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WO1998057638A1 - ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS - Google Patents

ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS Download PDF

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Publication number
WO1998057638A1
WO1998057638A1 PCT/US1998/012567 US9812567W WO9857638A1 WO 1998057638 A1 WO1998057638 A1 WO 1998057638A1 US 9812567 W US9812567 W US 9812567W WO 9857638 A1 WO9857638 A1 WO 9857638A1
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WO
WIPO (PCT)
Prior art keywords
difluorophenyl
ylamino
oxo
carboxylic acid
piperidin
Prior art date
Application number
PCT/US1998/012567
Other languages
French (fr)
Inventor
Michael A. Patane
Mark G. Bock
Randall C. Newton
Bharat Lagu
Original Assignee
Merck & Co., Inc.
Synaptic Pharmaceutical Corporation
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 GBGB9800217.3A external-priority patent/GB9800217D0/en
Application filed by Merck & Co., Inc., Synaptic Pharmaceutical Corporation filed Critical Merck & Co., Inc.
Priority to AU79726/98A priority Critical patent/AU7972698A/en
Priority to JP50471599A priority patent/JP2002511085A/en
Priority to EP98930307A priority patent/EP1023068A4/en
Priority to CA002294590A priority patent/CA2294590A1/en
Publication of WO1998057638A1 publication Critical patent/WO1998057638A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine. Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla.
  • the binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
  • alpha and beta receptors were further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources.
  • alpha and beta adrenergic receptors were further subdivided into alpha 1 ⁇ alpha 2 ⁇ Bi, and ⁇ 2 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
  • alpha 1 receptor subtypes The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha Id (formerly known as alpha la or la/Id), alpha lb and alpha la (formerly known as alpha lc) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities.
  • alpha la is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated “alpha lc” cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995).
  • alpha la is used throughout this application to refer to this subtype.
  • alpha 1 adrenoceptor subtypes were renamed alpha Id.
  • ATCC American Type Culture Collection
  • Benign prostatic hyperplasia also known as benign prostatic hypertrophy or BPH
  • BPH benign prostatic hypertrophy
  • the symptoms of the-condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
  • the male hormone ⁇ alpha- dihydrotestosterone has been identified as the principal culprit.
  • the continual production of 5a-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
  • alfuzosin which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia.
  • the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alphai subtype was reported.
  • combinations of 5a-reductase inhibitory compounds and alphal- adrenergic receptor blockers terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin
  • the instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha la adrenergic receptor.
  • the compounds of the present invention are alpha la adrenergic receptor antagonists.
  • the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
  • the present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the compounds antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha Id and alpha lb human adrenergic receptors and many other G-protein coupled receptors.
  • This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
  • the compounds of the present invention have the structure:
  • E, G, L and M are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH 2 ) ⁇ -4 ⁇ R 1 5, (CH 2 ) ⁇ -4N(Rl6)2, (CH 2 )0-4CN, (CH 2 )0-4CF 3 , (CH 2 ) ⁇ -4CO 2 R 16 , (CH 2 ) ⁇ -4CON(Rl6) 2 , (CH 2 )0-4SO 2 R 16 , or (CH2) ⁇ -4SO 2 N(Rl6) 2 ;
  • J is selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ Rl5, (CH 2 )l-4N(R 16 )2, (CH 2 )l-4CN, (CH 2 ) ⁇ -4CF3, (CH 2 )0-4CO2R 16 , (CH 2 )0-4CON(Rl6) 2 , (CH 2 ) ⁇ -4SO 2 R 16 , or
  • Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , NR 16 CORl8, NR ⁇ COR ⁇ ,
  • Ci-4 alkyl or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NRl ⁇ COR 18 , NR 16 COR 20 , NR 16 SO2R 18 , NRl6CONRl6CON(R 18 )2, (CH2) ⁇ -4C ⁇ 2R 16 , (CH 2 ) ⁇ -4CON(Rl6) 2 , (CH 2 )0-4SO 2 N(Rl6)2, (CH 2 ) ⁇ -4SO
  • R 2 and R ⁇ are each independently selected from hydrogen, C ⁇ -8 alkyl, C4-8 cycloalkyl, (CH )0-4CO 2 R 16 , (CH 2 ) ⁇ -4CON(Rl6) 2 ,
  • R3, R6, R9 an( j R10 are e ch independently selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH2)2-4 ⁇ R 15 or (CH2) ⁇ -4CF3;
  • R 4 is selected from hydrogen, (CH2) ⁇ -4COR!5, (CH2) ⁇ -4CN, (CH 2 ) ⁇ -
  • R is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH 2 )l-4 ⁇ Rl ⁇ or (CH 2 ) ⁇ -4CF 3 ;
  • R 8 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-40Rl 5 or (CH2) ⁇ -4CF 3 ;
  • RU and Rl 2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
  • Rl3 and Rl4 are each independently selected from hydrogen
  • Rl is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH 2 )0-4CF 3 ;
  • Rl6 and Rl 8 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
  • Rl9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)0-4ORl 5 or (CH2) ⁇ -4CF3;
  • R ⁇ is furanyl or Cl-8 alkyl furanyl
  • R 22 is piperazinyl or Cl-8 alkylpiperazinyl; W is O or NRH;
  • each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH2) ⁇ -4 ⁇ Rl or (CH2) ⁇ -4CF3;
  • Y is C 5 or N
  • Z is hydrogen, oxygen or sulphur
  • n, p and q are each independently an integer from zero to four; o is an integer from two to five; r is an integer from zero to one; t is an integer from zero to five; and the pharmaceutically acceptable salts thereof.
  • Rl is unsubstituted or mono- substituted phenyl; and R 2 is selected from hydrogen, Cl-8 alkyl, or (CH2)0-4CORl6; and R? is hydrogen; and M, E, J, G, L, R3 and R 6 are each hydrogen; and n and m are each one; then Q is selected from
  • Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 16 )2, NR1 6 C0R1 8 , NR1 6 C0N(R1 8 )2, NRI6SO2R 18 , NRl 6 SO2N(R 8 )2, ORl , (CH2) ⁇ -4C ⁇ 2Rl 6 , (CH2)0-4CON(Rl6)2, (CH2) ⁇ -4S ⁇ 2N(Rl 6 )2, (CH2)0-4SO2R 15 , or Cl-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl
  • R 4 is selected from (CH2) ⁇ -4CORl 5 , (CH 2 ) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH2)0-4CO2Rl 6 , (CH2)0-4CON(Rl6) 2 , (CH2) ⁇ -4S ⁇ 2Rl 5 or
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2) ⁇ -4CF3;
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , NR1 6 C0R1 8 , NRl 6 COR 2 0,
  • R 2 and R' are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH 2 )l-4CF 3 ;
  • Rl3 and Rl 4 are each independently selected from hydrogen,
  • (CH2)0-4CO2R1 or Cl-4 alkyl or unsubstituted, mono-, di- or tri- substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR ⁇ , halogen, Cl-4 alkyl or C3-8 cycloalkyl;
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2) ⁇ -4CF3;
  • Rl is ' selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , N 16C0R 8 , NR16CON(R18) 2 ,
  • R 2 and R" 7 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
  • R!3 and Rl 4 are each independently selected from hydrogen
  • a first class of the invention is the compound of the formula selected from
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , NR1 6 C0R1 8 , NRl6COR 0, NRl6C0N(Rl 8 )2, NRI6SO2RI 8 , O l , (CH2) ⁇ -2C ⁇ 2Rl 6 , (CH 2 ) ⁇ -
  • Ci-4 alkyl or unsubstituted thiazolyl; or unsubstituted isoquinolinyl;
  • R 2 and R '7 are each independently selected from hydrogen, C -Q alkyl, C4-6 cycloalkyl or (CH 2 )l-4CF3;
  • R4 is selected from hydrogen, CORl 5 , (CH2) ⁇ -2C ⁇ 2Rl 6 , S ⁇ 2Rl 5 or
  • R is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH 2 )l-3 ⁇ Rl ⁇ or (CH2) ⁇ -3CF3;
  • R 8 , R ⁇ and RlO are each independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl ⁇ or (CH2) ⁇ -2CF3;
  • Rl3 is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl ⁇ , (CH2) ⁇ -2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORl , CO2RI or Cl-4 alkyl;
  • Rl ⁇ is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH 2 )0-2CF 3 ;
  • Rl6 and Rl 8 are each independently selected from hydrogen, Ci-6 alkyl, C4-6 cycloalkyl or (CH2)l-2CF3;
  • R 9 is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH 2 )0-4 ⁇ Rl ⁇ or (CH 2 ) ⁇ -2CF3;
  • p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof.
  • p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof.
  • a second class of the invention is the compound of the formula
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , NR16COR1 8 , NRI6SO2RI 8 , ORl ⁇ , (CH 2 )0-2CO 2 Rl 6 , (CH 2 )0-2CON(Rl6)2, (CH 2 )0-2SO 2 Rl 5 , (CH 2 ) ⁇ - 2S02N(Rl6)2 or Cl-4 alkyl; or unsubstituted, mono- or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from CF3, cyano, nitro, amino, NR1 6 C0R1 8 , NRI6SO2RI 8 ,
  • R 2 and R ⁇ are each independently selected from hydrogen, Ci- ⁇ alkyl, C4-6 cycloalkyl or (CH )l-4CF3;
  • R 4 is selected from CORl ⁇ , (CH2) ⁇ -2C ⁇ 2Rl 6 , SO 2 Rl 5 or R ⁇ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3 ⁇ Rl ⁇ or (CH2) ⁇ -3CF3; and
  • R 8 , R9 and RlO are each independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl ⁇ or (CH2) ⁇ -2CF3;
  • Rl3 is selected from hydrogen, Ci- alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl ⁇ , (CH2) ⁇ -2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR ⁇ , CO2RI or Cl-4 alkyl;
  • Rl is selected from hydrogen, Cl- alkyl, C3-6 cycloalkyl or (CH 2 )0-2CF 3 ;
  • Rl6 and R 8 are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyl or (CH 2 )l-2CF 3 ;
  • Rl9 is selected from hydrogen, Cl- alkyl, C3-6 cycloalkyl, (CH 2 )0-4 ⁇ Rl ⁇ or (CH 2 ) ⁇ -2CF 3 ;
  • p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; and all other variables are as defined previously in the third embodiment; and the pharmaceutically acceptable salts thereof.
  • A is C-R17 or N
  • R 2 is selected from hydrogen or CH2CF3;
  • R9 is selected from hydrogen or Cl-4 alkyl
  • each Rl7 is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, N l ⁇ CORl 8 , NR16C0N(R1 8 )2, N 16CONR 6CON(R1 8 )2, NRI6SO2RI 8 , NRl6COR 0, ORl ⁇ , CO2RI 6 , CON(Rl6) 2 , SO 2 N(Rl6) 2 , SO2Rl 5 or Cl-4 alkyl;
  • each X is halogen
  • n is an integer from zero to one; and q and s are each independently an integer from zero to two; and all other variables are as defined above in the first class; and the pharmaceutically acceptable salts thereof.
  • A is C-Rl 7 or N;
  • R 2 is selected from hydrogen or CH2CF3;
  • R9 is selected from hydrogen or Cl-4 alkyl
  • each Rl? is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NR1 6 C0R1 8 , NR16SO2R1 8 , ORl ⁇ , CO2RI 6 , CON(Rl 6 )2, S ⁇ 2N(Rl 6 )2, SO2R 15 or C1-4 alkyl;
  • each X is halogen
  • n is an integer from zero to one; and q and s are each independently an integer from zero to two; and all other variables are as defined above in the second class; and the pharmaceutically acceptable salts thereof.
  • n is an integer from zero to one; and q and s are each independently an integer from zero to two; and all other variables are as defined above in the second class; and the pharmaceutically acceptable salts thereof.
  • each Rl7 is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NHCONH2, NHCONHCONH2, NHCO-furanyl, NHCONH Ci-4 alkyl, Cl-4 alkoxy, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2, SO2C1-4 alkyl, NHSO2C1-4 alkyl, SO2C1-4 alkylpiperazinyl or C1-4 alkyl;, and all other variables are as defined above in the first subclass; and the pharmaceutically acceptable salts thereof.
  • each Rl? is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, Cl-4 alkoxy, OCH2CF3, CO2-C1-4 alkyl, CONH2 or C1-4 alkyl; and all other variables are as defined above in the second subclass; and the pharmaceutically acceptable salts thereof.
  • Exemplifying the invention is the compound selected from
  • An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
  • An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH.
  • Another illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue.
  • More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
  • More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease.
  • Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia.
  • An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
  • An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
  • Representative compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor.
  • One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
  • Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alphald and alprenz adrenergic receptor subtypes, and many other G- protein coupled human receptors.
  • Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alphald and alprenz adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
  • G-protein coupled human receptors e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors.
  • the salts of the compounds of this invention refer to non- toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
  • compounds of this invention are used to reduce the acute symptoms of BPH.
  • compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride).
  • a more long-term anti-BPH therapeutics such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride).
  • these compounds may be used to induce highly tissue-specific, localized alpha la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha la receptor mediated central nervous system events.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
  • alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
  • aryl refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Ci-io
  • Ci-io shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • substituted shall be deemed to include multiple degrees of substitution by a named substituent.
  • poly- substituted as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent.
  • a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.
  • any substituent or variable e.g., X, Rl6, Rl 8
  • - N( l6)2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
  • substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • heterocycle or heterocyclic ring represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazol l, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl,
  • activated (+)-DHP refers to a N- 3-(activated)carbamate of the desired dihydropyrimidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5- methoxycarbonyl-6-methoxvmethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 2.
  • (S)-oxa refers to an oxazolidinone group of the formula
  • activated (S)-oxa refers to an N- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 3).
  • selective alpha la adrenergic receptor antagonist refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha Id, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
  • lower urinary tract tissue refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors.
  • the ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH.
  • the specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
  • the human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994.
  • the cloned human alpha la receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
  • Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the ⁇ - adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred.
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous
  • topical with or without occlusion
  • intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an alpha la antagonistic agent.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer s of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer s of hydrogels.
  • compositions of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day.
  • the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity.
  • co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable.
  • this includes administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2.
  • PROSCAR® also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example.
