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WO1999026923A1 - Derives de carboxamide de para-aminomethylaryl - Google Patents

Derives de carboxamide de para-aminomethylaryl Download PDF

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Publication number
WO1999026923A1
WO1999026923A1 PCT/US1998/024410 US9824410W WO9926923A1 WO 1999026923 A1 WO1999026923 A1 WO 1999026923A1 US 9824410 W US9824410 W US 9824410W WO 9926923 A1 WO9926923 A1 WO 9926923A1
Authority
WO
WIPO (PCT)
Prior art keywords
dicl
biphenylmethyl
optionally substituted
independently selected
compound
Prior art date
Application number
PCT/US1998/024410
Other languages
English (en)
Inventor
Stephen E. Delaszlo
William K. Hagmann
Original Assignee
Merck & Co., Inc.
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 GBGB9727220.7A external-priority patent/GB9727220D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU14114/99A priority Critical patent/AU1411499A/en
Publication of WO1999026923A1 publication Critical patent/WO1999026923A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/84—Sulfur atoms

Definitions

  • the present invention relates to novel p-aminomethylaryl carboxamide derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies.
  • This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
  • Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation.
  • Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins.
  • CAMs play an essential role in both normal and pathophysiological processes.
  • the integrin superfamily is made up of structurally and functionally related glycoproteins consisting of ⁇ and ⁇ heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type, (for reviews see: E. C. Butcher, Cell, £7, 1033 (1991); T. A. Springer, Cell, 76, 301 (1994); D. Cox et al., "The Pharmacology of the Integrins.” Medicinal Research Rev. 14, 195 (1994) and V. W.
  • VLA-4 very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ l
  • VLA-4 very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ l
  • CD49d/CD29 CD49d/CD29
  • ⁇ 4 ⁇ l is an integrin expressed on all leukocytes, except platelets and mature neutrophils, and is a key mediator of the cell-cell and cell-matrix interactions of leukocytes (see M. E. Hemler, "VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.” Ann. Rev. Immunol. 8, 365 (1990)).
  • VCAM-1 vascular cell adhesion molecule-1
  • FN fibronectin
  • VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation and on dendritic and macrophage-like cells.
  • VCAM-1 is produced by vascular endothelial cells in response to pro-inflammatory cytokines (See A. J. H. Gearing and W. Newman, "Circulating adhesion molecules in disease.”,
  • the CS-1 domain is a 25 amino acid sequence that arises by alternative splicing within a region of fibronectin.
  • a role for VLA-4/CS-1 interactions in inflammatory conditions has been proposed (see M. J. Elices, "The integrin 0C4 ⁇ (VLA-
  • c*4 ⁇ 7 (also referred to as LPAM-1 and 4 ⁇ p) is an integrin expressed on leukocytes and is a key mediator of leukocyte trafficking and homing in the gastrointestinal tract (see C. M. Parker et al., Proc. Natl. Acad. Sci. USA. &), 1924 (1992)).
  • the ligands for ⁇ 4 ⁇ 7 include mucosal addressing cell adhesion molecule-1 (MadCAM-1) and, upon activation of ⁇ 4 ⁇ 7, VCAM-1 and fibronectin (Fn).
  • MadCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells of gut-associated mucosal tissues of the small and large intestine ("Peyer's Patches") and lactating mammary glands. (See M. J. Briskin et al., Nature. 363. 461 (1993); A. Hamann et al., J. Immunol.. 152. 3282 (1994)). MadCAM-1 can be induced in vitro by proinflammatory stimuli (See E. E. Sikorski et al. J. Immunol.. 151. 5239 (1993)). MadCAM-1 is selectively expressed at sites of lymphocyte extravasation and specifically binds to the integrin, ⁇ 4 ⁇ 7.
  • Neutralizing anti- ⁇ 4 antibodies or blocking peptides that inhibit the interaction between VLA-4 and/or ⁇ 4 ⁇ 7 and their ligands have proven efficacious both prophylactically and therapeutically in several animal models of disease, including i) experimental allergic encephalomyelitis, a model of neuronal demyelination resembling multiple sclerosis (for example, see T. Yednock et al., "Prevention of experimental autoimmune encephalomyelitis by antibodies against 0C4 ⁇ integrin.” Nature. 356, (S (1993) and E. Keszthelyi et al., "Evidence for a prolonged role of 04 integrin throughout active experimental allergic encephalomyelitis.” Neurology.
  • VLA-4 interactions in other diseases including rheumatoid arthritis; various melanomas, carcinomas, and sarcomas; inflammatory lung disorders; atherosclerotic plaque formation; restenosis; and circulatory shock (for examples, see A. A. Postigo et al., "The ( ⁇ i/VCAM-l adhesion pathway in physiology and disease.”, Res. Immunol.. 144. 723 (1994) and J.-X. Gao and A. C. Issekutz, "Expression of VCAM-1 and VLA-4 dependent T-lymphocyte adhesion to dermal fibroblasts stimulated with proinflammatory cytokines.” Immunol. 89. 375 (1996)).
  • a humanized monoclonal antibody for example, see A. A. Postigo et al., "The ( ⁇ i/VCAM-l adhesion pathway in physiology and disease.”, Res. Immunol.. 144. 723 (1994) and J.-X. Gao
  • VLA-4 (Antegren® Athena Neurosciences/Elan ) against VLA-4 in clinical development for the treatment of "flares” associated with multiple sclerosis and a humanized monoclonal antibody (ACT-1® LeukoSite) against 4 ⁇ 7 in clinical development for the treatment of inflammatory bowel disease.
  • ACT-1® LeukoSite a humanized monoclonal antibody against 4 ⁇ 7 in clinical development for the treatment of inflammatory bowel disease.
