvdroazepinylcarbonyl ;-(DHeucvhamino)ethyπpyrrolidine-3- carboxylic acid Example 480A D-Leucine O-benzyl ester Tosylate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 g). The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).
Example 480B
N-Perhvdroazepinylcarbonyl-D-Leucine O-Benzyl ester To the compound resulting from Example 480A (1.0 g) dissolved in chloroform (20 mL) was added triethylamine (0.4 mL). The solution was cooled to 0 °C, and carbonyldiimidazole was added. After 1.5 hours, TLC indicated complete consumption of starting material, so hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 H3PO4 (2 x 20 mL), and brine (20 mL), dried over Na2Sθ4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 25 - 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).
Example 480C
N-Perhvdroazepinylcarbonyl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% palladium on carbon (10 mg). After flushing the flask with nitrogen, the reaction was stirred vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg). Example 480D frans. frans-2-(4-Methoxyphenyn-4-( 1 .3-benzodioxol-5-vn-1 - (cvanomethvπ-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 % wt. solution in toluene) dissolved in acetonitrile (2.0 mL) was added diisopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 mL). After 2 hours, TLC indicated complete comsumption of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with 20 - 40% EtOAc in hexanes to give the title compound as a coloriess""oil (0.28 g, 99%).
Example 480E frans. frans-2-(4-Methoxyphenvπ-4-(1 .3-benzodioxol-5-yπ-1 -(2- aminoethyl ι-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 g), and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) and extracted with 1 M HCI (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 x 2 mL). The combined organic extracts were dried with MgS04, filtered and evaporated to give the title compound as an unstable oil (0.14 g).
Example 480F frans. frans-2-(4-Methoxyphenvπ-4-( 1 .3-benzodioxol-5-yl ι-1 -(2-((N- (perhvdroazepinylcarbonvπieucvπamino ethvπ-pyrrolidine-3- carboxylic acid, ethyl ester The compound resulting from Example 480E (0.10 g) was dissolved in methylene chloride (3.0 mL), and the compound resulting from Example 480C (0.07 g) was added. The solution was cooled to 0 °C, and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 mL), and EtOAc (10 mL). The orgainc solution was washed with water (1 mL) and brine (1 mL), dried over MgS04, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50 - 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%).
Example 480G frans. frans-2-(4-Methoχyphenyn-4-( 1.3-benzodioxol-5-yl .- 1 -(2-((N-
(perhydroazepinylcarbonyl ιleucyπamino)ethvπpyrrolidine-3-carboxylic acid The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 mL) and 5 M. Naθμ (0.050 mL) was added. After 2 hours, additional 5 M NaOH (0.090 mL) was added. After an additional 3.5 hours, the reaction was evaporated. The residue was dissolved in water (5 mL) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 JN. H3PO4 to pH = 3. The solid which precipitated dissolved when the mixture was extracted with chloroform (3 x 3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgS04, filtered and evaporated to give the title compound as a tan solid (0.053 g). Purification by HPLC (Vydac mC18) eluting with a 10 - 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophiiization of the desired fractions. 1 H NMR (CDCI3, 300 MHz) δ 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87
(dd, J = 5.7, 5.7 Hz, 6H). 1.04-1.28 (m, 3H), 1.34-1.65 (m, 19H), 2.95 (br m, 2H), 3.15-3.40 (m, 14H), 3.40-3.55 (m, 4H), 3.58-3.68 (m, 2H), 3.70- 3.76 (br m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93 (s, 3H), 5.95 (s, 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (br m, 3H), 8.2 (br s, 1 H), 8.5 (br s, 1H). MS(DCI/NH3) m/e 623 (M+H)+. Anal calcd for C34H46N4O7 • 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.
Example 481 trans. frans-4-(1 .3-Benzodioxol-5-yO-2-(4-methoxyphenyl t- 1 -(N. N- di(n-hexyπaminocarbonylmethyl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.80-0.95 (m, 6H), 1.0 (m,
2H), 1.07 (1.55, J=m Hz, 14H), 2.70 (d, J=13 Hz, 1 H), 2.85-3.15 (m, 4H), 3.20-3.60 (m, 9H), 3.64 (d, J=10 Hz, 1 H), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H), 1 , 6.80-6.93 (m, 3H), 7.05 (2, 1 H), 7.35 (d, J=10 Hz, 2H). Anal calcd for C33H46N2O6 • 1.7 H2O: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52.
Example 482 frans. frans-4-(1 .4-Benzodioxan-6-vn-2-(4-fluorophenyh-1 -(N-butvl-
N-(3-methylphenyhaminocarbonylmethynpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7 Hz, 3H), 1.20-
1.35 (m, 2H), 1.35-1.40 (m, 2H), 2.32 (s, 3H), 2.5^-2.70 (m, 2H), 2.97 (t, J=7 Hz, 1H), 3.22 (d, J=14 Hz, 1H), 3.25-3.70 (m, 5H), 4.20 (m, 4H), 6.97 (d, J=2 Hz, 1H), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCl) m/e 547 (M+H)+. Anal calcd for C32H35N2O5F • 1.2 H2O: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70.
Example 483 frans.frans-4-M .3-Benzodioxol-5-vn-2-(4-methoxyphenyl )-1 -(((N- butyl-N-(3-nitrobenzyl .amino carbonyl ,methynpyrrolidine-3- carfroxyiic add Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CDCI3 ) δ (rotamer) 8.14 (2H, m), 8.05 (7.83) (1 H, m), 7.60-7.30 (3H, m), 7.13 (1 H, m), 7.10-6.70 (5H, m), 5.94 (2H, m), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, m), 4.10 (2H, m), 3.80 (3.76) (3H, s), 3.75-3.40 (3H, m), 3.20-2.80 (2H, m), 1.50 (1H, m), 1.30 (1H, m), 1.20-1.00 (2H, m), 0.91 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8 • 2.1 TFA: C, 52.44; H, 4.51 ; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.
Example 484 frans. frans-4-(1 .2-Dihydrobenzofuran-5-vh-2-(4-ethylphenyn-1 -(((N- butyl-N-(3.4-dimethoxybenzyπamino)carbonvπmethyπpyrrolidine-3- carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1 H (300MHz, CDCI3 ) δ (rotamer) 7.40 (2H, m), 7.30-7.10 (4H, m), 6.90-6.70 (3H, m), 6.48 (1H, m), 5.45 (1H, m), 4.65 (1 H, d, J=15), 4.57 (2H, dt, J=9, 3), 4.40-4.00 (5H, m), 3.87 (3.85) (3H, s), 3.84
(1 H, m), 3.63 (3.79) (31 '.. s), 2.5S (2H. m). 3 ?o (?H. t. J=10 . 2.90 (1 H, m), 2.64 (2H, q, J=8), 1.52 (1 H, m), 1.31 (2H, m), 1.22 (3H, dt, J=9, 2), 1.07 (1 H, m), 0.92 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 601 (M+H+).
Anal calcd for C36H44N2O6 • 1.35 TFA: C, 61.59; H, 6.06; N, 3.71.
Found: C, 61.69; H, 6.04; N, 3.63.
Example 485 frans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxvphenvn-1 -(((N- butyl-N-(4-heptyl)aminQ)carbQπyl)methyl)pyrrQlidiπe-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. H NMR (300 MHz, CD3OD) δ 0.71-1.04 (m, 11H), 1.07- 1.35 (m, 6H), 1.73-1.53 (m, 4H), 2.79-3.25 (m, 5H), 3.35-3.44 (m, 1 H), 3.51-3.68 (m, 3H), 3.78-3.89 (m, 1 H), 3.79 (s, 3H), 5.92 (m, 2H), 6.74 (dd, J=1.7, 8.1 Hz, 1 H), 6.85 (td, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 7.02 (dd, J=1.7, 9.5 Hz, 1H), 7.36 (m, 2H). MS (Cl.) m/e 553 (M+H+). Anal calcd for C32H44N2O6: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31 ; H,
7.89; N, 5.06.
Example 486 trans, trans-2- (4- Methy lcvclohexyπ-4-H .3-benzodioxol-5-vπ- 1 -(N.N- di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as an amorphous solid. "Η NMR (CDCI3, 300 MHz) δ 0.88 (3H, d, J = 7Hz), 0.92 (3H, t, J = 7Hz), 0.96 (3H, t, J = 7Hz), 1.05 (1H, m), 1.22-1.40 (7H, m), 1.45-1.65 (6H, m), 1.67-1.84 (4H, m),
3.17-3.45 (6H, m), 3.70 (1 H, brm), 3.82 (1H, dd, J = 9Hz, 15Hz), 3.86 (1 H, d, J = 15Hz), 5.93 (2H, s), 6.73 (1 H, d, J = 8Hz), 6.78 (1 H, dd, J = 2Hz, 8Hz), 6.88 (1 H, d, J = 2Hz). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H44N2O5 • 0.25 CF3CO2H : C, 66.96; H, 8.43; N, 5.29. Found: C, 66.79; H, 8.60; N, 4.87. Example 487 frans. frans-2-(2-Propylpentvh-4-( 1 .3-benzodioxol-5-vn-1 -(N .N-di(n- butvhaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) δ 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.12- 1.40 (13H, m), 1.42-1.68 (6H, m), 2.90 (1H, m), 3.14-3.30 (2H, m), 3.33 (4H, m), 3.72 (1 H, brm), 3.90 (1 H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal calcd for C30H4I3N2O5 • 0.35
CF3CO2H : C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98.
Example 488
(rang, fraπg-4-( 1 ,4-Benzodioxap-6-yi)-2-(4-flucrophenyl)-1 -(N,N-di(p- butyhaminocarbonylmethyl ,-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.83 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.90-1.17 (m, 4H), 1.20-1.65 (m, 5H), 2.77d (13, 1 H), 2.87 (dd, J=8, 2 Hz, 1 H), 2.95-3.60 (m, 7H), 3.71 (d, J=9 Hz, 1 H), 4.21 (s, 4H), 6.72 (d, 1 H), 6.91 (dd, J=8 Hz, 1 H), 6.97 (d, J=2 Hz, 1 H), 7.05 (t, J=7 Hz,
2H), 7.40-7.50 (m, 2H). MS (DCl) m/e 513 (M+H)+. Anal calcd for C29H37N205F - I .2C F3COOH: C, 58.07; H, 5.93; N, 4.31. Found: C,
57.94; H, 5.81 ; N, 4.56.
Example 489 frans. frans-2-(3-Methylpentyh-4-( 1 .3-benzodioxol-5-vn-1 -(N . N-di(n- butyl ,aminocarbonylmethyl ,-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.83 (3H, t, J = 7Hz), 0.85 (3H, d, J= 7Hz), 0.91 (3H, t, J = 7Hz),
0.97 (3H, t, J = 7Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7H, m), 1.43-1.68 (5H, m), 1.89 (1 H, m), 2.94 (1 H, t, J = 6Hz), 3.15-3.27 (3H, m), 3.29-3.60 (5H, m). 3.72 (1 H. brd, J = 6Hz), 3.92 (1 H, brd, J = 13.5Hz), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1 H, d. J = 8Hz), 6.78 (1 H, dd, J = 2Hz, 8Hz), 6.88 (1 H, d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5 • 0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.
Example 49Q frans. frans-2-(2-Ethylbutvn-4-( 1 .3-benzodioxol-5-vh-1 -(N .N-di(n- butyl ιaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared and isolated as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.13- 1.41 (13H, m), 1.43-1.72 (6H, m), 2.96 (1H, brm)r3.12-3.52 (6H, m), 3.55-3.70 (1 H, m), 3.70-3.86 (2H, m), 3.99 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1 H, dd, J = 2Hz, 8Hz), 6.88 (1 H, d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5 • 0.45 CF3CO2H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 5.08.
Example 491 frans. frans-2-(3-Fluoro-4-methoxyphenyπ-4-(1 .3-benzodioxol-5-vπ-
Figure imgf000437_0001
carboxylic acid
Using the procedures described in Example 66, the title compound was prepared. H NMR (CD3OD, 300 MHz) δ 0.74 (d, 3H, J=7), 0.83 (d, 3H, J=7), 0.94 (t, 3H, J=7), 1.44 (hex, 2H), 1.67 (m, 4H), 2.91 (d, 2H, J=8), 3.04 (dd, 2H, J=8,10), 3.1-3.6 (m, 5H), 3.78 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5.97 (s, 2H), 6.82 (d, 1H, J=8), 6.89 (dd, 1H, J=2, 8), 7.01 (d, 1H, J=2), 7.22 (t, 1H, J=9), 7.39 (m, 2H). MS (ESI) m/e 579 (M+H)+.
Example 492 frans. frans-2-(4-Methoxy-3-fluorophenyn-4-( 1 .3-benzodioxol-5-vn- 1 -r2-(N-propyl-N-f4-ethylpyrimidin-2-yllamino)ethyllpyrrolidine-3- carboxylic acid 1-Dimethy!amino-1-pentene-3-one, prepared by the method described in Syn. Comm. 12 (1), 35 (1982), was converted to 2-amino- 4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2-bromo-4-ethyl-pyrimidine with NaN02 and HBr, using the method of Helv. Chim. Acta 75, 1629 (1992). This bromopyrimidine was reacted with ethyl 2-(4- methoxphenyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -[2-(N-propylamino)propyl]- pyrrolidine-3-carboxylate, prepared using the procedures of Example 61 B, using the procedure for Example 418, to give the title compound as a white powder. 1μ NMR (300 MHz, CDCI3) δ 0.83 (t, J=7Hz, 3H), 1.11 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1 H), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (m, 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (d, J=4Hz, 1 H), 6.68 (d, J=8Hz, 1H), 6.79 (dd, J=2Hz, 8Hz, 1 H), 6.82 (t, J=9Hz, 1H), 6.92 (d, J=2Hz, 1 H), 7.05 (d, J=9Hz-r 1 H), 7.15 (dd, J=2Hz, 12Hz, 1 H), 8.10 (d, J=4Hz. 1H).
Example 493 trans. frans-4-( 1 .3-Benzodioxol-5-yn-2-(4-methoxyPhenvn- 1 -((N- butyl-N-(3.4-dimethylphenyπaminocarbony0methyπpyrrolidine-3- carboxyliς add
Using the procedures described in Example 1 , the title compound was prepared. 1 H NMR (300 MHz, CD3OD) δ 0.87 (t, J=7.3 Hz, 3H), 1.23- 1.36 (m, 2H), 1.38-1.43 (m, 2H), 2.22 (s, 3H), 2.29 (s, 3H), 2.79 (d, J=14.9 Hz, 1 H), 2.84 (dd, J=8.6, 9.7 Hz, 1 H), 3.16 (t, J=9.5 Hz, 1 H), 3.32 (d, J=15.3 Hz, 1 H), 3.43-3.61 (m, 4H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz,
1 H), 5.93 (s, 2H), 6.74 (m, 3H), 6.83 (m, 3H), 7.04 (d, J=1.7 Hz, 1 H), 7.1 1 (m, 3H). MS (Cl.) m/e 559(MH+). Anal calcd for C33H38N2θ6«0.3H2θ: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.
Example 494 frans. frans-2-(3-Methylpent-3-en-1 -yπ-4-( 1 .3-benzodioxol-5-yl ι-1 - (N.N-di(n-butyl .aminocarbonylmethvπ-pyrrolidine-3-carboxylic acid Using the procedure described in Example 1 , the title compound was prepared and isolated as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.22-1.40 (5H, m),
1.44-1.61 (8H, m), 1.82 (1 H, brm), 2.02 (2H, m), 3.05-3.30 (4H, m), 3.3.8 (1 H, m), 3.55 (1 H, brm), 3.85 (2H, m), 4.12 (1 H, brd, J = 15Hz), 5.11 (1 H, dd, J = 6Hz, 12Hz), 5.93 (2H, s), 6.73 (1 H, d, J = 8Hz), 6.78 (1 H, dd, J = 2Hz, 8Hz), 6.88 (1 H, d, J = 2Hz). MS (DCI/NH3) m/e 487 (M+H)+. Anal calcd for C28H42N2O5 • 0.7 CF3CO2H : C, 62.34; H, 7.60; N, 4.95. Found: C, 62.49; H, 7.43; N, 4./ . Example 495
1-(N-Phenylaminocarbonylmethyn-2-(4-methoxyphenyπ-4-(1.3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid
Example 495A N-Phenylbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 L) at -50 °C was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40 °C On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2S04) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.
Example 495B frans.frans-1 -(N-Phenylaminocarbonylmethyl1-2-(4-methoχyphenyl ι- 4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and the compound resulting from Exampe 495A, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 8.8 (bs, 1H) 7.49 (2H, d, =8Hz), 7.38 (4H, m), 7.11
(1H, tt, =8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, =2Hz), 5.98 (1H, d, J=2Hz), 3.94 (1H, d, =10Hz), 3.78 (3H, s), 3.70 (1H, ddd, =6, 5&3Hz), 3.42 (1H, dd, J=10&3Hz), 3.41 (1H, d, J=16Hz), 3.18 (1H, dd, =11&9Hz), 3.01 (1H, t, =10Hz), 2.93 (1H, d, J=16Hz). MS (DCl, NH3) m/e 475 (M+H+). Anal. Calc for C27H26N2O6 • 1 H2O: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38. Examole 496 frans. frans-1 -(N-(2.3-Dimethylphenvnaminocarbonylmethvh-2-f 4- methoxyphenvn-4-(1.3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) δ 8.68 (1H, bs), 7.64 (d, J=8Hz), 7.38, (2H, d, =8Hz), 7.09 (1H, t, J=8Hz), 6.97, (1H, d, =8Hz), 6.90 (1H, d, =2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, =8&3Hz), 6.76 (1H, d, =8Hz), 5.97 (1H, d, =2Hz), 5.96 (1H, d, =2Hz), 3.95 (1H, d, =10Hz), 3.80 (3H, s), 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, =10&3Hz), 3.44 (1H, d, =16Hz), 3.18 (1H, dd, J=11&9Hz), 3.06 (1H, t, =10Hz), 2.96 (1H, d, =16Hz), 2.31 (3H, s), 2.16 (3H, s). MS (DCl, NH3) me 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.5 H2O: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29.
Example 497 trans, trans- 1-(N-(2.4-Dimethylphen vhaminocarbon ylmethvπ-2-(4- methoxyphenvπ-4-(1.3-benzodioxol-5-yπpyrrolidine-3-carboxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) δ 8.60 (1H, bs), 7.78 (d, =8Hz), 7.38, (2H, d, =8Hz), 6.99 (1H, m), 6.95, (1H, d, J=8Hz), 6.94
(1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, =8&3Hz), 6.77 (1H, d, =8Hz), 5.97 (1H, d, =2Hz), 5.96 (1H, d, =2Hz), 3.92 (1H, d, =10Hz), 3.79 (3H, s), 3.68 (1H, ddd, =6, 5&3Hz), 3.43 (1H, dd, =10&3Hz), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, =11&9Hz), 3.04 (1H, t, =10Hz), 2.95 (1H, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCl, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.75 H2O: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13.
Example 498 frans. frans-1-(N-(2.5-Dimethylphenynaminocarbonylmethvn-2-(4- methoxyphenvπ-4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carhoxylic acid
Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) δ 8.62 (1H, bs), 7.79 (1H, bs),
7.38, (2H, d, J=8Hz), 7.03 (1H, d, J=8Hz), 6.95, (1H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, d, =SH.z), 5.9*7 (2H. s). 3.92 (1H. d. J=10Hz), 3.78 (3H, s), 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1 H, d, =16Hz), 3.18 (1H, dd, =11&9Hz), 3.04 (1H, t, =10Hz), 2.95 (1H, d, =16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCl, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.5 H2O: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5.89; N, 5.25.
Example 499 frans. frans-1 -(N-(3.4-Dimethylphenynaminocarbonylmethyl )-2-(4- methoxyphenvn-4-(1.3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. 1H NMR (300 MHz, CDCI3) δ 8.73 (1H, bs). 7.38 (2H, bd, J=8Hz), 7.30, (1H, d, J=3Hz), 7.20 (1H, bs), 7.08, (1H. d, J=8Hz), 7.01 (1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1H, bs), 6.80 (1 H, d, =8Hz), 5.99 (1 H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1 H, d, J=10Hz), 3.78 (3H. s). 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, =10&3Hz), 3.42 (1H. d.
J=16Hz). 3.18 (1H. dd, =11&9Hz), 3.04 (1H, t, J=10Hz), 2.95 (1H, d. J=16Hz), 2.25 (3H, s), 2.21 (3H, s). MS (DCl, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 ■ 0.75 H2O: C, 67.50; H, 6.15; N 5.43. Found: C, 67.24; H, 5.94; N, 5.20.
Example 500 frans. frans-1 -(N-(3.5-Dimethylphenynaminocarbonylmethyn-2-(4- methoxyphenyn-4-(1 .3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) δ 8.75 (1H, bs), 7.35, (2H, d, =8Hz), 7.10 (2H, s), 7.02 (1 H, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1H, d, =2Hz), 6.80, (1H, d, =8Hz), 6.76 (1H. bs). 5.99 (1H. d, J=3Hz). 5.98 (1H, d, J=3Hz). 3.92 (1H, d, J=10Hz), 3.79 (3H, s), 3.68 (1H, ddd. J=6, 5&3Hz), 3.40 (2H, m), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J=10Hz), 2.88 (1H, d, J=16Hz), 2.3 (6H, s). MS (DCl, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 ■ 0.5 H2O: C, 68.09; H, 6.11 ; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19. Example 501
Alternate Preparation of
(+)-trans. trans- 1 -(N. N-Di(n-butyl laminocarbonylmeth vh-2-(4- methoxyphenyn-4-(1 .3-benzodioxol-5-yl ιPyrrolidine-3-carboxylic acid Hydrochloride Salt
Example 501 A N. N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0 °C was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 °C Upon completion of the addition, the reaction mixture was stirred at 0 °C for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.
Example 501 B 5-(2-Nitrovinvh-1 .3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 °C After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 °C for 2 days to afford 15.94 kg (80%) of the title compound as a bright yellow solid. Example 501 C 4-Methoxybenzoyl acetate To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5 °C under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 °C The reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 °C and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20 °C The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
Example 501 D Ethyl 2-(4-methoxybenzovπ-4-nitromethyl-3-(1 .3-benzodioxol-5-yπ butyrate
To the compound resulting from Example 501 B (7.5 kg, 37.9 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example C (8.4 kg, 37.9 mol). The mixture was cooled to 17 °C, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about 15 minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (6.4 g, 0.095 mol) was added, and the mixture was stirred at 25 °C until HPLC shows less than 1 area % ketoester remaining. The reaction was concentrated to 32.2 kg which was determined by HPLC assay to be -14.9 kg (95%).
Example 501 E Ethyl cis. c/s-2-(4-methoxyphenvh-4-(1 .3-benzodioxol-5-yπ pyrrolidine-3-carboxylate Raney nickel (20.0 g), from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple. THF (20 mL), the crude compound resulting from Example 501 D (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at 60 psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area % nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and chased with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 N NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g (73%) of the title compound.
Example 501 F Ethyl trans. frans-2-(4-methoxyphenyπ-4-( 1 .3-benzodioxol-5-vπ pyrrolidine-3-carboxylate The solution of the compound resulting from Example 501 E (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 °C When HPLC shows <3% of the cis.cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound. Example 501 G Ethyl (2R.3R. 4SH+)-2-(4-methoxyphenvn-4-(1 .3-benzodioxol-5-yl, pyrrolidine-3-carboxylate. (SH+) mandelate salt The solution resulting from Example 501 F was chased with acetonitrile (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g (40%) of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexane- ethanol-diethylamine; flow - 1 ml_/min.; UV detection at 227 nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21 .0 min.
Example 501 H (2R.3R.4S)-(+)-2-(4-methoxyphenvh-4-(1 .3-benzodioxol-5-vn- 1 -rN.N- di(n-butyhaminocarbonylmethvπ- pyrrolidine-3-carboxylic acid The compound resulting from Example 501 G (20.0 g, 0.0383 mol) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 °C Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution (40%, 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH 5 with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound. Example 5011 (2R.3R.4S-)-r+ 2-(4-methoxyphenvh-4-(1 .3-benzodioxol-5-vn-1 -(N.N- di(n-butyπaminocarbonylmethylι- pyrrolidine-3-carboxylic acid hydrochloride salt
To a solution of the compound of Example 501 H in ethyl acetate at room temperature in a mechanically stirred vessel equipped with a thermocouple, was added 39.4 mL of 1 N HCI in ethanol (0.0394 mol) The resultant solution was filtered to remove foreign matter, concentrated In vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g (90%) of the title compound.
Example 502 trans. frans-2-(2-Methylpentyl .-4-M .3-benzodioxol-5-yl ι- 1 -(N,N- di(n-butyπaminocarbonylmethvh-pyrrolidine-3-carboxylic acid
Example 502A (±ι-Ethyl 3-methylhexanoate
To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of hexanes and 100mL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmo!) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50mL of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0g of the title rnmnnπn . Examole 502B (±)-Ethyl 5-methyl-3-oxooctanoate
To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964).
