EP1001764A1 - Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire - Google Patents

Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire

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Publication number
EP1001764A1
EP1001764A1 EP98926122A EP98926122A EP1001764A1 EP 1001764 A1 EP1001764 A1 EP 1001764A1 EP 98926122 A EP98926122 A EP 98926122A EP 98926122 A EP98926122 A EP 98926122A EP 1001764 A1 EP1001764 A1 EP 1001764A1
Authority
EP
European Patent Office
Prior art keywords
prolyl
dichlorobenzenesulfonyl
tyrosine
carbonyl
tetrahydroisoquinoline
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP98926122A
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German (de)
English (en)
Other versions
EP1001764A4 (fr
Inventor
Philippe L. Durette
William K. Hagmann
Malcolm Maccoss
Sander G. Mills
Richard A. Mumford
Gail M. Van Riper
Jack A. Schmidt
Nancy J. Kevin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
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Merck and Co Inc
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Publication date
Priority claimed from GBGB9714314.3A external-priority patent/GB9714314D0/en
Priority claimed from GBGB9800686.9A external-priority patent/GB9800686D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1001764A1 publication Critical patent/EP1001764A1/fr
Publication of EP1001764A4 publication Critical patent/EP1001764A4/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49d CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and ⁇ 4 ⁇ p ), thereby blocking the binding of VLA-4 integrin ("very late antigen-4"; CD49d CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and ⁇ 4 ⁇ p ), thereby blocking the binding of VLA-4 integrin ("very late antigen-4"; CD49d CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and ⁇ 4 ⁇ p ), thereby blocking the binding of VLA-4 integrin ("very late antigen-4"; CD49d CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and ⁇ 4 ⁇ p ), thereby blocking the binding of VLA-4 integrin ("very late antigen
  • 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.
  • 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 relates to heterocyclic amide 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.
  • CAMs cell adhesion molecules
  • selectins include the selectins, integrins, cadherins and immunoglobulins.
  • CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targetting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
  • 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. g7, 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. Engleman et al., "Cell Adhesion Integrins as Pharmaceutical Targets.” in Ann. Repts. in Medicinal Chemistry. Vol. 31, J. A. Bristol, Ed.; Acad. Press, NY, 1996, p. 191).
  • VLA-4 (“very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ i) is an integrin expressed on all leukocytes, except platelets and mature neutrophils, including dendritic cells and macrophage-like cells and is a key mediator of the cell-cell and cell-matrix interactions of of these cell types (see M. E. Hemler, "VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.” Ann. Rev. Immunol. 8, 365 (1990)).
  • the ligands for VLA-4 include vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin (FN).
  • VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation. (See R. Lobb et al. "Vascular Cell Adhesion Molecule 1.” in Cellular and Molecular Mechanisms of Inflammation, C. G. Cochrane and M. A. Gimbrone, Eds.; Acad. Press, San Diego, 1993, p. 151.) 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 ( 4 ⁇ (VLA-
  • ct4 ⁇ 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, 6JJ (1993) and E. Keszthelyi et al., "Evidence for a prolonged role of 0C4 integrin throughout active experimental allergic encephalomyelitis.” Neurology.
  • VLA-4 interactions in other diseases, including rheumatoid arthritis; various melanomas, carcinomas, and sarcomas; inflammatory lung disorders; acute respiratory distress syndrome (ARDS); atherosclerotic plaque formation; restenosis; uveitis and circulatory shock (for examples, see A. A. Postigo et al., "The ⁇ 4 ⁇ /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)).
  • 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.