  • peptidyl antagonists of VLA-4 have been described (D. Y. Jackson et al., "Potent ⁇ 4 ⁇ l peptide antagonists as potential anti-inflammatory agents", J. Med. Chem.. 40, 3359 (1997); H. N. Shroff et al., "Small peptide inhibitors of ⁇ 4 ⁇ 7 mediated MadCAM-1 adhesion to lymphocytes", Bioorg. Med. Chem. Lett.. 6, 2495 (1996); US 5,510,332, WO97/03094, WO
  • VLA-4- and 4 ⁇ 7-dependent cell adhesion that have improved pharmacokinetic and pharmacodynamic properties such as oral bioavailability and significant duration of action.
  • Such compounds would prove to be useful for the treatment, prevention or suppression of various pathologies mediated by VLA-4 and ⁇ 4 ⁇ 7 binding and cell adhesion and activation.
  • the compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49 ⁇ VCD29; or ⁇ 4 ⁇ l) and/or the 4 ⁇ 7 integrin (LPAM-1 and ⁇ 4 ⁇ p), thereby blocking the binding of VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin and/or 4 ⁇ 7 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin.
  • VLA-4 integrin very late antigen-4"; CD49 ⁇ VCD29; or ⁇ 4 ⁇ l
  • LPAM-1 and ⁇ 4 ⁇ p 4 ⁇ 7 integrin
  • these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation.
  • VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation are useful in the treatment, prevention and suppression of diseases mediated by VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation, such as multiple sclerosis, asthma, allergic rhinitis, allergic conjunctivitis, inflammatory lung diseases, rheumatoid arthritis, septic arthritis, type I diabetes, organ transplantation, restenosis, autologous bone marrow transplantation, inflammatory sequelae of viral infections, myocarditis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, psoriasis, tumor metastasis, and atherosclerosis.
  • diseases mediated by VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation such as multiple sclerosis, asthma, allergic rhinitis, allergic conjunctivitis, inflammatory lung diseases, rheum
  • the present invention provides novel compounds of Formula I
  • Ar is 1) optionally substituted six-membered 1,4-phenylene,
  • X is 1) a bond, or
  • Z is 1) -C(O)ORd
  • Rl is 1) Ci -ioalkyl, 2) C2-10alkenyl,
  • R2 is 1) hydrogen, 2) Ci-io alkyl,
  • Ci-ioalkyl optionally substituted with one to four substituents independently selected from R a , or
  • R4 is 1) hydrogen
  • R4 is a group selected from Rl; or R4 is joined to Ar at the ortho position to form a five or six membered aromatic, heteroaromatic, carbocylic or heterocyclic, ring containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; said ring is optionally substituted with 1-2 groups from Rb;
  • R5 is 1) hydrogen, 2) Ci-ioalkyl,
  • R6 is 1) hydrogen
  • R8 is 1) hydrogen, 2) Ci.ioalkyl,
  • R D is 1) a group selected from R a , 2) Ci-io alkyl,
  • R c is 1) halogen
  • Rd and R e are independently selected from the group consisting of
  • Cy Ci-ioalkyl wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R c ; or Rd and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R and Rg are independently selected from hydrogen, Ci-ifjalkyl, Cy and Cy Ci-ioalkyl; or R and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R n is 1) hydrogen, 2) Ci-ioalkyl,
  • alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R D ;
  • alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;
  • Cy and Cyl are independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is 0, 1 or 2; n is an integer from 1 to 10; and p is 0 or 1.
  • a subset of compounds of formula I are compounds wherein Rl is Cy or Cy-Ci-ioalkyl wherin alkyl and Cy are optionally substituted as provided above.
  • Rl Cy is preferably aryl optionally substituted with one or two substituents independently selected from Rb.
  • Ar is optionally substituted 1,4-phenylene.
  • L is 1) -C(O)- or
  • X is 1) a bond or
  • Ci- ⁇ alkyl is 1) H or
  • Cl-5alkyl is 1) Ci-ioalkyl, 2 2)) Cy-(Cyl) p ,
  • R 8 is 1) hydrogen
  • Rba is 1) halogen
  • X is 1) a bond, or
  • R5 IS 1) Cl-5alkyl
  • Cy-(Cyl) p -Cl-3alkyl wherein Cy and Cyl are optionally substituted with one to two substituents independently selected from R D ; Cy and Cyl are independently aryl or heteroaryl; R D is as defined above under formula I.
  • R5 is 1) Ci- ⁇ alkyl
  • Cy and Cyl are optionally substituted with one to two substituents independently selected from R D ; Cy and Cyl are independently aryl or heteroaryl; R D is as defined above under formula I.
  • Representative compounds of the present invention include the following:
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2- methyl-2-butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-m ethyl- 1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms. The term also inccludes monocyciic ring fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms.
  • the term also includes aryl group fused to a monocyciic cycloalkyl or monocyciic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3- dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like.
  • 1,4-Heteroarylene means a bivalent monocyciic heteroaryl group in which the two substituents are para to each other, and the numbers do not necessarily refer to the normal numbering of the ring system.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • Heterocyclyl means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms.
  • the term also includes monocyciic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • heterocyclyl examples include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3- dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • Halogen includes fluorine, chlorine, bromine and iodine. The following abbreviations are used:
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • VLA-4 and/or ⁇ 4 ⁇ 7 integrin makes them useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of VLA-4 and or ⁇ 4 ⁇ 7to their various respective ligands.
  • these antagonists will inhibit cell adhesion processes including cell activation, migration, proliferation and differentiation.
  • another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioration or suppression) of diseases or disorders or symptoms mediated by VLA-4 and/or oc4 ⁇ 7 binding and cell adhesion and activation, which comprises administering to a mammal an effective amount of a compound of
  • Such diseases, disorders, conditions or symptoms are for example (1) multiple sclerosis, (2) asthma, (3) allergic rhinitis, (4) allergic conjunctivitis, (5) inflammatory lung diseases, (6) rheumatoid arthritis, (7) septic arthritis, (8) type I diabetes, (9) organ transplantation rejection, (10) restenosis, (11) autologous bone marrow transplantation, (12) inflammatory sequelae of viral infections, (13) myocarditis, (14) inflammatory bowel disease including ulcerative colitis and Crohn's disease, (15) certain types of toxic and immune-based nephritis, (16) contact dermal hypersensitivity, (17) psoriasis, (18) tumor metastasis, (19) hepatitis, and (20) atherosclerosis.