Example 502C trans. frans-2-(2-Methy pentvn-4-( 1 .3-benzodioxol-5-yh-1 -(N .N- di(n-butyl ιaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 1 and substituting ethyl 5-methyl-3-oxooctanoate for ethyl (4-methoxybenzoyl)acetate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. Note that the multiplicity of the signals in the aryl region of the NMR spectrum reflects a 1 :1 mixture of diastereomers on the alkyl chain. 1 H NMR (CDCI3, 300 MHz) δ 0.8-1.0 (m, 12H), 1.2-1.4 (m, 7H), 1.45-1.6 (m, 6H), 1.6-1.74 (m, 1H), 1.8-2.0 (m, 1 H), 3.1-3.4 (m, 5H), 3.67-3.78 (m, 1 H), 3.8-3.91 (m, 1H), 4.0-4.2 (m, 2H), 4.3-4.5 (m, 2H), 5.93 (d, J=1.5 Hz, 2H), 6.73 (dd, J=8.1 , 1.2 Hz, 1 H), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 6.86 (dd, J=3.9, 1.5 Hz, 1H). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C2δH44N2θ5«1.0 TFA* 0.5 H2O: C, 58.91 ; H, 7.58; N, 4.58. Found: C, 58.91 ; H, 7.58; N, 4.45. Example 503 trans. frans-2-(2.2-Dimethylpentyl )-4-M .3-benzodioxol-5-vn-1 -( N. N- di( n-butyl ιaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3J_, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3- dimethylhexanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) δ 0.80-0^99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60- 3.69 (m, 1 H), 3.75-3.86 (m, 1 H), 3.95-4.16 (m, 2H), 4.28-4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1 H), 6.8 (dd, J=8.1 , 1.5 Hz, 1 H), 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N2θ5«1.05 TFA: C, 60.01 ; H, 7.62; N, 4.50. Found: C, 60.21 ; H, 7.37; N, 4.33.
Example 504 frans. frans-2-(2-( 1 .3-Dioxo-2-vnethyl >-4-( 1 .3-benzodioxol-5-vn- 1 - (N. N-di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Example 504A Ethyl 5-( 1 .3-dioxolvπ-3-oxopentanoate
The title compound was synthesized from ethyl acetoacetate and
2-bromomethyl- 1 ,3-dioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971 ).
Sodium hydride 4.97 g (0.124 mol), as a 60% mineral oil dispersion, was weighed into a 250 mL flask, into which 80 ml of tetrahydrofuran was directly added. The flask was capped with septum cap, flushed with nitrogen, and cooled in an ice bath. To above stirred slurry was added dropwise 15.0 mL (0.1 18 mol) ethyl acetoacetate. After the addition was complete, the resulting mixture was stirred at 0 °C for additional 10 min. To above mixture was then added 48.4 mL (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise mannpr The resultinα oranqe color solution was stirred for 10 min before 13.5 mL (0.130 mol) bromomethyl-1 ,3-dioxane was added in one portion. The reaction mixture was then allowed to warm to room temperature and stirred for additional 120 min before it was then quenched by slow addition of 9.8 ml (ca. 0.12 mol) concentrated hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was extracted thoroughly with additional ethyl ether. The ethereal extracts were combined, washed with 2x50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give an brown oily residue. The cruSe product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g (20%) of b-keto ester as a light yellow oil.
Example 504C frans. frans-2-(2-( 1 .3-Dioxo-2-yl ιethyn-4-( 1 .3-benzodioxol-5-yl )- 1 -
(N.N-di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502 and substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound. H NMR (CDCI3. 300 MHz) δ 0.93 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.38 (m, 4H), 1.52 (sextet, J = 7.9 Hz, 4H), 1.85-1.95 (m, 2H), 2.02-2.17 (m, 2H), 3.18 (dd, J = 6.0 Hz, 9.0 Hz, 2H), 3.30 (dd, J = 9.0 Hz, 18.0 Hz, 2H), 3.35 (m, 1 H), 3.79 (dd, J = 3.6 Hz, 6.9 Hz, 1 H), 3.83-3.88 (m, 3H), 3.97 (dd, J = 4.8 Hz, 6.0 Hz, 1 H), 4.05 (q, J = 9.6 Hz, 2H), 4.30-4.40 (m, 1 H), 4.37 (s, 2H), 4.87 (t, J = 3.6 Hz,
1 H), 5.94 (s, 2H), 6.73 (d, J = 8.1 Hz, 1 H), 6.79 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 6.87 (d, J = 1.8 Hz, 1 H). MS (APCI) (M+H)+ at m/e 505. Anal calcd for C27H40N2O7-1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H,
6.44; N, 4.27. Example 505 frans. frans-2-(2-(2-Tet rah vdro-2H-pyran ιethy I >-4-( 1 .3-benzodioxol- 5-yh-1 -(N . N-di(n-butvπ aminocarbonyl methy π-pyrrolidine-3- carboxylic acid Fxamole 505A Ethyl 5-(2-tetrahyriro-2H-Pyran)-3-oxopentanoate
Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow oil.
Example 505B frans. frans-2-(2-(2-Tetrahydro-2H-pyran)ethyn-4-( 1 .3-benzodioxol- 5-yπ-1 -(N.N-di(n-butyl )aminocarbonylmetHyl)-pyrrolidine-3- carboxylic acid
Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2H-pyran)-2-oxopentanoate for ethyl 3- methylhexanoate afforded the title compound as an amorphous solid.
1 H NMR (CDCI3, 300 MHz) as a mixture of two diastereoisomers: δ 0.89 (t, J = 8.1 Hz, 3H), 0.89 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 1.20-1.40 (m, 10H), 1.42-1.66 (m, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H), 3.10-3.29 (m. 8H), 3.29-3.52 (m, 6H), 3.54-3.81 (m, 6H), 4.01 (q, J = 9 Hz, 2H), 4.12-4.25 (m, 4H),
4.43 (d, J = 9 Hz, 2H), 4.50 (d, J = 2.7 Hz, 2H), 5.94 (s, 2H), 5.95 (s, 2H), 6.76 (s, 2H), 6.76 (s, 2H), 6.81 (s, 1 H), 6.81 (s, 1 H). MS (APCI) (M+H)+ at m/e 517. Anal calcd for C29H44N206-1 4 TFA: C, 56.48; H, 6.77; N,
4.14. Found: C, 56.46; H, 6.99; N, 3.83.
Example 506 trans. frans-2-(2.2.4-Trimethyl-3-pentenyn-4-( 1 .3-benzodioxol-5- ylb 1 -(N.N-di(n-butvπaminocarbonylmethyl ;-pyrrolidine-3-carboxylic add
Example 506A Methyl 3.3.5-trimethyl-4-hexenoate
To a slurry of isopropyltripenylphosphonium iodide (20.5g, 47mmol) in 200mL of tetrahydrofuran was added n-butyllithium (27mL of a 1.6M solution in hexane, 43mmol), and the solution was briefly warmed to 0°C After recooling, a solution of methyl 3,3-dimethyl-4- oxobutenoate (5.7g, 40mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 6 169 (1986) in 10mL of tetrahydrofuran was added, and the reaction was warmed to 0°C for 30min. The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1 g (30%) of the title "compound.
Example 506B trans. fraπs-2-(2.2.4-Trimethyl-3-pentenyl ι-4-( 1 .3-benzodioxol-5- yπ- 1 -(N . N-di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 1.1 1 (s, 3H), 1.13 (s, 3H), 1.24-1.37 (m, 4H), 1.46-1.59 (m, 4H), 1.61 (d, J=1.2 Hz, 3H), 1.69 (d, J=1.2 Hz, 3H), 2.04-2.11 (m, 2H), 3.10-3.20 (m, 2H), 3.30-3.39 (m, 3H), 3.67-3.82 (m, 2H), 3.95-4.08 (m, 1 H), 4.32 (m, 2H), 4.37-4.47 (m, 1 H), 4.99 (s, 1H), 5.95 (s, 2H), 6.73 (d, J=7.8 Hz, 1 H), 6.78 (dd, J=8.4, 1.2 Hz, 1 H), 6.84 (d,
J=1.2 Hz, 1H). MS (DCI/NH3) m/e 515 (M+H)+. Anal calcd for C30H46N2θ5«1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.
Example 507 trans. frans-2-(2.2. -Dimethyl-2-M .3-dioxolan-2-ynethyl ,-4-M .3- benzodioxol-5-vn-1 -(N .N-di(n-butyl ιaminocarbonylmethyn- pyrrolidine-3-carboxylic acid Example 507A Methyl 3.3-dimethyl-3-(1 .3-dioxolan-2-vnpropanoale
Methyl 3,3-dimethyl-4-oxobutanoate (10g, 70mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 1 6 169 (1986), was dissolved in 40mL of benzene, followed by addition of ethylene glycol (20mL), and p-toluenesulfonic acid monohydrate (1.3g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200mL of ether, washed with saturated sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g (94%) of the title compound.
Example 507B trans. frans-2-(2.2.-Dimethyl-2-M .3-dioxolan-2-vnethyl ,-4-M .3- benzodioxol-5-vπ-1 -(N.N-di(n-butvhaminocarbonylmethyl ι- pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502 and substituting methyl 3,3-dimethyl-3-( 1 ,3-dioxolan-2-yl)propanoate for ethyl 3- methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) δ 0.82-1.00 (m, 12H), 1.24-1.40 (m, 4H), 1.43-1.64 (m, 5H), 1.76- 1.84 (m, 1 H), 2.93-3.00 (m, 1 H), 3.15-3.47 (m, 6H), 3.60-3.70 (m, 3H), 3.74-3.95 (m, 5H), 4.48 (s, 1 H), 5.94 (m, 2H), 6.72 (d, J=8.0 Hz, 1 H), 6.83
(dd, J=8.0, 1.2 Hz, 1 H), 6.94 (d, J=1 .2 Hz, 1 H). MS (DCI/NH3) m/e 533
(M+H)+. Anal calcd for C29H44N2O7 «1.1 TFA-0.2 H2O: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25.
Example 508 frans. frans-2-(2-( 1 .3-Dioxo-2-yn ethyn-4- ( 1 .3-benzodioxol-5-yn- 1 - ['/V4 -h e ptyl-ΛA(2-methyl-3-fluorophenvπi amino carbonylmethyl]- pyrrolidine-3-carboxylic acid Example 508A 4-Heptanol
To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 20 mL of diethyl ether was added 370 mg (10.0 mmol) of UAIH4, in portions to keep ether reflux at a minimum. After 45 minutes, the reaction was quenched by sequential dropwise addition of 0.4 mL H2O, 0.4 mL 15% {w/v) NaOH( g), and 1.2 mL H2O. After stirring another 45 minutes, MgSθ4 was added until the salts were free flowing, then the reaction was filtered. The salts were washed with diethyl ether (3 x 5 mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g (100%).
Example 508B 4-Methanesulfonyloxyheptane
To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute. The mixture was stirred at 0 °C for 30 minutes, then extracted with
H2O (1 x 15 mL), 5% NH4OH (2 x 15 mL), 1 M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgS04, filtered, and concentrated to an oil. Yield 1.31g (94%). H NMR (300 MHz, CDCI3) d 0.96 (t, 6, J = 9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J = 5).
Example 508C 4-Fluoro-3-methylaniline
To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2g of 10% Pd-C The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil. Examole 508D A-Heptyl-4-fluoro-3-methylaniline
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4- methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHC03(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2 x 30 mL). The combined ether layers were back extracted with brine (1 x 30 mL), dried over MgSθ4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5: 2.5 hexanes: ethyl acetate, to give 2.56g (35%) of a pale yellow oil.
Example 508E /V.ΛA(4-Heptvπ-(4-fluoro-3-methyl ;phenylbromoacetamide
To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4- fluoro-3-methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 °C, then extracted with 1 M HCI (1 x 100 mL). The aqueous layer was back extracted with diethyl ether (1 x 50 mL), then the combined organic layers were washed with H2O (2 x 50 mL), saturated NaHCθ3(ag) (2 x 50 mL), and brine (1 x 50 mL), dried over MgS04, filtered, and concentrated in vacuo to an oil. This was purified via silica gel chromatography, eluting with 90:10 hexanes: ethyl acetate to give 7.48g (99%) of a light yellow oil. 1 H NMR (300 MHz, CDCI3) d 0.94 (t, 6, J = 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.31 (s,
1.5), 3.54 (s, 2), 4.72 (quintet, 1 , J = 5), 6.96-7.04 (m, 2), 7.07(d, 1 , J = 7). Example 508F trans. frans-2-(2-( 1 .3-Dioxol-2-vheth vH-4-d .3-benzodioxol-5-vh-1 -
[[/V4-heptyl-/V-(2-methyl-3-fluorophenvm amino carbonylmethyll- pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and Λ/,/y-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N- dibutylbromoacetamide afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) δ 0.93 (brt, 6HJT 1.23-1.47 (m, 8H),
1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9.0 Hz, 1 H), 3.52-3.67 (brm, 2H), 3.73 (t, J = 9.0 Hz, 1 H), 3.81 -4.02 (m, 6H), 4.13 (brm, 1 H), 4.72 (quintet, J = 6.9 Hz, 1 H), 4.86 (t, J = 4.0 Hz, 1 H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1 H), 6.78 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 6.85 (d, J = 1.8 Hz, 1 H), 6.96 (m, 2H), 7.08 (t, J = 9.0 Hz, 1 H). MS (DCI/NH3) (M+H)+ at m/e 599. Anal Calcd for C33H43N2O7F-O.8 TFA: C, 60.24; H, 6.40; N, 4.06. Found: C, 60.21 ; H, 6.14; N, 3.86.
Example 509 frans. frans-2-(2-( 1 .3-Dioxol-2-vnethvh-4-( 1 .3-benzodioxol-5-vn- 1 -
(N.N-di(n-butyl ιaminocarbonylmethvn-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5- (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6- methoxypiperonal for piperonal afforded the title compound as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.93 (t, J = 7.8 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H), 1.31 (m, 4H), 1.53 (m, 4H), 1.90 (m, 2H), 2.09 (m, 2H), 3.19 (dd, J = 8.4 Hz, 8.4 Hz, 2H), 3.30 (q, J = 9.6 Hz, 2H), 3.25-3.42 (m, 1 H), 3.73 (q, J = 10.5 Hz, 1 H), 3.78-3.94 (m, 4H), 3.88 (s, 3H), 3.96 (dd, J = 5.1 Hz, 6.0 Hz, 1 H), 4.03 (dd, J = 3.0 Hz, 6.3 Hz, 2H), 4.33 (m, 3H), 4.87 (t, J = 3.6 Hz, 1 H), 5.94 (s, 2H), 6.53 (d, J = 1.8 Hz, 1 H), 6.63 (d, J = 1.8 Hz, 1 H). MS (DCI/NH3) (M+H)+ at m/e 535. Anal calcd for C28H42N2O8-1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H,
6.66; N, 4.26. Example 510 frans. frans-2-((2-Methoxyphenoxyι-methvn-4-(1 .3-benzodioxol-5-yh- 1 -(N.N-di(n-butyl)aminocarbonylmethyh-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting o- methoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.15-1.35 (m, 4H), 1.40- 1.55 (m, 4H), 3.05-3.25 (m, 4H), 3.28-3.55 (m, 4H), 3.58-3.68 (m, 1 H), 3.75-3.80 (m, 1 H), 3.82 (s, 3H), 3.91 (d, J=14Hz, TH), 4.05-4.15 (m, 1H), 4.23-4.33 (m, 1 H),5.91 (s, 2H), 6.70 (d, J=8Hz, 1 H), 6.82-6.95 (m, 5H), 7.03 (s, 1H). MS (DCI/NH3) (M+H)+ at m/e 541. Anal calcd for C30H40N2O7: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61 ; N, 5.09.
Example 511
Figure imgf000456_0001
heptyl-N-(4-fluoro-β-methylphenvπ ιaminocarbonylmethyπ- pyrrolidine-3-carboxylic acid
Example 511 A trans, trans- N -fe rf-Butoxycarbonyl-2-(2.2-dimethylpentyn-4-M .3- benzodioxol-5-vn-Pyrrolidine-3-carboxylic add
Ethyl trans, frans-2-(2,2-dimethylpentyl)-4-(1 ,3-benzodioxol-5- yl)-pyrrolidine-3-carboxylate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 50mL of methylene chloride and di-ferf- butyldicarbonate (1.5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 50mL of ethanol followed by addition of sodium hydroxide (10mL of a 5M aqueous solution). After stirring for 20 hours at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water, and acidified with concentrated phosphoric acid. The mixture was extracted with chloroform (3X50mL), and the organic layers were washed wiith brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam.
Example 511 B
Methyl trans. frans-2-(2.2-dimethylpentvh-4-( 1 .3-benzodioxol-5-ylb
1 -(N-4-heptyl-N-(4-fluoro-3-methylphenyπ )aminocarbonylmethvh- pyrrolidine-3-carboxylate: As a single enantiomer
The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0°C, followed by addition of DMF (0.017mL, 5%), and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at 0°C under a stream of nitrogen. The residue was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazolidinone (1.2g, 6.8mmol) was dissolved in 30mL of THF followed by addition of n-butyllithium (4.0mL of a 1.6M solution in hexanes) at 0°C, and the slurry was stirred for 15min. The acid chloride was dissolved in 20mL of THF and cooled to 0°C, followed by dropwise addition of the lithium oxazolide suspension via cannula.
After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, 43%), then elution with 20% ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%). The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of trifluoroacetic acid was added. After 30min, the volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure.
The TFA salt was stirred with 4mL of acetonitrile followed by addition of diisopropylethyl amine (1.0mL, 5.7mmol), and N-4-heptyl- N-(4-fluoro-3-methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was warmed to 50°C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oil. The above amide (200mg, 0.26mmol) was dissolved in 2.0mL of
THF and 0.7mL of water. Solid lithium hydroxide monohydrate (22mg, 0.53mmol) was added at 0°C, followed by 30% hydrogen peroxide (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room temperature. After an additional hour, the reaction was partitioned between 1 :1 ethyl acetate:hexanes and water, 0.15g of sodium thiosulfate was added and the mixture was mixed thoroughly. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was dissolved in 2mL of ether, and 1 mL of methanol. A solution of (trimethylsilyl)diazomethane in hexanes was added dropwise until the yellow color remained. The reaction was quenched by addition of 2 drops of glacial acetic acid, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on 10g of silica gel eluting with 15- 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5°C).
Example 511C f2S.3R.4Sh trans. frans-2-(2.2-Dimethylpentyl .-4-(1 ,3-benzodioxol-5- yn- 1 -(N-4-heptyl-N-(4-fluoro-3- m ethyl phenyh'l ami nocarbonylmethyl)-pyrrolidine-3-carboxylate
The product from Example 510B (65mg, O.I Ommol) was dissolved in 1.0mL of methanol and sodium hydroxide (0.1 mL of a 5M aqueous solution) was added. After 2 hours, the reaction was warmed to reflux. After 6 hours, the reaction was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in water and acidified with concentrated phosphoric acid. The aqueous solution was washed with chloroform (3X5mL), which was then washed with brine, dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) d 0.78-0.95 (m, 15H), 1.04-1.46 (m, 12H), 1.76-2.95 (m, 2H), 2.31 (s, 3H), 3.23-3.33 (m, 1 H), 3.47-3.58 (m, 1 H), 3.6-3.75 (m, 2H), 3.80-3.95 (m, 2H), 4.05- 4.15 (m, 1 H), 4.73 (m, 1 H), 5.94 (s, 2H), 6.70-6.80 (m, 2H), 6.82-6.93 (m, 2H), 6.96-7.14 (m, 2H). MS (DCI/NH3) m/e 597 (M+H)+. Anal calcd for C35H49N2FO5 -0.05H2O -0.8TFA: C, 63.81 ; H, 7.30; N, 4.07. Found:
C, 63.84; H, 7.18; N, 3.94. [a" =+46° (c 2.7g/L, CHCI3)
Example 512 frans. fraπs-2-(2-(2-Oxopyrrolidin- 1 -yl ιethvn-4-( 1 .3-benzodioxol-5- yn-1 -(N.N-di(n-butyl ,aminocarbonylmethvn-pyrrolidine-3-carboxylic acid
Example 512A 2-Oxopyrrolidin-1 -ylpropionic acid
To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin- 1 - ylpropionitrile in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 °C over night. The reaction mixture was then allowed to cool t o room temperature, extracted with methylene chloride three times. The extracts were combined and washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g (25%) of acid as a brown oil.
Example 512B Ethyl 5-(2-oxopyrrolidin-1 -yl ;-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964). Example 512C trans. frans-2-(2-(2-Oxopyrrolidin- 1-v ethyπ-4-M.3-benzodioxol-5- yπ-1-fN.N-di(n-butvπaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl 3- methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) δ 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t,"J = 6.9 Hz, 2H), 2.12-
2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, 1H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H), 3.66 (t, J = 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS
(DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H4lN3θβ-1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.
Example 513 frans.frans-2-(2-(1.3-Dioxol-2-vnethyl ,-4-(7-methoxy-1.3- benzodioxol-5-vn-1-(N-4-heptyl-N-(4-fluoro-3- methylphenvh)aminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate, N-4- heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N.N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) δ 0.93 (br t, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9 Hz, 1H), 3.60-4.03 (m, 8H), 3.88 (s, 3H), 4.21 (brs, 1H), 4.72 (quintet, J = 6.6 Hz, 1H), 4.86 (t, J = 3.6 Hz, 1H), 5.93 (s, 2H), 6.49 (s, 1H), 6.61 (s, 1H), 6.96 (m, 2H), 7.08 (t, J = 9 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 629. Anal calcd for C34H45N2O8 -1.0 TFA: C, 58.21; H, 6.24; N, 3.77.
Found: C, 58.11; H, 6.11; N, 3.58. Example 514 trans. trans-2-(2.2-Dimethylpentyl ι-4-(7-methoxy- 1 .3-benzodioxol-5- yl ι- 1 -(N .N-di(n-butvπaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3-methylhexanoate and 6- methoxypiperonal for piperonal afforded the title compound as an amorphous solid. NMR (CDCI3, 300 MHz) δ 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0 96 (t, J = 6.9 Hz, 3H),
1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, 1 H), 3.86 (t, J = 10.5 Hz, 1 H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1 H), 4.12 (d, J = 16.8 Hz, 1 H), 4.29 (d, J = 16.8 Hz, 1 H), 4.41 (brm, 1 H), 5.94 (s, 1 H), 6.52 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 533. Anal calcd for C30H48N2O6-0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33.
Example 515 trans. trans-2-(2.2-dimethylpentyn-4-(2.3-dihvdro-benzof uran-5-yh-
1-(N.N-di(n-butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting ethyl 3,3-dimethylhexanoate for ethyl 3-methylhexanoate and 2,3-dihydro- benzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H2O. "Η NMR (300 MHz, CDCI3) δ 0.83 (s, 3H), 0.85 (s, 3H), 0.86 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.09-1.39 (m, 8H), 1.44-1.59 (m, 4H), 1.88 (dd, J=15.0, 7.2 Hz, 1 H), 2.00 (d, J=15.0 Hz, 1 H), 3.09 (m, 2H), 3.18 (t, J=9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 (q,
J=10.0 Hz, 1 H), 4.18 (d, J=16.8 Hz, 1 H), 4.30-4.45 (m, 2H), 4.55 (t, J=9.0 Hz, 2H), 6.70 (d, J=8.4 Hz, 1 H), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DCI/NH3) at m/e 501 (M+H)+. Anal calc'd for C3θH48N2θ4-1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, 62.19; H, 8.00; N, 4.43. Examole 516 frans. frans-2-(2.2. -Dimethyl-2-( 1 .3-dioxolan-2-vnethvn-4-( 1 - methoxy-1 .3-benzodioxol-5-yπ-1 -(N. N-di(n- butvπaminocarbonylmethyl )-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3-(1 ,3-dioxolan-2-yl)propanoate for ethyl 3- methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H2O. 1 H NMR (CDCI3, 300 MHz) δ 053 (t, J=7.2 Hz, 3H), 0.94
(t, J=7.2 Hz, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (m, 4H), 1.93 (dd, J=15.9, 6.0 Hz, 1 H), 2.13 (d, J=15.9 Hz, 1 H), 3.20 (dd, J=7.7, 7.7 Hz, 1 H), 3.26-3.40 (m, 3H), 3.60 (m, 1 H), 3.75-3.86 (m, 3H), 3.88 (s, 3H), 3.93-4.01 (m, 3H), 4.00-4.1 1 (m, 1 H), 4.23 (d, J=15.9 Hz, 1 H), 4.37-4.48 (m, 2H), 4.49 (s, 1 H), 5.94 (s, 2H), 6.51 (d, J=2.1 Hz,
1 H), 6.64 (d, J=2.1 Hz, 1 H). MS (DCI/NH3) at m/e 563 (M+H)+. Anal calcd for C30H46N2O8-0.9 TFA: C, 57.41 ; H, 7.11 ; N, 4.21 ; found: C, 57.35; H,
6.86; N, 4.05.
Example 517 frans. frans-2-(2-(2-Methoxyphenyl .-ethyπ-4-( 1 .3-benzodioxol-5-yn- 1 -(N . N-di(n-butyl)aminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting o- methoxyphenylpropionic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. H NMR (CDCI3, 300 MHz) δ 0.85 (t, J=7Hz, 3H), 0.91 (t, J=7Hz, 3H), 1.10-1.27 (m, 4H), 1.42- 1.60 (m, 4H), 1.72-1.89 (m, 1 H), 1 .91-2.02 (m, 1 H), 2.55-2.77 (m, 2H), 2.94 (t, J=6Hz, 1 H), 3.05-330 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, J=14Hz, 1 H), 3.77 (s, 3H), 5.91 (s, 2H), 6.70 (d, J=8Hz, 1 H), 6.78-6.88
(m, 3H),6.92 (d, J=2Hz, 1 H), 7.08-7.19 (m, 2H). MS (DCI/NH3) (M+H)+ at m/e 539. Anal calcd for C31 H42N2O6: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99. Example 518 trans. frans-2-(2.2-Dimethyl-3-(E)-pentenyπ-4-( 1 -methoxy-1 .3- benzodioxol-5-vh-1 -(N.N-di(n-butvhaminocarbonylmethyl i- pyrrolidine-3-carboxylic acid
Example 518A 4-Methyl-3-penten-2-ol
To a stirred solution of 3-methyl-2-butenal (8.7g, 103mmol) in 100mL of tetrahydrofuran under N2 at 0 °C was added methylmagnesium bromide (38mL of a 3.0M solution in ethyl ether, 114mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g (81%) of alcohol as a colorless oil.
Example 518B frans-Ethyl 3.3-dimethyl-4-pentenoate
A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) was heated at 150 °C for 7 hours. The product was then distilled under normal pressure (200-220 °C) to give 5.0g of crude ester as a colorless oil.
Example 518C trans. frans-2-(2.2-Dimethvi-3-(E)-pentenyπ-4-( 1 -methoxy-1 .3- benzodioxol-5-vπ-1 -(N.N-di(n-butvπaminocarbonylmethyh- pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, substituting frans-ethyl 3,3-dimethyl-4-pentenoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophilization from dilute aqueous TFA/CH3CN. H NMR (CDCI3, 300 MHz) δ 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, J=7.2 Hz, 4H), 1.58 (d, J=5.4 Hz, 3H), 1.92 (dd, J=15.0, 6.6 Hz, 1H), 2.04 (d, J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 (m, 3H), 3.75