  • One aspect of the present invention provides a method for the treatment of diseases, disorders, conditions or symptoms mediated by cell adhesion in a mammal which comprises administering to said mammal an effective amount of a compound Formula I:
  • R 1 is 1) Ci-ioalkyl
  • R2 is 1) hydrogen
  • heteroaryl-C ⁇ _ ⁇ oalkyl wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and aryl and heteroaryl optionally substituted with one to four substituents independently selected from R D ;
  • R3 is 1) hydrogen
  • R is 1) hydrogen, 2) Ci-ioalkyl, 3 C2-10alkenyl,
  • R3, R4 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteroatoms selected from N, O and S;
  • R5 is 1) hydrogen
  • heteroaryl-C ⁇ _ ⁇ oalkyl wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R ; or
  • R4, R5 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and
  • R6, R7 J and R ⁇ are each independently selected from the group consisting of
  • Rx a group selected from Rx; or two of R6, R7, and R8 and the atom to which both are attached, or two of R ⁇ , R7, and R8 and the two adjacent atoms to which they are attached, together form a 5-7 membered saturated or unsaturated monocyclic ring containing zero to three heteroatoms selected from N, O or S,
  • R a is 1) Cy, or
  • R D is 1) a group selected from R a ,
  • aryl Ci-ioalkyl 6) heteroaryl Ci-io alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;
  • R c is 1) halogen
  • R ⁇ and R e are independently selected from hydrogen, Ci-ioalkyl, C2-10 alkenyl, C2-10alkynyl, Cy and Cy Cl-l ⁇ alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R c ; or
  • R 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;
  • Rf and RS are independently selected from hydrogen, Ci-ioalkyl, Cy and Cy-Cl-loalkyl wherein Cy is optionally substituted with Ci-l ⁇ alkyl; or Rf and RS 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 ;
  • Ri 1 Ci-ioalkyl
  • alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;
  • R x is 1) -ORd
  • Ry is 1) a group selected from R x ,
  • heterocyclyl wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R x ;
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl
  • n is an integer from 1 to 2;
  • n is an integer from 1 to 10;
  • X is 1) -C(O)ORd
  • Y is 1) -C(O)-
  • Z and A are independently selected from -C- and -C-C-; B is selected from the group consisting of
  • Y is S(O)2 and Rl is Cl-ioalkyl, Cy or Cy-Ci-io alkyl wherein alkyl is optionally substituted with one to two substituents independently selected from R a , and Cy is optionally substituted with one to four substituents independently selected from Rb.
  • Rl is Cl-ioalkyl, Cy or Cy-Ci-io alkyl wherein alkyl is optionally substituted with one to two substituents independently selected from R a , and Cy is optionally substituted with one to four substituents independently selected from Rb.
  • Formula I are those of formula la, lb or Ic.
  • the cell adhesion is mediated by VLA-4.
  • Another aspect of the present invention provides novel compounds of Formula la:
  • Formula la are compounds wherein Z is C.
  • Formula la In another subset of Formula la are compounds wherein X is C(O)ORd.
  • Formula la are compounds wherein Rl is Cl-l ⁇ alkyl, Cy or Cy-Ci-ioalkyl wherein alkyl is optionally substituted with one to two substituents independently selected from R a , and Cy is optionally substituted with one to four substituents independently selected from Rb.
  • Rl Cy is preferably aryl optionally substituted with one to four substituents selected from BP.
  • Rl is phenyl with a substituent on the 3-position and optionally a second substituent; the more preferred substituents are selected from C ⁇ _ ⁇ o a lkoxy, halogen, cyano, and trifluoromethyl.
  • R-2 is H or Cl-6alkyl.
  • Preferred R-2 is H or Cl-3alkyl, more preferably H or methyl.
  • R-2 is H or Cl-6alkyl.
  • Preferred R-2 is H or Cl-3alkyl, more preferably H or methyl.
  • Formula la are compounds wherein
  • R is H or Cl-6alkyl.
  • Preferred R3 is H or Cl-3alkyl, more preferably H or methyl.
  • Formula la are compounds wherein R5 is H and R4 is Ci-ioalkyl or Cy-Ci-ioalkyl, wherein alkyl is optionally substituted with one to four substituents selected from phenyl and Rx, and Cy is optionally substituted with one to four substituents independently selected from Ry; or R4, R5 and the carbon to which they are attached together form a 3-7 membered mono- or bicyclic carbon only ring.
  • Cy is preferably aryl, more preferably phenyl.
  • R4 is phenyl-C ⁇ _3alkyl, wherein phenyl is optionally substituted with one or two groups selected from Ry.
  • R2 is H or Ci-6 alkyl, and Rl, R3, R4 and R5 are as defined previously under Formula I.