  • diseases, disorders, conditions or symptoms are for example (1) multiple sclerosis, (2) asthma, (3) allergic rhinitis, (4) allergic conjunctivitis, (5) inflammatory lung diseases, (6) rheumatoid arthritis, (7)
  • prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day.
  • ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
  • suitable propellants such as fluorocarbons or hydrocarbons.
  • suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:
  • VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973, WO96/31206 and WO98/42656;
  • steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone;
  • immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants;
  • antihistamines Hl- histamine antagonists
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the core of Formula I is the 4-aminomethyl substituted aromatic ring F in Scheme 1.
  • Several aminomethyl benzoic acids are commercially available (for example FMOC-(4-aminomethyl)-benzoic acid).
  • Other aminomethyl substituted aromatic or heteroaromatic acids of Formula I may be prepared as outlined in Scheme 1.
  • benzoic acid is exemplified; however, one skilled in the art will recognize the applicability of the reactions to other aromatic and heteroaromatic acids encompassed by the definition of Ar under formula I.
  • 4-alkylbenzoic acid esters A is brominated in the presence of N-bromosuccinimide (NBS) and a free radical initiator such as benzoylperoxide to give the bromide B.
  • NBS N-bromosuccinimide
  • Displacement of the bromine atom by potasium phthalimide provides C.
  • Saponification of the ester with a base such as sodium hydroxide provides the acid D, and removal of the phthalimide protecting group with hydrazine leads to the amino acid E.
  • R2 groups may be introduced onto E by reductive alkylation with R 2 CHO to give I.
  • Conversion to the FMOC protected aminomethyl benzic acid F may be achieved by treatment of E or I with FMOCCl in the presence of aqueous base. If an amine protecting group other than FMOC is required (such as t-butoxyoxycarbonyl or benzyloxycarbonyl) reagents and methods for its introduction and removal are known to those skilled in the art of organic synthesis may be used.
  • Reductive alkylation with a primary amine provides I.
  • Various conditions may be applied to accomplish the reductive alkylation reactions described herein. These include the use of reducing agents such as sodium cyanoborohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.
  • the reactions are generally performed in the presence of a week acid such as acetic acid in a solvent such as THF or dichloroethane.
  • R 2 CHO FMOCCl NaCNBH, Na 2 C0 3 , H 2 0, dioxane.
  • Handles are structures that facilitate the attachment of the amino acid to the resin but then enable the completed molecule to be cleaved from the resin as the carboxylic acid.
  • handles may include, but are not limited to: 4-(4- hydroxymethyl-3-methoxyphenoxybenzoic acid, 4-hydroxymethyl- phenoxyacetic acid and 3-(4-hydroxymethylphenoxy)propionic acid all attached to an amine containing resin through the carboxylic acid as an amide.
  • the Fmoc protecting group on C is removed with piperidine in DMF to yield free amine D.
  • the Fmoc-protected carboxylic acid derivative E is coupled to D employing standard peptide (in this instance, 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro- phosphate (HBTU), HOBt, and N,N-diisopropylethylamine (DIEA) in DMF to yield dipeptoid F.
  • the Fmoc group is removed with piperidine in DMF to yield the free amine G.
  • the amine is then derivatized with the appropriate R L group by sulfonylation or acylation to give H as indicated on the scheme.
  • the product of this reaction may in itself, be converted further to other R 1 groups by utilization of functional group interconversions well known to one skilled in the art.
  • L the nitrogen atom may be alkylated by an alkyl halide or under Mitsonobu conditions with an alcohol to give I.
  • the final product is removed from the resin with strong acid (in this instance, trifluoroacetic acid (TFA) in the presence, or absence (depending on the sensitivity of the product) of thioanisole and dithiane to yield compounds of the present invention of formula I .
  • strong acid in this instance, trifluoroacetic acid (TFA) in the presence, or absence (depending on the sensitivity of the product) of thioanisole and dithiane to yield compounds of the present invention of formula I .
  • TFA trifluoroacetic acid
  • the amine is then derivatized with the appropriate R L group by sulfonylation or acylation as indicated on the scheme to provide G.
  • the product of this reaction may in itself, be converted further to other R 1 groups by utilization of functional group interconversions well known to one skilled in the art.
  • the final product is prepared by acid catalysed removal of the t-butyl ester by treatment with an acid such as TFA.
  • biaryl includes aryl-heteroaryl groups
  • Scheme 4 Scheme 4
  • R 5 has the biaryl unit
  • Substituted aryl or heteroaryl boronic acids are coupled to A in the presence of a palladium(O) reagent, such as tetrakis(triphenyl- phosphine)palladium under Suzuki conditions (N. Miyaura et al., Synth. Commun., 1981, 11, 513-519) to yieldB.
  • a palladium(O) reagent such as tetrakis(triphenyl- phosphine)palladium under Suzuki conditions (N. Miyaura et al., Synth. Commun., 1981, 11, 513-519)
  • Tyrosine triflate starting materials are prepared by treatment of the tyrosine analog of A with triflic anhydride in pyridine. The carboxylic acid protecting group is then removed to give the corresponding compounds of Formula I. If the aryl or heteroaryl boronic acid is not commercially available, but the corresponding bromide or iodide is, then the bromide or iodide can be converted into the desired boronic acid by treatment with an alkyllithium reagent in tetrahydrofuran at low temperature followed by addition of trimethyl or triisopropyl borate. Hydrolysis to the boronic acid can be effected by treatment of the intermediate with aqueous base and then acid.