(m, 2H), 3.87 (s, 3H), 3.99 (q, J=9 Hz, 2H), 4.11-4.30 (m, 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 (s, 2H), 6.50 (d, J=1.8 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H). MS (DCI/NH3) at m/e 531 (M+H)+. Analysis calc'd for C30H46N2O6.O.95 TFA: C, 5955; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.
Example 519 trans. frans-2-(3-(2-pyridvπethyl ι-4-( 1 .3-benzodioxol-5-vh- 1 -(N .N- di(n-butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 519A 3-(2-Pyridvπ-propionic Acid
In a 50 mL round-bottomed flask equipped with a stirring bar was placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 °C After the addition was completed, the mixture was held at 50 °C until the color of the reaction mixture turned brown, then heated at 80 °C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for 5 min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, 78%). Example 519B trans. frans-2-(3-(2-pyridvnethvn-4-( 1 ,3-benzodioxol-5-yl ι- 1 -(N .N- di(n-butvπaminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) δ 8.65 (d, J=6.0 Hz, 1H), 8.06 (t, J=6.91 Hz, 1 H), 7.70 (d, J=9.0 Hz, 1H), 7.51 (t, J=6.91 Hz, 1 H), 6.82- 6.66 (m, 3H), 5.91 (s, 2H), 4.45 (s, 2H), 4.29-4.18Jm, 1H), 4.04 (dd, J=20.1 , 10.5 Hz, 1 H), 3.84 (t, J=12.6 Hz, 1 H), 3.62 (dd, J=13.8, 9.6 Hz, 1 H), 3.46-3.13 (m, 7H), 2.51 (broad s, 2H), 1.60-1.43 (m, 4H), 1.37-1.22 (m, 4H), 0.91 (t, J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 (M+H)+. Anal calcd for C29H3gN3θ5-1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81.
Example 520 (2S. 3R. 4S)-2-(2-(2-oxopyrrolidin- 1 -ynethyl ι-4-(1 .3-benzodioxol-5- yπ-1 -(N.N-di(n-butyπaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 520A
(2S. 3R. 4S,-Ethyl-2-f 2-, 2-oxopyrrolidin-1 -yl ,ethvn-4-M .3- benzodioxol-5-yl)pyrrolidine-3-carboxylate-(S>-Mandelate
The racemic amino ester from Example 512 (3.45g, 8.98mmol) in
10mL of ethyl acetate was treated with (S)-(+)-mandelic acid (0.75g, 4.93mmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring till the solution became light cloudy. The solution was left stirred at room temperature over night. The crystals was then collected by filtration, recrystalized from ethyl acetate/hexane twice to give a yield of 800 mg (17%) of pure salt. Example 520B
(2S. 3R. 4S,-Ethyl-2-(2-(2-oxopyrrolidin- 1 -yl )ethvn-4-r i .3- benzodioxol-5-vπ-1 -(N.N-di(n-butvπaminocarbonylmethyπ- pyrrolidine-3-carboxylate
To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added Λ , V-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.
Example 520C (2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -vnethvh-4-( 1 .3-benzodioxol-5- yπ-1 -( N.N-di(n-butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with CH3CN/TFA/H2O. H NMR (CDCI3, 300 MHz) δ 0.91 (t, J = 7.5 Hz, 3H),
0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J = 6.9 Hz, 2H), 2.12-2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (m, 1 H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1 H), 3.66 (t, J = 6.9 Hz, 1 H), 3.96 (m, 2H), 4.14 (m, 1 H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74
(d, J = 8.1 Hz, 1 H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 6.87 (d, J = 1.8 Hz, 1 H). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41 N3O6-0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84. Example 521 (2S. 3R. 4S)-2-(2-(2-oxoPyrrolidin- 1 -yl ,ethyl ,-4-( 1 .3- benzodioxol-5-yl ι-1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyπ)aminocarbonylmethvπ-pyrrolidine-3-carboxylic acid
Using the procedures described in Example 520, substituting N,N- (4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N- dibutylbromoacetamide afforded the title compound as an amorphous solid by lyophylization with C 3CN/TFA/H2θ. H NMR (CDCI3, 300 MHz) δ 0.85-0.98 (m, 6H), 1.22-1.55 (m, 8H), 2.04 (quintet, J=7.9 Hz, 4H),
2.32 (s, 3H), 2.36 (t, J=7.9 Hz, 2H), 2.61 (m, 1H), 3.14 (m, 1H), 3.25-3.61 (m, 5H), 3.66-3.77 (m, 1 H), 3.79-3.90 (m, 2H), 3.92-4.03 (m, 1 H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 (s, 2H), 6.71 (s, 2H), 6.78 (s, 1H), 6.93-7.13 (m, 3H); MS (DCI/NH3) at m/e 610 (M+H)+. Anal calc'd for C34H44N3O6FM .45 TFA: C, 57.18; H, 5.91 ; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.
Example 522 trans. frans-2-(2-( 1 -pvrazolynethvl ,-4-( 1 .3-benzodioxol-5-vn- 1 - (N.N-di(n-butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 522A 3-M -Pyrazolyπ-propionic Acid
In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification. Example 522B trans. frans-2-(2-M -pyrazolvl .ethvn-4-f 1 .3-benzodioxol-5-vn- 1 -
(N.N-di(n-butvπaminocarbonylmethvn-pyrrolidine-3-carboxylic acid
Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amoφhous solid 1 H NMR (CDCI3, 300 MHz) δ 7.56 (d, J=3.0 Hz, 1 H), 7.50 (d, J=3 Hz, 1 H), 6.83-6.66 (m, 3H), 6.28 (t, J=3 Hz, 1 H), 5.91 (s, 2H), 4.55-3.98 (m, 6H), 3.83-3.72 (t, J=10.5 Hz, 1 H), 3.61-3.40 (t, J=10.5 Hz, 1 H), 3.36-3.12 (m, 5H), 2.69-2.43 (m, 2H), 1.59-"l .42 (m, 4H), 1.38-1.21
(m, 4H), 0.91 (t, J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 (M+H)+. Anal calcd for C27H38N4O5O.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.
Example 523 trans. frans-2-(4-Methoxyphenyn-4-( 1 .3-benzodioxol-5-vh- 1 -r(N- butyl-N-(3-hydroxypropynamino')carbonylmethyll-pyrrolidine-3- carboxylic acid
Example 523A
N-Butyl-N-(3-hvdroxypropyl .-amine
To a solution of 15.9g (100 mmol) of methyl 3-/V-(n- butyl)aminopropionate in 150 mL of diethyl ether at 0 'C was added 50 mL (0.35 mmol) of 1.0M LiAIH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 *C for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H2O, 1.9 mL 15%w/v NaOH(ag), and 5.7 mL H2O. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was concentrated to 1 1.3 g (86%) of a light yellow oil.
Example 523B N-Butyl-N-(3-hvdroxypropyn-chloroacetamide
To an ice cooled solution of 1.31 g (10.0 mmol) of N-buiy\, N-{3- hydroxypropyl)amine in 20 mL of ethyl acetate was added a solution of 1.71g (10.0 mmol) of chloroacetic anhydride in 10mL of ethyl acetate. The mixture was stirred, and gradually warmed to room termperature over 18 hours. The reaction was extracted with H2O (1 x 50 mL), saturated NaHCθ3 (ag) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSθ4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate to give 723 mg (35%) of a light yellow oil.
Example 523C trans. frans-2-(4-Methoxyphenyl)-4-( 1 .3-benzodioxol-5-vπ- 1 -r(N- butyl-N-(3-hydroxypropyhamino)carbonylmethyl*l-pyrrolidine-3- carboxylic acid
Using the procedures described in Example 1 D, substituting N- butyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMSO as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA CH3CN. H NMR (CD3OD, 300 MHz) δ 0.78-0.95 (m, 3H), 1.00-1.80 (m, 4H), 2.80-3.65 (m, 15H), 3.80 (d, J=1.5 Hz, 2H), 5.93 (s, 2H), 6.72- 7.05 (m, 5H), 7.33-7.40 (m, 2H). MS (DCI/NH3) at m/e 513 (M+H)+. Anal calc'd for C28H36N207-1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C,
62.04; H, 7.21 ; N, 4.88.
Example 524 trans. frans-2-(4-Methoxyphenvh-4-( 1 .3-benzodioxol-5-yn- 1 -f(N- propyl-N-propoxyamino ιcarbonylmethyl]-pyrrolidine-3-carboxylic acid
Example 524A N-Boc-O-allylhvdroxylamine
O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath. Diisopropylethylamine (8mL) and di-t-butyldicarbonate (10.0g) were added. The mixture was stirred at ϋ°C for 1 hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil (6.5g) which was used without any further purification.
Example 524B N-Boc-N-propyl-O-a lylhydroxylamine
N-Boc-O-allylhydroxylamine (6.5g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0°C 1-lodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 0°C for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1 N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0g).
Example 524C
N-Boc-N-propyl-N- propoxyamine
N-Boc-N-propyl-O-allylhydroxylamine (6.0g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8g). Examole 524D N-Propyl-N- propoxyamine hydrochloride
N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCI/dioxane (10mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1 g) was collected by filtration and washed with diethyl ether.
Example 524E
N-propyl-N-propoxy-bromoacetamide
N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20°C Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -20°C for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1 N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35g). The product is a mixture of chloro- and bromoacetamides in a ratio of -3:1.
Example 524F trans. frans-2-(4-Methoxyphenyπ-4-( 1 .3-benzodioxol-5-yl )-1 -lϊN- butyl-N-(3-hvdroxypropyπaminθiCarbonylmethvπ-pyrrolidine-3- carboxylic acid
Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was purified by preparative HPLC (Vydac mC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was
Iyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) δ 0.87 (m, 6H, J=8Hz), 1.49 (m, 2H, J=8Hz), 1.61 (m, 2H, J=8Hz),
3.55 (m, 6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.00 (m, 2H), 4.13 (d, 2H, J=17Hz), 5.96 (s, 2H), 6.77 (d, 1H, J=9Hz), 6.90 (m, 3H), 7.05 (d, 1 H, J=1 Hz), 7.44 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C27H34N2O7 . 1.20 TFA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55.
Example 525 trans. frans-2-(4-Methoxyphenvh-4-( 1 .3-benzodioxol-5-vn-1 -f(N- butyl-N-propoxyamino')carbonylmethyl'l-pyrrolidine-3-carboxylic acid
Example 525A
N-buty -N-(2-hydroxyethvπ-amine
In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide was condensed at -78"C To this12.5 ml (120 mmol) of butylamine was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50"C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound.
Example 525B N-Butyl-N-(2-azidoethvh-chloroacetamide
To 500 mg of N-butyl, N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oil. Diethyl ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and 1.0g (16 mmol) of sodium azide was added. The reaction was stirred at 75 'C for 2 hours, then poured into 50 mL of 0.6M NaHC03(ag.) and extracted with diethyl ether (3 x 15 mL). The combined ether layers were back extracted with brine (1 x 15 mL), dried over MgSθ4, and filtered. To the ether solution was added 850 mg (4.97 mmol) of chloroacetic anhydride. The reaction was stirred for 10 min, then concentrated to an oil. This was taken up in 10 mL of saturated NaHC03(ag.) and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSθ4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg (17%) of an oil.
Example 525C trans. frans-2-(4-Methoxyphenyl ι-4-( 1 .3-benzodioxol-5-vπ-1 -r(N- b uty l-N -(2-aminoethyh amino) carbony I methyl*)-py rrolidi ne-3- carboxylic acid
According to the procedure of Example 523C, N-butyl-N-(2- azidoethyl)-chloroacetamide was coupled with e hyl 2-(4-
Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1 N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2S04. To 100 mg (0.10 mmol) of the azide was added 1 ml of 1 M HCI(ag.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1 % aqueous TFA gradient to give the title compound as its TFA salt. ' H NMR (CD3OD, 300 MHz) δ 0.92 (t, J=7.0 Hz, 3H), 0.96 (t, rotamer), 1.23 (m, 2H), 1.41 (m, 2H), 3.06 (m, 4H), 3.39 (m, 2H), 3.69 (m, 2H), 3.84 (s,
3H), 3.94 (m, 3H), 4.18 (m, 2H), 5.05 (bd, J=10.7 Hz, 1 H), 5.98 (s, 2H), 6.84 (d, J=7.7 Hz, 1 H), 6.93 (dd, J=1.8, 8.1 Hz, 1 H), 7.05 (m, 3H), 7.56 (m, 2H). MS (DCI/NH3) at m/e 498 (M+H)+. Anal calcd for C27H35N3θ6*3.15
TFA: C, 46.68. H, 4.49. N, 4.90. Found: C, 46.61 ; H, 4.73; N, 4.79. Example 526 trans. frans-2-(4-Methoxyphenyh-4-( 1 .3-benzodioxol-5-yn-1 -r(N- butyl-N-(3-aminopropyhamino)carbonylmethvn-pyrrolidine-3- carboxylic acid
To and ice-cold solution of the compound of Example 523C (100 mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of methanesulfonyl chloride, and 39 mL of triethylamine. The mixture was stirred for 20 min, then diluted with 1.5 mL of dichloromethane and extracted once with 5mL of water to which had been added 1 drop of 85% H3PO4, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x 2.5 mL), dried over MgSθ4, filtered, and concentrated to an oil. To a solution of 81 mg (0.13 mmol) of the mesylate in 1 ml of DMF was added 65 mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour at 50 'C, then poured into 10 mL of water and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSθ4, filtered, and concentrated to an oil.
This was purified via silica gel chromatography, eluting with 60:40 hexanes: ethyl acetate to give 57 mg of a colorless oil. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2S04. To this azide was added 1ml of 1 M
HCI(ag.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1 H NMR (Dβ-DMSO, 300 MHz) δ 0.85 (apparent q, J=6.8 Hz,
3H), 1.17 (m, 2H), 1.30 (m, 2H), 1.67 (m, 2H), 2.71 (m, 2H), 3.04 (m, 1H), 3.21 (m, 3H), 3.45 (m, 1 H), 3.75 (m, 3H), 3.97 (s, 3H), 3.85-4.80 (broad m, 3H), 6.03 (m, 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1 H), 6.92 (d, J=7.8 Hz, 1H), 7.01 (m, 2H), 7.16 (m, 1 H), 7.55 ( , 2H), 7.72 (m, 2H), 7.85 (m, 1 H); MS (DCI/NH3) (M+H)+ at m/e 512. Anal calcd for C28H37N3O6-3.0 TFA: C,
47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97. Example 527 trans. frans-2-(4-Methoxyphenvπ-4-( 1 .3-benzodioxol-5-yh- 1 -r(N- butyl-N-(3-di methyl ami nop roovh amino) carbon ylmethyn-pyrrolidine-3- carboxylic acid
Example 527A N-butyl-N-(3-bromopropyh bromoacetamide
To 1.50g (11.4 mmol) of N-butyl-N-(3-hydfόxy)propylamine was added 3 mL of 48% HBr(ag.), and 1.5 mL of cone. H2SO4. The reaction was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured over 50 mL of ice, and the solution was treated with 50 mL of 2M NaOH(ag.). The basic solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x 25 mL), dried, and filtered. To the ice cooled ethyl acetate solution was added 3ml of triethylamine, then 1.5 mL of bromoacetyl bromide as a solution in 3.5 mL of ethyl acetate. The reaction was stirred at 0 'C for 30 min, then extracted with 1 M HCI(ag.) (2 x 25 mL) saturated
NaHC03(ag.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgS04, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1.47g of a colorless oil.
Example 527B
Ethyl trans. frans-2-(4-Methoxyphenvh-4-(1 .3-benzodioxol-5-vπ-1 - r(N-butyl-N-(3-bromopropyπamino)carbonylmethyπ-pyrrolidine-3- carboxylate
According to the procedure of Example 523C, N-butyl-N-(3- bromopropyl-bromoacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. Example 527C trans. frans-2-(4-Methoxyphenvh-4-( 1 .3-benzodioxol-5-vπ-1 - (N- butyl-N-(3-dimethylaminopropyhamino'ιcarbonylmethyl1-pyrrolidine-3- carboxylic acid
To 400 mg (0.663 mmol) of the compound of Example 527B in 4 mL of absolute EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 *C for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was purified via silica gel chromatography, eluting with 9:1 CH2CI2: MeOH over about 20 mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1 N H3PO4. and the product was purified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) δ 0.92 (t, J=7.0 Hz, 3H), 1.22 (m, 2H), 1.39 (m, 2H), 1.90 (m, 2H), 2.87 (s, 6H), 3.07 (m, 4H), 3.24 (m, 1 H), 3.43 (m, 1H), 3.62 (m, 1 H), 3.84 (s, 3H), 3.88 (m, 3H), 4.07 (m, 1 H), 4.17 (m, 1 H), 4.97 (m, 1 H), 5.97 (s, 2H), 6.83 (d, J=8.1
Hz, 1 H), 6.93 (dd, J=1.7, 8.1 Hz, 1 H), 7.05 (m, 3H), 7.53 (m, 2H). MS (DCI/NH3) at m/e 540 (M+H)X Anal calcd for C3θH4l N3θ6β2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11 ; N, 4.62.
Example 528 trans. frans-2-(4-Methoxyphenyl i-4-( 1 .3-benzodioxol-5-yn- 1 -f(N- buty l-N-(3-trimethylammoniopropy πamino .carbonylmethyl*)- ρyrrolidine-3-carboxylic acid
Prepared according to the procedures of Example 527C, substituting aqueous Me3N for Me2NH. 1 H NMR (CD3OD, 300 MHz) δ 0.91 (m, 3H), 1.24 (m, 2H), 1.40 (m, 2H), 1.99 (m. 2H), 3.13 (s, 9H), 3.18 (s, rotamer), 3.20 (m, 3H), 3.39 (m, 4H), 3.72 (m, 1 H), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, 1 H), 5.19 (m, 1 H), 5.97 (s, 2H), 6.84 (d, J=8.1 Hz, 1 H), 6.96 (dd, J=1.7, 7.9 Hz, 1 H), 7.10 (m, 3H), 7.62 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+. Anal calcd for C31 H44N3O6O.I H20-1.65 TFA: C, 47.25. H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.
Example 529 trans. frans-2-(4-Methoxyphenyh-4-( 1 .3-benzodioxol-5-yl ι-1 -"(N- butyl-N-(4-aminobutvπamino)carbonylmethyll-pyrrolidine-3- carboxylic acid
Example 529A _ N-butyl-N-(4-hydroxybutyπ-amine
A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gm (20 mmol) of the resultant N-butyl -4- hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DIBAL(25%W). The solution was heated with stirring at 70 'C for 18 hours. After cooling to 0'C, the reaction was quenched with methanol (1/3 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2Sθ4.
Example 529B N-butyl-N-(4-hvdroxybutvπ-chloroacetamide
Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at 0*C, and then was allowed to warm to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography. Example 529C
Ethyl trans. frans-2- 4-MethoxyphenyH-4-(1 .3-benzodioxol-5-vn-1 ■ f(N-butyl-N-(4-hvdroxybutyl lamino)carbonylmethvn-pyrrolidine-3- carboxylate
According to the procedure of Example 523C, N-butyl-N-(4- hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidtne-3-carboxylate. The crude product was chromatographed on silica gel.
Example 529D Ethyl trans. frans-2-(4-Methoxyphenyh-4-( 1 .3-benzodioxol-5-vπ-1 f(N-butyl-N-(4-bromobutvπamino carbonylmethvπ-pyrrolidine-3- carboxylate
To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at 0*C for 2 hours and was slowly- warmed to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.
Example 529E trans. frans-2-(4-MethoxyphenyH-4-( 1 .3-benzodioxol-5-yl .-1 -r(N- butyl-N-(4-aminobutvπ amino ιcarbonylmethy l-pyrrolidine-3- carboxylic acid
To a solution of 0.135 gm (0.21 mmol) of the compound of Example 529D in 2 ml DMF was added 0.1 gm of sodium azide. Reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. After addition of water, the product was extracted into EtOAc. The crude product (1 17 mg) was dissolved in 10 ml ethanol under nitrogen atmosphere. To this 45 mgs of 10% Pd/C catalyst was added, the nitrogen from the reaction flask was evacuated and was flushed with hydrogen by placing a balloon filled with hydrogen. The reaction was allowed to stir for 4 hours under hydrogen atmosphere, and was worked up by filtering through a Celite pad. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1 N H3PO4, and the product was purified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) δ 0.90 (t, J=7 Hz, 3H), 1.10-1.65 (m, 6H), 2.85-2.95 (m, 2H), 3.00- 4.10 (m, 14H), 5.50 (d, J=3 Hz, 2H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, 1 H), 6.91 (dd, J=7 Hz, 1 H), 7.00-7.06 (m, 3H), 7.45-7.55"(m, 2H). MS
(DCI/NH3) at m/e 526 (M+H)+. Anal calc'd for C29H39N3O6.2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Found: C, 51.75; H, 5.31 ; N, 5.30.
Example 530 trans. frans-2-(4-Methoxyphenvπ-4-M .3-benzodioxol-5-yl .-1 -f(N- butyl-N-(4-dimethylaminobutynamino)carbonylmethyM-pyrrolidine-3- carboxylic acid
The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C 1 H NMR (CD3OD, 300 MHz) δ 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (m, 8H), 2.75 (d, J=7 Hz, 6H), 3.0- 4.25 (m, 16H), 5.97 (s, 2H), 6.83 (d, J=8 Hz, 1 H), 6.93 (dd, J=8 Hz, 1 H), 7.02-7.08 (m, 3H), 7.49-7.56 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+. Anal calc'd for C3i H43N3θβ*2.1 TFA: C, 53.31 ; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.
Example 531 trans. frans-2-(4-Methoxyphenyl)-4-( 1 .3-benzodioxol-5-yl ι-1 -'(N- butyl-N-(3-pyridyhamino ιcarbonylmethyl]-pyrrolidine-3-carboxylic add
Example 531 A N-butyl-N-(3-pyridyl ι-amine
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture was poured into 300 mL of 0.67M NaOH(ag.), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted with brine (1 x 50 mL), dried over MgS04, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18g (79%) of a colorless solid.
Example 531 B trans. frans-2-(4-Methoxyphenyπ-4-( 1 .3-benzodioxol-5-vπ-1 -f( N- butyl-N-(3-pyridvπamino)carbonylmethyπ-pyrrolidine-3-carboxylic acid
The compound of Example 531 A was reacted according to the procedures of Example 523, to give the title compound. H NMR (Dβ- DMSO, 300 MHz) δ 0.80 (t, J=6.4 Hz, 3H), 1.15-1.99 (m, 4H), 2.59 (m, 1H), 3.05 (m, 2H), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (t, J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 (s, 2H), 6.80 (m, 3H), 6.85 (d, J=8.1 Hz, 1 H), 6.98 (m, 2H), 7.04
(m, 1 H), 7.41 (dd, J=1 , 4.7 Hz, 8.1 H), 7.58 (m, 1 H), 8.36 (bs, 1 H), 8.54 (bs, 1 H), 12.24 (bs, 1 H). MS (DCI/NH3) at m/e 532 (M+H)+. Anal calcd for C30H33N3O6O.I H3PO4: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.
Example 532 trans. frans-2-(4-Methoxyphenvn-4-( 1 .3-benzodioxol-5-yl ι- 1 -r(N- butyl-N-(3-aminomethylphenvπaminθ ;carbonylmethvH-pyrrolidine-3- carboxylic acid
Example 532A N-butyl-N-(3-hvdroxymethylphenvn-amine
To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 ml DMSO was added 3.78 g (45 mmol) solid NaHC03 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 *C for 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.
Example 532B N-butyl-N-(3-hydroxymethylphenvh-bromoacetamide
To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to 0*C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at 0'C and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1 N H3PO4, water, and brine.
Example 532C Ethyl trans. frans-2-(4-Methoχyphenyl ;-4-( 1 .3-benzodioxol-5-vh-1 - (N-butyl-N-(3-chloromethylphenvπamino)carbonylmethyl1-pyrrolidine-
3-carboxylate
According to the procedure of Example 523C, N-butyl-N-(3- hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4-
Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.
The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0°C; 19 mg of LiCI was added, followed by 85 μl of thionyl chloride.
The mixture was allowed to stir for 30 min; water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2S04. Example 532D trans. frans-2-(4-Methoxyphenyn-4-M .3-benzodioxol-5-yn-1 -r( N- butyl-N-(3-aminomethylphenyπamino)carbonylmethvn-pyrrolidine-3- carboxylic acid
The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, 6.5 eq) of sodium azide. The resultant solution was heated at 115 °C for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2Sθ4-
Example 532E trans. frans-2- 4-Methoxyphenyh-4-( 1 .3-benzodioxol-5-vπ-1 -*(N- butyl-N-(3-aminomethylphenyhaminoιcarbonylmethvn-pyrrolidine-3- carboxylic acid
In a 50 ml round bottom flask 0.090 gm Tin (II) chloride was suspended in 1 ml acetonitrile. Triethylamine (0.2 mL) was added, followed by 0.19 ml of thiophenol ; the reaction mixture turned yellow. Reaction flask was cooled to O'C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI . The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1 N H3PO4, and the product was purified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) δ 0.88 (t, J=7 Hz, 3H), 1.15-1.45 (m, 4H), 3.40-4.20 (m, 14H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, 1 H), 6.88 (dd, J=8 Hz, 1 H), 6.97-7.20 (m, 5H), 7.40 (d, J=9 Hz, 2H), 7.56 (d, J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 (M+H)+. Anal calcd for C32H37N3θ6*4.2 TFA: C, 46.72; H, 4.00; N, 4.05. Found: C, 46.66; H, 4.06; N, 4.00. Example 533 trans. frans-2-(/4-Methoχyphenvn-4-( 1 .3-benzodioxol-5-yn-1 -r( N- butyl-N-(3-trimethylammoniomethylphenyπamino)carbonylmethvn- 5 pyrrolidine-3-carboxylic acid