  • X is CO2H; Rl is aryl optionally substituted with one to four substituents selected from Rb; R2 is H; R3 is H or Ci-3 alkyl; R4 is phenyl-Ci-3alkyl, wherein phenyl is optionally substituted with one or two groups selected from Ry; and R ⁇ is H.
  • R2 is H or Ci-3 alkyl
  • R ⁇ is H, Ci-6 alkyl, aryl, ORd, SRd, NRdRe, or NRdC(O)Re
  • R3 is H or Ci-6alkyl
  • Rb and Ry are as defined under Formula I.
  • B is C and Rb is halogen, Cl-lOalkoxy, cyano, or trifluoromethyl.
  • the present compounds are generally composed of three domains: 1) an acyl (including sulfonyl) moiety, 2) a cyclic amino acid 1, and 3) amino acid 2, and are named in a manner similar to that used to name oliogopeptides.
  • 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-methyl-l-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 includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion.
  • cycloalkyl examples 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 monocyclic cycloalkyl or monocyclic 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.
  • 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 examples 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 in which the point of attachment may be carbon or nitrogen.
  • the term also includes monocyclic 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.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4- pyridones attached through the nitrogen or N-substituted-(lH,3H)- pyrimidine-2,4-diones (N-substituted uracils).
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • 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.
  • any enantiomer of a compound of the general 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-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.
  • basic ion exchange resins such as
  • 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.
  • 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 ⁇ 4 ⁇ 7 binding and cell adhesion and activation, which comprises administering to a mammal an effective amount of a compound of Formula I.
  • 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, and (19) atherosclerosis.
  • 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.
  • 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 compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery systems for inhalation are 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 and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
  • MDI metered dose inhalation
  • DPI dry powder inhalation
  • 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.
  • the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
  • 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.
  • Such 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.
  • Combination Therapy 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 compound of Formula I When a compound of
  • Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, 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: (a) other VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO9640781, WO9622966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists) such as bromophenir amine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, di
  • 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 next Fmoc-protected amino acid derivative D is coupled to C employing standard peptide (in this instance, 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), HOBt, and N,N- d ⁇ sopropylethylamine (DIEA) in DMF) to yield dipeptide E.
  • standard peptide in this instance, 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), HOBt, and N,N- d ⁇ sopropylethylamine (DIEA) in DMF
  • the Fmoc group is removed with piperidine in DMF to yield the free amine F.
  • An acid chloride or isocyanate derivative is reacted with F in the presence of DIEA to yield G.
  • the final product is removed
  • Step A Loading of N-Fmoc-amino acid derivatives onto resins. N-Fmoc-amino acids were loaded on either Wang®
  • Chloro (2-chorotrityl) resin typically 0.2 mmol
  • Chloro (2-chorotrityl) resin typically 0.2 mmol
  • a solution of N- Fmoc-amino acid (0.2 mmol) in dimethylformamide (3 ml) was added to the resin, followed by the addition of N,N-diisopropylethylamine(0.4 mmol).
  • the resin was gently stirred for 2 hours, filtered and washed sequentially with dimethylformamide (3 times) and dichloromethane (3 times).
  • the resin was finally washed with 10% methanol in dichloromethane and vacuum dried.
  • the amino acid substitution value obtained after vacuum drying typically ranged between 0.05 to 0.1 mmol.
  • Step B Deprotection of the N-Fmoc group.
  • N-Fmoc protecting group was removed from the resin 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. Step C. Coupling of the next N-Fmoc-amino acid derivative
  • Step D Deprotection of the N-Fmoc group.
  • 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 sulfonyPation) of the terminal amino group.
  • the desired N-terminal capping reagent (sulfonyl) chloride or acyl chloride, or isocyanate) (0.4 mol) was dissolved in dimethylformamide (2 ml), mixed with N,N- diisopropylethylamine(0.8 mmol) and added to the resin from Step D. After approximately two hours, the resin was sequentially washed with dimethylformamide (3 times) and dichloromethane (3 times).
  • Step F Cleavage of the desired products from the resins.