  • PROSCAR® which is principally active in prostatic tissue due to its selectivity for human 5- a reductase isozyme 2
  • combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2 are useful in combination with compounds of this invention.
  • dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • a method of treating BPH comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH.
  • the dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist.
  • the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
  • compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a- reductase 1 inhibitor, such as 4,7b-dimethyl-4-aza-5a-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors.
  • BCE bromochloroethane
  • BINAP 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • Cbz-Cl benzyloxycarbonyl chloride
  • dba dibenzylideneacetone
  • DEAD diethylazodicarboxylate
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HOBt 1-hydroxy benzotriazole hydrate
  • i-PrOH 2-propanol
  • i-Pr2NEt diisopropylethylamine
  • LAH lithium aluminum hydride
  • mCPBA meta-chloroperbenzoic acid
  • NMR nuclear magnetic resonance
  • PCTLC preparative centrifugal thin layer chromatography
  • PEI polyethylenimine
  • TEBAC benzyltriethylammonium chloride
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above.
  • the preparation of key intermediates for the compounds of the present invention was accomplished via either Pd mediated coupling reactions or direct nucleophilic displacement, as outlined in Schemes 1 and 2.
  • the products, typically ketals, were deketalized under acidic conditions.
  • the resulting ketones can be further elaborated, for instance, via enolate alkylation.
  • the activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art.
  • oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)]
  • the starting materials are natural and unnatural amino acids.
  • some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with n-butyl lithium and addition to a THF solution of p-nitrophenylchloroformate produces the stable, isolable "activated'Oxazolidinone (oxa).
  • Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid.
  • Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate .
  • a strong base for instance, LiN(TMS)2
  • Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J. Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupaert et al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO96/25934, published August 29, 1996.
  • the dihydropyrimidinones and oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case.
  • the absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists. SCHEME 1
  • R >1"7 Me, OMe, OCH 3 , OCH 2 CF 3
  • N-(2-(2.2.2-Trifluoroethoxy)phenyl)-4-piperidone propylene ketal (51)
  • a solution of 50 (1.786 g, 7.00 mmol) and 4-piperidone propylene ketal (2.645 g, 16.82 mmol) in toluene (30 mL) was treated with sodium tert-butoxide (1.88 g, 19.56 mmol), (S)-BINAP (44 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) at room temperature.
  • the mixture was heated in an oil bath (80 °C, 3 h).
  • the mixture was diluted with ether and brine.
  • the aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure.
  • PCTLC SiO 2 , 6mm, 20%
  • N-(2-Cvanophenyl)-2-pyrrolidinone (58) A solution of oxalyl chloride (1.58 g, 12.46 mmol) in dichloromethane (50 mL) was treated with DMSO (1.95 g, 24.94 mmol) at -78 °C. The mixture was stirred at -78 °C (10 min) followed by addition of a solution of 57 (2.34 g, 12.43 mmol) in dichloromethane (20 mL) over 10 min. The mixture was stirred at -78 °C (30 min) followed by addition of a triethylamine (4.28 g, 42.33 mmol) over 5 min.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2, 3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H 2 O then neutralized with 10% aqueous HCI solution.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 5.36 g, 17.0 mmol
  • a methanol 150 ml
  • IN NaOH 10 ml
  • the resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo.
  • the solid was dissolved in CH 2 C1 2 and H 2 O then neutralized with 10% aqueous HCI solution.
  • Compounds of the invention can be prepared by reacting the product obtained in Example 72 with a l-aryl-4-(2- aminoethylamino)piperidine (e.g., compound 42 of Example 40) in accordance with Scheme 2.
  • Compounds of the invention can also be prepared by preparing the nitrophenoxy derivative of the compound of Example 73 in accordance with the procedure set forth in Example 72 and then reacting the derivative with a l-aryl-4-(2- aminoethylamino)piperidine in accordance with Scheme 2.
  • 100 mg of the compound of Example 9 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
  • the assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine.
  • the assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
  • the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
  • Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at"38,000Xg for 30'.
  • the binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaCl2 and lmg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol.
  • the assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 128
  • Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
  • Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
  • Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
  • Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed. The tissue is placed in a Petri dish containing oxygenated
  • the tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
  • a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
  • EC50 values are calculated for each group using GraphPad Inplot software.
  • x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.

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Abstract

This invention relates to certain novel compounds and derivates thereof, their synthesis, and their use as alpha 1a adrenergic receptor antogonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

Description

TITLE OF THE INVENTION
ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS
This application claims the benefit of U.S. Provisional Application No. 60/050,959, filed June 18, 1997.
FIELD OF THE INVENTION:
This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
BACKGROUND OF THE INVENTION Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine. Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1} alpha 2} Bi, and β2 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a^ Adrenoreceptors: Molecular Biolosrv. Biochemistry and Pharmacologv. (Progress in Basic and Clinical Pharmacologv series, Karger, 1991), wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'- terminus of alpha adrenergic receptors), agonist structure- activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha- adrenergic receptor affinity was explored. The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha Id (formerly known as alpha la or la/Id), alpha lb and alpha la (formerly known as alpha lc) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation "alpha la" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "alpha lc" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha la is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha la was renamed alpha Id. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn- Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the-condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
In benign prostatic hyperplasia, the male hormone δalpha- dihydrotestosterone has been identified as the principal culprit. The continual production of 5a-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.'s product PROSCAR® (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5a-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly. In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alphai subtype was reported. In addition, in WO 92/161213, combinations of 5a-reductase inhibitory compounds and alphal- adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha Id, alpha lb, or alpha la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non- selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha Id and alpha lb receptors in the peripheral vasculature, e.g., hypotension and syncope.
The recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor enables identification of compounds which specifically interact with the human alpha la adrenergic receptor. [PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has now made possible the identification of selective human alpha la adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha la adrenergic receptor.
It is an object of the present invention to identify compounds which bind to the alpha la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha la adrenergic receptor. It is another object of the invention to identify alpha la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha la adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
It has now been found that the compounds of the present invention are alpha la adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
SUMMARY OF THE INVENTION The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha Id and alpha lb human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc. The compounds of the present invention have the structure:
Figure imgf000007_0001
wherein Q is selected from
Figure imgf000008_0001
E, G, L and M are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θR15, (CH2)θ-4N(Rl6)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)θ-4CO2R16, (CH2)θ-4CON(Rl6)2, (CH2)0-4SO2R16, or (CH2)θ-4SO2N(Rl6)2; J is selected from hydrogen, Cχ-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH2)l-4N(R16)2, (CH2)l-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)θ-4SO2R16, or
Figure imgf000009_0001
Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16CORl8, NR^COR^,
NR!6CON(R18)2, NR16C0NR16C0N(R18)2, NR!6Sθ2R18, NR16SO2N(Rl8)2, ORlδ, (CH2)0-4CO2R16,
(CH2)0-4CON(Rl6)2, (CH2)θ-4SO2N(Rl6)2, (CH2)0-4SO2R15,
(CH2)0-4SO2R22 or
Ci-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NRl^COR18, NR16COR20, NR16SO2R18, NRl6CONRl6CON(R18)2, (CH2)θ-4Cθ2R16, (CH2)θ-4CON(Rl6)2, (CH2)0-4SO2N(Rl6)2, (CH2)θ-4SO2R15, (CH2)θ-4SO2R22, phenyl, ORlδ, halogen,
Ci-4 alkyl or C3-8 cycloalkyl;
R2 and R^ are each independently selected from hydrogen, Cχ-8 alkyl, C4-8 cycloalkyl, (CH )0-4CO2R16, (CH2)θ-4CON(Rl6)2,
(CH2)0-4CORl6, (CH )2-4θR15, (CH2)i-4CF3, (CH2)θ-4SO2R16, (CH2)0-4SO2N(Rl6)2 or (CH2)l-4CN;
R3, R6, R9 an(j R10 are e ch independently selected from hydrogen, Cχ-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR15 or (CH2)θ-4CF3;
R4 is selected from hydrogen, (CH2)θ-4COR!5, (CH2)θ-4CN, (CH2)θ-
4CF3,
(CH2)0-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)θ-4SO2R15 or
Figure imgf000010_0001
R is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRlδ or (CH2)θ-4CF3;
R8 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-40Rl5 or (CH2)θ-4CF3;
RU and Rl2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
Rl3 and Rl4 are each independently selected from hydrogen,
Ci-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH2)θ-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, CO2RI , ORlδ, (CH2)0-4CON(Rl6)2,
(CH2)θ-4Cθ2Rl or Ci-4 alkyl; or unsubstituted, mono- or poly- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, ORlδ, halogen, C1-.4 alkyl or C3-8 cycloalkyl;
Rl is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;
Rl6 and Rl8 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
Rl9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)0-4ORl5 or (CH2)θ-4CF3;
R ^ is furanyl or Cl-8 alkyl furanyl;
R22 is piperazinyl or Cl-8 alkylpiperazinyl; W is O or NRH;
each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θRl or (CH2)θ-4CF3;
Y is C 5 or N;
Z is hydrogen, oxygen or sulphur;
m, n, p and q are each independently an integer from zero to four; o is an integer from two to five; r is an integer from zero to one; t is an integer from zero to five; and the pharmaceutically acceptable salts thereof.
In one aspect of the invention is the compound as just described with the proviso that: when Rl is unsubstituted or mono- substituted phenyl; and R2 is selected from hydrogen, Cl-8 alkyl, or (CH2)0-4CORl6; and R? is hydrogen; and M, E, J, G, L, R3 and R6 are each hydrogen; and n and m are each one; then Q is selected from
Figure imgf000011_0001
Figure imgf000012_0001
In a first embodiment of the invention are the compounds having the structure set forth above, wherein
Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R16)2, NR16C0R18, NR16C0N(R18)2, NRI6SO2R18, NRl6SO2N(R 8)2, ORl , (CH2)θ-4Cθ2Rl6, (CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2N(Rl6)2, (CH2)0-4SO2R15, or Cl-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NRlβCORl8, NRI6SO2RI8, (CH2)0-4CO2Rl6, (CH2)0-4CON(Rl6)2, (CH2)0-4SO2N(R16)2, (CH2)θ-4SO2Rl5, phenyl, O l , halogen, Cl-4 alkyl or C3-8 cycloalkyl; and
R4 is selected from (CH2)θ-4CORl5, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2Rl6, (CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2Rl5 or
(CH2)θ-4Sθ2N(Rl")2; and all other variables are as previously defined; and the pharmaceutically acceptable salts thereof. An aspect of the invention is the compound as just described in this embodiment with the proviso set forth in the preceding paragraph.
In a second embodiment of the invention is the compound of the formula
Figure imgf000013_0001
wherein
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-4CF3;
Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16C0R18, NRl6COR20,
NRl6CON(Rl8)2, NRl6C0NRl6C0N(Rl8)2, NRI6SO2RI8, NR 6SO2N(RlS)2, ORlδ, (CH2)0-4CO2R16,
(CH2)0-4CON(Rl6)2, (CH2)0-4SO2N(Rl6)2, (CH2)θ-4Sθ2Rl5,
(CH2)0-4SO2R22 or
Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NR16COR18, NR16COR20, NRI6SO2 I8, NRlβCONR 6GON(R 8)2, (CH2)0-4CO2 l6, (CH2)θ-4CON(Rl6)2, (CH2)0-4SO2N(Rl6)2, (CH2)θ-4Sθ2Rl5, (CH2)θ-4Sθ2R22, phenyl, ORlδ, halogen,
Cl-4 alkyl or C3-8 cycloalkyl;
R2 and R' are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3; Rl3 and Rl4 are each independently selected from hydrogen,
Ci-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRlδ, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORlδ, (CH2)θ-4CON(Rl6)2,
(CH2)0-4CO2R1 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri- substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR δ, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
n is an integer from zero to two; m is an integer from zero to one; and o is an integer from two to four; and all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof.
In a third embodiment of the invention is the compound of the formula
Figure imgf000014_0001
wherein E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-4CF3;
Rl is' selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, N 16C0R 8, NR16CON(R18)2,
NRI6SO2 I8, NRl6S02N( l8)2, ORlδ, (CH2)0-4CO2 l6, (CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2N(Rl6)2, (CH2)θ-4Sθ2Rl5 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NR16C0 18, NRI6SO2RI8, (CH2)0-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)θ-4SO2N(Rl6)2, (CH2)θ-4Sθ2Rl5, phenyl, ORlδ, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R2 and R"7 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
R!3 and Rl4 are each independently selected from hydrogen,
Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORlδ, (CH2)θ-4CON(Rl6)2, (CH2)0-4CO2Rl or Cl-4 alkyl; or unsubstituted, mono-, di- or tri- substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, ORlδ, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
n is an integer from zero to two; o is an integer from two to four; and all other variables are as defined in the first embodiment; and the pharmaceutically acceptable salts thereof. In a first class of the invention is the compound of the formula selected from
Figure imgf000015_0001
wherein Q is selected from
Figure imgf000016_0001
Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16C0R18, NRl6COR 0, NRl6C0N(Rl8)2, NRI6SO2RI8, O l , (CH2)θ-2Cθ2Rl6, (CH2)θ-
2CON(Rl6)2, (CH2)0-2Sθ2Rlδ, (CH2)θ-2Sθ2N( 6)2, (CH2)θ-2Sθ2R22 or Ci-4 alkyl; or unsubstituted, mono- or di-substituted pyridyl or pyrimidinyl wherein the substituents on the pyridyl or the pyrimidinyl are independently selected from CF3, cyano, nitro, amino, NRl^CORl , N l6CO 0, NRl6CON(Rl8)2, NR16S02R18, (CH2)θ-2Cθ2Rl6,
Figure imgf000016_0002
(CH2)0-2SO2Rlδ, (CH2)0-2SO2N(Rl6)2, O l , halogen , (CH2)θ-2Sθ2R22 or
Ci-4 alkyl; or unsubstituted thiazolyl; or unsubstituted isoquinolinyl;
R2 and R'7 are each independently selected from hydrogen, C -Q alkyl, C4-6 cycloalkyl or (CH2)l-4CF3;
R4 is selected from hydrogen, CORl5, (CH2)θ-2Cθ2Rl6, Sθ2Rl5 or
Figure imgf000017_0001
R is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)l-3θRlδ or (CH2)θ-3CF3; and
R8, R^ and RlO are each independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θRlδ or (CH2)θ-2CF3;
Rl3 is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θRlδ, (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORl , CO2RI or Cl-4 alkyl;
Rlδ is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (CH2)0-2CF3;
Rl6 and Rl8 are each independently selected from hydrogen, Ci-6 alkyl, C4-6 cycloalkyl or (CH2)l-2CF3;
R 9 is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)0-4θRlδ or (CH2)θ-2CF3;
p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof. In a second class of the invention is the compound of the formula
Figure imgf000018_0001
wherein Q is selected from
Figure imgf000018_0002
Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16COR18, NRI6SO2RI8, ORlδ, (CH2)0-2CO2Rl6, (CH2)0-2CON(Rl6)2, (CH2)0-2SO2Rl5, (CH2)θ- 2S02N(Rl6)2 or Cl-4 alkyl; or unsubstituted, mono- or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from CF3, cyano, nitro, amino, NR16C0R18, NRI6SO2RI8,
(CH2)0-2CO2Rl6, (CH2)0-2CON(Rl6)2, (CH2)θ-2SO2Rlδ, (CH2)o-2SO2N(Rl6)2, ORlδ, halogen or Ci-4 alkyl;
R2 and R^ are each independently selected from hydrogen, Ci-β alkyl, C4-6 cycloalkyl or (CH )l-4CF3;
R4 is selected from CORlδ, (CH2)θ-2Cθ2Rl6, SO2Rl5 or
Figure imgf000018_0003
Rδ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3θRlδ or (CH2)θ-3CF3; and
R8, R9 and RlO are each independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θRlδ or (CH2)θ-2CF3;
Rl3 is selected from hydrogen, Ci- alkyl, C3-6 cycloalkyl, (CH2)2-4θRlδ, (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR δ, CO2RI or Cl-4 alkyl;
Rl is selected from hydrogen, Cl- alkyl, C3-6 cycloalkyl or (CH2)0-2CF3;
Rl6 and R 8 are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyl or (CH2)l-2CF3;
Rl9 is selected from hydrogen, Cl- alkyl, C3-6 cycloalkyl, (CH2)0-4θRlδ or (CH2)θ-2CF3;
p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; and all other variables are as defined previously in the third embodiment; and the pharmaceutically acceptable salts thereof.