  • Aryl boronates which may also be utilized in coupling reactions in place of aryl boronic acids may be prepared by palladium catalyzed boronation of aryl iodides and bromides as decribed in J. Org Chem , 1995, 60, 7508-7510.
  • Y Br, I, OS0 2 CF 3
  • Aryl heteroaryl or aryl
  • the aryl coupling reaction may be performed by application of Stille-type carbon-carbon bond forming conditions (Scheme 5). (A.M. Echavarren and J.K. Stille, J. Am. Chem. Soc. 1987, 109, 5478-5486).
  • the aryl bromide or iodide intermediate A is converted into its trimethyltin derivative B using hexamethylditin in the presence of palladium(O) and lithium chloride and then reacted with an appropriately substituted aryl or heteroaryl bromide, iodide, or triflate in the presence of a palladium reagent, such as tetrakis(triphenyl- phosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(0), in a suitable solvent, such as toluene, dioxane, DMF, or l-methyl-2- pyrrolidinone, to give intermediate C.
  • a palladium reagent such as tetrakis(triphenyl- phosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(0)
  • a suitable solvent such as toluene, dioxane
  • Aryl boronates may also be utilized in coupling reactions in place of aryl stannane. They may be prepared by palladium catalyzed boronation of aryl iodides and bromides as decribed in J. Org Chem, 1995, 60, 7508-7510. The resulting boronate may then be coupled to aryl bromide or iodide to provide C. Scheme 5
  • Y Br, I, OS0 2 CF 3
  • Ar aryl or heteroaryl
  • N-FMOC-(L)-2'-cvano-biphenylalanine Step A. N-FMOC-(L)-4-iodophenylalanine. t-butyl ester.
  • Step B N-FMOC-(L)-4-trimethylstannylphenylalanine. t-butyl ester.
  • Step C N-FMOC-(L)-2'-cvano-biphenylalanine. t-butyl ester.
  • Step B N-(Boc)-(S)-2'-methoxy-biphenylalanine t-butyl ester 7.97 g (0.018 m) of the product of Step A was dissolved in 160 ml of 2:1 toluene: ethanol. To this solution was added 2.99 g (0.0198 m) 2- methoxyphenylboronic acid, 0.69 g of tetrakistriphenylphosphine palladium (0) and 22.7 ml (0.45 m) of 2.0 M sodium carbonate in water. The reaction mixture was degassed three times and then heated at 90° O for 90 minutes at which time the reaction mixture was black.
  • biphenyl unless otherwise specified, means 4-biphenyl.
  • Step A Loading of N-Fmoc-amino acid derivatives onto resins.
  • Tantagel resin see structure below.
  • Sasrin resin commercially available
  • Wang resin was also utilized successfully.
  • the N-Fmoc- amino acids commercially available or preloaded on resin) were loaded onto the resin previously functionalized with the appropriate linker to provide, for example in the case of Tantagel resin:
  • the resin was prepared in the following fashion (Tantagel resin used as an example): 25 grams of Tantagel amine resin (commercially available) was swollen in methylene chloride (150 ml). To this mixture was added 3.74 g of 4-hydroxymethyl-3-methoxy- phenoxybutyric acid (commercially available), 2.1 g of N- hydroxybenzotriazole (HOBt) and 1.88 g of diisopropyl carbodiimide. The mixture was stirred over night at room temperature, filtered and the residue was washed with methylene chloride (3 x 150 ml), MeOH ( 3 x 150 ml), methylene chloride (3 x 150 ml) and ether ( 3 x 100 ml). The residue was dried in vacuo to give the handle derivatized resin ready for loading with the appropriate amino acid.
  • the resin (2.0 g, 0.54 mmol) was swollen in 50% THF/CH 2 C1 2 and suspended in 5 ml of the same solvent. 5 mg of dimethylaminopyridine (DMAP) was added followed by 1.0 mmol of the amino acid N-protected with the fluorenylmethoxycarbamate (FMOC) group. EDC (1.0 mmol) was added and the mixture was agitated over night. The mixture was filtered and then resubmitted to the same conditions for 4 hours.
  • DMAP dimethylaminopyridine
  • FMOC fluorenylmethoxycarbamate
  • Step B Deprotection of the N-Fmoc group.
  • the N-Fmoc protecting group was removed from the resin (75 mg , 0.015 mmol) from Step A by treatment with 20% piperidine in dimethylformamide for 30 minutes. Following filtration, the resin was washed sequentially with dimethylformamide (3 times), dichloromethane (1 time) and dimethylformamide (2 times) and used in the subsequent reaction.
  • the N-Fmoc protecting group was removed from the resin from Step C by the procedure described in Step B and used in the subsequent reaction.
  • Step E Acylation (or sulfonylation) of the terminal amino group.
  • N-terminal capping reagent (acylchloride) (0.06 moi) was dissolved in 50% CH 2 C1 2 /THF (2 ml), mixed with N,N-diisopropylethylamine(0.8 mmol) and added to the resin from Step D. After agitating over night, the resin was sequentially washed (3 x 3 ml 50% THF/CH 2 C1 2 ), 3 x 3 ml CH 2 C1 2 , 3 x 3 ml MeOH, 3 x 3 ml CH 2 C1 2
  • Step G Alkylation of sulfonamide.
  • Step H Further modifications of product of Step E and Step F
  • the product of Step E and Step F may be further modified by
  • Step I Cleavage of the desired products from the resins.
  • the final desired products were cleaved from the resins from Step E-H by mixing with a solution of 5% trifluoroacetic acid in CH 2 C1 2 (3 x 3 ml for 10 minutes each) and filtering. The filtrate was concentrated in vacuo. The residue was dissolved in 50% CH 3 CN/H 2 0 and lyophilised.
  • t-butyl tyrosine and t-butyl aspartate commercially available SASRIN resins was utilised and 1% trifluoroacetic acid in CH 2 C1 2 (10 x 1 ml for 3 minutes) was used for cleavage.
  • 95%TF A/water was used (3 x 1 ml for 10 min).