  • the final desired products were cleaved from the resins from Step E by gently stirring with a solution of trifluoroacetic acid:thioanisole:ethanedithiol (95:2.5:2.5); 3 hours for Wang® resin and 30 minutes for the Chloro (2-chorotrityl) resin. Following filtration, the solvents were removed by evaporation and the residue dissolved in acetonitrile (3 mL). Insoluble material was removed by filtration. The final products were purified by reverse phase chromatography with a linear gradient of buffer A (0.1% trifluoroacetic acid in water) and buffer B (0.1% trifluoroacetic acid in acetonitrile) and isolated by lyophilization. Molecular ions were obtained by electrospray ionization mass spectrometry or matrix- assisted laser desorption ionization time-of-flight mass spectrometry to confirm the structure of each peptide.
  • N-(2-naphthalenesulfonyl)-l,2,3,4-tetrahydro 481 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • N-(4-methoxybenzenesulfonyl)-l,2,3,4-tetrahydro 461 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • N-(l-naphthalenesulfonyl)-l,2,3,4-tetrahydro 481 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • N-(3-toluenesulfonyl)-l,2,3,4-tetrahydro 445 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • N-(2,4-difluorobenzenesulfonyl)-l,2,3,4- 467 tetrahydro isoquinoline-3(S)-carbonyl-(L)- norleucine
  • N-(2-cyanobenzenesulfonyl)-l,2,3,4-tetrahydro 456 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • N-(4-cyanobenzenesulfonyl)-l,2,3,4-tetrahydro 456 isoquinoline-3(S)-carbonyl-(L)-norleucine
  • Step B N-(Benzyloxycarbonyl)-(L)-prolyl-(L)-3-(2- naphthyPalanine. tert-butyl ester.
  • Step C (L)-Prolyl-(L)-3-(2-naphthyl)alanine. tert-butyl ester.
  • a solution of N-(benzyloxycarbonyl)-(L)-prolyl-(L)-2- naphthylalanine tert-butyl ester (870 mg, 1.73 mmol) in methanol (30 mL) was hydrogenated under an atmosphere of hydrogen gas in the presence of 10% palladium-on-charcoal (75 mg) until complete disappearance of starting material (several hours) as indicated by TLC (30% ethyl acetate in hexane).
  • Step D N-(3.5-Dichlorobenzenesulfonyl))-(L)-prolyl-(L)-3- (2- naphthyPalanine. tert-butyl ester.
  • Step E N-(3.5-Dichlorobenzenesulfonyl))-(L)-prolyl-(L)-3- (2- naphthyPalanine.
  • Step A N-(3-trifluoromethylphenylsulfonyl)-(L)- 2(S)-methyl-prolyl- (L)-4-aminophenylalanine. methyl ester.
  • Step B N-(3-trifluoromethylphenylsulfonyl)-(L)- 2(S)-methyl-prolyl-
  • Step C N-(3-trifluoromethylphenylsulfonyl)-(L)- 2(S)-methyl-prolyl-
  • Step A 4-Iodo-(L)-Phenylalanine. tert-butyl ester hydrochloride.
  • N-Boc-4-iodo-(L)-phenylalanine 1.0 g, 2.56 mmol
  • methylene chloride 7 mL
  • cyclohexane 14 mL
  • t-butyl trichloroacetimidate 0.48 mL, 2.68 mmol
  • boron trifluoride-etherate 48 ⁇ L.
  • the reaction mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere and then treated a second time with the same amounts of t-butyl trichloroacetimidate and boron trifluoride-etherate as above. After stirring overnight, a third addition was made, and the mixture was stirred a further 3 hours. The mixture was then filtered and the filtrate evaporated.
  • the product was obtained pure by silica gel chromatography eluting with 10% diethyl ether in hexane; yield 650 mg.
  • the product was treated with IM HCl in ethyl acetate (7.3 mL) for 18 hours at room temperature.
  • Step B N-(3.5-Dichlorobenzenesulfonyl)-(L)-proline
  • the methyl ester was obtained pure by silica gel chromatography eluting with 10% acetone in hexane; yield 1.49 g. It was then taken up in ethanol (50 L) and treated with 0.2 N sodium hydroxide (26.6 mL) for 1.5 hours at room temperature. The mixture was acidified with glacial acetic acid, concentrated, the residue taken up in methylene chloride, washed with water, saturated brine solution, dried (Na2SO4), and evaporated to give the title compound; yield 1.4 g. 400 MHz iH NMR (CD3OD): ⁇ 1.80-2.15 (m, 4H); 3.35-4.45 (m, 2H); 4.30 (dd, IH); 7.76 (m, IH); 7.83 (m, 2H).