In a first subclass of the invention is the compound of the formula
Figure imgf000019_0001
wherein Q is selected from
Figure imgf000020_0001
A is C-R17 or N;
R2 is selected from hydrogen or CH2CF3;
R9 is selected from hydrogen or Cl-4 alkyl;
each Rl7 is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, N l^CORl8, NR16C0N(R18)2, N 16CONR 6CON(R18)2, NRI6SO2RI8, NRl6COR 0, ORlδ, CO2RI6, CON(Rl6)2, SO2N(Rl6)2, SO2Rl5 or Cl-4 alkyl;
each X is halogen;
n is an integer from zero to one; and q and s are each independently an integer from zero to two; and all other variables are as defined above in the first class; and the pharmaceutically acceptable salts thereof.
In a second subclass of the invention is the compound of the formula
Figure imgf000021_0001
wherein Q is selected from
Figure imgf000021_0002
A is C-Rl7 or N;
R2 is selected from hydrogen or CH2CF3;
R9 is selected from hydrogen or Cl-4 alkyl;
each Rl? is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NR16C0R18, NR16SO2R18, ORlδ, CO2RI6, CON(Rl6)2, Sθ2N(Rl6)2, SO2R15 or C1-4 alkyl;
each X is halogen;
n is an integer from zero to one; and q and s are each independently an integer from zero to two; and all other variables are as defined above in the second class; and the pharmaceutically acceptable salts thereof. In a first illustration of the invention is the compound of the formula
Figure imgf000022_0001
wherein Q is selected from
Figure imgf000022_0002
and all other variables are as defined above in the first subclass; and the pharmaceutically acceptable salts thereof.
In a second illustration of the invention is the compound of the formula
Figure imgf000022_0003
wherein Q is selected from
Figure imgf000022_0004
each Rl7 is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NHCONH2, NHCONHCONH2, NHCO-furanyl, NHCONH Ci-4 alkyl, Cl-4 alkoxy, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2, SO2C1-4 alkyl, NHSO2C1-4 alkyl, SO2C1-4 alkylpiperazinyl or C1-4 alkyl;, and all other variables are as defined above in the first subclass; and the pharmaceutically acceptable salts thereof.
In a third illustration of the invention is the compound, of the formula
Figure imgf000023_0001
wherein Q is selected from
Figure imgf000023_0002
each Rl? is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, Cl-4 alkoxy, OCH2CF3, CO2-C1-4 alkyl, CONH2 or C1-4 alkyl; and all other variables are as defined above in the second subclass; and the pharmaceutically acceptable salts thereof.
Exemplifying the invention is the compound selected from
N-(2-(l-(2-cyanophenyl)piperidin-4-ylamino)ethyl)-2-(3,4- difluorophenyl)acetamide; 4-(3,4-difluorophenyl)-6-methoxymethyl-3-(2-(l-(2-nitrophenyl)-piperidin- 4-ylamino)ethylcarbamoyl)-2-oxo-l,2,3,4-tetrahydropvrimidine-5- carboxylic acid methyl ester;
3-(2-(l-(2-cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-o-tolylpiperidin-4- ylamino)ethylcarbamoyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cyanophenyl)piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-6-methoxymethyl-3-(2-(l-(2- methoxyphenyl)piperidin-4-ylamino) ethylcarbamoyl)-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-( l-(2-cyano-4-trifluoromethylphenyl)piperidin-4- ylamino)ethylcarbamoyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-(l-(2-cyano-4-methylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-(l-(4-cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- diflUorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
3-(2-(l-(2-cyano-4-fluorophenyl)-piperidin-4-ylamino)ethylcarbamoyl)-4- (3 ,4-difluorophenyl )-6-methoxymethyl-2-oxo- 1 , 2 ,3 ,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; 4-(3,4-difluorophenyl)-3-(2-(l-(2-methoxycarbonylphenyl)piperidin-4- ylamino)ethylcarbamoyl)-6-methoxvmethyl-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-((l-(2- cyanophenyl) piperidin-4-yl)-(2,2,2-trifluoroethyl)amino)ethyl)amide;
4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2-(2,2,2- trifluoroethoxy)phenyl) piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-(2,2,2- trifluoroethoxy) phenyl )piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cyanophenyl) pyrrolidin-3-ylamino)ethyl)amide;
2-(3,4-difluorophenyl)-N-(2-(l-(2-nitrophenyl)piperidin-4- ylamino)ethyl)acetamide;
N-(2-(l-(2-aminophenyl)piperidin-4-ylamino)ethyl)-2-(3,4- difluorophenyl)acetamide;
2-(3,4-difluorophenyl)-4-oxothiazolidine-3-carboxylic acid (2-(l-(2- cyanophenyl) piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid (2-(l- (2-cyanophenyl) piperidin-4-ylamino)ethyl)amide;
3-(2-(l-(2-carbamoylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- carbamoylphenyl) piperidin-4-ylamino)ethyl)amide; 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4-fluoro- 2-methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide; or
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide;
and the pharmaceutically acceptable salts thereof.
Also exemplifying the invention is the compound selected from
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(3-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(5-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(4-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- methylpyridinyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluoroρhenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- bromopyridyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluoroρhenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,6- bistrifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluoroρhenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6-N- acetylaminopyridyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
and the pharmaceutically acceptable salts thereof.
Further exemplifying the invention is the compound selected from
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-methoxyphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluoromethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(4- methoxyphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4-methoxyphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(2,4-difluorophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2,4- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- sulfonamidophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- methanesulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluormethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyanophenyl)pyrrolodin-3-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l- (phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(3- fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(4- carboxylmethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyano-5-fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(3,5- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(3,5-difluorophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-carboxymethylphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,6- bistrifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,5- dichlorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- sulfonylmethylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyιϊmidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(2-(2- aminophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- nitrophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- carboxamidoaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N-l- imidocarbonic diamidyl) phenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l- (2-nitrophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N-(2- furanyl)carbonylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4-N- methylpiperazinyl)sulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl) -l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- carbόxymethylphenyl)piperidin-4-yl-l-methylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
r4,S 4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(2-(l-N-(3- V- methylureyl)phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; and the pharmaceutically acceptable salts thereof.
An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Another example of the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
Further exemplifying the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH. Another illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride. Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue.
More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia. An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof. An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure. Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alphald and alphalb adrenergic receptor subtypes, and many other G- protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alphald and alphalb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in BPH. For use in medicine, the salts of the compounds of this invention refer to non- toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha la receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Ci-io) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. The term "poly- substituted" as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent. Preferably, a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.
It is intended that the definition of any substituent or variable (e.g., X, Rl6, Rl8) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, - N( l6)2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
The term "Z is hydrogen," when refering to the "Q" group
Figure imgf000036_0001
refers to the moiety
Figure imgf000036_0002
The term heterocycle or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazol l, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The terms "(+)-DHP" and "DHP" as used herein, refers to a dihydropyrimidinone group of the formula
Figure imgf000037_0001
for example:
Figure imgf000038_0001
The term "activated (+)-DHP," as used herein, refers to a N- 3-(activated)carbamate of the desired dihydropyrimidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5- methoxycarbonyl-6-methoxvmethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 2.
The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula
Figure imgf000038_0002
for example,
Figure imgf000038_0003
The term "activated (S)-oxa" as used herein, refers to an N- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 3).
The term "thienyl," as used herein, refers to the group
Figure imgf000039_0001
The term "selective alpha la adrenergic receptor antagonist," as used herein, refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha Id, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
The term "lower urinary tract tissue," as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic
Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
The ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994. The cloned human alpha la receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the β- adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha la adrenergic receptor antagonists.
The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha la antagonistic agent.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or nece'ssary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer s of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required. The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day.
Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5- a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041; WO93/23040; WO93/23039; WO93/23376; WO93/23419, EP 0572165; WO93/23051. The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist. Preferably, the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a- reductase 1 inhibitor, such as 4,7b-dimethyl-4-aza-5a-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
Aq = aqueous Ac = acetyl AcOH = acetic acid BCE = bromochloroethane BINAP = 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl
Boc or BOC = t-butyloxycarbonyl
BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride Cbz-Cl = benzyloxycarbonyl chloride dba = dibenzylideneacetone DEAD = diethylazodicarboxylate
DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide
EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride Et = ethyl
Et3N = triethylamine
EtOAc = ethyl acetate
EtOH = ethanol
FABLRMS = fast atom bombardment low resolution mass spectroscopy
HPLC = high performance liquid chromatography
HOAc = acetic acid
HOBt = 1-hydroxy benzotriazole hydrate i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine
LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid Me = methyl MeOH = methanol NMR = nuclear magnetic resonance PCTLC = preparative centrifugal thin layer chromatography PEI = polyethylenimine Ph = phenyl pTOS = p-toluenesulfonic acid
RT = retention time
TEBAC = benzyltriethylammonium chloride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography
TMS = trimethylsilyl
The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above. The preparation of key intermediates for the compounds of the present invention was accomplished via either Pd mediated coupling reactions or direct nucleophilic displacement, as outlined in Schemes 1 and 2. The products, typically ketals, were deketalized under acidic conditions. The resulting ketones can be further elaborated, for instance, via enolate alkylation. The resultant alpha substituted ketones were further elaborated by reductive amination with mono or unprotected diamino portions. After deprotection of the required intermediates, the selective acylation of the primary amines was accomplished by treatment with nearly equimolar quantities of the activated termini species (i.e., the "Q" groups).
The activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art. For example, oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)] The starting materials, in general, are natural and unnatural amino acids. For instance, some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with n-butyl lithium and addition to a THF solution of p-nitrophenylchloroformate produces the stable, isolable "activated'Oxazolidinone (oxa).
Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid.
Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate .
Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J. Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupaert et al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO96/25934, published August 29, 1996.
The dihydropyrimidinones and oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists. SCHEME 1
Figure imgf000051_0001
Figure imgf000051_0002
Pd2(dba)3 NaOtBu/P(o-tolyl) or BINAP
R >1"7 = Me, OMe, OCH3, OCH2CF3
R -
Figure imgf000051_0003
C02Me, CONH2, S02NH2
Figure imgf000051_0004
Benzene/reflux 2) NaCNBH3/MeOH
SCHEME 2
Figure imgf000052_0001
Similarly, heteroaryl variants are synthesized as shown in Schemes 3 A and 3B. SCHEME 3A
Figure imgf000053_0001
SCHEME 3B
AqHCI
AcOH
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0003
Pyrrolidinyl and azetidinyl analogs are prepared as shown in Schemes 4 and 5. Addition of 3-hydroxypyrrolidine to, for instance, 2- fluorobenzonitrile, followed by Swern oxidation provided the required N- aryl-3-oxopyrrolidine. Reductive animation with mono N-Boc ethylenediamine, followed by, HCl-EtOAc protection and selective acylation provided the representative example as shown in Scheme 4. The azetidinyl analog was prepared in analogous fashion starting from 3-hydroxy azetidine as shown in Scheme 5.
SCHEME 4
Figure imgf000055_0001
Figure imgf000055_0002
SCHEME 5
Figure imgf000056_0001
Additional anlaogs are prepared utilizing the procedures of
Schemes 6-9. SCHEME 6
Figure imgf000057_0001
SCHEME 7
Figure imgf000058_0001
SCHEME 8
Figure imgf000059_0001
R .117/ = CN, N02, Me, OMe P = BOC
HCI P = H»HCI EtOAc
Figure imgf000059_0002
SCHEME 9
Figure imgf000060_0001
SCHEME 9 (CONT'D)
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. EXAMPLE 1
Figure imgf000062_0001
A solution of ethylenediamine (39.8 g, 0.663 mole) in THF (1 L) was cooled to 0 °C and treated with a solution of άi-tert- butyldicarbonate (22.2 g, 0.101 mole) in THF (500 mL) dropwise over 6h. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in ethyl acetate and brine. The organic layer was washed with two additional portions of brine and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound (1) as a pale yellow liquid.