To a stirred solution of 0.128 gm of the compound of Example 532C in 0.5 ml methanol, 0.25 ml of an aqueous solution of trimethylamine was added. The mixture was allowed to stir at room i o temperature under nitrogen atmosphere for 4 hours. 1N HCI was added; the aqueous was washed with ether to extract organic impurities. The aqueous layer was dried azeotropically with toluene, and the residue was dried under high vacuum. Yield 0.115 gm. 1 H NMR (300 MHz, D6- DMSO) δ 0.83 (t, J=7 Hz, 3H), 1.15-1.40 (m, 4H), 2.62 (s, 2H), 3.35 (s,
15 9H), 3.40-3.80 (m, 10H), 4.47 (s, 2H), 6.00 (s, J=3 Hz, 2H), 6.75-6.90 (m,
3H), 7.25-7.37 (m, 2H), 7.45-7.60 (m, 3H). MS (DCI/NH3) at m/e 602
(M+H)+.
Example 534 20 ^ R3R4S>-2-(3-Fluoro-4-methoxyphenvn-4-( 1 .3-benzodioxol-5-vn i -
(2-(N-propyl-N-pentanesulfonylamino)ethvn-pyrrolidine-3-carboxylic acid
Example 534A 25 Ethyl (3-fluoro-4-methoxy)benzoylacetate
Sodium hydride (17g of a 60% suspension in mineral oil) is washed three times with toluene. The powder is suspended in 138 mL of toluene, and 35 mL of diethyl carbonate is added. The mixture is
30 heated to 90 °C, and a solution of 25 g of 3-fluoro-4- methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then the reaction is cooled to room temperature. A solution of 50 ml of concentrated HCI in 75 ml of ice water is added slowly, and the mixture
35 is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product is dried over Na2Sθ4 and decolorized with charcoal to give 34.5 g (97%) of the title compound.
Example 534B Ethyl 2-(3-Fluoro-4-methoxyphenvπ-4-M .3-benzodioxol-5-vn- pyrrolidine-3-carboxylate
The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3- benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 min. An additional 0.1 g of DBU was added, and the solution was stirred for 1 hour. The solvents were removed in vacuo; toluene was added, along with brine containing 3 ml of concentrated HCI. The mixture was extracted twice with toluene; the organics were dried over MgSθ4. The residue was flashed on silica, using CH2CI2 to elute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2CI2. Yield 10.13 g = 66%. The product is combined with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN are added, along with a trace of bromcresol green as indicator. A solution of 1 :2 concentrated HCI/EtOH is added dropwise to maintain pH at green- yellow; after color persists, the reaction mixture is stirred for an additional 20 min. The solvents are removed in vacuo; the residue is stirred with mixture of toluene and KHCO3 solution. The organic phase is washed with water and brine, and dried over MgS04. The crude product is purified by flash chromatography on silica, eluting with 2:1 EtOAc/hexanes. Yield 5.92 g (58%) of a 2:1 mixture of trans-trans and cis-trans isomers. Examole 534C Ethyl (■?R3R4S*)-2-(3-Fluoro-4-methoxyphenvh-4-( 1 .3-benzodioxol-
5-vπ-pyrrolidine-3-carboxylate
To the racemic amino ester above (15.0 g, 38.8 mmol), dissolved in 75 ml methylene chloride and cooled in an ice bath, was added Boc anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room temperature, the solution was concentrated in vacuo ; the residue was dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium hyroxide in 19 ml water. The solution was warmed until all was soluble. After stirring for 2 hours at room temperature, the solution was concentrated and redissolved in 200 mi of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The combined aqueous phases were acidified with 7.5 g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1 :1 etheπhexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-methylbenzylamine. After heating to dissolve the acid, 80 ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-168°C After one recrystaliization, chiral HPLC analysis, using a Regis Whelk-O column, indicated >99.5 % e.e. The salt was dissolved in 500 ml of 36% HCI in ethanol; a white solid forms. The resultant suspension was heated for 16 hours at 52°C After concentrating in vacuo, the residue was combined with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2S04) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate to get 6.9 g (99%) of the resolved amino ester. Example 534D
Ethyl /2R3R45)-2-(3-Fluoro-4-methoxyphenyn-4-M .3-benzodioxol-
5-yh1 -(2-( N-propylamino*ιethyl)-pyrrolidine-3-carboxylate
The compound of Example 534C was dissolved in 1,2- dibromoethane ( 10 mL per 1 g of starting material ); diisopropylethylamine (1 mL per 1 g of starting material ) and Nal ( 100 mg per 1 g of starting material) were added, and the mixture was stirred at 100°C for 1 hour. Toluene was added, and the mixture was washed with bicarbonate. The solvents were concentrated, and the resultant black residue was chromatographed on silica gel, eluting with 4:1 hexane-EtOAc to give the N-(2-bromoethyl)pyrrolidine (85-92%). This compound was combined with n-propylamine (3.5 eq.) and Nal (10% by weight of bromide) in ethanol ( 5 mL per 1 g of bromide), and was heated at 80°C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2Sθ4), and concentrated. More toluene was added, and removed in vacuo, to get rid of the primary amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the desired product (86-93% yield), which was used for the next step without further purification.
Example 534E 1-Pentanesulfonyl chloride
1 -Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60 °C for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of
SOCI2. The residue is partitioned between CH2CI2 and ice water; the organic layer is dried over Na2S04 . The crude product is purified by distillation (bp 54-56 °C @ 0.5 mm Hg) to give a clear oil, 61 % yield. Example 534F ( R3R4S)-2-(3-Fluoro-4-methoxyρhenvh-4-( 1 .3-benzodioxol-5-yh 1 - (2-(N-propyl-N-pentanesulfonylamino)ethvh-Pyrrolidine-3-carboxylic acid
The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N.N- diisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHC03 solution, 1 N H3PO4, and brine, dried over Na2S04 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with 40% EtOAc/hexane to give 220 mg of product (85%). This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H2O. This mixture was stirred for 3 hours at room temperature. The solution was concentrated in vacuo using low (<40°C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2Sθ4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.
Example 534H ι R3R4S)-2-(3-Fluoro-4-methoxyphenvn-4-( 1 .3-benzodioxol-5-yni - (2-(N-propyl-N-pentanesulfonylamino)ethyπ-pyrrolidine-3-carboxylic acid, hydrochloride salt
The free amine is dissolved in iPrOH; a slight excess of HCI in iPrOH is added, and the solution is concentrated in vacuo. More IPA is added, and the solution is reconcentrated. The resultant sticky material Is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 °C Yield 95%.
Example 535
The compounds in Table 3C may be prepared using methods presented in the above Examples.
Table 3C
Figure imgf000488_0001
Figure imgf000488_0002
Figure imgf000489_0001
8
Figure imgf000489_0002
10
Figure imgf000489_0003
3 14
Figure imgf000490_0001
17 18
Figure imgf000490_0002
19 20
Figure imgf000491_0001
23 24
Figure imgf000491_0002
5 26
Figure imgf000492_0001
7 28
Figure imgf000492_0002
9 30
Figure imgf000492_0003
31 32
Figure imgf000492_0004
34
Figure imgf000493_0001
41
ri u -iCOOH
Figure imgf000493_0002
43
r rrύ*»
Figure imgf000494_0001
45
Figure imgf000494_0002
6 47
Figure imgf000494_0003
8 49
Figure imgf000494_0004
0 51
54 55
Figure imgf000495_0002
56 57
Figure imgf000495_0003
8 59
Figure imgf000496_0001
0 61
Figure imgf000496_0002
2 63
Figure imgf000496_0003
4 65
Figure imgf000496_0004
67
Figure imgf000497_0001
69
Figure imgf000497_0002
71
Figure imgf000497_0003
73
COOH
Figure imgf000497_0004
Figure imgf000498_0001
80 81
Figure imgf000498_0002
Figure imgf000499_0001
86 87
Figure imgf000499_0002
88 89
Figure imgf000499_0003
90 91
Figure imgf000500_0001
94 95
Figure imgf000500_0002
96 97
Figure imgf000500_0003
98 99
Figure imgf000501_0001
100 101
Figure imgf000501_0002
102 103
Figure imgf000501_0003
104 105
Figure imgf000501_0004
106 107
Figure imgf000502_0001
108 109
Figure imgf000502_0002
110 111
Figure imgf000502_0003
112 113
Figure imgf000502_0004
114 115
Figure imgf000503_0001
116 117
Figure imgf000503_0002
118 119
Figure imgf000503_0003
120 121
Figure imgf000503_0004
122 123
Figure imgf000504_0001
124 125
Figure imgf000504_0002
126 127
Figure imgf000504_0003
128 129
Figure imgf000504_0004
130 131
Figure imgf000505_0001
132 133
Figure imgf000505_0002
134 135
Figure imgf000505_0003
136 137
Figure imgf000505_0004
138 139
Figure imgf000506_0001
142 143
Figure imgf000506_0002
144 145
χγ ό*»
Figure imgf000506_0003
146 147
Figure imgf000507_0001
148 149
Figure imgf000507_0002
150 151
Figure imgf000507_0003
152 153
Figure imgf000507_0004
154 155
Figure imgf000508_0001
156 157
Figure imgf000508_0002
157 159
H2 QrTNό-ooH
Figure imgf000508_0003
160 161
Figure imgf000508_0004
162 163
Figure imgf000509_0001
164 165
Figure imgf000509_0002
166 167
Figure imgf000509_0003
168 169
Figure imgf000509_0004
Figure imgf000510_0001
172 173
Figure imgf000510_0002
174 175
'τ rTό-ooH
Figure imgf000510_0003
176 177
Figure imgf000510_0004
Figure imgf000511_0001
181 180
Figure imgf000511_0002
182 183
Figure imgf000511_0003
184 185
Figure imgf000511_0004
186 187
cr ό- -COOH
Figure imgf000512_0001
188 189
Figure imgf000512_0002
190 191
Figure imgf000512_0003
192 193
Figure imgf000512_0004
194 195
Figure imgf000513_0001
196 197
Figure imgf000513_0002
198 199
Figure imgf000513_0003
200 201
Figure imgf000513_0004
202 203
Figure imgf000514_0001
204 205
Figure imgf000514_0002
206 207
Figure imgf000514_0003
208 209
Figure imgf000514_0004
210 211
Figure imgf000515_0001
212 213
Figure imgf000515_0002
214 215
Figure imgf000515_0003
216 217
Figure imgf000515_0004
218 219
Figure imgf000516_0001
220 221
Figure imgf000516_0002
222 223
Figure imgf000516_0003
224 225
Figure imgf000516_0004
226 227
Figure imgf000517_0001
230 231
Figure imgf000517_0002
232 233
Figure imgf000517_0003
Figure imgf000518_0001
Figure imgf000518_0002
242 243
Figure imgf000519_0001
244 245
Figure imgf000519_0002
246 247
Figure imgf000519_0003
248 249
Figure imgf000519_0004
Figure imgf000520_0001
Figure imgf000520_0002
Figure imgf000521_0001
Figure imgf000521_0002
266 267
Figure imgf000522_0001
268 269
Figure imgf000522_0002
270 271
Figure imgf000522_0003
272 273
Figure imgf000522_0004
274 275
278 279
Figure imgf000523_0002
280 281
Figure imgf000523_0003
Figure imgf000524_0001
Figure imgf000524_0002
290 291
Figure imgf000525_0001
292 293
Figure imgf000525_0002
294 295
Figure imgf000525_0003
296 297
Figure imgf000525_0004
298 299
Figure imgf000526_0001
300 301
Figure imgf000526_0002
302 303
Figure imgf000526_0003
304 305
Figure imgf000526_0004
306 307
Figure imgf000527_0001
308 309
Figure imgf000527_0002
310 311
Figure imgf000527_0003
312 313
Figure imgf000527_0004
Figure imgf000528_0001
322 323
Figure imgf000529_0001
324 325
Figure imgf000529_0002
328 329
Figure imgf000529_0003
330 331
Figure imgf000530_0001
332 333
Figure imgf000530_0002
334 335
Figure imgf000530_0003
336 337
Figure imgf000530_0004
338 339
Figure imgf000531_0001
340 341
Figure imgf000531_0002
342 343
Figure imgf000531_0003
344 345
Figure imgf000531_0004
346 347
Figure imgf000532_0001
348 349
Figure imgf000532_0002
Figure imgf000532_0003
352 353
Figure imgf000532_0004
354 355
Figure imgf000533_0001
356 357
Figure imgf000533_0002
358 359
Figure imgf000533_0003
362 363
Figure imgf000534_0001
364 365
Figure imgf000534_0002
366 367
Figure imgf000534_0003
368 369
Figure imgf000534_0004
Figure imgf000535_0001
378 379
Figure imgf000536_0001
380 381
Figure imgf000536_0002
382 383
Figure imgf000536_0003
384 385
Figure imgf000536_0004
Figure imgf000537_0001
Figure imgf000537_0002
Figure imgf000538_0001
400 401
Figure imgf000538_0002
Figure imgf000539_0001
406 407
Figure imgf000539_0002
Figure imgf000539_0003
Figure imgf000540_0001
412 413
Figure imgf000540_0002
414 415
Figure imgf000540_0003
418 419
Figure imgf000541_0001
423
Figure imgf000541_0002
424 425
Figure imgf000541_0003
426 427
Figure imgf000542_0001
428 429
Figure imgf000542_0002
430 431
Figure imgf000542_0003
Figure imgf000542_0004
Figure imgf000543_0001
436 437
Figure imgf000543_0002
438 439
Figure imgf000543_0003
Figure imgf000543_0004
442 443
Figure imgf000544_0001
444 445
Figure imgf000544_0002
446 447
Figure imgf000544_0003
448 449
Figure imgf000544_0004
450 451
Figure imgf000545_0001
452 453
Figure imgf000545_0002
454 455
Figure imgf000545_0003
456 457
Figure imgf000545_0004
458 459
Figure imgf000546_0001
462 463
Figure imgf000546_0002
464 465
Figure imgf000546_0003
466 467
Figure imgf000547_0001
468 469
Figure imgf000547_0002
470 471
Figure imgf000547_0003
472 473
Figure imgf000547_0004
474 475
Figure imgf000548_0001
476 477
Figure imgf000548_0002
478 479
Figure imgf000548_0003
480 481
Figure imgf000548_0004
482 483
Figure imgf000549_0001
484 485
Figure imgf000549_0002
486 487
Figure imgf000549_0003
488 489
Figure imgf000549_0004
490 491
Figure imgf000550_0001
494 495
Figure imgf000550_0002
496 497
Figure imgf000550_0003
Figure imgf000551_0001
500 501
Figure imgf000551_0002
502 503
Figure imgf000551_0003
504 505
Figure imgf000551_0004
Figure imgf000552_0001
Figure imgf000552_0002
510 511
Figure imgf000552_0003
512 513
Figure imgf000552_0004
514 515
Figure imgf000553_0001
516 517
Figure imgf000553_0002
518 519
Figure imgf000553_0003
520 521
^
Figure imgf000553_0004
Figure imgf000554_0001
Figure imgf000554_0002
530 531
Figure imgf000555_0001
532 533
Figure imgf000555_0002
534 535
Figure imgf000555_0003
Figure imgf000556_0001
Figure imgf000556_0002
546 547
Figure imgf000557_0001
548 549
Figure imgf000557_0002
550 551
Figure imgf000558_0001
556 557
Figure imgf000558_0002
558 559
Figure imgf000558_0003
560 561
Figure imgf000558_0004
Figure imgf000559_0001
Figure imgf000559_0002
Figure imgf000560_0001
Figure imgf000561_0001
586 587
Figure imgf000562_0001
Figure imgf000563_0001
Figure imgf000564_0001
Figure imgf000564_0002
Figure imgf000565_0001
Figure imgf000565_0002
618 619
Figure imgf000566_0001
620 621
Figure imgf000566_0002
622 623
Figure imgf000566_0003
624 625
Figure imgf000566_0004
626 627
Figure imgf000567_0001
628 629
Figure imgf000567_0002
630 631
Figure imgf000567_0003
632 633
Figure imgf000567_0004
Figure imgf000568_0001
636 637
Figure imgf000568_0002
638 639
Figure imgf000568_0003
Figure imgf000568_0004
642 643
Figure imgf000569_0001
644 645
Figure imgf000569_0002
646 647
Figure imgf000569_0003
648 649
Figure imgf000569_0004
Figure imgf000570_0001
652 653
Figure imgf000570_0002
Figure imgf000570_0003
Figure imgf000570_0004
658 659
Figure imgf000571_0001
660 661
Figure imgf000571_0002
662 663
Figure imgf000571_0003
664 665
Figure imgf000571_0004
666 667
Figure imgf000572_0001
668 669
Figure imgf000572_0002
Figure imgf000572_0003
672 673
Figure imgf000572_0004
674 675
Figure imgf000573_0001
676 677
Figure imgf000573_0002
678 679
Figure imgf000573_0003
680 681
Figure imgf000573_0004
682 683
Figure imgf000574_0001
688 689
Figure imgf000574_0002
690 691
Figure imgf000575_0001
692 693
Figure imgf000575_0002
694 695
Figure imgf000575_0003
696 697
Figure imgf000575_0004
698 699
Figure imgf000576_0001
706 707
Figure imgf000577_0001
708 709
Figure imgf000577_0002
710 711
Figure imgf000577_0003
712 713
Figure imgf000577_0004
714 715
Figure imgf000578_0001
722 723
Figure imgf000579_0001
724 725
Figure imgf000579_0002
726 727
Figure imgf000579_0003
729
Figure imgf000580_0001
Figure imgf000580_0002
736 737
Figure imgf000581_0001
738 739
Figure imgf000581_0002
740 741
Figure imgf000581_0003
742 743
Figure imgf000581_0004
Figure imgf000582_0001
Figure imgf000582_0002
752 753
Figure imgf000583_0001
754 755
Figure imgf000583_0002
756 757
Figure imgf000583_0003
758 759
Figure imgf000583_0004
760 761
Figure imgf000584_0001
Figure imgf000584_0002
Figure imgf000584_0003
Figure imgf000585_0001
770 771
Figure imgf000585_0002
772 773
Figure imgf000585_0003
774 775
Figure imgf000585_0004
Figure imgf000586_0001
780 781
Figure imgf000586_0002
782 783
Figure imgf000586_0003
784 785
Figure imgf000587_0001
786 787
Figure imgf000587_0002
788 789
Figure imgf000587_0003
Figure imgf000588_0001
794 795
Figure imgf000588_0002
796 797
Figure imgf000588_0003
798 799
Figure imgf000588_0004
800 801
Figure imgf000589_0001
802 803
Figure imgf000589_0002
804 805
Figure imgf000589_0003
808 809
Figure imgf000590_0001
810 811
Figure imgf000590_0002
812 813
Figure imgf000590_0003
816 817
Figure imgf000591_0001
824 825
Figure imgf000592_0001
828 829
Figure imgf000592_0002
832 833
Figure imgf000593_0001
Figure imgf000594_0001
842 843
Figure imgf000594_0002
844 845
Figure imgf000594_0003
846 847
Figure imgf000594_0004
848 849
Figure imgf000595_0001
850 851
Figure imgf000595_0002
852 853
Figure imgf000595_0003
856 857
Figure imgf000596_0001
858 859
Figure imgf000596_0002
860 861
Figure imgf000596_0003
862 863
Figure imgf000596_0004
864 865
Figure imgf000597_0001
866 867
Figure imgf000597_0002
868 869
Figure imgf000597_0003
872 873
Figure imgf000598_0001
874 875
Figure imgf000598_0002
876 877
Figure imgf000598_0003
878 879
Figure imgf000598_0004
Figure imgf000599_0001
882 883
Figure imgf000599_0002
884 885
Figure imgf000599_0003
886 887
Figure imgf000599_0004
888 889
Figure imgf000600_0001
890 891
Figure imgf000600_0002
892 893
Figure imgf000600_0003
896 897
Figure imgf000601_0001
898 899
Figure imgf000601_0002
900 901
Figure imgf000601_0003
902 903
Figure imgf000601_0004
904 905
Figure imgf000602_0001
906 907
Figure imgf000602_0002
908 909
Figure imgf000602_0003
Figure imgf000602_0004
912 913
Figure imgf000603_0001
914 915
Figure imgf000603_0002
916 917
Figure imgf000603_0003
918 919
Figure imgf000603_0004
920 921
Figure imgf000604_0001
922 923
Figure imgf000604_0002
924 925
Figure imgf000604_0003
926 927
Figure imgf000604_0004
928 929
Figure imgf000605_0001
930 931
Figure imgf000605_0002
932 933
Figure imgf000605_0003
934 935
Figure imgf000605_0004
936 937
Figure imgf000606_0001
938 939
Figure imgf000606_0002
942 943
Figure imgf000606_0003
944 945
Figure imgf000607_0001
946 947
Figure imgf000607_0002
948 949
Figure imgf000607_0003
950 951
Figure imgf000607_0004
952 953
Figure imgf000608_0001
954 955
Figure imgf000608_0002
958 959
Figure imgf000608_0003
960 961
Figure imgf000609_0001
962 963
Figure imgf000609_0002
964 965
Figure imgf000609_0003
966 967
Figure imgf000609_0004
968 969
Figure imgf000610_0001
974 975
Figure imgf000610_0002
Figure imgf000611_0001
Figure imgf000611_0002
984 985
Figure imgf000612_0001
986 987
Figure imgf000612_0002
988 989
Figure imgf000612_0003
990 991
Figure imgf000612_0004
992 993
Figure imgf000613_0001
994 995
Figure imgf000613_0002
998 999
Figure imgf000613_0003
Figure imgf000614_0001
1002 1003
Figure imgf000614_0002
1004 1005
Figure imgf000614_0003
1006 1007
Figure imgf000614_0004
Figure imgf000615_0001
Figure imgf000615_0002
1012
1013
Figure imgf000615_0003
Figure imgf000616_0001
1018 1019
Figure imgf000616_0002
1020 1021
Figure imgf000616_0003
1022 1023
Figure imgf000616_0004
1024 1025
Figure imgf000617_0001
1026 1027
Figure imgf000617_0002
1028 1029
Figure imgf000617_0003
1030 1031
Figure imgf000617_0004
Figure imgf000618_0001
1034 1035
Figure imgf000618_0002
1036 1037
Figure imgf000618_0003
1038 1039
Figure imgf000618_0004
1040 1041
Figure imgf000619_0001
1042 1043
Figure imgf000619_0002
1044 1045
Figure imgf000619_0003
1046 1047
Figure imgf000619_0004
1048 1049
Figure imgf000620_0001
Figure imgf000620_0002
1056 1057
Figure imgf000621_0001
Figure imgf000621_0002
1060 1061
Figure imgf000621_0003
1064 1065
Figure imgf000622_0001
1066 1067
Figure imgf000622_0002
1068 1069
Figure imgf000622_0003
1070 1071
Figure imgf000622_0004
1072 1073
Figure imgf000623_0001
1074 1075
Figure imgf000623_0002
1076 1077
Figure imgf000623_0003
1078 1079
Figure imgf000623_0004
1080 1081
Figure imgf000624_0001
1082 1083
Figure imgf000624_0002
1084 1085
Figure imgf000624_0003
1086 1087
Figure imgf000624_0004
1088 1089
Figure imgf000625_0001
1092 1093
Figure imgf000625_0002
1094 1095
Figure imgf000625_0003
Figure imgf000626_0001
1100 1101
Figure imgf000626_0002
Figure imgf000626_0003
Figure imgf000627_0001
1106 1107
Figure imgf000627_0002
1108 1109
Figure imgf000627_0003
1110 1111
Figure imgf000627_0004
1112 1113
Figure imgf000628_0001
1114 1115
Figure imgf000628_0002
1116 1117
Figure imgf000628_0003
1118 1119
Figure imgf000628_0004
1120 1121
Figure imgf000629_0001
1122 1123
Figure imgf000629_0002
1124 1125
Figure imgf000629_0003
1126 1127
Figure imgf000629_0004
1128 1129
Figure imgf000630_0001
1130 1131
Figure imgf000630_0002
1132 1133
Figure imgf000630_0003
1134 1135
Figure imgf000630_0004
1136 1137
Figure imgf000631_0001
1138 1139
Figure imgf000631_0002
1140 1141
Figure imgf000631_0003
1142 1143
Figure imgf000631_0004
1144 1145
Figure imgf000632_0001
1148 1149
Figure imgf000632_0002
1150 1151
Figure imgf000632_0003
Figure imgf000633_0001
1156 1157
Figure imgf000633_0002
1158 1159
Figure imgf000633_0003
1160 1161
Figure imgf000634_0001
1162 1163
Figure imgf000634_0002
1164 1165
Figure imgf000634_0003
1166 1167
Figure imgf000634_0004
Figure imgf000635_0001
1170 1171
Figure imgf000635_0002
1172 1173
Figure imgf000635_0003
1174 1175
Figure imgf000635_0004
1176 1177
Figure imgf000636_0001
1178 1179
Figure imgf000636_0002
1180 1181
Figure imgf000636_0003
1182 1183
Figure imgf000636_0004
Figure imgf000637_0001
1186 1187
Figure imgf000637_0002
1188 1189
Figure imgf000637_0003
190 1191
Figure imgf000637_0004
1192 1193
Figure imgf000638_0001
1194 1195
Figure imgf000638_0002
1196 1197
Figure imgf000638_0003
1198 1199
Figure imgf000638_0004
1200 1201
Figure imgf000639_0001
1206 1207
Figure imgf000639_0002
1208 1209
Figure imgf000640_0001
1212 1213
Figure imgf000640_0002
1214 1215
Figure imgf000640_0003
1216 1217
Figure imgf000641_0001
1218 1219
Figure imgf000641_0002
1220 1221
Figure imgf000641_0003
1222 1223
Figure imgf000641_0004
1224 1225
Figure imgf000642_0001
1226 1227
Figure imgf000642_0002
1228 1229
Figure imgf000642_0003
1230 1231
Figure imgf000642_0004
1232 1233
Figure imgf000643_0001
1234 1235
Figure imgf000643_0002
1236 1237
Figure imgf000643_0003
1238 1239
Figure imgf000643_0004
1240 1241
Figure imgf000644_0001
1242 1243
Figure imgf000644_0002
1244 1245
Figure imgf000644_0003
1246 1247
Figure imgf000644_0004
1248 1249
Figure imgf000645_0001
1250 1251
Figure imgf000645_0002
1252 1253
Figure imgf000645_0003
1254 1255
Figure imgf000645_0004
1256 1257
cr - COOH
Figure imgf000646_0001
1258 1259
Figure imgf000646_0002
1260 1261
Figure imgf000646_0003
1262 1263
Figure imgf000646_0004
1264 1265
Figure imgf000647_0001
1266 1267