  • Step C N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4- iodophenylalanine. tert-butyl ester.
  • Step D N-(3.5-dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(4 > - fluorobenzoyl)phenylalanine ⁇ tert-butyl ester.
  • Step E N- 3.5-dichorobenzenesulfonyl - L -prolyl- L -4- 4 , - fluorobenzoyDphenylalanine
  • Step A N-(3.5-dichlorobenzenesulfonyP-(L)-prolyl-(L)-4-
  • Step B N-(3.5-dichlorobenzenesulfonvP-(L)-prolyl-(L)-4- (4-fluorobenzyPphenylalanine
  • Step A N-Boc-4-(2-nitrophenoxy)-(L)-phenylalanine. methyl ester
  • Step B 4-(2-nitrophenoxy)-(L)-phenylalanine. methyl ester hydrochloride
  • N-Boc-4-(2-nitrophenoxy)-(L)-phenylalanine, methyl ester (600 mg) was stirred in a solution of IN hydrochloric acid in ethyl acetate (10 mL) for 18 hours at room temperature. A precipitate formed, the solvent was removed by rotoevaporation, and co-evaporated with Et 2 O (2x). The solid was than suspended with ethyl acetate, filtered, washed with diethyl ether, and allowed to air dry. The title compound was recovered (490 mg) and used in the subsequent reaction without further purification.
  • Step C N-(3.5-DichlorobenzenesulfonvP-(L)-prolyl-(L)-4-(2- nitrophenoxy)phenylalanine. methyl ester.
  • Step B N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(2- aminophenoxy)-phenylalanine
  • N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(2- aminophenoxy)-phenylalanine, methyl ester was hydrolyzed by the procedure in Example 289, step D to afford N-(3,5- dichlorobenzenesulfonyl)-(L)-pro ⁇ yl-(L)-4-(2-aminophenoxy)- phenylalanine.
  • Step A N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(2- acetylaminophenoxy)-phenylalanine. methyl ester
  • Step B N-(3.5-DichlorobenzenesulfonvP-(L)-prolyl-(L)-4-(2- acetylaminophenoxy)-phenylalanine
  • N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(2- acetylaminophenoxy)-phenylalanine, methyl ester was hydrolyzed by the procedure in Example 289, step D to afford N-(3,5- dichlorobenzenesulfonyl)-(L)-prolyl-(L)-4-(2-acetylaminophenoxy)- phenylalanine.
  • Step A N-Boc-4-(2-cyanophenoxy)-phenylalanine. methyl ester
  • Step B 4-(2-cyanophenoxy)-phenylalanine. methyl ester.hydrochloride
  • the reaction was performed by an analogous procedure as described in Example 289, step B to yield the title compound.
  • Step C N-Boc-2-(S)-methyl-(L)-prolyl-4-(2-cyanophenoxy)- phenylalanine. methyl ester
  • Step D N-Boc-2-(S)-methyl-(L)-prolyl-4-(2-cvanophenoxy)- phenylalanine. methyl ester hydrochloride
  • Step E N-(3.5-DichlorobenzenesulfonyP-2-(S)-methyl-(L)-prolyl-
  • Step A N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O-tert- butyl-tyrosine. methyl ester.
  • 3,5-dichlorobenzenesulfonyl-(L)-proline from Example 284, Step B
  • 1-hydroxybenzotriazole hydrate 782.3 mg, 5.78 mmole
  • N-methylmorpholine (1.45mL, 13.1 mmole
  • (L)-O-tert-butyl-tyrosine methyl ester hydrochloride (1.58 gm, 6.31 mmole)
  • l-ethyl-3-(3-dimethylamino-propyl) carbodiimde (1.41 gm, 7.36 mmole).
  • Step B N-(3.5-DichlorobenzenesulfonvP-(L)-prolyl-(L)-O-tert- butyl-tyrosine.