EXAMPLE 2
Figure imgf000062_0002
A/-(2-Cvanophenyl)-4-piperidone ethylene ketal (4)
A solution of 2-fluorobenzonitrile (2.75 g, 22.7 mmol) and 4- piperidone ethylene ketal (4.25 g, 29.7 mmol) in DMF (40 mL) was heated to 120 °C for 4 h. The resulting mixture was cooled to room temperature overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2Sθ4, and concentrated under reduced pressure to afford the title compound (4). The crude product was used directly. EXAMPLE 3
Figure imgf000063_0001
N-(2-Cvanophenyl)-4-piperidone (5)
A solution of 4 (533 mg, 2.18 mmol) in ether (10 mL) was treated with 5% aqueous HCI (20 mL). The mixture was stirred at room temperature (11 d). The reaction was diluted with ether and neutralized with sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (Si02, 4mm, 20% EtOAc-80% hexane) afforded the title compound (5).
IH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 201 g/mole (M++H, C12H12N2O = 201 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.32 min; focus = 215 nm; 97.5% pure.
EXAMPLE 4
Figure imgf000063_0002
-N-(2-(l-(2-Cyanophenyl)piperidin-4-ylamino)ethyl)-2-(3,4-difluoro- phenvDacetamide (6) A solution of 5 (190 mg, 0.94 mmol), N-(2-aminoethyl)-l-(3,4- difluorophenyDacetamide (120 mg, 0.56 mmol), and acetic acid (168 mg, 2.79 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (35 mg, 0.56 mmol) at room temperature. The resulting mixture was stirred at room temperature (30 min). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (Siθ2, 4mm, 10% EtOH-90% CHCI3) afforded the title compound (6) which was converted to the hydrochloride salt after treatment with methanolic HCI. H NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 399 g/mole (M++H, C22H24F2N4O = 399 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 7.97 min; focus = 215 nm; 98.5% pure.
EXAMPLE 5
Figure imgf000064_0001
N-(2-Nitrophenyl)-4-piperidone ethylene ketal (7)
A solution of l-fluoro-2-nitrobenzene (5.80 g, 41.1 mmol) and 4-piperidone ethylene ketal (6.68 g, 46.6 mmol) in THF (100 mL) was stirred at room temperature (2 h). The resulting mixture was washed with water and sodium bicarbonate solution. The aqueous layer was extracted with two portions of ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (10% ethyl acetate / hexane) afforded the title compound (7). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 265 g/mole (M++H, Ci3Hι6N2O = 265 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.12 min; focus = 215 nm; 100% pure.
EXAMPLE 6
Figure imgf000065_0001
-N-(2-Nitrophenyl)-4-piperidone (8)
A solution of 7 (7.44 g, 28.1 mmol) in ether (300 mL) was treated with 5% aqueous HCI (150 mL). The mixture was stirred at room temperature (5 d). The reaction was quenched with solid sodium bicarbonate. The aqueous layer was extracted with three additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (20% ethyl acetate / hexane) afforded the title compound (8). H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 221 g/mole (M++H, CιιHi2N2O3 = 221 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.81 min; focus = 215 nm; 100% pure. EXAMPLE 7
Figure imgf000066_0001
(2-(l-(2-Nitro-phenyl)-piperidin-4-ylamino)-ethyl)-carbamic acid tert- butyl ester (9) A solution of 8 (945 mg, 4.29 mmol), 1 (695 mg, 4.33 mmol), and acetic acid (1.31 g, 21.8 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (270 mg, 4.29 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (Siθ2, 6mm, 10% EtOH-90% CHC13) afforded the title compound (9). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 365 g/mole (M++H, C18H28N4O4 = 365 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.90 min; focus = 215 nm; 99% pure.
EXAMPLE 8
Figure imgf000067_0001
Nι-(l-(2-Nitrophenyl)piperidin-4-yl)ethane-1.2-diamine (10)
A solution of 9 (576 mg, 1.66 mmol) in ethyl acetate (50 mL) was cooled to 0°C and treated with anhydrous HCI (5 min). The mixture was stirred at room temperature (2h). The solvent was removed in vacuo and the residue disolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (10). The crude product was used directly.
EXAMPLE 9
Figure imgf000067_0002
(4S)-4-(3;4-Difluorophenyl)-6-methoxymethyl-3-(2.(l-(2- nitrophenyl)piperidin-4-ylamino)ethylcarbamoyl)-2-oxo-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (11)
A solution of 2 (53 mg, 0.11 mmol) in dichloromethane (1 mL) was treated with a solution of 10 (35 mg, 0.13 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature (30 min). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 1% NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (11) which was converted to the hydrochloride salt after treatment with methanolic HCI. lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 603 g/mole (M++H, C28H32F2N6O7 = 603 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 9.53 min; focus = 215 nm; 100% pure.
EXAMPLE 10
Figure imgf000068_0001
(2-( l-(2-Cyanophenyl)piperidin-4-ylamino)ethyl)carbamic acid tert-butyl ester (12) A solution of 5 (200 mg, 1.00 mmol), 1 (161 mg, 1.00 mmol), and acetic acid (300 mg, 5.00 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (66 mg, 1.05 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with three additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (Siθ2, 4mm, 10% EtOH-90% CHCI3) afforded the title compound (12). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 345 g/mole (M++H, Cι9H28N O2 = 345 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.66 min; focus = 215 nm; 92% pure.
EXAMPLE 11
Figure imgf000069_0001
2-(4-(2-Aminoethylamino)piperidin-l-yl)benzonitrile (13)
A solution of 12 (256 mg, 0.74 mmol) in ethyl acetate (50 mL) was cooled to 0°C and treated with anhydrous HCI (1 min). The mixture was stirred at room temperature (1 h). The solvent was removed in vacuo and the residue disolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (13). The crude product was used directly.
FABLRMS m e 245 g/mole (M++H, C1 H2oN4 = 245 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 5.15 min; focus = 215 nm; 93.5% pure. EXAMPLE 12
Figure imgf000070_0001
(4S)-3-(2-(l-(2-Cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester (14)
A solution of 2 (77 mg, 0.16 mmol) in dichloromethane (1 mL) was treated with a solution of 13 (50 mg, 0.20 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature (1 h). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (Si02, 2mm, 1% NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (14) which was converted to the hydrochloride salt after treatment with methanolic HCI. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 583 g/mole (M++H, C29H32F2N6O5 = 583 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.34 min; focus = 215 nm; 100% pure. EXAMPLE 13
Figure imgf000071_0001
(2-(l-o-Tolyl-piperidin-4-ylamino)-ethyl)-carbamic acid ert-butyl ester (15) Following the procedure of Example 7, but using N-o-tolyl-4- piperidone in place of N-(2-nitrophenyl)-4-piperidone, the crude compound was obtained. PCTLC (Si02, 2mm, 10% EtOH-90% CHC13) afforded the title compound (15).
FABLRMS m e 334 g/mole (M++H, C19H31N3O2 = 334 g/mole.)
EXAMPLE 14
Figure imgf000071_0002
Ni-(l-o-Tolylpiperidin-4-yl)ethane-l,2-diamine (16) A solution of 15 (115 mg, 0.344 mmol) in ethyl acetate (2 mL) was treated with sat'd HCl/EtOAc solution (3 mL) at room temperature. The mixture was stirred at room temperature (1 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (16). The crude product was used directly. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 4.82 min; focus = 215 nm; 98.5% pure.
EXAMPLE 15
Figure imgf000072_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-o- tolylpiperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4-tetrahydro-pyri
5-carboxylic acid methyl ester (17) A solution of 16 (51 mg, 0.218 mmol) in dichloromethane (1 mL) was treated with solid 2 (88 mg, 0.184 mmol) at room temperature.
The mixture was stirred at room temperature (30 min). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 1%
NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (17) which was converted to the hydrochloride salt after treatment with methanolic HCI. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 572 g/mole (M++H, C29H35F2N5θ5 = 572 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.11 min; focus = 215 nm; 100% pure. EXAMPLE 16
Figure imgf000073_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cvanophenyl)piperidin-4-ylamino)ethyl)amide (18)
A solution of 13 (61 mg, 0.249 mmol) in dichloromethane (2 mL) was treated with solid 3 (66 mg, 0.181 mmol) at room temperature.
The mixture was stirred at room temperature overnight. The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 10%
EtOH-90% CHCI3) afforded the title compound (18) which was converted to the hydrochloride salt after treatment with methanolic HCI. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 470 g/mole (M++H, C24H25F2N5O3 = 470 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.31 min; focus = 215 nm; 97% pure. Anal. Calcd for C24H25F2N5O3 • 0.90 HCI • 0.40 H2O: C =
56.08, H = 5.33, N = 13.63. Found: C = 56.13, H = 5.34, N = 13.24. EXAMPLE 17
Figure imgf000074_0001
N-(2-Methoχyphenyl)-4-piperidone ethylene ketal (19)
A solution of 2-bromoanisole (6.00 g, 32.08 mmol) and 4- piperidone ethylene ketal (5.54 g, 38.69 mmol) in toluene (250 mL) was treated with sodium tert-butoxide (4.40 g, 45.76 mmol), tri-o- tolylphosphine (411 mg, 1.35 mmol), and tris(dibenzylideneacetone)dipalladium(0) (295 mg, 0.32 mmol) at room temperature. The mixture was heated in an oil bath (100 °C, 2 h). The mixture was diluted with ether and the organics washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (20% ethyl acetate / hexane) afforded the title compound (19).
EXAMPLE 18
Figure imgf000074_0002
N-(2-Methoxynhenyl)-4-piperidone (20)
A solution of 19 (570 mg, 2.28 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCI (5 mL) was heated in an oil bath (50 °C) overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO , and concentrated under reduced pressure. PCTLC (SiO2, 2mm, CHCI3) afforded the title compound (20)
!H NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m e 206 g/mole (M++H, C12H15NO2 = 206 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 3.07 min; focus = 215 nm; 99% pure.
EXAMPLE 19
Figure imgf000075_0001
(2-( l-(2-Methoxyphenyl)piperidin-4-ylamino)-ethyl)carbamic acid tert- butyl ester (21) A solution of 20 (186 mg, 0.906 mmol), 1 (153 mg, 0.955 mmol), and acetic acid (288 mg, 4.80 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (63 mg, 1.00 mmol) at room temperature. The resulting mixture was stirred at room temperature (2 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2mm, 10% EtOH; 90% CHCI3) afforded the title compound (21). H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 350 g/mole (M++H, C19H31N3O3 = 350 g/mole.) EXAMPLE 20
Figure imgf000076_0001
Nι-(l-(2-MethoxyOhenyl)piperidin-4-yl)ethane-l,2-diamine (22)
Following the procedure of Example 14, but using (21) in place of (15), the title compound (22) was obtained. The crude product was used directly.
FABLRMS m/e 250 g/mole (M++H, Cι4H23N3O = 250 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 3.60 min; focus = 215 nm; 100% pure.
EXAMPLE 21
Figure imgf000076_0002
(4S')-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(2-(l-(2-methoxyphenyl)- piperidin-4-ylamino) ethylcarbamoyl)-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid methyl ester (23)
Following the procedure of Example 15, but using (22) in place of (16), the crude product (23) was obtained. PCTLC (SiO2, 2mm,
10% EtOH-90% CHCI3) afforded the title compound (23) which was converted to the hydrochloride salt after treatment with methanolic HCI. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 588 g/mole (M++H, C29H35F2N5O6 = 588 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.70 min; focus = 215 nm; 96.3% pure. Anal. Calcd for C29H35F2N O6 • 2.00 HCI • 0.50 H2O: C =
52.02, H = 5.72, N = 10.46. Found: C = 52.04, H = 5.78, N = 10.30.
EXAMPLE 22
Figure imgf000077_0001
-N-(2-Cyano-4-trifluoromethylphenyl)-4-piperidone propylene ketal (24) A solution of 2-fluoro-5-trifluoromethylbenzonitrile (2.01 g,
10.61 mmol) and 4-piperidone propylene ketal (1.71 g, 10.9 mmol) in THF (10 mL) was stirred at room temperature (1 h). The resulting mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (24).
FABLRMS m/e 327 g/mole (M++H, Ci6Hι7F3N2O2 = 327 g/mole.")
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 11.04 min; focus = 255 nm; 97.2% pure. EXAMPLE 23
Figure imgf000078_0001
N-(2-Cvano-4-trifluoromethylphenyl)-4-piperidone (25)
A solution of 24 (1.70 g, 5.20 mmol) in ether (20 mL) was treated with 6N aqueous HCI (50 mL). The mixture was stirred at room temperature (20 min). The reaction mixture was neutralized with sodium carbonate solution and solid sodium hydroxide. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6mm, 10% EtOH-90% CHClg) afforded the title compound (25). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 269 g/mole (M++H, C13H11F3N2O = 269 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 9.35 min; focus = 215 nm; 98.9% pure.
EXAMPLE 24
Figure imgf000078_0002
(2-(l-(2-Cyano-4-trifluoromethylphenyl)piperidin-4-ylamino)- ethyPcarbamic acid tert-butyl ester (26) A solution of 25 (535 mg, 1.99 mmol), 1 (335 mg, 2.09 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol(2 mL)/dichloroethane(l mL) was treated with sodium cyanoborohydride (130 mg, 2.06 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4mm, 10% EtOH-90% CHCI3) afforded the title compound (26).
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.16 min; focus = 215 nm; 100% pure.
EXAMPLE 25
Figure imgf000079_0001
2-(4-(2-Aminoethylamino)piperidin-l-yl)-5-trifluoromethyl- benzonitrile (27) Following the procedure of Example 14, but using (26) in place of (15), the title compound (27) was obtained.
FABLRMS m/e 313 g/mole (M++H, Ci5H19F3N = 313 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 6.81 min; focus = 215 nm; 95.2% pure. EXAMPLE 26
Figure imgf000080_0001
(4-S)-3-(2-(l-(2-Cyano-4-trifluoromethylphenyl)piperidin-4-ylamino)- ethylcarbamoyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (28) ^___
Following the procedure of Example 15, but using (27) in place of (16), the crude product was obtained. PCTLC (SiO2, 2mm, 1%
NH4OEt-10% EtOH-90% CHC13) afforded the title compound (28) which was converted to the hydrochloride salt after treatment with methanolic HCI.
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 651 g/mole (M++H, C3oH3iF5N6O5 = 651 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 10.49 min; focus = 215 nm; 97.7% pure.