  • the eluant was run into 20% pyridine in methanol and the mixture was concentrated in vacuo. Purity was assesed by HPLC and molecular ions were obtained by electrospray ionization mass spectrometry to confirm the structure of each compound.
  • the carbon atom to which R5 is attached has the same stereo configuration as the corresponding carbon atom of the L-amino acid starting material, except when marked with *, the starting amino acid is a dl mixture, and when marked with #, the starting amino acid is a D-amino acid.
  • 2-MPUPA is 4-(N'-(2- methylphenyl)ureido)phenylacetyl.
  • Sulfonamide of Example 13 was alkylated in accordance with the procedure described in Step G of the General Procedure above to provide the title compound.
  • Step A Preparation of N-[4-(N-Fmoc-aminomethyl)benzoyl]-(L)-4- fluorophenylalanine, t-butyl ester: 0.3 g (0.8 mmol) of N-FMOC-4-aminomethylbenzoic acid (see general method above), 0.19g (0.80 mmol) L-4-fluorophenylalanine-t- butyl ester, 0.40g (1.20 mmol) HBTU and 0.16 g (1.20 mmol) of N- hydroxybenzotriazole hydrate were combined in 10 ml of dry DMF. The mixture was treated with 0.52 g ( 4.02 mmol) of diisopropylethylamine.
  • reaction mixture was stirred for 1 hours, diluted with 50 ml of EtOAc and washed with IN HCI (2 x 15 ml), saturated sodium bicarbonate solution (2 x 15 ml) and brine (1 x 15 ml).
  • the organic phase was dried over MgSO 4 , filtered and concentrated in vacuo.
  • Step B Preparation of N-[4-(aminom ethyl )benzoyl]-(L)-4- fluorophenyl, t-butyl ester:
  • Step A The product of Step A was dissolved in 8 ml of CH 2 C1 2 and 2 ml of piperidine for 1 hour. The reaction mixture was diluted with EtOAc and washed with water, saturated sodium bicarbonate and brine. The reaction mixture was dried over MgSO 4 , filtered and concentrated in vacuo to give the desired product.
  • Step C Preparation of t-butyl ester of the title compound: To a solution of 0.025 g (0.067 mmol) of the product of Step B in 3 ml of CH 2 C1 2 and 0.024 ml (0.134 mmol) of diisopropylethylamine was added 16.45 mg of 3,5-dichlorophenylsulfonyl chloride. The reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was purified by preparatory thin layer chromatography over silica gel eluting with 40% EtOAc/hexanes to give the product as a foam.
  • Step B diethylamine was used in place of piperidine for removal of the FMOC group.
  • the product was purified by Biotage flash chromatography over silica gel eluting with 10%MeOH/CH 2 Cl 2 followed by 1% NH 4 OH, 14% MeOH 85% CH 2 C1 2 to give the intermediate amine.
  • the amine (0.1 g (0.21 mmol) was sulfonylated by 3,5-dichlorosulfonylchloride (56.7 mg (0.23 mmol) in 5 ml of CH 2 C1 2 in the presence of 33.2 mg (0.42 mmol) of pyridine. After 4 hours the reaction mixture was diluted with EtOAc and washed with IN HCI, saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparatory flash chromatography eluting with 30% EtOAc/hexanes to give the desired product.
  • Step B Preparation of the title compound: The product of Step A was stirred in 50% TFA/CH 2 C1 2 for 3 hours and concentrated in vacuo to give the desired product. .
  • H-NMR CD 3 OD, 400MHz: 3.05 (dd, 2H); 4.20 (s, 2H); 4.85 (dd, IH); 7.05 (d, 2H); 7.25 (d, 2H); 7.55-7.65 (m, 7H).
  • Step A of Example 45 The product of Step A of Example 45 (0.2 g (0.3 mmol) was combined in 4 ml of dioxane with 0.135 g (0.4 mmol) of hexamethylditin, 13.9 mg (0.33 mmol) of lithium chloride, 1.6 mg (0.006 mmol) of triphenylphosphine and 26.3 mg (0.015 mmol) of tetrakistriphenylphosphine. The mixture was heated to 80° C for 60 minutes at which time the reaction mixture turned black. The mixture was diluted with EtOAc and was washed with water and brine and was dried over MgSO 4 . The mixture was filtered and the solution was concentrated in vacuo.
  • Step B Preparation of the t-butyl ester of the title compound: To a solution of 50 mg (0.0725 mmol) of the product of Step A in 1.5 ml of toluene was added 33.2 mg (0.145 mmol) of 2-iodobenzonitrile and 10 mg of bistriphenylphosphine palladium dichloride. The solution was heated to 100° C overnight. The reaction mixture was diluted with EtOAc and washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparatory thin layer chromatography eluting with 35% EtOAc/hexanes to provide the product.
  • Step A The product of Step A was stirred for 2 hours with
  • Step B Preparation of Methyl 4-((N-3,5-dichlorophenylsulfonyl)- aminomethyl)-3-(fluoro)-benzoate.
  • 0.38 g (2.1 mmol) of the product of Step A was dissolved in 5 ml of CH 2 C1 2 and treated with 0.33g (4.1 mmol) pyridine at 0°C.
  • 0.56 g (2.3 mmol) of 3,5-dichlorphenylsulfonyl chloride was allowed to warm to room temperature over night. Dilution with ethyl acetate gave a white precipitate which was recovered by filtration. Recovered 0.32 g.
  • Example 59 The procedure described in Example 59 was followed using ethyl (5-(chloromethyl)-2-furancarboxylate as the starting material. During Step B a mixture of the desired product and an unknown side product formed. The mixture was carried through the remainder of the synthesis and provided the desired product.
  • Example 59 The procedure described in Example 59 was followed using methyl (4-(bromomethyl)-3-(methoxy)-benzoate as the starting material.
  • the coupling with biphenyl alanine was carried out on Wang resin as described above to give the desired product.