Figure imgf000647_0002
1268 1269
Figure imgf000647_0003
1270 1271
Figure imgf000647_0004
1272 1273
Figure imgf000648_0001
1274 1275
Figure imgf000648_0002
1276 1277
Figure imgf000648_0003
1278 1279
Figure imgf000648_0004
1280 1281
Figure imgf000649_0001
1282 1283
Figure imgf000649_0002
1284 1285
Figure imgf000649_0003
1286 1287
Figure imgf000649_0004
1288 1289
Figure imgf000650_0001
1290 1291
Figure imgf000650_0002
1292 1293
Figure imgf000650_0003
1294 1295
Figure imgf000650_0004
Figure imgf000651_0001
Figure imgf000651_0002
1304 1305
Figure imgf000652_0001
1306 1307
Figure imgf000652_0002
1308 1309
Figure imgf000652_0003
1310 1311
Figure imgf000652_0004
Figure imgf000653_0001
Figure imgf000653_0002
Figure imgf000654_0001
Figure imgf000654_0002
Figure imgf000654_0003
1328 1329
Figure imgf000655_0001
1330 1331
Figure imgf000655_0002
1332 1333
Figure imgf000655_0003
1334 1335
Figure imgf000655_0004
1336 1337
Figure imgf000656_0001
1338 1339
Figure imgf000656_0002
1340 1341
Figure imgf000656_0003
1342 1343
Figure imgf000656_0004
1344 1345
Figure imgf000657_0001
1346 1347
Figure imgf000657_0002
1348 1349
Figure imgf000657_0003
1350 1351
Figure imgf000657_0004
1352 1353
Figure imgf000658_0001
1354 1355
Figure imgf000658_0002
1356 1357
Figure imgf000658_0003
1358 1359
Figure imgf000658_0004
1360 1361
Figure imgf000659_0001
1362 1363
Figure imgf000659_0002
1364 1365
Figure imgf000659_0003
1366 1367
Figure imgf000659_0004
1368 1369
Figure imgf000660_0001
1370 1371
Figure imgf000660_0002
1372 1373
Figure imgf000660_0003
1374 1375
Figure imgf000660_0004
Figure imgf000661_0001
1378
1379
Figure imgf000661_0002
1380 1381
Figure imgf000661_0003
Figure imgf000662_0001
1388
1389
zYr COOH
Figure imgf000662_0002
Figure imgf000662_0003
1392
1393
Figure imgf000663_0001
1400 1401
Figure imgf000664_0001
1402 1403
Figure imgf000664_0002
1404 1405
Figure imgf000664_0003
1406 1407
Figure imgf000664_0004
1408 1409
Figure imgf000665_0001
1410 1411
Figure imgf000665_0002
1412 1413
Figure imgf000665_0003
1414 1415
Figure imgf000665_0004
1416 1417
Figure imgf000666_0001
1422 1423
Figure imgf000666_0002
1424 1425
Figure imgf000667_0001
1432 1433
Figure imgf000668_0001
1436 1437
Figure imgf000668_0002
Figure imgf000669_0001
1446 1447
Figure imgf000669_0002
Figure imgf000670_0001
1452 1453
Figure imgf000670_0002
Figure imgf000670_0003
1456 1457
Figure imgf000671_0001
1460 1461
Figure imgf000671_0002
Figure imgf000672_0001
Figure imgf000672_0002
1468 1469
Figure imgf000672_0003
1470 1471
Figure imgf000672_0004
Figure imgf000673_0001
Figure imgf000673_0002
1476 1477
Figure imgf000673_0003
Figure imgf000674_0001
Figure imgf000674_0002
Figure imgf000675_0001
Figure imgf000675_0002
1496
-riYn —
Figure imgf000676_0001
1498 1599
Figure imgf000676_0002
1502 1503
Figure imgf000676_0003
Figure imgf000677_0001
1506 1507
Figure imgf000677_0002
Figure imgf000678_0001
Figure imgf000678_0002
1516 1517
Figure imgf000678_0003
1518 1519
Figure imgf000678_0004
Figure imgf000679_0001
Figure imgf000679_0002
Figure imgf000679_0003
1528 1529
Figure imgf000680_0001
Figure imgf000680_0002
1534 1534
Figure imgf000680_0003
Figure imgf000681_0001
1544 1545
Figure imgf000682_0001
1550 1551
Figure imgf000682_0002
1552 1553
Figure imgf000683_0001
Figure imgf000683_0002
Figure imgf000684_0001
Figure imgf000684_0002
Figure imgf000684_0003
Figure imgf000685_0001
1572 1573
Figure imgf000685_0002
1574 1575
Figure imgf000685_0003
Figure imgf000686_0001
Figure imgf000687_0001
1588 1589
Figure imgf000687_0002
Figure imgf000688_0001
Figure imgf000688_0002
1596 1597
Figure imgf000688_0003
1598 1599
Figure imgf000688_0004
1600 1601
Figure imgf000689_0001
1604 1605
Figure imgf000689_0002
1606 1607
Figure imgf000689_0003
1608 1609
Figure imgf000690_0001
1610 161 1
Figure imgf000690_0002
1612 1613
Figure imgf000690_0003
1614 1615
H2NYYVk)- COOH
Figure imgf000690_0004
1616 1617
Figure imgf000691_0001
1620 1621
Figure imgf000691_0002
1622 1623
Figure imgf000691_0003
Figure imgf000692_0001
Figure imgf000692_0002
Figure imgf000693_0001
Figure imgf000693_0002
1640 1641
Figure imgf000694_0001
1642 1643
Figure imgf000694_0002
1644 1645
Figure imgf000694_0003
1646 1647
Figure imgf000694_0004
Figure imgf000695_0001
1650 1651
Figure imgf000695_0002
1652 1653
Figure imgf000695_0003
1654 1655
Figure imgf000695_0004
1656 1657
Figure imgf000696_0001
1658 1659
Figure imgf000696_0002
1660 1661
Figure imgf000696_0003
1664 1665
Figure imgf000697_0001
1666 1667
Figure imgf000697_0002
1668 1669
Figure imgf000697_0003
1670 1671
Figure imgf000697_0004
1672 1673
Figure imgf000698_0001
1674 1675
Figure imgf000698_0002
1676 1677
Figure imgf000698_0003
1678 1679
Figure imgf000698_0004
1680 1681
Figure imgf000699_0001
1682 1683
Figure imgf000699_0002
1684 1685
Figure imgf000699_0003
1686 1687
Figure imgf000699_0004
1688 1689
Figure imgf000700_0001
1692 1693
ό- iCOOH
Figure imgf000700_0002
1694 1695
Figure imgf000700_0003
1696 1697
Figure imgf000701_0001
1698 1699
Figure imgf000701_0002
1700 1701
Figure imgf000701_0003
1704 1705
Figure imgf000702_0001
1706 1707
Figure imgf000702_0002
1708 1709
Figure imgf000702_0003
1710 1711
Figure imgf000702_0004
1712 1713
Figure imgf000703_0001
1714 1715
Figure imgf000703_0002
1716 1717
Figure imgf000703_0003
1718 1719
Figure imgf000703_0004
1720 1721
Figure imgf000704_0001
1722 1723
Figure imgf000704_0002
1724 1725
Figure imgf000704_0003
Figure imgf000704_0004
1728 1729
Figure imgf000705_0001
1730 1731
Figure imgf000705_0002
1732 1733
Figure imgf000705_0003
1734 1735
Figure imgf000705_0004
1736 1737
Figure imgf000706_0001
1738 1739
Figure imgf000706_0002
1740 1741
Figure imgf000706_0003
1742 1743
Figure imgf000706_0004
1744 1745
Figure imgf000707_0001
1746 1747
Figure imgf000707_0002
1748 1749
Figure imgf000707_0003
1750 1751
Figure imgf000707_0004
1752 1753
Figure imgf000708_0001
1754 1755
Figure imgf000708_0002
1756 1757
Figure imgf000708_0003
1758 1759
Figure imgf000708_0004
1760 1761
Figure imgf000709_0001
1762 1763
Figure imgf000709_0002
1764 1765
Figure imgf000709_0003
1766 1767
Figure imgf000709_0004
1768 1769
Figure imgf000710_0001
1770 1771
1772 1773
Figure imgf000710_0003
1774 1775
Figure imgf000710_0004
Figure imgf000711_0001
Figure imgf000711_0002
Example 536 r S.3 4SI-2-f2.2-DimethylDentyn-4-r7-methoxy-1 .3-benzodioxol-5- vh-1 -(N.N-di(:n-butyl ,aminocarbonylmethyn-pyrrolidιne-3-carboyylic acid
Example 536A Ethvl 5.5-dimethyl-3-oxooctanoate
Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3_L, 7425 (1990). To a solution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, cooled to 0°C, was added a solution of 30 g of NaOH in 150 mL of water. The resultant solution was warmed to ambient temperature and stirred overnight. Solvents were removed in vacuo; the residue was taken up in 700 mL of water, and extracted twice with 1 :1 ether/hexanes. The aqueous layer was acidified to pH3 with 1 N HCI and extracted twice with hexanes. The combined hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of the crude product is dissolved in 150 mL of THF; 27.3 g of 1 ,1 '-carbonyldiimidazole is added portionwise, to control gas evolution. In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride are combined in 350 mL of THF (overhead mechanical stirring) and warmed to 50°C for 3 hrs. This mixture is cooled to ambient temperature, and the above acid imidazolide solution is added. The resultant slurry is stirred overnight. Ether (600 mL), hexanes (600 mL) and aqueous 1 N phosphoric acid (500 mL) are added, and the mixture is sitrred for 30 min. The aqueous layer is separated; the organics are washed sequentially with bicarb (2X), water and brine. The organics are dried over sodium sulfate, filtered and concentrated to give 30.2 g (95% yield) of a colorless liquid.
Example 536B 4-Methoxy-6-(2-nitrovinyn-1 .3-benzodioxole
3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is added, and the mixture is heated to 50°C for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for 20 min. The solution is filtered; the filtrate is washed with water, then ether, to give^51.8 g of a yellow solid.
Example 536C
Ethyl trans. frans-2-f2.2-Dimethylpentvn-4- '7-rnethoxv-1 .3- benzodioxol-5-yn-pyrrolidine-3-carboxylate
The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 g of the compound of Example 536B in 40 mL of THF. DBU (0.5 mL) was added, and the mixture was stirred at ambient temperature for 6 hrs, during which time it turns reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with aqueous 1 N phosphoric acid and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst (washed sequentially with water and ethanol) was added, followed by 10 mL of acetic acid. The resultant mixture was hydrogenated under 4 atmospheres of hydrogen until hydrogen uptake ceased (~ 3 hrs). The catalyst was removed by filtration; solvents were removed in vacuo. The residue was dissolved in 90 mL of 2:1 ethanol THF; 30 mg of bromcresol green indicator was added, followed by 30 mL of 1N sodium cyanoborohydride in THF. Concentrated HCI was added dropwise to maintain pH at the indicator point, over 1 hr. The resultant solution was stirred overnight at ambient temperature. Bicarb was added, and the solvents were removed in vacuo; the residue was partitioned between water and EtOAc. The organic material was washed with water (2X) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in 100 mL of acetonitrile; 10 mL of Hϋnig's base was added, and the solution was warmed to 40°C overnight. Removal of solvents in vacuo provided 5.0 g of a yellowish oil. Example 536P
Ethyl f2S.3R4^-2-(2.2-Dimethylpentyl)-4-('7-methoxy-1 .3- benzodioxol-5-yn-pyrrolidine-3-carboxylate
The crude compound of Example 536C (2.0 g) was combined with 4 mL of triethylamine in 40 mL of THF; 2.0 g of di-ferf-butyldicarbonate was added, and the mixture was stirred at ambient temperature for 5 hrs. Solvents were removed in vacuo, and the residue was taken up in 60 mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was added, and the resultant solution was stirred overnight. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified with aqueous 1 N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g of a colorless oil. A sample of this material (0.734 g, 1.58 mmol) was combined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL of DMF. The resultant solution was stirred at ambient temperature for 1 hr, then was poured onto 50 mL of 0.6M sodium bicarbonate solution and extracted (3 X 15 mL) with ether. The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a foam, which was dissolved in 5 mL of THF and cooled to 0°C. Simultaneously, 0.418 g (2.37 mmol) of R-4- benzyl-2-oxazolidinone was combined with -0.1 mg of pyreneacetic acid in 5 mL of THF and cooled to 0°C. N-butyllithium (1.6M in hexanes) was added to a red endpoint (persists -10 sec), and the solution was stirred for 10 min. The solution was transferred into the solution of the pentafluorophenyl ester, and the resultant solution was stirred at 0°C for 40 min. Solvents were removed in vacuo; the residue was taken up in bicarb and extracted with ether (3 X 10 mL). The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture of diasteromeric products was separated by flash chromatography on silica gel, eluting with a gradient from 4:1->3:1->2:1 hexanes/EtOAc, giving 423 mg of the faster-moving and 389 mg of the slower-moving diastereomer, respectively. The faster-moving diastereomer was dissolved in 2 mL of a 2.0M solution of sodium methoxide in methanol (freshly prepared, containing 5% methyl formate by volume) and stirred at ambient temperature for 16 hrs. Solvents were removed in vacuo, and the residue was partitioned between ether and aqueous 1 N sodium hydroxide. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 4:1 hexanes/EtOAc. The resultant material was dissolved in 5 mL of TFA and stirred at ambient temperature for 1 hr. Solvents were removed in vacuo; the residue was suspended in bicarb and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 98 mg of product.
Example 536E [^g,3fi,4S]-2-(2,2-Dimethylpentyl)-4-(7-methQxy-1 ,3-benzPdioxQl-5- yn-1 -(N.N-di(n-butyl ,aminocarbonylmethyn-pyrrolidine-3-carboxylic acid
The compound of Example 536D (48 mg) was combined with 35 mg of the compound of Example 501 A in 3 mL of acetonitrile; 0.5 mL of Hϋnig's base was added, and the solution was allowed to stir overnight at ambient temperature. Solvents were removed in vacuo; the residue was partitioned between EtOAc and aqueous 1N phosphoric acid. The organic layer was washed with bicarb and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexanes/EtOAc. • The product was dissolved in 4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, and the resultant solution was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified to pH 3 with aqueous 1N phosphoric acid and extracted with
EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a colorless oil. Lyophilization from acetonitrile/0.1% aqueous TFA gave 56 mg of a white solid. 1H NMR (CDCI3, 300 MHz) d 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, 1 H), 3.86 (t, J = 10.5 Hz, 1 H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1 H), 4.12 (d, J = 16.8 Hz, 1H), 4.29 (d, J = 16.8 Hz, 1 H), 4.41 (brm, 1 H), 5.94 (s, 1 H), 6.52 (d, J = 1.8 Hz, 1 H), 6.67 (d, J = 1.8 Hz, 1H). MS (ESI) (M+H)+ at m/e 533. Anal calcd for C3θH 8N206-0.7 TFA: C, 61.57; H, 8.01 ; N, 4.57. Found: C, 61.59; H, 8.20;
N, 4.63.
Example 537 r S.3R4SI-2-(2.2-Dimethylpentyn-4-π .3-benzodioxol-5-vn-1 - .N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
Example 537A Ethyl trans. fraπs-2-(2.2-Dimethylpentyn-4-M .3-benzodioxol-5-yl ι- pyrrolidine-3-carboxylate
Prepared according to the procedures of Example 536C above, substituting the compound of Example 501 B (5-(2-nitrovinyl)-1 ,3- benxodioxole) for 4-methoxy-6-(2-nitrovinyl)-1 ,3-benzodioxole.
Example 537B Ethyl [2S.3R4S]-2-(,2.2-Dimethylpentyn-4-π .3-benzodioxol-5-yn- pyrrolidine-3-carboxvlate
The compound of Example 537A (6.8 g) was dissolved in 100 mL of ether; a solution of 1.6 g of (S)-(+)-mandelic acid in 60 mL of ether was added, the total volume was made up to -200 mL, and the solution was seeded. The mixture was stirred slowly overnight. The resultant crystals were collected by filtration and recrystallized from ether/EtOAc to give 1.8 g of a white solid. Thsi material was partitioned between bicarb and ether; the ether layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the enantiomerically pure product (>98% e.e.). Examplg 537C r2S.3R4Sl-2-f2.2-Dimethylpentvh-4-f 1 .3-henzodioxol-5-yh- 1 -c N . N- dif n-butyl ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Prepared from the compound of Example 537B according to the procedures of Example 536E. 1 H NMR (CDCI3, 300 MHz) d 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60-3.69 (m, 1 H), 3.75-3.86 (m, 1 H), 3.95-4.16 (m, 2H), 4.28- 4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1 H), 6.8 (dd, J=8.1 , 1.5 Hz, 1 H), 6.87 (d, J=1.8 Hz, 1H). MS (APCI+) m/e 503 (M+H)+.
Example 538 rgS.3R4Sl-2-f2.2-Dimethyl pentyl ,-4-M .3-benzodioxol-5-vn- 1 -f (N- propoxy. N-fn-butvn ιaminocarbonylmethvn-pyrrolidine-3-carboxylic acid
Example 538A N-Boc-N-butyl-O-allylhvdroxylamine
O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath. Diisopropylethylamine (8mL) and di-t-butyidicarbonate (10.0g) were added. The mixture was stirred at 0°C for one hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1 N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil (6.5g). This crude product was dissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over five minutes. The resulting mixture was stirred for 30 minutes at 0°C. 1-lodobutane (4.1 mL) was added dropwise to the mixture. The reaction was stirred at 0°C for one hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1 N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).
Example 538B N-butyl-N-propoxyamine trifluoroacetate
The compound of Example 538A (6.0 g) was dissolved in EtOAc
(100 mL). 10% Palladium-on-carbon (0.5 g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give a colorless oil (5.8 g). A sample of the resultant material (1.15 g) was dissolved in CH2CI2 (5 mL) and cooled in an ice bath. Trifluoroacetic acid (3mL) was added and the solution stirred cold for two hours. The solvent was removed in vacuo , care being taken not to allow the solution to warm above room temperature. The residue contained considerable TFA and was used without further purification.
Example 538C N-butyl-N-propoxy-bromoacetamide
The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL) and cooled to -20°C. Hϋnig's base (5.5 mL) was added slowly. Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. The solution was stirred at -20°C for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1 N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.65 g) which was used without further ourification. Example 538D r S.3R4Sl-2-f2.2-DimethvlDentyn-4-π .3-benzodioxol-5-vn- 1 - ( N- propoxy, N-fn-butvmaminocarbonylmethyn-pyrrolidine-3-carboxvlic acid
The compound of Example 537B was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 539 r^S.3R4Sl-2-f2.2-Dimethylpentyn-4-(/ 1 .3-benzodioxol-5-vn- 1 -f f N- prQPQxy, N-(n-propyn ιaminocarbonylmethyπ-pyrrolidine-3-carboxylic acid
Example 539A
N-propyl-N-propoxy bromoacetamide
Prepared according to the procedures of Example 538A-C, substituting iodopropane for iodobutane in Example 538A.
Example 539B f S.3R4S]-2-f2.2-Dimethylpentyh-4-n .3-benzodioxol-5-yn-1 -. (N- propoxy. N-fn-propymaminocarbonylmethylkpyrrolidine-3-carboxylic acid
The compound of Example 537B was reacted with the compound of Example 539A according to the procedures of Example 536E. Example 540 r S.3R4SI-2-(2.2-DimethylDentvn-4-f7-methoxy-1 .3-benzodioxol-5- yl)-1 -((N-prQPQXy, N-(n-butyl))aminocarbonylmethyn-pyrrolidine-3- carboxvlic acid
The compound of Example 536D was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 541 f S.3R4S)-2-(2.2-Dimethylpentyl)-4-(/7-methoxy-1 .3-benzodioxol-5- yl)-1 -((N-propcχy, N-(n-propyl))aminocarbonylmethylkρyrrolidine-3- carboxylic acid
The compound of Example 536D was reacted with the compound of Example 539A according to the procedures of Example 536E.
Example 542 f S.3R4S|-2-(2.2-Dimethylpent-3-enyπ-4-f 1 .3-benzodioxol-5-vn- 1 - ((N-propoxy. N-(n-butyn taminocarbonylmethvπ-pyrrolidine-3- carboxylic acid
Example 542A frans-Ethyl 3.3-dimethyl-4-hexenoate
A mixture of 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74mmol) and propionic acid (0.28 mL, 3.7 mmol) was heated at 150°C for 7 hr. The product was then distilled under normal pressure (200-220 °C) to give 5.0 g of crude ester as a colorless oil .
Example 542B Ethyl frans. fraπs-2-f 2.2-Dimethylpent-3-enyn-4-M .3-benzodioxol-5- vn-pyrrolidine-3-carboxylate
The title compound is prepared according to the procedures of
Examples 536A and 536C, substituting the compound of Example 542A for ethyl 3,3-dimethylhexanoate in Example 536A and the compound of Example 501 B (5-(2-nitrovinyl)-1 ,3-benxodioxole) for 4-methoxy-6-(2- nitrovinyl)-1 ,3-benzodioxole in Example 536C.
Example 542C
Ethvl r£S.3R4S1-2-,2.2-Dimethylpent-3-enyn-4-π .3-benzodioxol-5- yl)-pyrrolidine-3-carbpχylate
The compound of Example 542B was resolved according to the procedure described in Example 537B.
Example 542D
'£S.3R4S]-2-.2.2-Dimethylpent-3-enylk4-π .3-benzodioxol-5-yl)-1 - ((N-propoxy. N-ι/n-butyl))aminocarbonylmethyh-pyrrolidine-3- carboxylic acid
The compound of Example 542C was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 543 f S.3R4S|-2-f2.2-Dimethylpent-3-enyh-4-M .3-benzodioxol-5-yn-1 - ((N-propoxy. N-(n-propyl)ιaminocarbonylmethyl)-pyrrolidine-3- carboxyiic a id
The compound of Example 542C was reacted with the compound of
Example 539A according to the procedures of Example 536E.
Example 544 r^g,3R4S]-2-(2,2-Pimethyipent-3-enyl)-4-(7-methcχy-1 ,3- benzodioxol-5-yn-1 -(bN-propoxy. N-f n-butyl ■ laminocarbonylmethyl)- pyrrolidine-3-carboxylic acid Example 544A
Ethyl frar?s. fra/7^2-f2.2-Dimethylpent-3-enyn-4-f7-methoxy- 1 .3- benzodioxol-5-yl1-pyrrolidine-3-carboxylate
The title compound is prepared according to the procedures of
Examples 536 A and 536C, substituting the compound of Example 542 A for ethyl 3,3-dimethylhexanoate in Example 536A.
Example 544B Ethyl f^g,3R4g|-2-(2.2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yh-pyrrolidine-3-carboxylate
The compound of Example 544A was resolved according to the procedure described in Example 536D.
Example 544C r£S.3R4Sl-2-(2.2-Dimethylpent-3-enylk4-, 7-methoxy- 1 .3-
Figure imgf000722_0001
pyrrolidine-3-carboxylic acid
The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E.
Example 545 f S.3R4Sl-2-f2.2-Dimethylpent-3-enyn-4-, 7-methoxy-1 .3- benzodioxol-5-yn-1 -((N-propoxy. N-fn-propyn .aminocarbonylmethvn- pyrrolidine-3-carboxylic acid
The compound of Example 544B was reacted with the compound oτ Example 539A according to the procedures of Example 536E.
Example 546 r S.3R4S1-2-f2-f2-Pyridyl ,ethyl ,-4-M .3-benzodioxol-5-vn- 1 -rrΛ 4 - heptyl-Λ^-methyl-S-fluorophenvn] amino carbonylmethyll- pyrrolidine-3-carboxylic acid Example 546A Ethvl frans. frans-2-.2-l /2-pyridynethyn-4-n .3-benzodioxol-5-yn-
Pyrrolidine-3-carboxylate
The title compound is prepared according to the procedures of
Examples 536A and 536C, substituting the compound of Example 519A for 3,3-dimethylhexanoic acid in Example 536A.
Example 546B Ethyl r2S.3R4Sl-2-f2-f2-pyridynethvn-4-f 1 .3-benzodioxol-5-vn- pyrrolidine-3-carboxylate
The compound of Example 546A (1.5 g) was dissolved in CH2CI2 (25 mL). Di-t-butyldicarbonate (0.9 g) was added and the solution stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc (50 mL), washed with water (1x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL). The organic layer was dried with sodium sulfate and evaporated in vacuo to give an oil with was purified by flash chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes to give a colorless oil (1.5 g). The oil was dissolved in EtOH (10 mL) and 50% NaOH solution (0.5 mL) and water (5 mL) were added. The mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo and the residue taken up in EtOAc (25 mL) and acidified with 1 N H3PO4 (10 mL). The layers were separated and the organic layer dried with sodium sulfate and evaporated to give a white semi-solid (1.3 g). A sample of the resultant Boc-protected amino acid (0.9 g) was dissolved in DMF (5 mL). (S)-Phenylalaninol (0.32 g), HOOBt (0.33 g), and EDCl (0.40 g) were added and the solution sitrred overnight at room temperature. Water (50 mL) was added and the mixture extracted with EtOAc (3x25 mL). The organic layers were combined, washed with water (2x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a yellow oil; tic indicated the presence of two diastereomeric products. The diastereomeric amides were separated by flash chromatography on silica gel eluting with 1/12/12 EtOH/EtOAc/hexanes to give faster- (450 mg) and slower-moving isomers (400 mg). The faster-moving diastereomer (400 mg) was taken up in 6N HCI and heated at reflux overnight. The solvent was evaporated and the residue was taken up in toluene (75 mL) and evaporated. This was repeated two additional times to give a brown solid, which was dissolved in EtOH (50mL). 4N HCI/dioxane (10 mL) was added and the solution heated at reflux overnight. The EtOH was evaporated and the residue taken up in EtOAc which was treated with saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash chromatography on silica gel eluting with 30% EtOH/EtOAc gave a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional purification.