Anal. Calcd for C3oH3iF5N6O5 • 1.15 HCI: C = 52.03, H = 4.68, N = 12.14. Found: C = 52.17, H = 4.45, N = 11.76.
EXAMPLE 27
Figure imgf000081_0001
N-(2-Cvano-4-methylphenyl)-4-piperidone propylene ketal (29)
A solution of 2-fluoro-5-methylbenzonitrile (2.76 g, 20.4 mmol) and 4-piperidone propylene ketal (3.39 g, 21.5 mmol) in DMF (50 mL) was heated in an oil bath (90 °C, 20 h). The mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6mm, 50 - 0% hexane/ CHC13) afforded the title compound (29). H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 273 g/mole (M++H, C16H20N2O2 = 273 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.97 min; focus = 215 nm; 97.8% pure.
EXAMPLE 28
Figure imgf000081_0002
N-(2-Cyano-4-methylphenyl)-4-piperidone (30) A solution of 29 (549 mg, 2.00 mmol) in ether (20 mL) was treated with 3N aqueous HCI (25 mL). The mixture was stirred at room temperature (24 h). The solvent was removed in vacuo and the residue dissolved in 6N HCI (25 mL) and acetic acid (10 mL). The mixture was stirred at room temperature (3 h). The reaction mixture was neutralized with sodium carbonate solution and the aqueous layer was extracted with three portions of ether. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (30). FABLRMS m e 215 g/mole (M++H, Ci3H14N2O = 215 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.55 min; focus = 215 nm; 88.5% pure.
EXAMPLE 29
Figure imgf000082_0001
(2-(l-(2-Cyano-4-methylphenyl)piperidin-4-ylamino)ethyl)carbamic acid tert-butyl ester (31) Following the procedure of Example 7, but using (30) in place of (8), the crude product was obtained. PCTLC (SiO , 4mm, 10%
EtOH-90% CHCI3) afforded the title compound (31).
FABLRMS m/e 359 g/mole (M++H, C2oH30N4θ2 = 359 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.36 min; focus = 215 nm; 100% pure. EXAMPLE 30
Figure imgf000083_0001
2-(4-(2-Aminoethylamino)piperidin-l-yl)-5-methylbenzonitrile (32)
Following the procedure of Example 14, but using (31) in place of (15), the title compound (32) was obtained.
FABLRMS m/e 259 g/mole (M++H, C15H22N4 = 259 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 5.98 min; focus = 215 nm; 100% pure.
EXAMPLE 31
Figure imgf000083_0002
(4S)-3-(2-(l-(2-Cyano-4-methylphenyl)piperidin-4-amino)ethylcarbamoyl)-
4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1 ,2 ,3 ,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (33)
Following the procedure of Example 15, but using (32) in place of (16), the crude product was obtained. PCTLC (SiO2, 2mm, 10%
EtOH; 90% CHCI3) afforded the title compound (33) as the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 597 g/mole (M++H, C3oH34F2N6O5 = 597 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.79 min; focus = 215 nm; 99.7% pure.
EXAMPLE 32
Figure imgf000084_0001
7Vr-(4-Cyanophenyl)-4-piperidone propylene ketal (34) A mixture of 4-fluorobenzonitrile (1.22 g, 10.0 mmol) and 4- piperidone propylene ketal (2.02 g, 12.85 mmol) was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over
Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6mm, 10%
EtOH-90% CHCI3) afforded the title compound (34). lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 259 g/mole (M++H, Ci5Hι8N2O2 = 259 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.62 min; focus = 215 nm; 100% pure. EXAMPLE 33
Figure imgf000085_0001
A^-(4-Cvanophenyl)-4-piperidone (35)
A solution of 34 (915 mg, 3.54 mmol) in ether (6 mL) was treated with 6N aqueous HCI (25 mL). The mixture was stirred at room temperature (2 d). The solvent was removed in vacuo and the residue dissolved in 3N HCI (25 mL) and acetic acid (20 mL). The mixture was stirred at room temperature (2 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4mm, 10% EtOH-90% CHC13) afforded the title compound (35). HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 6.86 min; focus = 215 nm; 99% pure.
EXAMPLE 34
Figure imgf000085_0002
(2-(l-(4-Cyanophenyl)piperidin-4-ylamino)ethyl)carbamic acid tert-butyl ester (36)
A solution of 35 (415 mg, 2.07 mmol), 1 (343 mg, 2.14 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (140 mg, 2.23 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 h). The solvent was removed in vacuo. PCTLC (SiO2, 4mm, 10%
EtOH-90% CHC13) afforded the title compound (36). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 345 g/mole (M++H, Ci9H28N O2 = 345 g/mole.)
EXAMPLE 35
Figure imgf000086_0001
4-(4-(2-Aminoethylamino)piperidin-l-yl)benzonitrile (37)
Following the procedure of Example 14, but using (36) in place of (15), the title compound (37) was obtained. FABLRMS m e 245 g/mole (M++H, Cι4H20N4 = 245 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 4.91 min; focus = 215 nm; 94.3% pure.
EXAMPLE 36
Figure imgf000086_0002
(4S)-3-(2-(l-(4-Cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester (38)
Following the procedure of Example 12, but using (37) in place of (13), the crude product was obtained. PCTLC (SiO2, 2mm, 10%
EtOH-90% CHC13) afforded the title compound (38) as the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 583 g/mole (M++H, C29H32F2N6O5 = 583 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.11 min; focus = 215 nm; 96.9% pure. Anal. Calcd for C29H32F2N6O5 • 0.95 HCI • 0.60 water: C =
55.45, H = 5.48, N = 13.38 Found: C = 55.49, H = 5.47, N = 13.03.
EXAMPLE 37
Figure imgf000087_0001
N-(2-Cvano-4-fluorophenyl)-4-piperidone propylene ketal (39)
A mixture of 2,5-difluorobenzonitrile (2.272 g, 16.33 mmol) and 4-piperidone propylene ketal (2.570 g, 16.34 mmol) was stirred at room temperature (11 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6mm, 20%
EtOAc-80% hexane) afforded the title compound (39). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 277 g/mole (M++H, Cι5H17FN2O2 = 277 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.31 min; focus = 215 nm; 99.3% pure.
EXAMPLE 38
Figure imgf000088_0001
N-(2-Cyano-4-fluorophenyl)-4-piperidone (40)
A solution of 39 (1.483 g, 5.36 mmol) in 6N aqueous HCI (25 mL) was treated with acetic acid (50 mL) at room temperature. The mixture was stirred at room temperature (3 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with three additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO , 6mm, 20% EtOAc-80% hexane) afforded the title compound (40). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 219 g/mole (M++H, Cι2HnFN2O = 219 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.95 min; focus = 215 nm; 98.2% pure. EXAMPLE 39
Figure imgf000089_0001
(2-(l-(2-Cyano-4-fluorophenyl)piperidin-4-ylamino)ethyl)carbamic acid tert-butyl ester (41) Following the procedure of Example 19, but using (40) in place of (20), the crude product was obtained. PCTLC (SiO2, 4mm, 1%
NH OEt-10% EtOH-90% CHC13) afforded the title compound (41).
FABLRMS m/e 363 g/mole (M++H, Ci9H27FN4O2 = 363 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.37 min; focus = 215 nm; 99% pure.
EXAMPLE 40
Figure imgf000089_0002
2-(4-(2-Aminoethylamino)piperidin-l-yl)-5-fluorobenzonitrile (42)
Following the procedure of Example 14, but using (41) in place of (14), the title compound (42) was obtained.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 5.84 min; focus = 215 nm; 100% pure. EXAMPLE 41
Figure imgf000090_0001
(4-S)-3-(2-(l-(2-Cyano-4-fluorophenyl)-piperidin-4-ylamino)ethyl- carbamoyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (43)
Following the procedure of Example 12, but using (42) in place of (13), the crude product was obtained. PCTLC (Siθ2, 2mm, 1%
NH4OEt-10% EtOH-90% CHC13) afforded the title compound (43) which was converted to the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 601 g/mole (M++H, C29H3iF3N6O5 = 601 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.75 min; focus = 215 nm; 100% pure. Anal. Calcd for C29H31F3N6θ5 • 1.10 HCI: C = 54.36, H =
5.05, N = 13.12 Found: C = 54.28, H = 5.20, N = 13.34.
EXAMPLE 42
Figure imgf000090_0002
■N-(2-Carbomethoxyphenyl)-4-piperidone propylene ketal (44)
A mixture of methyl 2-fluorobenzoate (16.0 g, 103.8 mmol) and 4-piperidone propylene ketal (9.8 g, 62.3 mmol) was stirred at room temperature (8 d). Flash chromatography on silica gel (10% MeOH-90% CHCI3) afforded the title compound (44). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 292 g/mole (M++H, Cι6H2ιNO = 292 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 4.96 min; focus = 215 nm; 93.2% pure.
EXAMPLE 43
Figure imgf000091_0001
N-(2-Carbomethoxyphenyl)-4-piperidone (45)
A mixture of 44 (5.3 g, 18 mmol) in methanolic HCI (200 mL) was heated in an oil bath (50 °C, lh). The resulting mixture was cooled, diluted with water (50 mL), and stirred at room temperature (30 min). The solvent volume was reduced in vacuo and neutralized with sodium carbonate. The aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6mm, 10% EtOH-90% CHCI3) afforded the title compound (45). lH NMR (CDCI3, 400 MHz) consistent with assigned structure. EXAMPLE 44
Figure imgf000092_0001
2-(4-(2- er£-Butoxycarbonylaminoethylamino)piperidin-l-yl)benzoic acid methyl ester (46) A solution of 45 (195 mg, 0.836 mmol), 1 (175 mg, 1.09 mmol), and acetic acid (251 mg, 4.19 mmol) in methanol (3 mL)/ dichloroethane (1 mL) was treated with sodium cyanoborohydride (55 mg, 0.875 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4mm, 1% NH4OEt-10% EtOH-90% CHC13) afforded the title compound (46). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 6.61 min; focus = 215 nm; 94.2% pure.
EXAMPLE 45
Figure imgf000092_0002
2-(4-(2-Aminoethylamino)piperidin-l-yl)benzoic acid methyl ester (47). Following the procedure of Example 14, but using (46) in place of (15), the title compound (47) was obtained.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 4.64 min; focus = 215 nm; 92.4% pure.
EXAMPLE 46
Figure imgf000093_0001
(4S)-4-(3,4-Difluorophenyl)-3-(2-(l-(2-methoxycarbonylphenyl)piperidin-4- ylamino)ethylcarbamoyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (48)
A solution of 2 (75 mg, 0.157 mmol) in dichloromethane (1 mL) was treated with a solution of 47 (43 mg, 0.155 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (Si02, 2mm, 1% NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (48) which was converted to the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 616 g/mole (M++H, C3oH35F2N5O7 = 616 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.66 min; focus = 215 nm; 97.1% pure.
EXAMPLE 47
Figure imgf000094_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-((l-(2- cvanophenyl) piperidin-4-yl)-(2,2.2-trifluoroethyl)amino)ethyl)amide (49)
A solution of 18 (36 mg, 0.076 mmol) and cesium carbonate (50 mg, 0.153 mmol) in acetonitrile (100 mL) was treated with 2,2,2- trifluoroethyliodide (21.3 mg, 0.101 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were concentrated under reduced pressure and purified by PCTLC (SiO2, 4mm,
1% NH4OEt-l% NH4OEt-10% EtOH-90% CHCI3) to afford the title compound (49) which was converted to the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 553 g/mole (M++H, C26H26F5N5θ3 = 553 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.95 min; focus = 215 nm; 92.3% pure. EXAMPLE 48
Figure imgf000095_0001
l-Bromo-2-(2.2.2-trifluoroethoxy)benzene (50) A solution of 2-bromophenol (5.89 g, 34.0 mmol) and 2,2,2- trifluoroethyliodide (16.8 g, 80.0 mmol) in DMF (60 mL) was treated with potassium carbonate (24.1 g, 174 mmol) at room temperature. The resulting mixture was heated in an oil bath (60 °C, 2 d). The solvent was removed in vacuo and the residue dissolved in ether and water. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with three portions of 1M NaOH solution and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound (50). lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 11.42 min; focus = 215 nm; 93.2% pure.
EXAMPLE 49
Figure imgf000095_0002
N-(2-(2.2.2-Trifluoroethoxy)phenyl)-4-piperidone propylene ketal (51) A solution of 50 (1.786 g, 7.00 mmol) and 4-piperidone propylene ketal (2.645 g, 16.82 mmol) in toluene (30 mL) was treated with sodium tert-butoxide (1.88 g, 19.56 mmol), (S)-BINAP (44 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) at room temperature. The mixture was heated in an oil bath (80 °C, 3 h). The mixture was diluted with ether and brine. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6mm, 20%
EtOAc-80% hexane) afforded the title compound (51). lH NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS m/e 332 g/mole (M++H, Cι6H2oF3NO3 = 332 g/mole.)
EXAMPLE 50
Figure imgf000096_0001
N-(o-(2.2,2-Trifluoroethoxy)phenyl)-4-piperidone (52)
A solution of 51 (410 mg, 1.23 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCI (5 mL) was heated in an oil bath (60 °C) overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4mm, 10% EtOH-90% CHCI3) afforded the title compound
(52) " lH NMR (CDCI3, 400 MHz) consistent with assigned structure. EXAMPLE 51
Figure imgf000097_0001
(2-(l-(2-(2,2,2-Trifluoroethoxy)phenyl)piperidin-4-ylannno)ethyl)- carbamic acid tert-hutyl ester (53) Following the procedure of Example 19, but using (52) in place of (20), the crude product was obtained. PCTLC (SiO2, 4mm, 1%
NH4OEt-10% EtOH-90% CHC13) afforded the title compound (53). lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 418 g/mole (M++H, C20H3oF3N3θ3 = 418 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) RT = 8.04 min; focus = 215 nm; 97.4% pure.
EXAMPLE 52
Figure imgf000097_0002
Nl-(l-(2-(2,2,2-Trifluoroethoxy)phenyl)piperidin-4-yl)ethane-l,2-diamine
(54) Following the procedure of Example 14, but using (53) in place of (15), the title compound (54) was obtained. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 5.84 min; focus = 215 nm; 100% pure.