  • the solvent was removed by rotoevaporation and the residue dissolved in dichloromethane and water.
  • the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 20 mL).
  • the organic layers were combined, and successively washed with water, saturated salt solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by rotoevaporation.
  • Step A N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O-tert- butyl-tyrosine. tert-butyl ester
  • step C N-(3,5- dichlorobenzenesulfonyl)-(L)-proline was coupled with (L)-O-tert- butyl-tyrosine, tert-butyl ester hydrochloride.
  • the product was purified by flash column chromatography on silica gel eluted with
  • Step B N-(3.5-DichlorobenzenesulfonyP-(L)-prolyl-(L)-tyrosine. tert-butyl ester
  • Step C N-(3.5-dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O-methyl- tyrosine.
  • Step D N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O-methyl- tyrosine.
  • Step A N-(3.5-dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O- cyanomethyl-tyrosine.
  • tert-butyl ester To a solution of N-(3,5-dichlorobenzenesulfonyl)-(L)- prolyl-(L)-tyrosine, tert-butyl ester (200 mg, 0.368 mmole, obtained from Example 299, Step A) dissolved in 2.0 mL of dry dimethylformamide was added bromoacetonitrile (353.1 mg, 2.94 mmole) and anhydrous potassium carbonate (152.6 mg, 1.10 mmole).
  • Step B N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O-
  • Step C N-(3.5-Dichlorobenzenesulfonyl)-(L)-prolyl-(L)-O- (5-tetrazolyl)methyl-tyrosine
  • Step B N-t-Butyloxycarbonyl-(L)-2(S)-methyl-prolyl-(L)-N ⁇ - benzyl-histidine. methyl ester.
  • Step C (L)-2(S)-Methyl-prolyl-(L)-N E - benzyl-histidine. methyl ester, dihydrochloride.
  • Step D N-(3.5-Dichlorobenzenesulfonyl)-(L)-2(S)-methyl- prolyl-(L)-N ⁇ -benzyl-histidine r methyl ester.
  • Step E N-(3.5-DichlorobenzenesulfonvP-(L)-2(S)-methyl- prolyl-(L)-N ⁇ -benzyl-histidine.
  • Step A 2-Amino-2-norbornanecarboxylic acid, methyl ester hydrochoride. To 25 mL of methanol at 0 °C was added thionyl chloride
  • Step B N-Benzenesulfonyl-(L)-prolyl-2-amino-2- norbornanecarboxylic acid, methyl ester
  • Step C N- Benzenesulfonyl-(L)-prolyl-2-amino-2- norbornanecarboxylic acid
  • N-phenylsulfonyl-(L)-prolyl-2-amino-2- norbornanecarboxylic acid, methyl ester 210 mg, 0.2 mmol
  • 3 mL of 1:1 aqueous sodium hydroxide (1 M) and methanol was stirred at room temperature for 2 weeks.
  • the reaction was quenched with concentrated hydrochloric acid (0.2 mL), and the resulting mixture was partitioned between saturated salt solution and ethyl acetate.
  • the product was extracted with ethyl acetate and was purified by flash chromatography on silica gel eluted with 100:5:1 methylene chloride/methanol/acetic acid to give the product as a mixture of diastereomers.
  • Step A N-Benzenesulfonyl-(L)-prolyl-3(R)-methyl- phenylalanine. methyl ester.
  • the title compound was prepared by the procedure described in Example 289 Steps A - C starting from (L)-3(R)-methyl- phenylalanine (prepared by the procedure of Hruby and coworkers: Tetrahedron, 1992. 48, 4733).
  • Step B N-Benzenesulfonyl-(L)-prolyl-3(R)-methyl- phenylalanine.
  • Step A N-Phenylsulfonyl-(L)-prolyl-(L)-2.3-methano- phenylalanine. methyl ester and N-Phenylsulfonyl-(L)-prolyl-(D)-2.3- methano-phenylalanine. methyl ester.
  • Step B N-Phenylsulfonyl-(L)-prolyl-(L)-2.3-methano- phenylalanine and N-phenylsulfonyl-(L)-prolyl-(D)-2.3-methano- phenylalanine.