  • FABMS C 27 H 33 Cl 2 N 2 O 6 S , : Calc: 573; Obs.: 573, 590.
  • Step A Preparation of ethyl-4-(bromomethyl)-2-(methyl)-benzoate.
  • Step A Preparatioin of N-Boc-L-4-(3-methyl-1.2.4-oxadiazol-5-yl)- phenylalanine. t-butyl ester.
  • N-Boc-(L)-4- iodophenylalanine t-butyl ester in 3.0 ml of toluene contained in a 5 ml round bottom flash fitted with a condenser topped with a T-valve (one side of which is connected to a balloon of carbon monoxide the other side to a vacuum source) was added 0.15 g (2.1 mmol) of methyl amide oxime, 25 mg of bistriphenylphosphine palladium dichloride and 0.14 g (1.4 mmol) of triethylamine.
  • the vessel was evacuated and flushed with CO gas three times and then heated at 90° C under CO overnight.
  • the reaction mixture was diluted with 25 ml of ethyl acetate and washed with water (2 x 25 ml) and brine (1 x 25 ml).
  • the mixture was filtered and concentrated in vacuo.
  • the residue was purified by Biotage flash chromatography eluted with 15% ethyl acetate/hexanes to give 0.18g of the desired product (63% yield).
  • Step B Preparation of 4-[N-(3,5-dichlorphenylsulfonyl)- aminomethyl] -benzoic acid.
  • 0.3 g (1.98 mmol) of 4-aminomethylbenzoic acid was dissolved in 4.1 ml of IN NaOH solution and 4 ml of dioxane.
  • a solution of 3,5-dichlorphenyl sulfonyl chloride in 4 ml of dioxane was stirred over night at room temperature, acidfied and filtered to give 0.42 g of the desired acid.
  • N-Boc-L-4-(3-methyl-l,2,4-oxadiazol-5-yl)-phenylalanine t- butyl ester (0.18g, 0.46 mmol) was stirred overnight with 5 equivalents of 1.5M HCl/ethyl acetate solution. The resulting white precipitate was filtered and dried in vacuo to give 0.12 g (0.35 mmol) of the amine hydrochloride.
  • Step A Preparation of methyl R,S-4-(l-bromoethyl)-benzoate.
  • 2.5g (10 mmol) of 4-(l-bromoethyl)-benzoic acid was dissolved in 100 ml of methanol and treated with 1 ml of concentrated sulfuric acid. The solution was stirred for 18 hours, concentrated in vacuo and the residue was dissolved in 100 ml of EtOAc. The solution was washed with saturated sodium bicarbonate solution (3 x 25 ml) and was dried over MgSO 4 , filtered and was concentrated in vacuo to give 1.5 g of an oil.
  • 300 MHz iH NMR (CDC1 3 ) 2.05 (d, 3H); 3.91 (s, 3H); 5.20 (q, IH); 7.50 (d, 2H); 8.00 (d, 2H).
  • Step B Preparation of R,S-4-(l-((N-3,5-dichlorophenylsulfonyl)- amino)-ethyl)-benzoic acid
  • Step A The product of Step A was committed to the sequence described in Example 59 Steps A-C to give the desired product.
  • Step B The product of Step B was coupled to L-biphenylalanine Wang resin in the usual manner, washed and cleaved to give the desired product.
  • FABMS Calc. C ⁇ H ⁇ S j Cl,; 597; Obs.: 615 .
  • Example 64 Step B was coupled with 2'- methoxy-biphenylalanine t-butyl ester hydrochloride as in Example 59 Step D.
  • the product following purification by preparatory thin layer chromatography eluting 30% EtOAc/hexanes was treated with 50% TFA/CH 2 C1 2 for 2 hours and was concentrated in vacuo to give the desired product as a glass.
  • Step A Preparation of 4-(N-CBz-aminomethyl)-benzoic acid.
  • Step B Preparation of 0-t-butyl-N-[4-(N-Cbz-aminomethyl)benzoyl]- (L)-tyrosine, methyl ester
  • Step D Preparation of 0-( l-pyrrolidinylcarbonyl)-N- [4-(N-Cbz- aminomethyl)benzoyl]-(L)-tyrosine, methyl ester 1.3 ml of a 1M solution of sodium hexamethyldisilazide in
  • THF was added to a solution of 0.5 g of the product of Step A in 8 ml of THF at 0°C.
  • the reaction mixture was stirred at 0°C for 1 hour.
  • 120 mg (2.2 mmol) of pyrolidine carbonyl chloride was added in 2 ml of THF.
  • the reaction mixture was stirred at O°C for 30 minutes and then at room temperature for 90 minutes.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicaronate solution and brine and was dried over MgSO4.
  • Step A Preparation ofO- [2-(ethoxy )ethyl] -N- [4-(N-Cbz- aminomethyl)benzoyl]-(L)-tyrosine, methyl ester
  • Example 66 Step C 0.3 g (0.65 mmol) of the product of Example 66 Step C was dissolved in 10 ml of dry DMF and was treated with 0.5 g (3.24 mmol) of bromoethyl ethyl ether and 0.44g (3.24 mmol) of potassium carbonate. The mixture was heated to 50° C for 4 hours at which time a further 0.5 g of bromoethyl ethyl ether was added. The mixture was heated overnight at 50°C. The mixture was diluted with ethyl acetate and was washed with water, sodium bicarbonate solution and brine.
  • Example 66 The procedure described in Example 66 was utilized, alkylating the tyrosine oxygen with t-butyl bromoacetate. The alkylation was complete within 4 hours. Purification of the alkylated product was carried out by Biotage flash chromatography over silica gel eluting with 15% EtOAc/CH 2 Cl 2 . The final product was isolated as described previously. 400 MHz iH NMR (CD 3 OD):1.45 (s, 9H); 3.06 and 3.23 (ABdd, 2H); 4.20 (s, 2H); 4.52 (s, 2H); 4.80 ( , IH); 6.83 (m, 2H); 7.19 (t, 2H); 7.25 (m, 2H); 6.58-6.65 (m, 3H).