EXAMPLE 53
Figure imgf000098_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2-(2,2,2- trifluoroethoxy)phenyl) piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (55) A solution of 54 (74 mg, 0.233 mmol) in dichloromethane (1 mL) was treated with 2 (122 mg, 0.255 mmol) at room temperature. The mixture was stirred at room temperature (5 min). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 1%
NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (55) as the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
. FABLRMS m/e 656 g/mole (M++H, C30H34F5N5O6 = 656 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.86 min; focus = 215 nm; 100% pure. EXAMPLE 54
Figure imgf000099_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-
(2.2.2-trifluoroethoxy)phenyl)piperidin-4-ylamino)ethyl)amide (56) A solution of 54 (94 mg, 0.296 mmol) in dichloromethane (1 mL) was treated with 3 (109 mg, 0.299 mmol) at room temperature. The mixture was stirred at room temperature (20 min). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 1%
NH4OEt-10% EtOH-90% CHC13) afforded the title compound (56) which was converted to the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 543 g/mole (M++H, C25H27F5N4O = 543 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.81 min; focus = 215 nm; 99.2% pure. Anal. Calcd for C25H27F5N4θ4 • 0.75 HCI • 1.80 water: C =
49.85, H = 5.25, N = 9.30 Found: C = 49.85, H = 5.25, N = 8.91. EXAMPLE 55
Figure imgf000100_0001
N-(2-Cvanophenyl)-pyrolidin-2-ol (57)
A mixture of 2-fluorobenzonitrile (4.03 g, 33.2 mmol) and pyrolidin-2-ol (2.92 g, 33.5 mmol) was treated with diisopropylethylamine
(4.37 g, 33.8 mmol) at room temperature. The mixture was stirred at room temperature (5 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over
Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6mm, 20%
EtOAc-80% hexane) afforded the title compound (57).
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.18 min; focus = 215 nm; 98.9% pure.
EXAMPLE 56
Figure imgf000100_0002
N-(2-Cvanophenyl)-2-pyrrolidinone (58) A solution of oxalyl chloride (1.58 g, 12.46 mmol) in dichloromethane (50 mL) was treated with DMSO (1.95 g, 24.94 mmol) at -78 °C. The mixture was stirred at -78 °C (10 min) followed by addition of a solution of 57 (2.34 g, 12.43 mmol) in dichloromethane (20 mL) over 10 min. The mixture was stirred at -78 °C (30 min) followed by addition of a triethylamine (4.28 g, 42.33 mmol) over 5 min. The mixture was warmed to room temperature and diluted with water (20 mL). The organic extract was washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6mm, 10% EtOH-90% CHCI3) afforded the title compound (58). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.70 min; focus = 215 nm; 99.1% pure.
EXAMPLE 57
Figure imgf000101_0001
2-(3-(2-Aminoethylamino)pyrrolidin-l-yl)benzonitrile (59)
A solution of 58 (1.33 g, 7.13 mmol), ethylenediamine (4.44 g, 73.9 mmol), and p-tolylsulfonic acid (75 mg, 0.394 mmol) in benzene (80 mL) was refluxed (1 h) with removal of water. The solvent was removed in vacuo and the residue dissolved in methanol (40 mL) and treated with sodium cyanoborohydride (480 mg, 7.64 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6mm, 1% NH4OEt-10% EtOH-90% CHCI3) afforded the title compound (59)
FABLRMS m/e 231 g/mole (M++H, Cι3H18N4 = 231 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 5.27 min; focus = 215 nm; 98.7% pure. EXAMPLE 58
Figure imgf000102_0001
(4»S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cvanophenyl) pyrrolidin-3-ylamino)ethyl)amide (60)
A solution of 59 (115 mg, 0.499 mmol) in dichloromethane (2 mL) was treated with 3 (164 mg, 0.450 mmol) at room temperature. The mixture was stirred at room temperature (1 h). The mixture was diluted with sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 2mm, 1%
NH4OEt-10% EtOH-90% CHC13) afforded the title compound (60) which was converted to the hydrochloride salt after treatment with EtOAc/HCl. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 456 g/mole (M++H, C23H23F2N5O3 = 456 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.69 min; focus = 215 nm; 100% pure. Anal. Calcd for C23H23F2N5O3 • 0.70 HCI • 0.90 water: C =
55.56, H = 5.17, N = 14.09 Found: C = 55.52, H = 5.16, N = 13.72. EXAMPLE 59
Figure imgf000103_0001
2-(3,4-Difluorophenyl)-.N-(2-(l-(2-nitrophenyl)piperidin-4- ylamino)ethyl)acetamide (61) A solution of -ϋV-(2-nitrophenyl)piperid-4-one (128.7 mg,
0.5844 mmol), -N-(2-aminoethyl)-l-(3,4-difluorophenyl)acetamide (125.2 mg, 0.5844 mmol), and acetic acid (175 mg, 2.922 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (37 mg, 0.5844 mmol) at room temperature. The resulting mixture was stirred at room temperature (50 min). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2 mm, 0 - 5% MeOH - CHC13) afforded the title compound
(61). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 419.22 g/mole (M++H, C2ιH24N4O3F2 = 419.45 g/mole.)
Anal. Calcd for C2iH24N O3F2 • 2 HCI & 0.45 H2O: C =
50.49, H = 5.43, N = 11.22. Found: C = 50.52, H = 5.37, N = 11.04.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.19 min; focus = 215 nm; 98.7% pure. EXAMPLE 60
Figure imgf000104_0001
N-(2-(l-(2-Aminophenyl)piperidin-4-ylamino)ethyl)-2-(3,4- difluorophenvPacetamide (62)
A solution of nitroaryl (75 mg, 0.1801 mmol) and 10% Pd-C (50 mg) in THF (10 mL) was stirred at room temperature under a hydrogen atmosphere (2 h). The resulting mixture was filtered through Celite, washed with EtOH and concentrated under reduced pressure affording the title compound (62). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 389.19 g/mole (M++H, C2iH26N4OF2 =
389.46 g/mole.)
Anal. Calcd for C2ιH26N O3F2 • 3 HCI: C = 50.66, H = 5.87,
N = 11.25. Found: C = 50.91, H = 6.15, N = 11.29.
EXAMPLE 61
Figure imgf000104_0002
2-(3,4-Difluorophenyl)-4-oxothiazolidine-3-carboxylic acid (2-(l-(2- cvanophenyl) piperidin-4-ylamino)ethyl)amide (63)
A solution of amine (60 mg, 0.2456 mmol) in DMF (1 mL) was treated with a solution of the activated thiazolidinone (0.2456 mmol) in dichloromethane (1 mL) at room temperature (1 h). The resulting yellow reaction mixture was concentrated in vacuo and submitted to PCTLC (Si02, 1 cm, 0 - 10% MeOH-CHCl3) providing the desired product
(63). lH NMR (CDC13, 400 MHz) consistent with assigned structure.
Anal. Calcd for C24H25N5O2SF2 • 0.4 DMF: C = 58.79, H =
5.44, N = 14.69. Found: C = 58.93, H = 5.07, N = 15.09.
EXAMPLE 62
Figure imgf000105_0001
(4ιS,5i?)-4-(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-cvanophenyl) piperidin-4-ylamino)ethyl)amide (64)
A solution of amine (19.4 mg, 0.0793 mmol) in CHCI3 (1 mL) was treated with a solution of the activated oxazolidinone (0.0793 mmol) in DCM (1 mL) at room temperature. The mixture was stirred at room temperature (1 h). The resulting yellow reaction mixture was concentrated in vacuo and submitted to PCTLC (SiO2, 1 cm, 0 - 10%
MeOH-CHCl3) providing the desired product (64). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
Anal. Calcd for C25H27N5O3F2 • 0.4 CHCI3 : C = 57.42, H =
5.20, N = 13.18. Found: C = 57.27, H = 5.49, N = 13.51.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 9.10 (cis) and 9.31 (trans) min; focus = 215 nm; 95.5:4.5 pure. EXAMPLE 63
Figure imgf000106_0001
A -(2-Benzamido)-4-piperidone ethylene ketal (65)
A mixture of 2-fluorobenzamide (7.0 g, 50.0 mmol) and 4- piperidone ethylene ketal (7.16 g, 50.0 mmol) was heated at 100 °C (7 d). The solvent was removed in vacuo and triturated with ether affording the title compound (65). lH NMR (DMSO-d6, 300 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 4.49 min; focus = 215 nm; 100% pure.
EXAMPLE 64
Figure imgf000106_0002
66
-ZV-(2-Benzamido)-4-piperidone (66)
A solution of the ketal (13.2 mg, 46.753 mmol) in acetic acid (50 mL) and 6N aqueous HCI (50 mL) was heated at 60 °C (12 h), 80% conversion. The solvent was removed in vacuo, neutralized with 25% aqueous NaOH, extracted with CHCI3 (3 x 250 mL), the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give (66) which was used without further purification. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
EXAMPLE 65
Figure imgf000107_0001
2-(4-(2-Aminoethylamino)piperidin-l-yl)benzamide (67)
A solution of the piperidone (2.5 g, 11.4543 mmol), ethylene diamine (6.89 g, 114.543 mmol) and p-toluene sulphonic acid (0.105 g, 0.57272 mmol) in benzene (100 mL) was refluxed under a Dean-Stark trap until cessation of water azeotrope. The solvent was removed in vacuo , diluted with MeOH (50 mL) and treated with NaBH3CN (0.714 g,
11.4543 mmol) at room temperature (1 h). The solvent was removed in vacuo , diluted with DCM (50 mL) and saturated aqueous sodium bicarbonate (25 mL), partitioned, extracted with DCM (2 x 50 mL), washed with saturated aqueous sodium bicarbonate (2 x 25 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo and submitted to PCTLC (SiO2, 6 mm, 80/20/2 CHCl3-MeOH-NH4OH) affording the titled amine (67). H NMR (CDCI3, 400 MHz) 9.60 (br s, 1 H), 8.16 (dd, 1 H), 7.45 (dd, 1 H), 7.22 (m, 2 H), 5.87 (br s, 1 H), 3.20 (br d, 2 H), 2.70 - 2.90 (m, 6 H), 2.65 (m, 1 H), 2.07 (br d, 2 H). 1.56 (br ddd, 2 H).
EXAMPLE 66
Figure imgf000108_0001
(4-S)-3-(2-(l-(2-Carbamoylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-
(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester (68) __
The amine (55 mg, 0.21 mmol) was dissolved in THF and treated with 2 (100 mg, 0.21). The resulting yellow reaction mixture was concentrated in vacuo and submitted to PCTLC (SiO2, 2 mm, CHCI3 -
90/10/1 CHCl3-MeOH-NH4OH) providing the desired product (68) and a minor less polar material. lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
Anal. Calcd for C29H34N6O6F2 • 0.1 hexane & 1.25 H2O: C
= 56.27, H = 6.05, N = 13.30. Found: C = 56.54, H = 5.65, N = 12.91. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.83 min; focus = 215 nm; 98.8% pure.
EXAMPLE 67
Figure imgf000109_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- carbamoylphenyl) piperidin-4-ylamino)ethyl)amide (69) A solution of the amine (72 mg, 0.2745 mmol) in THF (1 mL) was treated with the activated (S)-oxazolidinone (100 mg, 0.2745 mmol) at room temperature. The resulting yellow reaction mixture was concentrated in vacuo and submitted to PCTLC (Siθ2, 2 mm, CHCI3 -
90/10/1 CHCl3-MeOH-NH4OH) providing the desired product (69). lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 6.72 min; focus = 215 nm; 99.2% pure. Anal. Calcd for C24H27F2N O4 • 2.0 HCI • 1.65 water: C =
48.84, H = 5.52, N = 11.87 Found: C = 48.87, H = 5.64, N = 11.99.
EXAMPLE 68
Figure imgf000109_0002
(4ιS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4- fluoro-2-methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide (70)
Following the methodology described herein, compound 70 was prepared. lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.4 min; focus = 215 nm; 99.2% pure. Anal. Calcd for C25H27F3N O5 • 2.0 HCI • 0.35 water:
C = 50.06, H = 4.99, N = 9.34 Found: C = 50.06, H = 4.96, N = 9.27.
EXAMPLE 69
Figure imgf000110_0001
(4ιS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide (71)
Following the procedure of Example 16, but using (47) in place of (13), the title compound (71) was obtained. H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 503 g/mole (M++H, C25H sF2N4θ5 = 503 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.8 min; focus = 215 nm; 99.2% pure. Anal. Calcd for C25H28F2N4O5 • 1.95 HCI: C = 52.34, H 5.26, N = 9.77 Found: C = 52.33, H = 5.16, N = 9.63.
EXAMPLE 70
Figure imgf000111_0001
Mixture of (4-S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and (ιS-4)-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2.3.4.5-tetrahvdropyrimidine
To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2, 3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH2C12 and H2O then neutralized with 10% aqueous HCI solution. The organic layer was dried over Na2SO4, concentrated, and purified by PCTLC (7% MeOH in CHC13 with 2% NH4OH) to afford a 2.65 g mixture of the title compounds (71% yield). The *H NMR was consistent with the assigned structure.
MS (FAB) 255 (M+l)
EXAMPLE 71
Figure imgf000112_0001
Mixture of (4-S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and (4S)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-2.3.4.5-tetrahvdropyrimidine
To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (5.36 g, 17.0 mmol) in a methanol (150 ml) was added IN NaOH (10 ml). The resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH2C12 and H2O then neutralized with 10% aqueous HCI solution. The organic layer was dried over Na2SO4, concentrated, and purified by PCTLC (7% MeOH in CHC13 with 2% NH4OH) to afford a 2.35 g mixture of the title compounds (54% yield). The 'H NMR was consistent with the assigned structure. MS (FAB) 255 (M+l)
EXAMPLE 72
Figure imgf000112_0002
(4-S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)- 2-oxo-1.2.3.4-tetrahvdropyrimidine-5-carboxylic acid methyl ester The title compound was prepared by treating the mixture obtained from Example 70 or Example 71 (1.93 g, 7.59 mmol) with lithium diisopropylamide (2.0M THF solution, 1.1 equivalents) in THF at -78 °C for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. 0.488 g of the title compound was obtained in a 15% yield. The Η NMR was consistent with the assigned structure.