Example 546C r S.3R4Sl-2-t 2-(2-pyridvnethyn-4-n .3-benzodioxol-5-vn-1 -rr/v- 4 - heptyl-Λ/-(2-methyl-3-fluorophenyπ*l amino carbonylmethyll- pyrrolidine-3-carboxylic acid
The compound of Example 546B was reacted with the compound of
Example 508E according to the procedures of Example 536E.
Example 547 r2S.3R4Sl-2-, 4-Methoxyphenyn-4-f 1 .3-benzodioxol-5-vn-1 -r(N-butyl- N- -dimethylaminobutyl , amino , carbonylmethyll-Dyrrolidine-3- carboxylic acid
Example 547A N-butyl-4-hvdroxybutyramide
To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85°C for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid. Example 547B N-butyl-4-hydroxybutyl chloroacetamide
To an ice cooled solution of 3.40 g (91.9 mmol) of LiAIH4 in 90 mL of THF was added 2.4 mL of 98% H2SO4, dropwise, with stirring. After bubbling had ceased, a solution of 4.7 g of the compound of Example 547A in 10mL of THF was added. The mixture was stirred at reflux for 24 hr, then cooled with an ice bath and quenched by sequential dropwise addition of 1.7 mL H2O, and 17 mL of 25% w/v aqueous NaOH. The white precipitate was filtered, and washed with about 50 mL of THF. The combined filtrate and washings were concentrated to 3.85 g of an oil. To an ice cooled solution of this material in 35 mL of ethyl acetate was added a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mL of ethyl acetate. The solution was stirred at 0°C for 30 min, then extracted with saturated aqueous NaHC03 solution (1 x 25 mL), 2M NaOH (1 x 25 mL), 5% NH4OH (1 x 25 mL), 1 M HCI (1 x 25 mL), and brine (1 x 25 mL), dried over MgS04, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol, to give 1.52 g (31 %) of a colorless oil.
Example 547C
Ethyl '2S.3R4S1-2- 4-Methoxyphenylk4-M .3-benzodioxol-5-vn- 1 -rι N- butyl-N- -hydroxybutyhamino^carbonylmethyπ-pyrrolidine-3- carboxylate
To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl [2S,3R4S]-2-(4-Methoxyphenyl)-4-( 1 ,3- benzodioxol-5-yl)-pyrrolidine-3-carboxylate (prepared by neutralization of the compound of Example 501 G), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3 x 25 mL). The combined ether layers were washed with water (1 x 25 mL), 4% {v/v ) H3PO4 (1 x 25 mL), saturated aqueous NaHC03 solution (1 x 25 mL), and brine (1 x 25 mL), dried over MgS04. filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol to give 3.0g (79%) of a colorless oil.
Example 547D Ethyl r S.3R4Sl-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1 -r(N- butyl-N-f4-bromobutvhamino ,carbonylmethyl1-pyrrolidine-3- carboxylate
To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0 °C for 20 min. The reaction was diluted with 75 mL of diethyl ether, then extracted with saturated aqueous NaHC03 solution (2 x 25 mL), 5% NH4OH (2 x 25 mL), and brine (1 x 25 mL), dried over MgSθ4, filtered, and concentrated to 3.0 g of a colorless oil. To this material In 45 mL of DMF was added 6.0 g (69 mmol) of LiBr. The reaction warmed to about 50 °C, then gradually cooled. The solution was stirred at ambient temperature for 4h, then poured into 450 mL of water, and extracted with diethyl ether (3 x 100 mL). The combined ether layers were back extracted with water (1 x 100 mL), and brine (1 x 100 mL), dried over MgSθ4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g (90%) of a colorless oil.
Example 547E f S.3R4S|-2-, 4-Methoxyphenvn-4-M .3-benzodioxol-5-yn- 1 -f (N-butyl-
N-(4-dimethylaminobutyl ιamino .carbonylmethyl1-pyrrolidine-3- carboxylic acid
To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethyiamine in ethanol; the resultant solution was heated at reflux for 75 min. Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. i he resuitani maieriai was taken uμ if. C of 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1 M HCI (~7 mL required). The mixture was extracted with EtOAc (3X); the aqueous layer was concentrated in vacuo. The residue was washed 3X with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam.
Example 548 f2S.3R4S]-2-{2.2-Dimethylpentyl ,-4-M .3-benzodioxol-5-yl ,- 1 -f(N- butyl-N-M-dimethylaminobutyl , amino , carbonylmethyl]-pyrrolidine-3- carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 537B (ethyl [2S,3R4S]-2-(2,2-
Dimethylpentyl)-4-( 1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate) in Example 547C.
Example 549 r S.3R4Sl-2-( 2.2-Dimethylpentyn-4-(/7-methoxy- 1 .3-benzodioxol-5- vn-1 - (N-butyl-N-f4-dimethylaminobutyhamino ιcarbonylmethyll- pyrrolidine-3-carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 536D (ethyl [2S,3R4S]-2-(2,2-
Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate) in Example 547C.
Example 550 r2S.3R4S|-2-l 2.2-Dimethylpent-3-envn-4-(, 1 .3-benzodioxol-5-vn- 1 - r(N-butyl-N-(4-dimethylaminobutyl , amino , carbonylmethyll-pyrrolidine-
3-carboxylic acid
Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,3R4S]-2-(2,2- Dimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3- carboxylate) in Example 547C.
Example 551 r2S.3R si-2-(2.2-Dimethylpent-3-envh-4-(7-methoxy-1 .3- benzodioxol-5-yn-1 -r(N-butyl-N- - dimethvlaminobutyhamino*)carbonylmethyn-pyrrolidine-3-carboxvlic add
Prepared according to the procedures of Example 547, substituting the compound of Example 544A (ethyl [2S,3R4S]-2-(2,2- Dimethylpent-3-enyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)- pyrrolidine-3-carboxylate) in Example 547C.
Example 552 r S.3R4S|-2-t 2.2-Dimethylpent-3-enyn-4-M .3-benzodioxol-5-yn- 1 - f(N .N-di(nbutynamino^carbonylmethyl]-pyrrolidine-3-carboxylic acid
Prepared according to the procedures of Example 1 , substituting the compound of Example 541 C (ethyl[2S,3R4S]-2-(2,2-Dimethylpent-3- enyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate).
Example 553 f S.3R4S|-2-(2.2-Dimethylpent-3-enyn-4-(/7-methoxy- 1 .3- benzodioxol-5-yn-1 -[(N.N-dit,n-butynamino^carbonylmethvn- pyrrolidine-3-carboxylic acid
Prepared according to the procesures of Example 1 , substituting the compound of Example 544B (ethyl [2S,3R4S]-2-(2,2-Dimethylpent-3- enyl )-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate) .
As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor. As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.
Binding Assay
ETA. Receptor Preparation of membranes from MMQ cells:
MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells)] cells from 150 mL culture flasks were collected by centrifugation (1000xg for 10 min) and then homogenized in 25 mL of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA , 0.1 mM PMSF, and 5 μg/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80°C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. r125| ET-1 binding to membranes:
Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCl2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 μg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of [1 25I]ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times. Nonspecific binding was determined in the presence of 1 μM ET-1. The data are shown in Table 4. The per cent inhibition at a concentration of 1 mM is shown. The data show that the compounds of the invention bind to the endothelin receptor. Table 4
Binding Data
Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 μM μM
Figure imgf000730_0001
Figure imgf000731_0001
Figure imgf000732_0001
Figure imgf000733_0001
Figure imgf000734_0001
Figure imgf000735_0001
Figure imgf000736_0001
As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the described compounds to inhibit ET-1 -induced phosphatidylinositol hydrolysis was measured.
Determination of Phosphatidylinositol (P\) Hydrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 μCi/mL of [3H]myo-inositoi in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and 10 mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of 1.5 mL of 1 :2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1 :1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 μL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1- X8 (Bio-Rad). The IC50 is the concentration of test compound required to inhibit the ET-induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.
Table 5 Phosphatidylinositol Hydrolysis
Figure imgf000738_0001
Table 6 ETA/ETB Selectivity
MMQ cells, porcine cerebellar tissues (known to contain ETβ receptors) and Chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA , 0.1 mM PMSF, 5 μg/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disruptor. The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitor and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 °C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCl2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 μg/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition binding studies, membranes (0.02 mg) were incubated with 0.1 nM of [125I]ET-1 (for ETA assay in MMQ or CHO cells transfected with human ETA receptor) or [125l]ET-3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETβ receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters
(Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence of 1 μM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors.
Table 6
EXAMPLE rET-A rET-A pET-B Selectivity hET-A hET-B Selectivity
NO. (%l @ IC50 IC50 (rA/pB IC50 IC50 (hA/hB
1 μM) ( n M ) ( n M ) ratio) ( n M) ( n M) ratio)
502 95.7 3.0 71,000 23,000
503 97.0 1.4 50,000 35,000 0.92 52,000 56,000
504 97.1 3.1 >100,000 >32,000 4.6 >100,000 >21,000
505 95.8 2.0 60,000 30,000 5.7 68,000 12,000
506 99.7 3.2 >100,000 >31,000 3.0 61,000 20,000 507 99.3 3.0 >100,000 >33,000 1.63 >100,000 >60,000
508 97.6 1.9 45,000 23,000 2.1 51,000 24,000
509 100 0.56 30,000 53,000 0.51 23,000 45,000
510 100 0.50 35,000 68,000 1.0 11,000 11,000
511 99.2 0.81 N.D. 0.60 15,000 25,000
512 98.9 0.42 >80,000 >190,000 0.58 60,000 >102,000
513 98.0 0.30 8,800 29,000 0.36 14,000 37,000
514 100 1.0 26,000 26,000 0.36 9,800 29,000
515 99.1 1.6 >62,000 >37,000 6.7 >100,000 >15,000
516 99.7 0.71 29,000 40,000 1.8 37,000 21,000
517 94.1 1.0 30,000 30,000 0.43 12,000 29,000
518 96.3 1.3 85,000 63,000 0.31 38,000 124,000
519 99.1 0.38 14,000 36,000 0.23 19,000 83,000
520 97.4 0.20 28,000 130,000
521 100 0.67 37,000 54,000
523 99.0 0.42 360 880 0.33 290 880
524 99.2 0.79 1,700 2,100 0.82 890 1,100
525 100 8.2 560 70 526 100 42 — — 17 7,400 440
527 96.6 7.9 10,000 1,300
528 98.3 11 43,000 3.800
529 98.1 3.6 6,300 1,700
531 99.8 1.2 — — 0.71 870 1 ,200
532 100 5.1 3,200 630
533 97.9 76 7,900 100 40 22,000 560
534 0.12 0.36 3.0 0.08 0.28 3.5
536 100 0.52 17,000 33,000 0.92 52,000 56,000
537 97.2 0.96 5,900 6,200 0.23 1,900 8,200
552 97.3 0.78 7100,000 7125,000 1.0 >96,000 >96,000
553 100 0.26 42,400 160,000 0.29 39,500 136,000
Determination of Plasma Protein Binding
A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 10X into PBS. A 0.4 mL sample of this secondary stock solution was added to 3.6 mL of fresh plasma, and incubated at room temperature for 1 hour. A 1 mL sample of this incubation mixture was transferred to a Centrifree ultrafiltration tube. The sample was centrifuged in a fixed-bucket rotor for approximately 2 min and the filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 μL sample of the ultrafiltrate was transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 μL sample was injected and the concentration of drug in the ultrafiltrate was determined by HPLC analysis compared against a standard sample prepared identically in the absence of plasma. Ultrafiltrate concentrations are calculated from a calibration curve. Protein binding is calculated according to the equation:
739 %PB = [1-(Cu/Ci)] * 100%
where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration. The percent of bound compound is listed in Table 7.
Table 7.
Example #43 > 99.5 % bound Example #530 78% bound
Example #531 92% bound
Example #532 96.8% bound
Example #533 82.6% bound
It has been demonstrated in the literature (Wu-Wong, et al., Life Sci. 1996, 58,
1839-1847, and references contained therein) that compounds which are highly protein bound show decreased potency in vitro in the presence of plasma proteins. A decrease in in vitro potency may correspondingly result in reduced in vivo potency. An endothelin antagonist which has reduced protein binding might be expected to be less susceptible to this effect, and thus be more potent as an in vivo agent.
The ability of "reduced protein binding" endothelin antagonists to exhibit enhance activity in the presence of serum albumin has been demonstrated through the following study: A series of binding curves is recorded for a given antagonist, each experiment performed in the presence of increasing concentrations of serum albumin.
Protocol for Albumin-induced binding shift studies: Binding assays were performed in 96-well microtiter plates precoated with 0.1 % BSA unless otherwise indicated. Membranes were diluted in Buffer B (20mM Tris, 100mM NaCl, 10mM MgCI2, pH 7.4, 0.1 mM PMSF, 5mg/mL Pepstatin A, 0.025% bacitracin and 3 mM EDTA) to a final concentration of 0.05 mg/ml of protein. Varying concentrations of human serum albumin (HSA) were added as indicated. In competition studies, membranes were incubated with 0.1 nM of [1 25|]EJ jη
740 Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25°C. After incubation, unbound ligands were separated from bound ligands by vacuum filtration using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., Watertown, MA), followed by washing the filter strips with saline (1 ml) for three times. Nonspecific binding was determined in the presence of 1 μM ET-1.
Figure 1A.
Figure imgf000743_0003
Figure imgf000743_0001
[Example 43], M >98% Protein Bound
Figure IB. Figure lC.
Figure imgf000743_0002
0" IO'2 10"1 10-" 1CT 1(T
[Example 531], M [Example 530], M
92% protein bound 78% Protein Bound
Figure 1
Inhibition of [125I]ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either 0%, 0.2%, 1 %, or 5% HSA, and
741 assays were performed as described above. The results are expressed as % of control binding, with [125I]ET-1 binding in the absence of antagonist defining 100%. Each point represents the mean (±S.D.) of three determinations.
As observed in Figure 1 A, a compound which is highly protein bound (Example 4
>98% bound) shows a rightward shift of the binding curve (toward decreasing potency in the presence of increasing albumin levels. The compound of Example 531 (Figure 1 B in which protein binding is reduced to 92%, shows a substantial diminution of this rightward shift; the shift is completely eliminated with the compound of Example 530 (Figure 1 C), in which protein binding is reduced to 78%. This experiment demonstrates that a reduction in protein binding translates into increased potency in the presence of plasma proteins, and suggests that such compounds may exhibit enhanced in vivo activity.
The observed reduction in protein binding, in compounds which retain high affinit for endothelin receptors, appears linked to the placement of "basic" functionality (group which carry a positive charge at physiological pH).
Such compounds also exhibit improved solubility in aqueous solutions, as demonstrated below (Table 1 ) in an experiment in which maximum solubility was measured in aqueous media at varying pH at about 25 °C. These results indicate that compounds that contain charged groups on the amide sidechain exhibit increased solubility over a significant range of pH. Such increased aqueous solubility, coupled wit the enhanced potency resulting from decreased protein binding, might make such compounds preferred for development as parenteral agents. Table 8 presents the pH- Solubility profiles for representative compounds of the present invention.
Table 8.
pH [Example 43] (mg/m [Example 531 ] (mg/
5.1 0.08 > 3.3
6.5 0.51 > 3.4
7.1 0.99 3.54
7.6 1 .14 3.55 The present invention provides less protein bound compounds having improved in vitro and in vivo activity as pharmaceutical agents. The present invention also provides compounds that show that the affinity of hydrophobic acids for plasma protein may be reduced by attaching a counterbalanced charge at a biologically acceptab site. For example, protein binding is reduced by attaching a "basic" functionality (group which carry a positive charge at physiological pH) on the amide sidechain (see Formula wherein R3 has an amide sidechain).
The present invention covers compounds having the formula XII:
Figure imgf000745_0001
XII wherein
Z is -C(Ri8)(Ri9)- or -C(O)- wherein Rιs and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
R is -(CH2)πrw wherein m is an integer from 0 to 6 and W is
(a) -C(O)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyi, (d) -CN,
(e) -C(O)NHRi7 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy,
(j) alkoxy, (k) sulfonamido,
(I) -C(O)NHS(O)2Ri6 wherein R-| 6 is loweralkyl, haloalkyi, aryl or dialkylamino, (m) -S(O)2NHC(O)Ri 6 wherein R1 6 is defined as above,
(
Figure imgf000746_0001
q) ,
N
■r
(r)
Figure imgf000746_0002
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkeny!, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl,
744 heterocyclic, (heterocyclic)alkyl and (Raa)(R b'N"Rcc" wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; R3 is (a)R4-C(O)-R5-, R4-C(O)-R5- N(R6)- , wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R2o) Rδ- or
-R8a-N(R2o)- «8" wherein Rs and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi or cycloalkylalkyl or (v) -O-R9- or -Rgg-O-Rg- wherein R9 and R9a are independently selected from alkylene; R4 and RQ are (Rn )(Ri 2)N- wherein Rn and R12 are independently selected from
(1 ) hydrogen,
(2) loweralkyl,
(3) haloalkyi, (4) alkoxyalkyl,
(5) haloalkoxyalkyi,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyi, (9) cycloalkylalkyl,
(10) aryl,
(1 1 ) heterocyclic,
(12) arylalkyi,
(1 3) (heterocyclic)alkyl, (14) hydroxyalkyi,
(1 5) alkoxy,
(16) aminoalkyl,
(1 7) trialkylaminoalkyl,
(18) alkylaminoalkyl, (1 9) dialkylaminoalkyl,
(20) carboxyalkyl,
(21 ) (cycloalkyl)aminoalkyl,
(22) (cycloalkyl)alkylaminoalkyl,
(23) (heterocyclic)aminoalkyl, and (24) (heterocyclic)aminoalkyl, with the proviso that at least one of R and R12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic)aminoalkyl, and (heterocyciic)alkylaminoalkyl; or a pharmaceutically acceptable salt thereof.
745 Preferred compounds having reduced protein binding are shown in Table wherein R may be selected from the substituents shown in Table 9B. Table 9A.
Figure imgf000748_0001
746
Figure imgf000749_0001
Figure imgf000750_0001
Table 9B.
Figure imgf000750_0002
48
Figure imgf000751_0001
9
Figure imgf000752_0001
For the purposes of this disclosure, the term "(cycloalkyl)aminoalkyl" as used herein refers a cycloalkyi moiety attached to the parent compound through an aminoalkyl. Examples of (cycloalkyl)aminoalkyl include (cyclohexane)aminopropyl, (cyclohexane)aminoethyl, and the like. The term "(heterocyclic)aminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an aminoalkyl. Examples of (heterocyclic)aminoalkyl include (pyridine)aminopropyl, (benzofuran)aminopropyl, (tetrahydopyran)aminoethyl, and the like.
The term "(cycloalkyl)alkylaminoalkyf' refers to a cycloalkyi moiety attached to the parent compound through an alkylaminoalkyl. Examples of
(cycloalkyl)alkylaminoalkyl include (cyclohexane)ethylaminomethyl, (cyclopentane)methylaminoisopropyl, and the like.
The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an alkylaminoalkyl. Examples of (heterocyclic)alkylaminoalkyl include (pyridine)ethylaminopropyl,
(benzofuran)methylaminoisobutyl, (tetrahydopyran)methylaminoethyl, and the like. The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 10 131 (1983).
The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990). The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990).
The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).
The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J. Neurosurg. 66 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991). The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82. (1991).
The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 83 1762 (1989).
The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989).
The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990). The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. 79 619 (1990).
The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol. and Pharmacol. 67 1213 (1989).
The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).
The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods described in Bobik, et al., Am. J. Physiol.
258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990).
751 The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).
The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 19 .840-846 (1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic. The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).
The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin. Invest. 87 1867 (1991).
The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat. Acad. Sci. 92 2691 (1995). The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol. Exp. Therap. 271 156 (1994).
The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269).
752 The ability of the compounds of the invention to treat ischemia-repurfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, 9, 201-207).
The ability of the compounds of the invention to treat angina, pulmonary hypertension, raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27).
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other
753 representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception, especially treatment of bone pain associated with bone cancer. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phosphoiipids or other lipid substances. Liposomes are formed by mono- or multi- lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically aceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the
755 like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
A representative solid dosage form, for example, a tablet or a capsule, comprises:
Compound of the invention: 35% w/w
Starch, Pregelatinized, NF 50% w/w Microcrystalline Cellulose, NF 10% w/w
Talc, Powder, USP 5% w/w
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, fiunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof. Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof.
Representative angiotensin II antagonists include DUP 753, A-81988 and the like. Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
756 Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
757