  • Example 64 Step B The product of Example 64 Step B was commited to the methods described in the case of Example 59, sulfonylating with 3- cyanophenylsulfonyl chloride and the coupling the saponified product with 2'-cyano-biphenylalanine on Wang resin as in the general procedure to give the desired product.
  • FABMS Calc. C 32 H 36 N 4 O 5 S ⁇ ; 578; Obs.: 579 EXAMPLE 71
  • Step A Preparation of CS-1 Coated Plates
  • BSA bovine serum albumin
  • PBS phosphate buffered saline
  • SPDP 3-(2- pyridyldithio) propionic acid N-hydroxysuccinimide ester
  • the CS-1 peptide (Cys-Leu-His-Gly-Pro-Glu-Ile- Leu-Asp-VaPro-Ser-Thr), which was synthesized by conventional solid phase chemistry and purified by reverse phase HPLC, was next added to the derivatized BSA at a concentration of 2.5 ⁇ g/ml and allowed to react for 2 hours at room temperature. The plates were washed twice with PBS and stored at 4°C.
  • Glutamine Fluorescence activated cell sorter analysis with specific monoclonal antibodies confirmed that the cells expressed both the ⁇ 4 and ⁇ l chains of VLA-4. The cells were centrifuged at 400xg for five minutes and washed twice with PBS. The cells were incubated at a
  • the fluorescently labeled Jurkat cells were washed two times in PBS and resuspended in RPMI containing 0.25% BSA at a final concentration of 2.0 x 10 cells/ml.
  • Step C Assay Procedure
  • Compounds of this invention were prepared in DMSO at lOOx the desired final assay concentration. Final concentrations were selected from a range between 0.001 nM-100 ⁇ M.
  • Three ⁇ L of diluted compound, or vehicle alone, were premixed with 300 ⁇ L of cell suspension in 96-well polystyrene plates with round bottom wells. 100 ⁇ L aliquots of the cell /compound mixture were then transferred in duplicate to CS-1 coated wells. The cells were next incubated for 30 minutes at room temperature. The non-adherent cells were removed by two gentle washings with PBS.
  • Step A Preparation of VCAM-Ig.
  • the signal peptide as well as domains 1 and 2 of human VCAM were amplified by PCR using the human VCAM cDNA (R & D Systems) as template and the following primer sequences: 3'-PCR primer:5'-AATTATAATTTGATCAACTTAC CTGTCAATTCTTTTACAGCCTGCC-3'; 5'-PCR primer:
  • the 5'-PCR primer contained EcoRI and PvuII restriction sites followed by a Kozak consensus sequence (CCACC) proximal to the initiator methionine ATG.
  • the 3'-PCR primer contained a Bell site and a splice donor sequence. PCR was performed for 30 cycles using the following parameters: 1 min. at 94 C, 2 min. at 55 C, and 2 min. at 72 C.
  • the pig-Tail vector contains the genomic fragment which encodes the hinge region, CH2 and CH3 of human IgGl (GenBank Accession no. Z17370).
  • the DNA sequence of the resulting VCAM fragment was verified using Sequenase (US Biochemical, Cleveland, OH).
  • the fragment encoding the entire VCAM-Ig fusion was subsequently excised from pig-Tail with EcoRI and Notl and ligated to pCI-neo (Promega, Madison, WI) digested with EcoRI and Notl.
  • the resulting vector, designated pCI-neo/VCAM-Ig was transfected into CHO-K1 (ATCC CCL 61) cells using calcium-phosphate DNA precipitation (Specialty Media, Lavalette, NJ).
  • VCAM-Ig producing clones were selected according to standard protocols using 0.2-0.8 mg/ml active G418 (Gibco, Grand Island, NY), expanded, and cell supernatants were screened for their ability to mediate Jurkat adhesion to wells previously coated with 1.5 ⁇ g/ml (total protein) goat anti-human IgG (Sigma, St. Louis, MO).
  • a positive CHO-Kl/VCAM-Ig clone was subsequently adapted to CHO-SFM serum-free media (Gibco) and maintained under selection for stable expression of VCAM-Ig.
  • VCAM- Ig was purified from crude culture supernatants by affinity chromatography on Protein A/G Sepharose (Pierce, Rockford, IL) according to the manufacturer's instructions and desalted into 50 mM sodium phosphate buffer, pH 7.6, by ultrafiltration on a YM-30 membrane (Amicon, Beverly, MA).
  • Step B Preparation of I-VCAM-Ig.
  • Step C VCAM-Ig Binding Assay.
  • Compounds of this invention were prepared in DMSO at lOOx the desired final assay concentration. Final concentrations were selected from a range between 0.001 nM-100 ⁇ M.
  • Jurkat cells were centrifuged at 400x g for five minutes and resuspended in binding buffer (25 mM HEPES, 150 mM NaCI, 3 mM KCl, 2 mM glucose, 0.1% bovine serum albumin, pH 7.4). The cells were centrifuged again and resuspended in binding buffer supplemented with MnCl 2 at a final concentration of 1 mM.
  • Compounds were assayed in Millipore MHVB multiscreen plates (cat# MHVBN4550, Millipore Corp., MA) by making the following additions to duplicate wells: (i) 200 ⁇ L of binding buffer
  • Step A ⁇ Cell line.
  • RPMI-8866 cells (a human B cell line ⁇ ⁇ ; a gift from Prof. John Wilkins, University of Manitoba, Canada) were grown in RPMI/10% fetal calf serum/ 100 U penicillin/100 ⁇ g streptomycin/2 mM L-glutamine at 37° C, 5 % carbon dioxide. The cells were pelleted at 1000 rpm for 5 minutes and then washed twice and resuspended in binding buffer (25 mM HEPES, 150 mM NaCI , 0.1 % BSA, 3 mM KCl, 2 mM Glucose, pH 7.4).