EXAMPLE 73
Figure imgf000113_0001
Mixture of (4-R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3,4- tetrahydropyrimidine and (4i?)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-2.3.4.5-tetrahydropyrimidine
The title compounds were prepared from (4R)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3, 4-tetrahydropyrimidine-5- carboxylic acid methyl ester (5.0 g, 17.7 mmol) using the procedure described in Example 70. A mixture of 2.0 g of the title compounds was obtained in 50% yield. The *H NMR was consistent with the assigned structure.
MS (FAB) 255 (M+l)
Compounds of the invention can be prepared by reacting the product obtained in Example 72 with a l-aryl-4-(2- aminoethylamino)piperidine (e.g., compound 42 of Example 40) in accordance with Scheme 2. Compounds of the invention can also be prepared by preparing the nitrophenoxy derivative of the compound of Example 73 in accordance with the procedure set forth in Example 72 and then reacting the derivative with a l-aryl-4-(2- aminoethylamino)piperidine in accordance with Scheme 2.
The following compounds were prepared in accordance with procedures set forth in the preceding Examples and Schemes.
EXAMPLE 74
Figure imgf000114_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(3- trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 514 g/mole (M++H, C23H24F5N5θ3 = 513 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C23H24F5N5O3 • 1.55 TFA • 0.40 H2O: C = 44.89, H = 3.82, N = 10.03. Found: C = 44.90, H = 3.79, N = 10.01. EXAMPLE 75
Figure imgf000115_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester H NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 627 g/mole (M++H, C28H3iF5N6O5 = 626 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C28H3ιF5N6θ5 • 1.55 TFA • 0.30 H2O: C =
46.19, H = 4.13, N = 10.39. Found: C = 46.18, H = 4.05, N = 10.50.
EXAMPLE 76
Figure imgf000115_0002
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(4- trifluoromethylpyrimidyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 515 g/mole (M++H, C22H23F5N6O3 = 514 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >98% pure.
Anal. Calcd for C22H23F5N6O3: C = 51.36, H = 4.51, N =
16.34. Found: C = 51.37, H = 4.45, N = 16.29.
EXAMPLE 77
Figure imgf000116_0001
(4-S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(2-(4- trifluoromethylpyrimidinyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 628 g/mole (M++H, C27H29F5N6O5 = 627 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C27H29F5N6O • 0.05 CHCI3: C = 51.36, H =
4.63, N = 15.50. Found: C = 51.13, H = 4.63, N = 15.81. EXAMPLE 78
Figure imgf000117_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2- pyrimidinylpiperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester H NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C26H3ιF2N7O5 • 1.0 H20: C = 54.06, H =
5.76, N = 16.98. Found: C = 54.07, H = 5.53, N = 16.82.
EXAMPLE 79
Figure imgf000117_0002
(4<S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- methoxyphenyl)piperidin-4-ylamino)ethyl)amide
!H NMR (CDCI3, 400 MHz) consistent with assigned structure. HPLC (Nydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CΝ, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C24H28F2N4θ4 • 2.0 HCI, 1.65 H2O, and 0.3
EtOAc: C = 50.14, H = 5.96, N = 9.28. Found: C = 50.12, H = 5.81, N = 9.27.
EXAMPLE 80
Figure imgf000118_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2- pyrimidinylpiperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.4% pure.
Anal. Calcd for C2ιH24F2N6O3 • 3.0 HCI and 0.45 EtOAc:
C = 45.98, H = 5.18, N = 14.11. Found: C = 45.68, H = 5.34, N = 14.13.
EXAMPLE 81
Figure imgf000118_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluoromethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.2% pure.
Anal. Calcd for C29H32F5N5θ5 • 1.0 HCI and 1.6 H2O: C =
50.41, H = 5.28, N = 10.14. Found: C = 50.38, H = 5.18, N = 10.36.
EXAMPLE 82
Figure imgf000119_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2- thiazolylpiperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.4% pure.
Anal. Calcd for C2 H3oF2N6O S • 0.15 CH2C12 and 0.25
Et2O: C = 52.70, H = 5.55, N = 14.10. Found: C = 52.71, H = 5.53, N = 13.97. EXAMPLE 83
Figure imgf000120_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2- (thiazolyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.3% pure.
Anal. Calcd for C20H23F2N5O3S • 0.25 H2O: C = 52.68, H
5.19, N = 15.36. Found: C = 52.67, H = 5.28, N = 15.22.
EXAMPLE 84
(4S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(2-(3- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C28H34F2N6O5 • 0.15 CH3CI: C = 57.25, H
= 5.83, N = 14.23. Found: C = 57.06, H = 5.68, N = 14.22.
EXAMPLE 85
Figure imgf000121_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 97.3% pure.
Anal. Calcd for C28H34F2N6O5 • 0.30 CH3CI: C = 55.86, H
= 5.68, N = 13.81. Found: C = 55.71, H = 5.56, N = 14.15.
EXAMPLE 86
Figure imgf000121_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(4- methoxyphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C29H35F2N5O6 • 2.0 HCI, 1.1 H2O, and 0.55 Et2O: C = 51.96, H = 6.25, N = 9.71. Found: C = 51.96, H = 5.97, N = 9.72.
EXAMPLE 87
Figure imgf000122_0001
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4- methoxyphenyl)piperidin-4-ylamino)ethyl)amide
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C24H28F2N4θ4 • 2.0 HCI, 1.7 H2O, and 0.4
Et2O: C = 50.52, H = 6.21, N = 9.21. Found: C = 50.54, H = 5.82, N = 9.12. EXAMPLE 88
Figure imgf000123_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.2% pure.
Anal. Calcd for C 4H28F2N4θ4 • 1.45 TFA: C = 46.86, H =
4.13, N = 10.61. Found: C = 46.90, H = 3.76, N = 10.91.
EXAMPLE 89
Figure imgf000123_0002
(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(5- trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 96.8% pure.
Anal. Calcd for C24H28F2N4θ4 • 1.25 TFA and 0.95 H2O: C
= 45.50, H = 4.07, N = 10.41. Found: C = 45.34, H = 3.72, N = 10.80.
EXAMPLE 90
Figure imgf000124_0001
(4ιS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(2,4- difluorophenyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C23H2 F4N4O3 • 1.40 HCI: C = 51.97, H =
4.82, N = 10.54. Found: C = 52.02, H = 4.90, N = 10.71.
EXAMPLE 91
Figure imgf000124_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2,4- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C28H3iF4N5O5 • 1.30 HCI: C = 52.46, H =
5.08, N = 10.93. Found: C = 52.42, H = 5.18, N = 10.76.
EXAMPLE 92
Figure imgf000125_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.7% pure.
Anal. Calcd for C28H3iF5N6O5 • 0.15 CH2C12: C = 52.88, H
= 4.93, N = 13.15. Found: C = 53.04, H = 4.98, N = 12.77. EXAMPLE 93
(4»S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(4- trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
FABLRMS m/e 514.08 g/mole (M++H, C23H24F5N5θ3 =
513.46 g/mole.)
EXAMPLE 94
Figure imgf000126_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- sulfonamidophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 637 g/mole (M++H, C28H34F N6O7S =
636.676 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.8% pure.
EXAMPLE 95
Figure imgf000127_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(2- methanesulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 635 g/mole (M++H, C29H3 F2N5O7S =
634.68 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.1% pure.
Anal. Calcd for C29H34F2N O7S • 0.95 HCI: C = 51.69, H =
5.30, N = 10.39. Found: C = 51.67, H = 5.31, N = 10.05. EXAMPLE 96
Figure imgf000128_0001
(4-S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluormethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 642 g/mole (M++H, C29H32F5N5θ6 =
641.596 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 97
Figure imgf000128_0002
(4-S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyanophenyl)azetidin-3-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 554 g/mole (M++H, C27H27F2N6O5 =
553.547 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure.
EXAMPLE 98
Figure imgf000129_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- methylpyridinyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 573 g/mole (M++H, C28H34F2N6O5 = 572.62 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure.
EXAMPLE 99
Figure imgf000130_0001
(4-S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyanophenyl)pvrrolodin-3-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 569 g/mole (M++H, C28H3oF2N6O5 =
568.582 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.
EXAMPLE 100
Figure imgf000130_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l- (phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 558 g/mole (M++H, C28H33F2N5θ5 =
557.599 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 101
Figure imgf000131_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(3- fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 576 g/mole (M++H, C28H32F3N5θ5 =
575.589 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure. EXAMPLE 102
Figure imgf000132_0001
(4-S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(4- carboxymethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 616 g/mole (M++H, C3oH35F2N5O7 =
615.635 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >99% pure.
EXAMPLE 103
Figure imgf000132_0002
(4-S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(2-cyano-6- fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 601 g/mole (M++H, C29H3iF3N6O5 =
600.603 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.7% pure.
EXAMPLE 104
Figure imgf000133_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(l-(3,5- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 594 g/mole (M++H, C28H3ιF4N5θ5 =
593.583 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 97.8% pure. EXAMPLE 105
Figure imgf000134_0001
(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(3,5- difluorophenyl)piperidin-4-ylamino)ethyl)amide H NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 481 g/mole (M++H, C23H2 F N4θ3 =
480.463 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 97.1% pure.
EXAMPLE 106
Figure imgf000134_0002
(4<S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- carboxymethylphenyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 503 g/mole (M++H, C25H28F2N4O5 =
502.523 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.5% pure.
EXAMPLE 107
Figure imgf000135_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- bromopyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 637 g/mole (M++H, C27H3ιF2N6O5 =
637.486 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.4% pure. EXAMPLE 108
Figure imgf000136_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,6- bistrifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 695 g/mole (M++H, C29H3oF8N6O5 =
694.587 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.3% pure.
EXAMPLE 109
Figure imgf000136_0002
(4jS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cvano-4-fluorophenyl)piperidin-4-ylamino)ethyl)amide H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 488 g/mole (M++H, C 4H24F2N5O3 =
487.485 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.3% pure.
EXAMPLE 110
Figure imgf000137_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6-iV- acetylaminopyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 615 g/mole (M++H, C30H36F2N6O6 = 614.65 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.2% pure. EXAMPLE 111
Figure imgf000138_0001
(4-S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,5- dichlorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 626 g/mole (M++H, C28H3iCl2F2N5O5 =
626.489 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.4% pure.
EXAMPLE 112
Figure imgf000138_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- methanesulfonylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- 1.2.3.4-tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 651 g/mole (M++H, C29H36F2N6O7S =
650.709 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 113
Figure imgf000139_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- aminophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 573 g/mole (M++H, C28H34F2N6O5 =
572.617 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. EXAMPLE 114
Figure imgf000140_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- nitrophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 617 g/mole (M++H, C29H3 F2N6O7 =
616.629 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 115
Figure imgf000140_0002
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- carboxamidoaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 616 g/mole (M++H, C29H35F2N7O6 =
615.644 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.4% pure.
EXAMPLE 116
Figure imgf000141_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N-l- imidocarbonic diamidyl)phenyl)piperidin-4-ylamino)ethylcarbamoyl)- 1.2.3.4-tetrahydropyrimidine-5-carboxylic acid methyl ester H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 659 g/mole (M++H, C30H36F2N8O7 = 658.66 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.9% pure. EXAMPLE 117
Figure imgf000142_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(l- isoquinolinyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 609 g/mole (M++H, C3iH34F2N6O5 =
608.651 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure.
EXAMPLE 118
Figure imgf000142_0002
(4-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- nitrophenyl)piperidin-4-ylamino)ethyl)amide lH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 504 g/mole (M++H, C2 H27F2N5O5 =
503.510 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 119
Figure imgf000143_0001
(4S')-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-A^-(2- furanyl)carbonylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)-
1.2.3.4-tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 667 g/mole (M++H, C32H36F2N6O7 = 608.651 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 99% pure.
EXAMPLE 120
Figure imgf000144_0001
(4S)-4-(3,4-Difluorophenyl)-2-oxo-3-(2-(2-(2- arboxymethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahvdro-4H-furo[3.4dlpyrimidine lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m e 570 g/mole (M++H, C28H 9F2N5O6 =
569.571 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 97.9% pure.
EXAMPLE 121
Figure imgf000144_0002
(4-S)-4-(3,4-Difluorophenyl)-6-methoxvmethyl-2-oxo-3-(2-(2-(4-N- methylpiperazinyl)sulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl) -1.2.3.4-tetrahvdropyrimidine-5-carboxylic acid methyl ester !H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 720 g/mole (M++H, C33H43F2N7O7S =
719.816 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98.5% pure.
EXAMPLE 122
Figure imgf000145_0001
(4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- carboxymethylphenyl)piperidin-4-yl-l-methylamino)eth 1.2.3.4-tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 630 g/mole (M++H, C3ιH37F2N5θ7 =
629.662 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 97.3% pure. EXAMPLE 123
Figure imgf000146_0001
r4S -4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(l-A^-(3-N- methylureyl)phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahvdropyrimidine-5-carboxylic acid methyl ester lH NMR (CDC13, 400 MHz) consistent with assigned structure.
FABLRMS m/e 630 g/mole (M++H, C3oH37F2N7O6 =
629.669 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 124
As a specific embodiment of an oral composition, 100 mg of the compound of Example 9 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
EXAMPLE 125
Screening assay: Alpha la Adrenergic Receptor Binding
Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [ 25 I]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values < 50 nM.
EXAMPLE 126
Selective Binding assays
Membranes prepared from stably transfected human alpha Id and alpha lb cell lines (ATCC CRL 11138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, membranes prepared from cell lines transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki).
EXAMPLE 127
EXEMPLARY COUNTERSCREENS
1. Assay Title: Dopamine D2, D3, D4 in vitro screen
The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4. Method:
Modified from NanTol et al (1991); Nature (Vol 350) Pg 610- 613. Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl 5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KC1, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes in a total volume of 500 μl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 μM apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
2. Assay Title: Serotonin 5HTla
The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
Method:
Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at"38,000Xg for 30'. The binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaCl2 and lmg/ml ascorbate. Non-specific binding is defined using 10 μM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 128
EXEMPLARY FUNCTIONAL ASSAYS
In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed:
1. In vitro Rat, Dog and Human Prostate and Dog Urethra
Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed. The tissue is placed in a Petri dish containing oxygenated
Krebs solution [NaCl, 118 mM; KC1, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% CO2/95% O2. The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, K values are calculated according to the following formula Kb = HB1. x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.
2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs
PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction. Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.
METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
Phenylephrine, an alpha 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the EDδo's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg,. iv) determined. The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula:
Figure imgf000153_0001
wherein Q is selected from
Figure imgf000153_0002
Figure imgf000154_0001
E, G, L and M are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θRl5, (CH2)θ-4N(Rl6)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R16, (CH2)θ-4CON(Rl6)2, (CH2)0-4SO2Rl6, or (CH2)θ-4Sθ2N(R 6)2;
J is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH )l-4N(Rl6)2, (CH2)i- CN, (CH2)0-4CF3, (CH2)o-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2Rl6, or
Figure imgf000154_0002
Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16C0R18, NR16COR20, NRl6C0N(Rl8)2, NR16CON 16CON(R18)2, NR 6S02R18, NRl6S02N(Rl8)2, ORlδ, (CH2)0-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)0-4SO2N(Rl6)2, (CH2)0-4SO2Rl5, (CH2)0-4SO2R22 or Cl-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, pyrimidinyl, thienyl,thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NR 6C0R18, NR16C0R20, NR16Sθ2 l8, NR 6C0NR 6C0N(Rl8)2, (CH2)θ-4Cθ2Rl6, (CH2)0-4CON(Rl6)2,
(CH2)0-4Sθ2N(Rl6)2, (CH2)0-4SO2R15, (CH2)0-4SO2R22, phenyl, OR 5, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R2 and R^ are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl, (CH2)θ-4Cθ2Rl6, (CH2)θ-4CON(Rl6)2, (CH2)0-4CORl6, (CH2)2-4θRl5, (CH2)l-4CF3, (CH2)θ-4Sθ2Rl6, (CH2)0-4SO2N(R16)2 or (CH2)l-4CN;
R3, R6, R9 and R O are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θRl5 or (CH2)θ-4CF3;
R4 is selected from hydrogen, (CH2)θ-4COR15, (CH2)θ-4CN, (CH2)0- 4CF3,
(CH2)0-4CO2R16, (CH2)o-4CON(Rl6)2, (CH2)0-4SO2R15 or
Figure imgf000155_0001
R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)ι_4θRl5 or (CH2)0-4CF3;
R8 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θRl5 or (CH2)θ-4CF3;
Rll and R 2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
Rl3 and Rl4 are each independently selected from hydrogen,
Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH2)θ-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, CO2R 6, OR15, (CH2)0-4CON(Rl6)2,
(CH2)θ-4Cθ2Rl or Cι_4 alkyl; or unsubstituted, mono- or poly- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, ORl5, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
Rl5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)o-4CF3; R 6 and Rl8 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
R1^ is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)0-4θR15 or (CH2)θ-4CF3;
R2^ is furanyl or Cl-8 alkyl furanyl;
R22 is piperazinyl or Cl-8 alkylpiperazinyl;
W is O or NR ;
each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θRl5 or (CH2)θ-4CF3;
Y is CRl5 or N;
Z is hydrogen, oxygen or sulphur;
m, n, p and q are each independently an integer from zero to four; o is an integer from two to five; r is an integer from zero to one; t is an integer from zero to five; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1, wherein Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16C0R18, NR16C0N(R 8)2, NR16Sθ2Rl8. NRl6SO2N(R 8)2, ORlδ, (CH2)0-4CO2R16,
(CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2N(Rl6)2, (CH2)θ-4Sθ2Rl5 or Cl-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NR 6COR S, NRl6S02Rl8, (CH2)θ-4Cθ2Rl6, (CH2)θ-4CON(R 6)2, (CH2)0-4SO2N(Rl6)2, (CH2)0-4SO2R15, phenyl, ORlδ, halogen, Ci-4 alkyl or C3-8 cycloalkyl; and
R4 is selected from (CH2)θ-4CORl5, (CH2)θ-4CN, (CH2)θ-4CF3,
(CH2)0-4CO2R16, (CH2)0-4CON(Rl6)2, (CH2)θ-4Sθ2R15 or
Figure imgf000157_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 1, of the formula
Figure imgf000157_0002
wherein
E, G, L, M and J are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-4CF3;
Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R!6)2, NR16CORl8, NRl6COR20,
NRl6CON(Rl8)2, NR16CONR 6CON(R18)2, NR16S02R18, NRl6SO2N(Rl8)2, ORlδ, (CH2)θ-4Cθ2Rl6, (CH2)0-4CON(Rl6)2, (CH2)θ-4SO2N(Rl6)2, (CH2)0-4SO2Rl5, (CH2)o-'4SO2R22 or Ci-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, isoquinolinyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, NR16C0R18, NR16COR20, NRl6Sθ2R18, NR16C0NR16C0N(R18)2, (CH2)θ-4Cθ2Rl6, (CH2)0-4CON(R16)2, (CH2)0-4SO2N(Rl6)2, (CH2)θ-4Sθ2R15, (CH2)o-4SO2R22, phenyl, OR δ, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R2 and R^ are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
Rl3 and Rl4 are each independently selected from hydrogen,
Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θRl5, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORlδ, (CH2)0-4CON(R 6)2, (CH2)θ-4Cθ2R 6 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri- substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, ORlδ, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
n is an integer from zero to two; m is an integer from zero to one; and o is an integer from two to four; or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 3, of the formula selected from
Figure imgf000158_0001
wherein Q is selected from
Figure imgf000159_0001
Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, NR16COR18, NR16C0R20, NRl6C0N(Rl8)2, NRI6SO2RI8, ORlδ, (CH2)θ-2Cθ2Rl6, (CH2)θ-
2CON(Rl6)2, (CH2)0-2SO2R15, (CH2)θ-2SO2N(Rl6)2, (CH2)o-2SO2R22 or Ci-4 alkyl; or unsubstituted, mono- or di-substituted pyridyl or pyrimidinyl wherein the substituents on the pyridyl or the pyrimidinyl are independently selected from CF3, cyano, nitro, amino, NR16C0R1 , NR16COR 0, NRl6CON(Rl8)2, NRl6S02R18, (CH2)θ-2Cθ2R16,
Figure imgf000159_0002
(CH2)0-2SO2Rlδ, (CH2)o-2SO2N(Rl6)2, ORlδ, halogen , (CH2)Q-2SO2R22 or
Ci-4 alkyl; or unsubstituted thiazolyl; or unsubstituted isoquinolinyl;
R2 and R? are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyl or (CH2)ι_4CF3;
R4 is selected from hydrogen, CORl5, (CH2)θ-2CO2Rl6, SO2R15 or
Figure imgf000160_0001
is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3θR15 or (CH2)θ-3CF3; and
R , R9 and R O are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θRlδ or (CH2)θ-2CF3;
Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 5, (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, ORlδ, CO2RI or Cl-4 alkyl;
R δ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)0-2CF3;
Rl6 and are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyl or (CH2)l-2CF3;
Rl9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)0-4ORl5 or (CH2)θ-2CF3;
p is an integer from one to two; q is an integer from zero to three; t is an integer from zero to four; or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 4, selected from
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(4-trifluoromethylpyrimidyl)piperidin-4-ylamino)ethyl)amide; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4- trifluoromethylpyrimidinyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2- pyrimidinylpiperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2- pyrimidinylpiperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2- pyrimidinylpiperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2- pyrimidinylpiperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2- thiazolylpiperidin-4-ylamino)ethylcarbamoyl)- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2- (thiazolyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyanophenyl)azetidin-3-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(l- isoquinolinyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-Difluorophenyl)-2-oxo-3-(2-(2-(2-carboxymethylphenyl) piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4-tetrahydro-4H- furo[3,4d]pyrimidine;
and the pharmaceutically acceptable salts thereof.
The compound of Claim 4, of the formula
Figure imgf000162_0001
wherein Q is selected from
Figure imgf000162_0002
A is C-R17 or N;
R2 is selected from hydrogen or CH2CF3;
R9 is selected from hydrogen or Cl-4 alkyl; each R 7 is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NR 6C0R18, NR16C0N(R18)2, NR16C0NR16C0N(R18)2, NR 6SO2R18, NR16COR20, ORlδ, CO2R16, CON
(Rl6)2, SO2N(R 6)2, SO2 l5 or Cl-4 alkyl;
each X is halogen;
n is an integer from zero to one; and q and s are each independently an integer from zero to two; or a pharmaceutically acceptable salt thereof.
7. The compound of Claim 6, of the formula
Figure imgf000163_0001
wherein Q is selected from
Figure imgf000163_0002
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7, selected from
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(3-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- methylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(5- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(5-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4- trifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(4-trifluoromethylpyridyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- methylpyridinyl)piperidin-4-ylamino)ethylcarbamoyl)- 1,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6- bromopyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,6- bistrifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(6-N- acetylaminopyridyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
and the pharmaceutically acceptable salts thereof.
9. The compound of Claim 6, of the formula
Figure imgf000165_0001
wherein Q is selected from
Figure imgf000165_0002
each Rl? is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, NHCONH2, NHCONHCONH2, NHCO-furanyl, NHCONH Cl-4 alkyl, Cl-4 alkoxy, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2, SO2C1-4 alkyl, NHSO2C1-4 alkyl, SO2C1-4 alkylpiperazinyl or C1-4 alkyl;,
or a pharmaceutically acceptable salt thereof.
10. The compound of Claim 9, selected from N-(2-(l-(2-cyanophenyl)piperidin-4-ylamino)ethyl)-2-(3,4- difluorophenyl)acetamide;
4-(3,4-difluorophenyl)-6-methoxymethyl-3-(2-(l-(2-nitrophenyl)-piperidin- 4-ylamino)ethylcarbamoyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
3-(2-(l-(2-cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-o-tolylpiperidin-4- ylamino)ethylcarbamoyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cyanophenyl)piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-6-methoxymethyl-3-(2-(l-(2- methoxyphenyl)piperidin-4-ylamino) ethylcarbamoyl)-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-(l-(2-cyano-4-trifluoromethylphenyl)piperidin-4- ylamino)ethylcarbamoyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-(l-(2-cyano-4-methylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-4- (3,4-diflύorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
3-(2-(l-(4-cyanophenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester; 3-(2-(l-(2-cyano-4-fluorophenyl)-piperidin-4-ylamino)ethylcarbamoyl)-4- (3 ,4-difluorophenyl )-6-methoxymethyl-2-oxo- 1 ,2 ,3 ,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-3-(2-(l-(2-methoxycarbonylphenyl)piperidin-4- ylamino)ethylcarbamoyl)-6-methoxymethyl-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-((l-(2- cyanophenyl) piperidin-4-yl)-(2,2,2-trifluoroethyl)amino)ethyl)amide;
4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2-(2,2,2- trifluoroethoxy)phenyl) piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-(2,2,2- trifluoroethoxy) phenyl)piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- cyanophenyl) pyrrolidin-3-ylamino)ethyl)amide;
2-(3,4-difluorophenyl)-N-(2-(l-(2-nitrophenyl)piperidin-4- ylamino)ethyl)acetamide;
N-(2-(l-(2-aminophenyl)piperidin-4-ylamino)ethyl)-2-(3,4- difluorophenyl )acetamide ;
2-(3,4-difluorophenyl)-4-oxothiazolidine-3-carboxylic acid (2-(l-(2- cyanopheήyl) piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid (2-(l- (2-cyanophenyl) piperidin-4-ylamino)ethyl)amide; 3-(2-(l-(2-carbamoylphenyl)piperidin-4-ylamino)ethylcarbamoyl)-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- carbamoylphenyl) piperidin-4-ylamino)ethyl)amide;
4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4-fluoro- 2-methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide; or
4-(3,4-difluorophe,nyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2- methoxycarbonylphenyl)piperidin-4-ylamino)ethyl)amide;
and the pharmaceutically acceptable salts thereof.
11. The compound of Claim 9, selected from
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-methoxyphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluoromethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(4- methoxyphenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(4-methoxyphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(2-(2,4-difluorophenyl)piperidin-4-ylamino)ethyl)amide; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2,4- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- sulfonamidophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- methanesulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- trifluormethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyanophenyl)pyrrolodin-3-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l- (phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(3- fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(4- carboxylmethylphenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(2- cyano-5-fluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(l-(3,5- difluorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(3,5-difluorophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-carboxymethylphenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,6- bistrifluoromethylpyridyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l-(2-cyano-4-fluorophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(3,5- dichlorophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- sulfonylmethylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- aminophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydrόpyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- nitrophenyl)piperidin-4-ylamino)ethylcarbamoyl)-l, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester; 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N- carboxamidoaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N-l- imidocarbonic diamidyl) phenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
4S-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (2-(l- (2-nitrophenyl)piperidin-4-ylamino)ethyl)amide;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2-N-(2- furanyl)carbonylaminophenyl)piperidin-4-ylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(4-N- methylpiperazinyl)sulfonylphenyl)piperidin-4-ylamino)ethylcarbamoyl) -l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(2- carboxymethylphenyl)piperidin-4-yl-l-methylamino)ethylcarbamoyl)- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester;
r4-S 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-(2-(2-(l-N-(3-Λ^- methylureyl)phenyl)piperidin-4-ylamino)ethylcarbamoyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester;
and the pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
13. The composition of Claim 12 further comprising a testosterone 5-alpha reductase inhibitor.
14. The composition of Claim 13, wherein the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
15. The composition of Claim 14, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
16. The composition of Claim 15, wherein the testosterone 5-alpha reductase inhibitor is finasteride.
17. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
18. A process for making a pharmacuetical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
19. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
20. The method of Claim 19, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
21. The method of Claim 19, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
22. The method of Claim 21, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
23. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 12.
24. The method of Claim 23, wherein the composition further comprises a therapeutically effective amount of a testosterone 5- alpha reductase inhibitor.
25. A method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
26. The method of Claim 21, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
27. The method of Claim 27, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
28. The method of Claim 23, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
29. A method of treating a condition which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of the compound of Claim 1 effective to treat the condition.
30. A method of eliciting an alpha la antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
PCT/US1998/012567 1997-06-18 1998-06-17 ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS WO1998057638A1 (en)

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EP98930307A EP1023068A4 (en) 1997-06-18 1998-06-17 ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS
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US6320049B1 (en) 1997-08-05 2001-11-20 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6339090B1 (en) 1998-07-30 2002-01-15 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
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US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
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US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
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CA2294590A1 (en) 1998-12-23

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