Claims

OΔ1MSWhat is claimed is:
1 . A compound of the formula:
Figure imgf000760_0001
wherein
Z is -C(Ri8)(Ri9)- or -C(O)- wherein Rie and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyi,
(d) -CN, (e) -C(0)NHRi7 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy,
(k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 wherein R16 is loweralkyl, haloalkyi, aryl or dialkylamino, (m) -S(0)2NHC(0)Ri6 wherein R16 is defined as above,
Figure imgf000760_0002
Figure imgf000761_0001
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxya cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkeny I, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of !
R2 is other than hydrogen; R3 is (a)R4-C(0)-R5-, R -R5a-, R4-C(0)-R5- N(R6)- , R6-S(0)2-R7- or
R26-S(0)-R27- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv)
-N(R2o)-R╬▓- or -R8a-N(R20)-R8- wherein Re and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -Rgg-O-Rg- wherein Rg and R9a are independently selected from alkylene; R╬┤a is (i) alkylene or (ii) alkenylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i)-R╬╣ o- or -R10a"N(R2i)-R╬╣o- wherein R10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi; R4 and Re are independently selected from the group consisting of
(i) (R╬╣ ╬╣)(Ri2)N- wherein Rn and R12 are independently selected f rom
( 1 ) hydrogen,
(2) loweralkyl , (3) haloalkyi ,
(4) alkoxyalkyl,
(5) haloalkoxyalkyi,
(6) alkenyl,
(7) alkynyl, (8) cycloalkyi,
(9) cycloalkylalkyl,
( 1 0) aryl,
(11 ) heterocyclic,
( 1 2) arylalkyi , ( 13) (heterocyclic)alkyl,
( 1 4) hydroxyalkyi,
( 1 5) alkoxy,
( 1 6) aminoalkyl,
( 17) trialkylaminoalkyl, ( 1 8) alkylaminoalkyl, (1 9) dialkylaminoalkyl, and
(20) carboxyalkyl i i) loweralkyl, i i i ) alkenyl,
85 iv) alkynyl, v) cycloalkyi, vi) cycloalkylalkyl, vii) aryl, vi i i) arylalkyi,
90 ix) heterocyclic, x) (heterocyclic)alkyl, xi) alkoxyalkyl, xi i) hydroxyalkyi, x i i i) haloalkyi,
95 xiv) haloalkenyl, xv) haloalkoxyalkyi, xvi) haloalkoxy, xvii) alkoxyhaloalkyl, xviii) alkylaminoalkyl,
100 xix) dialkylaminoalkyl, xx) alkoxy, and
Figure imgf000763_0001
wherein z is 0-5 and R7a is alkylene; 105 R26 is (i) loweralkyl, (ii) haloalkyi, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyi, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyi, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyi; and R27 is alkylene or alkenylene; 110 (b) R22-0-C(0)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl,
(c) lowe ralkyl, 115 (d) alkenyl,
(e) alkynyl,
(f) cycloalkyi,
(g) cycloalkylalkyl, (h) aryl,
120 ( i ) arylalkyi,
(j ) aryloxyalkyl,
(k) heterocyclic,
( I) (heterocyclic)alkyl,
(m) alkoxyalkyl,
125 (n) aikoxyalkoxyalkyi, o r
(o) R13-C(0)-CH(R14)- wherein R 3 is amino, alkylamino or dialkylamino and R 4 is aryl or
Ri 5-C(0)- wherein R15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof. 130
2. The compound according to Claim 1 wherein n is 0 and Z is -CH2-.
3. The compound according to Claim 1 wherein n is 1 and Z is -CH2-.
4. The compound according to Claim 1 wherein n is 0, Z is -CH -, and R3 is R4-C(0)-R5- , R6-S0 -R7- or R26-S(0)-R27- wherein 4' R5┬╗ R6> R7> R26 anc' R27 are as defined therein.
5. The compound according to Claim 1 wherein n. is 0, Z is -CH2-, and R3 is alkoxyalkyl or aikoxyalkoxyalkyi.
6. The compound according to Claim 1 wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-R5- wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein R7 is alkylene, R27 is alkylene and Re and R26 are as defined
5 therein.
7. The compound according to Claim 1 wherein n is 0, Z is -CH - and R3 is R4-C(0)-N(R2o)-R╬┤- or R6-S(0)2-N(R2i )-R╬╣o- wherein R8 and Rio are alkylene and R4, RQ, R20 and R21 are as defined therein.
8. The compound according to Claim 1 wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(0)-NHS(0)2R-j 6 wherein R16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyi, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) arylalkyi, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri 2)N- wherein R^ and R1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyi and R5 is alkylene; or R3 is R4-C(0)-N(R2o)-Rs- or
R6-S(0)2-N(R2i )-R╬╣ o- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi, R8 and R10 are alkylene and R20 and R21 are loweralkyl; or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein RQ is loweralkyl or haloalkyi, R7 is alkylene, R26 is loweralkyl and R27 is alkylene.
9. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi,- (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyi, (x) aryloxyalkyl,
(xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C(0)-N(R o)-R╬┤- or Re-S(0)2-N(R2╬╣ )-R╬╣o- wherein R8 and R1 0 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and RQ is loweralkyl, haloalkyi, alkoxyalkyl, aryl or arylalkyi.
10. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R╬╣ 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,
4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyi, (x) aryloxyalkyl,
(xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyi, 8- methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R^ and R1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl, arylalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, and trialkylaminoalkyl.
1 1 . The compound according to Claim 1 wherein n is 0, R is -C(0) -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R 6 wherein R-|6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) loweralkyl (ii) alkenyl, (iii) arylalkyi, (iv) aryloxyalkyl, (v) heterocyclic, (vi) heterocyclic (alkyl), (vii) aryl, (viii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ is loweralkyl, and R-j 2 is aryl or arylalkyi.
12. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) phenyl or (ii) substituted or unsubstituted 4- methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-
4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy, and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2i)-R╬╣ o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi.
13. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy and alkoxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl,
7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(0)2-N(R2i )-R╬╣ o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi.
14. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R16 wherein R1 6 is loweralkyl or haloalkyi,
Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyρhenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl,
4-pentafluoroethylphenyl, 4-methoxy methoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
15. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl or haloalkyi, Z is -CH2-, Ri is loweralkyl, alkoxyalkyl, or alkenyl, R is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R and R12 are independently selected from loweralkyl, aryl hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyi .
16. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C(0)-Rs- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
17. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R^ is loweralkyl and R12 is aryl.
18. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro- 4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4- ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7- methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R1 t is alkyl and R1 2 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
19. A compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, i is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R^ and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
20. A compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R^ and R12 is alkyl.
21 . The compound according to Claim 1 of the formula:
Figure imgf000770_0001
wherein
Z is -C(Ri╬┤)(Ri 9)- or -C(O)- wherein R╬╣ 8 and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ; R is -(CH2)m- wherein m is an integer from 0 to 6 and W is (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 wherein R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0) Ri 6 wherein R╬╣ 6 is loweralkyl, haloalkyi, aryl or dialkylamino,
(m) -S(0)2NHC(0)R 6 wherein R16 is defined as above,
Figure imgf000771_0001
O 99/06397
-770-
Figure imgf000772_0001
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alky lam inocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkeny I, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-RCc" wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R-, and R2 is other than hydrogen;
R3 is (a) R4-C(0)-R -, R4-Rsa-, Re-S(0)2-R7- or R2e-S(0)-R27- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv)
-N(R2o)-R╬┤- or -R8a-N(R2o)-R8- wherein Rs and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi or cycloalkylalkyl or (v) -O-R9- or -R9a-0-R9- wherein Rg and R9a are independently selected from alkylene;
R╬┤a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv)
-N(R2╬╣ )-R╬╣ o- or -R1 0a-N(R2i )-R╬╣ o- wherein R10 and R1 0a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi; R4 and RQ are independently selected from the group consisting of (0 (Rn)(Ri2)N- wherein Rn and R12 are independently selected from 1) hydrogen,
[2] loweralkyl,
[3) haloalkyi,
4) alkoxyalkyl,
.5) haloalkoxyalkyi,
[6) alkenyl,
[7) alkynyl,
!8) cycloalkyi,
[9) cycloalkylalkyl,
'10) aryl,
: i) heterocyclic,
;i2) arylalkyi,
;i3) (heterocyclic)alkyl,
:i ) hydroxyalkyi,
[15) alkoxy,
(16) aminoalkyl, and
(17) trialkylaminoalkyl,
(ϋ) loweralkyl,
(iii) alke nyl,
(iv) alky nyl,
(v) cycl< Dalkyl,
(vi) cycl< Dalkylalkyl,
(vii) aryl,
(viii) arylalkyi,
(ix) hete rocyclic,
(x) (heterocyclic)alkyl,
(xi) alko xyalkyl,
(xii) hydroxyalkyi,
(xiii) haloalkyi,
(xiv) haloalkenyl,
(xv) haloalkoxyalkyi,
(xvi) haloalkoxy,
(xvii) alkoxyhaloalkyl,
(x v iii' alky aminoalkyl, 95 (xix) dialkylaminoalkyl,
(xx) alkoxy, and
/\ H
<CH N N' R7a
(xxi) o
100 wherein z is 0-5 and R7a is alkylene;
R26 is (i) loweralkyl, (ii) haloalkyi, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyi, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyi, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyi; and 105 R27 is alkylene or alkenylene;
(b) R22-0-C(0)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl, 110 (c) loweralkyl,
(d) alkenyl,
(e) alkynyl,
(f ) cycloalkyi,
(g) cycloalkylalkyl, 115 (h) aryl ,
( i ) arylalkyi , (j ) aryloxyalkyl, (k) heterocyclic, ( I) (heterocyclic)alkyl, 120 (m) alkoxyalkyl,
(n) aikoxyalkoxyalkyi, o r (0) Ri3-C(0)-CH(R╬╣4)- wherein R13 is amino, alkylamino or dialkylamino and R╬╣ 4 is aryl or R╬╣ s-C(0)- wherein R 5 is amino, alkylamino or 125 dialkylamino; or a pharmaceutically acceptable salt thereof. O 99/06397 -773-
22. The compound according to Claim 21 wherein n is 0 and Z is -CH2-.
23. The compound according to Claim 21 wherein n is 1 and Z is -CH2-.
24. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-R5- , R6-S02-R7- or R26-S(0)-R27- wherein R4, R5, R6, R7, R26 and R27 are as defined therein.
25. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or aikoxyalkoxyalkyi.
26. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene or R3 is R6-S(0)2- 7- or R26-S(0)-R27- wherein R7 is alkylene, R 7 is alkylene and RQ and R 6 are as defined therein.
27. The compound according to Claim 21 wherein n is 0, Z is -CH2- and R3 is R -C(0)-N(R2o)-R╬┤- or R6-S(0)2-N(R2╬╣)-R╬╣o- wherein R╬┤ and R10 are alkylene and R4, RQ, R20 and R21 are as defined therein.
28. The compound according to Claim 21 wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(0)-NHS(0)2R16 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyi, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) aryalkyi, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn )(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyi and R5 is alkylene; or
R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and Re is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi,
R╬┤ and R10 are alkylene and R o and R ╬╣ are loweralkyl; or
R3 is R6-S(0)2-R - or R2e-S(0)-R27- wherein RQ is loweralkyl or haloalkyi, R7 is alkylene,
R26 is loweralkyl and
R27 is alkylene.
29. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,
4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryoxyalkyl,
(xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-N(R20)-Rs- or R6-S(O)2-N(R2╬╣ )-R1 0- wherein Re and R10 are alkylene, R20 and R21 are loweralkyl,
R is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R╬▓ is loweralkyl, haloalkyi, alkoxyalkyl, aryl or arylalkyi.
30. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,
4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryoxyalkyl,
(xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn )(R╬╣2)N- wherein R and R1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl and arylalkyi, heterocyclic, hydroxyalkyi, alkoxy, aminoalkyl, and trialkylaminoalkyl.
31 . The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) loweralkyl or (ii) alkenyl, (iii) aryalkyi, (iv) aryoxyalkyl, (v) heterocyclic (alkyl), (vi) aryl, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (R╬╣ ╬╣ )(R-i 2)N- wherein R is loweralkyl and R1 2 is aryl or arylalkyi.
32. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is (i) phenyl or (ii) substituted or unsubstituted 4- methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-
4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2i )-R╬╣ o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi.
33 The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R1 6 wherein R16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl,
4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy and alkoxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl,
7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(0)2-N(R2i )-R╬╣ o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi.
34. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2Ri 6 wherein R1 6 is loweralkyl or haloalkyi,
Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl,
4-pentafluoroethylphenyl, 4-methoxy methoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, aryl arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
35. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R╬╣ 6 wherein R1 6 is loweralkyl or haloalkyi, Z is -CH2-, Ri is loweralkyl, alkoxyalkyl or alkenyl, R2 is 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn)(R╬╣2)N- wherein R^ and R12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
36. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R-j -, and R1 2 are independently selected from loweralkyl.
37. The compound according to Claim 21 wherein n is 0, R is -C(0) -G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl,
4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn )(R╬╣2)N- wherein R^ is loweralkyl and R12 is aryl.
38. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro- 4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4- ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7- methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2╬╣ )-R o- wherein R10 is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl or haloalkoxyalkyi and R ╬╣ is loweralkyl, haloalkyi or alkoxyalkyl.
39. The compound according to Claim 21 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -C H2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R5 is alkylene and R4 is (Rn)(R╬╣2)N- wherein R and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, and heterocyclic.
40. A compound according to Claim 21 wherein n is 0, R is
-C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R╬┤- wherein R5 is alkylene and R4 is (Rn )(R╬╣2)N- wherein R^ and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R11 and R12 is alkyl
41 . A compound selected from the group consisting of fra/7s-fra/7S-2-(4-Methoxphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[3-(N- p ropy l-N- π-pentanesu If ony lam in o)propyl]-py rrolidi ne-3- carboxylic acid; trans, fra/7s-2-(4-Methoxymethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3- carboxylic acid; trans, fra/7s-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol -5-yl)-1 -[2-
(N- propyl-N-A7-pentanesulfonyiamino)ethyl]pyrrolidine-3- carboxylic acid; trans, trans-2-{3, 4- Di met hoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-
( N-propyl-N-n-hexanesu If ony lam ino)ethy I] py rrolidi ne-3- carboxylic acid; trans, trans-2-{ 4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N- propyl-N-A7-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, frans-2-(3,4-Dif luoropheny l)-4-(1 , 3-benzodioxol-5-yl)-1 -(((N, N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, traπs-2-{3, 4- D if I uorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N- propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, frat/s-2-(3-Fluoro-4-methoxyρhenyl)-4-(1 ,3-benzodioxol-5-yl)-
1 -[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3- carboxylic acid; trans, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)- pyrrolidine-3-carboxylic acid; trans, f/rans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-isobutyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; frans, fra/7s-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, frans-2-(4-Methoxy-3-f I uorophenyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; frans, fraπs-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)- amino)ethyl]pyrrolidine-3-carboxylic acid; trans, frans-2-(1 ,4-Benzodioxan-6-yl)-4-(7-methoxy-1 ,3-benzodioxol- 5-yl)-1 -[2-(N-propyl-N-(r?- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; f a/7S,f/-ans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3- carboxylic acid; frans, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)- ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (3- Fluoro-4-methoxypheny I )-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-(2-methoxyethyl)-N-
(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)- ethyl]pyrrolidine-3-carboxylic acid; trans, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)- pyrrolidine-3-carboxylic acid; trans, frans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-(2- methy lpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; and frans, frarjs-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-isobuty l-N- (butanes u If ony lam in o))ethy I) pyrrol idine-3- carboxylic acid; trans, fraπs-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fraπs, fraπs-2-(2-(1 ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 - (N,N-di(n-butyl)am inocarbony lmethyl)-pyrrolidine-3-carboxylic acid; trans, frar/s-2-(2-(2-Tetrahydro-2H-py ran )ethyl)-4-(1 ,3-benzodioxol- 5-y I)- 1 -(N, N-di( n-buty l)am inocarbony! methy l)-pyrro lidine-3- carboxylic acid; trans, frar>s-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 ,3-benzodioxol-5- y I)- 1 -(N,N-di(n-butyl)am inocarbony I methy l)-pyrrolidine-3- carboxylic acid; trans, frans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3- benzodioxol-5-y I)- 1 -(N,N-di (n-buty I) ami no carbony I methy I)- pyrrolidine-3-carboxylic acid; trans, fraπs-2-(2-(1 ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 - [[Λ/-4-heptyl-Λ/-(2-methyl-3-fluorophenyl)] am inocarbony I methy l]-pyrrolidine-3-carboxy lie acid; trans, frar>s-2-(2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid trans, frans-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(N,N-di (n-buty l)aminocarbony I methy l)-py rrolidi ne-3- carboxylic acid; 2S,3R,4S;-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-4- heptyl-N-(4-f I uoro-3-methylphenyl))am inocarbony Imethyl)- pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyrrol id in-1 -yl)ethyl)-4-( 1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; (2S,3fl,4Sj-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid trans, frans-2-(2-( 1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- 100 benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- methylpheny I) )aminocarbonylmethyl)-py rrolidi ne-3-carboxy lie acid; trans, frans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- 105. carboxylic acid; trans, trans-2- (2, 2-di methy ipentyl)-4-(2, 3-d ihydro-benzof uran-5-y I)-
1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; trans, trans-2-{2, 2 , -Dimethyl-2-(1 , 3-dioxolan-2-yl)ethyl)-4-(7- 110 methoxy-1 ,3-benzodioxol-5-yl)-1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1 ,3- be nzodioxol-5-y I)- 1 -(N,N-di (n-buty I) aminocarbonyl methy I)- pyrrolidine-3-carboxylic acid; 115 trans, fraπs-2-(2,2-Dimethyl-3-(EJ-pentenyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di (n-buty l)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 120 (2S, 3R, 4SJ-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- y I)- 1 -(N, N-d i( n-buty I) am inocarbony I methy I )-py rrolidi ne-3- carboxylic acid; {2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5- yl)- 1 -(N-4-heptyl-N-(4-fl uoro-3- 125 meth y Iphe n l)) am inocarbony I met hyl)-pyrrolidine-3-carboxy lie acid; trans, frans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -
(N,N-di (n-buty I) aminocarbonyl methy l)-pyrrol id ine-3-carboxy lie acid; 130 trans, frans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[(N- b uty l-N-(4-di methy lam inobutyl)ami no) carbony Imethyl]- pyrrolidine-3-carboxylic acid; (^fl,3fl,4Sj-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3- 135 carboxylic acid; 2S,3 ?,4S -2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3 ?,4SJ-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 ,3-benzodioxol-5- yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- 140 carboxylic acid;
/2S,3/?,4SJ-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; 2S,3r?,4S;-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-benzodioxol-5-yl)- 145 1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; and t"2S,3f?,4S;-2-(2-(2-Methoxyphenyl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1 - (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 150 or a pharmaceutically acceptable salt thereof.
42. A compound of the formula:
Figure imgf000785_0001
5 wherein n is 0 or 1 ; m is 0 to 6; W is (a) -C(0) -G where G is hydrogen or a carboxy protecting group,
(b) -P03H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi, 10 (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 where Ri e is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0)2NHC(0)R╬╣e,
Figure imgf000786_0001
Figure imgf000787_0001
Ri an 2 are independently se ected rom hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
43. The compound of Claim 42 wherein m is zero or 1 ;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
44. The compound of Claim 42 wherein n and m are both 0;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from lowe alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
45. The compound according to Claim 42 of the formula:
Figure imgf000788_0001
wherein n is 0 or 1 ; m is 0 to 6; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi, (d) -CN,
(e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino, (m) -S(0)2NHC(0)R╬╣e,
Figure imgf000788_0002
Figure imgf000789_0001
T \ s=o
(s) py H
Figure imgf000789_0002
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkeny I, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
46. The compound according to Claim 45 wherein m is zero or 1 ; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
47. The compound according to Claim 45 wherein n and m are both 0;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fiuorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
48. The substantially pure compound (+)-trans,trans-2-(4- Methoxyphenyl)-4-(1 ,3-benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof.
49. The substantially pure compound (2S,3R,4S)-2-{2,2-
Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a salt or ester thereof.
50. A compound of the formula
Figure imgf000791_0001
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene;
Q is a leaving group; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino,
(m) -S(0)2NHC(0)R╬╣e,
Figure imgf000791_0002
Figure imgf000792_0001
R and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and
R2 is other than hydrogen; or a salt thereof.
51 . The compound according to Claim 50 wherein m is zero or 1 ; R5b is alkylene; Q is a leaving group; and
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
52. The compound according to Claim 50 wherein n and m are both 0; R5b is alkylene;
Q is a leaving group; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer thereof.
53. The compound according to Claim 50 of the formula
Figure imgf000793_0001
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene;
Q is a leaving group;
W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2,
(c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl, (g) dialkylaminocarbonyl,
(h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2R╬╣ 6 where R1 6 is loweralkyl, haloalkyi, phenyl dialkylamino, (m) -S(0)2NHC(0)R╬╣e,
Figure imgf000794_0001
Figure imgf000795_0001
(t) H , or
Figure imgf000795_0002
R and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkeny I, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N"Rcc" wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
54. The compound according to Claim 53 wherein m is zero or 1 ; R5b is alkylene; Q is a leaving group; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)- isomer thereof.
55. The compound according to Claim 53 wherein n and m are both 0; R5b is alkylene; Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fiuorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer thereof.
56. A compound of the formula
Figure imgf000797_0001
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 where R 7 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 where R╬╣ 6 is loweralkyl, haloalkyi, phenyl or dialkylamino,
(m) -S(0)2NHC(0)R╬╣e,
Figure imgf000797_0002
Figure imgf000798_0001
b
(r)
Figure imgf000798_0002
Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alky lam inocarbony lalky I, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and
R2 is other than hydrogen; or a salt thereof.
57. The compound according to Claim 56 wherein m is zero or 1 ; R5b is alkylene; 20a 's hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; and W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
58. The compound according to Claim 56 wherein n and m are both 0; R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
59. The compound according to Claim 56 of the formula
NHRgoa
Figure imgf000799_0001
wherein n is 0 or 1 ; m is 0 to 6; R5b is alkylene; R2oa 's hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(0)NHRi7 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy, (j) alkoxy, (k) sulfonamido,
(I) -C(0)NHS(0)2Ri 6 where R16 is loweralkyl, haloalkyi, phenyl or dialkylamino,
(m) -S(0)2NHC(0)R╬╣e,
Figure imgf000800_0001
N^ ┬░N
S=0
(s) ΛX H
J
Figure imgf000801_0001
(t) H
Figure imgf000801_0002
R and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and
(Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and
Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
60. The compound according to Claim 59 wherein m is zero or 1 ; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; and
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
61. The compound according to Claim 58 wherein n and m are both 0; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2- fluorophenyl, 4-methoxy methoxyphenyl, 4-hydroxy phenyl, 4-t-butylphenyl, 1,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1 ,3- benzodioxoiyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
62. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier.
63. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 21 and a pharmaceutically acceptable carrier.
64. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S, 3R,4S -2-(2,2-Dimethyipentyl)- 4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier.
65. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3f?,4S -2-3-Fluoro-4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)- pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier.
66. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
67. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.
68. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S, 3 4S -2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.
69. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R, 4SJ-2-3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-(2- (N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
70. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
71. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
72. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.
73. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of 2S,3R,4Sb2-(2,2-Dimethylpentyl)-4- (7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid.
74. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S -2-3-Fluoro-4- methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)- pyrrolidine-3-carboxylic acid.
75. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21.
76. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3/?,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.
77. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of f2S,3R,4S 2-3-Fluoro-4-methoxypheny!)-4-(1,3- benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
78. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1 in combination with one or more cardiovascular agents.
79. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents.
80. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R, S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)- 1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid in combination with one or more cardiovascular agents.
81. A process for the preparation of a compound of the formula:
Figure imgf000807_0001
wherein E is a carboxy-protecting group and Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula:
Figure imgf000807_0002
wherein E, R1 and R2 are defined as above and b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids.
82. The process of Claim 71 wherein E is loweralkyl, R1 is aryl and R2 is heterocyclic.
83. The process of Claim 71 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
84. The process of Claim 71 wherein E is loweralkyl, R1 is -methoxyphenyl and R2 is 1 ,3-benzodioxol-5-yl.
85. A process for the preparation of a compound of the formula:
Figure imgf000808_0001
wherein E is a carboxy-protecting group and Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula:
Figure imgf000808_0002
wherein E, R1 and R2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, and c) epimerization of the product of step b) with a base.
86. The process of Claim 75 wherein E is loweralkyl, R1 is aryl and R2 is heterocyclic.
87. The process of Claim 75 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
88. The process of Claim 75 wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1 ,3-benzodioxol-5-yl.
89. A process for the preparation of a compound of the formula:
Figure imgf000809_0001
wherein E is a carboxy-protecting group, Ri and R are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl and R3 is R4-C(O)-Rs- wherein R5 is alkylene and R is (Rn)(Ri2)N- wherein Rn and R12 are independently selected from (1) loweralkyl, (2) haloalkyi,
(3) alkoxyalkyl,
(4) haloalkoxyalkyi, (5) alkenyl,
(6) alkynyl,
(7) cycloalkyi,
(8) cycloalkylalkyl,
(9) aryl,
(10) heterocyclic,
(11) arylalkyi and
(12) (heterocyclic)alkyl;
(13) hydroxyalkyi,
(14) alkoxy,
(15) aminoalkyl, and
(16) trialkylaminoalkyl, or a salt thereof, comprising a) catalytic lydrogenation of a compound of the formula:
Figure imgf000810_0001
wherein E, R1 and R2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, c) epimerization of the product of step b) with a base and d) alkyation of the product of step c) with a compound of the formula R3-X wherein X is a leaving group and R3 is defined as above.
90. The process of Claim 79 wherein E is loweralkyl, R1 is aryl, R2 is heterocyclic and R3 is -CH2C(0)NR11R12 wherein R^ and R12 are independently selected from the group consisting of loweralkyl.
91. The process of Claim 79 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
92. The process of Claim 79 wherein E is loweralkyl, R1 is 4-methoxyphenyl, R is 1,3-benzodioxol-5-yl, R3 is -CH2C(0)N(n-Bu)2 and X is a halogen or sulfonate leaving group.
93. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula:
Figure imgf000811_0001
wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1 ,3-benzodioxol-5-yl, or a salt thereof, comprising reacting a mixture of the (+) and (-) enantiomers of the compound of the formula:
Figure imgf000811_0002
wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1 ,3-benzodioxol-5-yl with
S-(+)- mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer.
94. A compound of the formula:
Figure imgf000812_0001
wherein
Z is -C(Ri╬┤)(Ri9)- or -C(O)- wherein Rig and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is
(a) -C(O) -G wherein G is hydrogen or a carboxy protecting group,
(b) -PO3H2,
(c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyi,
(d) -CN,
(e) -C(O)NHR-| 7 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl, (h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(I) -C(O)NHS(O)2Ri 6 wherein R-| 6 is loweralkyl, haloalkyi, aryl or dialkylamino, (m) -S(O)2NHC(O)Ri 6 wherein R1 6 is defined as above,
Figure imgf000813_0001
Rl and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyl, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyi, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(R b)N-Rcc- wherein Raa is aryl or arylalkyi, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
R3 is (a)R -C(O)-R5-, R4-C(O)-R5- N(R╬▓)- , wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R2o)-R8- or
-R8a-N(R20>-R8- wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi or cycloalkylalkyl or (v) -O-R9- or -R9a-O-
R9- wherein R9 and R9a are independently selected from alkylene;
R and R are (Rn )(Ri 2) - wherein Rn and R12 are independently selected from
(1 ) hydrogen,
(2) loweralkyl,
(3) haloalkyi,
(4) alkoxyalkyl,
(5) haloalkoxyalkyi,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyi,
(9) cycloalkylalkyl,
( 10) aryl, (1 1 ) heterocyclic,
(12) arylalkyi,
(13) (heterocyclic)alkyl,
(14) hydroxyalkyi,
(15) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl,
(20) carboxyalkyl,
(21 ) (cycloalkyl)aminoalkyl,
(22) (cycloalkyl)alkylaminoalkyl,
(23) (heterocyclic)aminoalkyl, and
(24) (heterocyclic)aminoalkyl, with the proviso that at least one of R and R12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic)aminoalkyl, and (heterocyclic)alkylaminoalkyl; eutically acceptable salt thereof.
95. A compound selected from the group consisting of:
Figure imgf000816_0001
Figure imgf000817_0001
Figure imgf000818_0001
wherein R is selected from the group consisting of:
Figure imgf000818_0002
Figure imgf000819_0001
(CH3)3N -, f
Figure imgf000819_0002
Figure imgf000819_0003
Figure imgf000820_0001
96. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia, atherosclerosis, coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising a therapeutically effective amount of a compound of claim 94, wherein said compound has an attached charged functionality which reduces the degree of plasma protein binding of the compound.
97. A method of improving the in vivo activity of compounds by reducing the amount of compound bound to protein by attaching a charged functionality to the compound.
98. A method of claim 97 wherein the charged functionality carries a positive charge at physiological pH.
PCT/US1998/015479 1996-02-13 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists WO1999006397A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002297894A CA2297894A1 (en) 1997-08-04 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists
IL13417598A IL134175A0 (en) 1997-08-04 1998-07-27 Endothelin antagonists
PL98342500A PL342500A1 (en) 1997-08-04 1998-07-27 Derivatives of pyrolydin-3-carboxylic acid and their application as endothelin antagonists
HU0003484A HUP0003484A3 (en) 1997-08-04 1998-07-27 Pyrrolidine-3-crboxylic acid derivatives and their use as endothelin antagonists
NZ502395A NZ502395A (en) 1997-08-04 1998-07-27 4-Benzodioxolyl substituted pyrrolidine-3-carboxylic acid derivatives useful as endothelin antagonists
BR9815296-3A BR9815296A (en) 1997-08-04 1998-07-27 Derivatives of 3-pyrrolidine carboxylic acid and use of them as endothelin antagonists
AU85921/98A AU748469B2 (en) 1996-02-13 1998-07-27 Endothelin antagonists
SK145-2000A SK1452000A3 (en) 1997-08-04 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists
JP2000505155A JP2001512119A (en) 1997-08-04 1998-07-27 Endothelin antagonist
EP98937139A EP1003740A2 (en) 1997-08-04 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagoists
NO20000542A NO20000542L (en) 1997-08-04 2000-02-02 Endothelin antagonists
BG104216A BG104216A (en) 1997-08-04 2000-03-02 Derivatives of pyrrolidine-3-carbonic acids and their application as endotheline antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/905,913 US6162927A (en) 1994-08-19 1997-08-04 Endothelin antagonists
US4895598A 1998-03-27 1998-03-27
US09/048,955 1998-03-27
US08/905,913 1998-03-27