  • binding buffer 25 mM HEPES, 150 mM NaCI , 0.1 % BSA, 3 mM KCl, 2 mM Glucose, pH 7.4
  • Step B VCAM-Ig Binding Assay.
  • Compounds of this invention were prepared in DMSO at lOOx the desired final assay concentration. Final concentrations were selected from a range between 0.001 nM-100 ⁇ M.
  • Compounds were assayed in Millipore MHVB multiscreen plates (Cat# MHVBN4550) by making the following sequential additions to duplicate wells: (i) 100 ⁇ l/well of binding buffer containing 1.5 mM MnCl 2 ; (ii) 10 ⁇ l/well 125 I-
  • VCAM-Ig in binding buffer (final assay concentration ⁇ 500 pM); (iii) 1.5 ⁇ l/well test compound or DMSO alone; (iv) 38 ⁇ well RPMI-8866 cell suspension (1.25 x 10 6 cells/well).
  • the plates were incubated at room temperature for 45 minutes on a plate shaker at 200 rpm, filtered on a vacuum box, and washed on the same apparatus by the addition of 100 ⁇ L of binding buffer containing 1 mM MnCl 2 . After insertion of the multiscreen plates into adapter plates (Packard, Meriden, CT, cat# 6005178), 100 ⁇ L of Microscint-20 (Packard cat# 6013621) was added to each well.
  • adapter plates Packard, Meriden, CT, cat# 6005178

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des carboxamides de para-aminométhylaryl selon la formule (I), qui sont des antagonistes de VLA-4 et/ou α4β7, et en tant que tels sont utiles pour inhiber ou prévenir l'adhésion cellulaire et les pathologies induites par les adhésions cellulaires. Ces composés peuvent être formulés en compositions pharmaceutiques et peuvent être utilisés pour traiter l'asthme, les allergies, l'inflammation, la sclérose en plaques, et d'autres troubles inflammatoires et autoimmunes.
PCT/US1998/024410 1997-11-20 1998-11-17 Derives de carboxamide de para-aminomethylaryl WO1999026923A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14114/99A AU1411499A (en) 1997-11-20 1998-11-17 Para-aminomethylaryl carboxamide derivatives

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US6622897P 1997-11-20 1997-11-20
US60/066,228 1997-11-20
GB9727220.7 1997-12-23
GBGB9727220.7A GB9727220D0 (en) 1997-12-23 1997-12-23 Para-aminomethylaryl carboxamide derivatives

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WO1999049856A2 (fr) * 1998-03-27 1999-10-07 Genentech, Inc. Antagonistes destines au traitement de troubles induits par le recepteur d'adhesion de cd11/cd18
WO2001070670A1 (fr) * 2000-03-23 2001-09-27 Ajinomoto Co., Inc. Nouveau derive de phenylalanine
WO2002030875A1 (fr) * 2000-10-09 2002-04-18 Bayer Aktiengesellschaft Derives de beta-amino-acide utilises comme antagonistes du recepteur de l'integrine
EP1243577A1 (fr) * 1999-12-28 2002-09-25 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
US6630503B1 (en) 1999-08-13 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
WO2004014844A2 (fr) * 2002-08-09 2004-02-19 Transtech Pharma, Inc. Composes aryle et heteroaryle et procedes de modulation de la coagulation
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
WO2005014533A2 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes d'utilisation
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
US6916933B2 (en) 1999-12-06 2005-07-12 Hoffman-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
JP2006515276A (ja) * 2002-10-22 2006-05-25 オスコテック株式会社 骨粗鬆症の予防及び治療効果を有するフラン誘導体並びにこれを含む薬学的組成物
US7064229B2 (en) 2001-07-06 2006-06-20 Bayer Healthcare Ag Succinic acid derivatives
WO2006068213A1 (fr) 2004-12-24 2006-06-29 Toray Industries, Inc. Derive de la glycine et son utilisation
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
WO2007145282A1 (fr) 2006-06-14 2007-12-21 Toray Industries, Inc. Agent thérapeutique ou prophylactique destiné à traiter une dermatite allergique
WO2007148648A1 (fr) 2006-06-19 2007-12-27 Toray Industries, Inc. Agent thérapeutique ou prophylactique pour la sclérose en plaques
WO2007148676A1 (fr) 2006-06-20 2007-12-27 Toray Industries, Inc. Agent thérapeutique ou prophylactique pour la leucémie
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
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WO2010020556A1 (fr) * 2008-08-22 2010-02-25 Evotec Neurosciences Gmbh Nouveaux antagonistes du récepteur de la bradykinine b1
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EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors

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EA007852B1 (ru) * 1998-03-27 2007-02-27 Джинентех, Инк. Соединения для лечения расстройств, опосредованных рецепторами адгезии cd11/cd18
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
US6630503B1 (en) 1999-08-13 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
US6916933B2 (en) 1999-12-06 2005-07-12 Hoffman-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
EP1243577A4 (fr) * 1999-12-28 2005-06-08 Ajinomoto Kk Nouveaux derives de phenylalanine
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US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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US7105520B2 (en) 2000-03-23 2006-09-12 Ajinomoto Co., Inc. Phenylalanine derivatives
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US7091242B2 (en) 2000-10-09 2006-08-15 Bayer Aktiengesellschaft Beta-amino acid derivatives as integrin receptor antagonists
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US7064229B2 (en) 2001-07-06 2006-06-20 Bayer Healthcare Ag Succinic acid derivatives
US7691843B2 (en) 2002-07-11 2010-04-06 Pfizer Inc. N-hydroxyamide derivatives possessing antibacterial activity
JP2005535710A (ja) * 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド アリールおよびヘテロアリール化合物ならびに凝固を調節する方法
WO2004014844A3 (fr) * 2002-08-09 2005-04-28 Transtech Pharma Inc Composes aryle et heteroaryle et procedes de modulation de la coagulation
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WO2005014533A2 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes d'utilisation
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