Publications (2)

Publication Number Publication Date
WO1999006397A2 true WO1999006397A2 (en) 1999-02-11
WO1999006397A3 WO1999006397A3 (en) 1999-12-09

Family

ID=26726720

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/015479 WO1999006397A2 (en) 1996-02-13 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists

Country Status (16)

Country Link
EP (1) EP1003740A2 (en)
JP (1) JP2001512119A (en)
CN (1) CN1301264A (en)
AU (1) AU748469B2 (en)
BG (1) BG104216A (en)
BR (1) BR9815296A (en)
CA (1) CA2297894A1 (en)
HU (1) HUP0003484A3 (en)
IL (1) IL134175A0 (en)
NO (1) NO20000542L (en)
NZ (1) NZ502395A (en)
PL (1) PL342500A1 (en)
SK (1) SK1452000A3 (en)
TR (4) TR200501137T2 (en)
TW (1) TW552260B (en)
WO (1) WO1999006397A2 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1097236A1 (en) * 1998-07-15 2001-05-09 Bristol-Myers Squibb Company Stereoselective reductive amination of ketones
WO2002011713A2 (en) 2000-08-07 2002-02-14 Abbott Laboratories Methods of treating bone cancer and the pain associated therewith using endothelin antagonists
WO2002051836A1 (en) * 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
WO2002085351A1 (en) * 2001-04-11 2002-10-31 Abbott Laboratories Favorable modulation of health-related quality of life and health-related quality-adjusted time-to-progression of disease in patients with prostate cancer
WO2007034406A1 (en) * 2005-09-22 2007-03-29 Actelion Pharmaceuticals Ltd Pyrrolidine-3-carboxylic acid amide derivatives and their use as inhibitors of renin
WO2011114103A1 (en) 2010-03-18 2011-09-22 Biolipox Ab Pyrimidinones for use as medicaments
US8569341B2 (en) 2010-06-04 2013-10-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US8623819B2 (en) 2007-08-22 2014-01-07 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8952036B2 (en) 2013-02-28 2015-02-10 Amgen Inc. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9376425B2 (en) 2011-09-27 2016-06-28 Amgen, Inc. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2874015B1 (en) * 2004-08-05 2006-09-15 Sanofi Synthelabo N- (1H-INDOLYL) -1H-INDOLE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2880625B1 (en) * 2005-01-07 2007-03-09 Sanofi Aventis Sa N- (HETEROARYL) -1H-INDOLE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
CN104262329A (en) * 2014-10-22 2015-01-07 南京友杰医药科技有限公司 Preparation method for anti-form atrasentan
WO2023030470A1 (en) * 2021-09-03 2023-03-09 深圳信立泰药业股份有限公司 Endothelin a (eta) receptor antagonist compound, preparation method therefor and medical use thereof
WO2024022262A1 (en) * 2022-07-25 2024-02-01 深圳信立泰药业股份有限公司 Salt of endothelin a (eta) receptor antagonist compound, and preparation method therefor and medical use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0439444A2 (en) * 1990-01-22 1991-07-31 Monsanto Company Synthesis of chiral pyrrolidine and piperidine glycosidase inhibitors
WO1996006095A1 (en) * 1994-08-19 1996-02-29 Abbott Laboratories Endothelin antagonists
WO1997030046A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
US5668164A (en) * 1996-07-12 1997-09-16 Abbott Laboratories Process for synthesis of chiral cis-and trans-3-amino-4 substituted pyrrolidine compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0439444A2 (en) * 1990-01-22 1991-07-31 Monsanto Company Synthesis of chiral pyrrolidine and piperidine glycosidase inhibitors
WO1996006095A1 (en) * 1994-08-19 1996-02-29 Abbott Laboratories Endothelin antagonists
WO1997030046A1 (en) * 1996-02-13 1997-08-21 Abbott Laboratories 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
US5668164A (en) * 1996-07-12 1997-09-16 Abbott Laboratories Process for synthesis of chiral cis-and trans-3-amino-4 substituted pyrrolidine compounds

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A. S. TASKER ET. AL.: "Potent and Selective Non-benzodioxole Containing Endothelin A Receptor Antagonists"" JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 3, 31 January 1997 (1997-01-31), pages 322-30, XP002082166 *
C. R. CRAIG ET. AL.: "Modern Pharmacology, Third Edition" , LITTLE, BROWN AND COMPANY , BOSTON, US XP002118728 page 33, column 2 -page 35, column 1 *
H-S JAE ET. AL.: "Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists. 2. Sulfonamide based ETA-ETB Mixed Antagonists." JOURNAL OF MEDICINAL CHEMISTRY , vol. 40, no. 20, 26 September 1997 (1997-09-26), pages 3217-27, XP002082169 *
J. G. TOPLISS: "Quantitiative Structure-Activity Relationships of Drugs" , ACADEMIC PRESS , NEW YORK, US XP002118726 page 453, paragraph 2 -page 456, paragraph 2 *
J. K. SEYDAL ET. AL. : "Chemische Struktur und biologische Aktivit{t von Wirkstoffen. " 1979 , VERLAG CHEMIE , WEINHEIM, DE XP002118727 page 124, paragraph 2 -page 126, paragraph 2 *
M. WINN ET. AL.: "2,4-Diarylpyrrolidine-3-carboxylci Acids- Potent ETA Selective Endothelin Receptor Antagonists. 1. Discovery of A-127722. " JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 5, 1 March 1996 (1996-03-01), pages 1039-48, XP002082167 *
S. S. BHAGWAT ET. AL.: "Synthesis of Enantiomerically Pure Pyrrolidinones as Endothelin Receptor Antagonists." TETRAHEDRON LETTERS, vol. 37, no. 27, 1996, pages 4627-30, XP002082168 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1097236A1 (en) * 1998-07-15 2001-05-09 Bristol-Myers Squibb Company Stereoselective reductive amination of ketones
EP1097236A4 (en) * 1998-07-15 2006-10-04 Bristol Myers Squibb Co Stereoselective reductive amination of ketones
WO2002011713A2 (en) 2000-08-07 2002-02-14 Abbott Laboratories Methods of treating bone cancer and the pain associated therewith using endothelin antagonists
WO2002011713A3 (en) * 2000-08-07 2003-07-17 Abbott Lab Methods of treating bone cancer and the pain associated therewith using endothelin antagonists
WO2002051836A1 (en) * 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
WO2002085351A1 (en) * 2001-04-11 2002-10-31 Abbott Laboratories Favorable modulation of health-related quality of life and health-related quality-adjusted time-to-progression of disease in patients with prostate cancer
WO2007034406A1 (en) * 2005-09-22 2007-03-29 Actelion Pharmaceuticals Ltd Pyrrolidine-3-carboxylic acid amide derivatives and their use as inhibitors of renin
US9592231B2 (en) 2007-08-22 2017-03-14 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8623819B2 (en) 2007-08-22 2014-01-07 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
US8865650B2 (en) 2007-08-22 2014-10-21 AbbVie Deutschland GmbH & Co. KG Therapy for complications of diabetes
WO2011114103A1 (en) 2010-03-18 2011-09-22 Biolipox Ab Pyrimidinones for use as medicaments
US9296736B2 (en) 2010-06-04 2016-03-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US8569341B2 (en) 2010-06-04 2013-10-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9593129B2 (en) 2010-06-04 2017-03-14 Amgen, Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9376425B2 (en) 2011-09-27 2016-06-28 Amgen, Inc. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer
US8952036B2 (en) 2013-02-28 2015-02-10 Amgen Inc. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9623018B2 (en) 2013-06-10 2017-04-18 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9757367B2 (en) 2013-06-10 2017-09-12 Amgen Inc. Calcium propane-2-sulfinate dihydrate
US9801867B2 (en) 2013-06-10 2017-10-31 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9855259B2 (en) 2013-06-10 2018-01-02 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor

Also Published As

Publication number Publication date
WO1999006397A3 (en) 1999-12-09
BR9815296A (en) 2001-11-20
TR200501137T2 (en) 2005-12-21
HUP0003484A3 (en) 2002-02-28
TR200101233T2 (en) 2002-06-21
IL134175A0 (en) 2001-04-30
CN1301264A (en) 2001-06-27
EP1003740A2 (en) 2000-05-31
PL342500A1 (en) 2001-06-04
AU748469B2 (en) 2002-06-06
NZ502395A (en) 2002-08-28
TR200101234T2 (en) 2002-06-21
CA2297894A1 (en) 1999-02-11
AU8592198A (en) 1999-02-22
BG104216A (en) 2000-12-29
NO20000542L (en) 2000-04-04
NO20000542D0 (en) 2000-02-02
SK1452000A3 (en) 2001-05-10
TR200000993T2 (en) 2000-12-21
JP2001512119A (en) 2001-08-21
HUP0003484A2 (en) 2002-01-28
TW552260B (en) 2003-09-11

Similar Documents

Publication Publication Date Title
US6462194B1 (en) Endothelin antagonists
JP3741441B2 (en) Endothelin antagonist
ES2259803T3 (en) NEW PIRROLIDINE DERIVATIVES SUBSTITUTED WITH BENZO-1,3-DIOXOLILO AND BENZOFURANILO AS AN ENDOSTELINE ANTAGONISTS.
WO1999006397A2 (en) Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists
US6946481B1 (en) Endothelin antagonists
WO2002017912A1 (en) Endothelin antagonists
US7365093B2 (en) Endothelin antagonists
EP0888340A1 (en) 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
WO1998057933A1 (en) Pyrrolidine carboxylic acid derivatives as endothelin antagonists
AU781355B2 (en) Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
AU2005201160B2 (en) Endothelin antagonists
AU725122B2 (en) Endothelin antagonists
NZ514170A (en) Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
CZ2000348A3 (en) Pyrrolidine-3-karboxylic acid derivatives and their use as endothelin antagonists
EP0991620A1 (en) Pyrrolidine carboxylic acid derivatives as endothelin antagonists
NZ514171A (en) Benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
AU2008201198A1 (en) Endothelin anatagonists

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 134175

Country of ref document: IL

Ref document number: 98809462.2

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 502395

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2297894

Country of ref document: CA

Ref document number: 2297894

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV2000-348

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 1452000

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 1020007001234

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/001283

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1998937139

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 85921/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2000/00993

Country of ref document: TR

WWP Wipo information: published in national office

Ref document number: 1998937139

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2000-348

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020007001234

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2001/01233

Country of ref document: TR

Ref document number: 2001/01234

Country of ref document: TR

WWG Wipo information: grant in national office

Ref document number: 85921/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2005/01137

Country of ref document: TR

WWR Wipo information: refused in national office

Ref document number: PV2000-348

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: 1020007001234

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: 1998937139

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998937139

Country of ref document: EP