  • Step A N-(3-Fluorobenzenesulfonyl)-(L)-prolyl-(L)-4- trimethylstannylphenylalanine. tert-butyl ester.
  • N-(3,5-Dichlorobenzenesulfonyl)-(L)-2(S)-methyl-prolyl- (L)-4-trimethylstannylphenylalanine, tert-butyl ester was prepared from N-(3,5-dichlorobenzenesulfonyl)-(L)-2(S)-methyl-prolyl-(L)-4- iodophenylalanine, tert-butyl ester by an analogous procedure.
  • Step B N-(3.5-Dichlorobenzenesulfonyl)-(L)-2(S)-methyl-prolyl-
  • Step C N-(3.5-DichlorobenzenesulfonyP-(L)-2(S)-methyl-prolyl- (L)-4-(5-((lH.3H)-1.3-dimethylpyrimidine-2.4-dione))phenylalanine
  • the tert-butyl ester of N-(3,5-dichlorobenzenesulfonyl)- (L)-2(S)-methyl-prolyl-(L)-4-(5-((lH,3H)-l,3-dimethylpyrimidine-2,4- dione))-phenylalanine, tert butyl ester (24 mg, 0.035 mmol) was stirred in a solution of trifluoroacetic acid (170 ⁇ L, 2.2 mmol) in methylene chloride (1.0 mL) according to the procedure described in Example 225, Step E to yield the title compound.
  • Step A Preparation of CS-1 Coated Plates.
  • Untreated 96 well polystyrene flat bottom plates were coated with bovine serum albumin (BSA; 20 ⁇ g/ml) for 2 hours at room temperature and washed twice with phosphate buffered saline (PBS).
  • BSA bovine serum albumin
  • PBS phosphate buffered saline
  • the albumin coating was next derivatized with 10 ⁇ g/ml 3-(2- pyridyldithio) propionic acid N-hydroxysuccinimide ester (SPDP), a heterobifunctional crosslinker, for 30 minutes at room temperature and washed twice with PBS.
  • SPDP 3-(2- pyridyldithio) propionic acid N-hydroxysuccinimide ester
  • the CS-1 peptide (Cys-Leu-His-Gly-Pro-Glu-Ile- Leu-Asp-Val-Pro-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.
  • Step B Preparation of Fluorescentlv Labeled Jurkat Cells.
  • the cells were incubated at a concentration of 2 x 10 cells/ml in PBS containing a 1 ⁇ M concentration of a fluorogenic esterase substrate (2', 7'-bis-(2-carboxyethyl)-5-(and -6)- carboxyfluorescein, acetoxymethyl ester; BCECF-AM; Molecular Probes Inc., Eugene, Oregon; catalog #B-1150) for 30-60 minutes at 37°C in a 5% CO2/air incubator.
  • 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.
  • 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.
  • VCAM GenBank Accession no. M30257
  • human VCAM cDNA R & D Systems
  • 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 amplified region encoded the following sequence of human VCAM-1: MPGKMWILGASNILWIMFAASQAFKIETTPESRYLAQIGDSVSLTC STTGCESPFFSWRTQIDSPLNGKVTNEGTTSTLTMNPVSFGNEHSYLC TATCESRKLEKGI VEIYSFPKDPEIHLSGPLEAGKPITVKCSVADVY PFDRLEIDLLKGDHLMKS EFLEDADRKSLETKSLEVTFTPVIEDIGKV LVCRAKLHIDEMDSVPTVRQAVKEL.
  • the resulting PCR product of 650 bp was digested with EcoRI and Bell and ligated to expression vector pig-Tail (R & D Systems, Minneapolis, MN) digested with EcoRI and BamHl.
  • 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 NotI and ligated to pCI-neo (Promega, Madison, WI) digested with EcoRI and NotI.
  • 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).
  • Stable 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).
  • 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 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 400xg for five minutes and resuspended in binding buffer (25 mM HEPES, 150 mM NaCI, 3 mM KC1, 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
  • I-VCAM-Ig in the absence of cells was usually less than 5% of that observed using cells in the presence of vehicle. Percent inhibition was then calculated for each test well and the IC 50 was determined from a ten point titration using a validated four parameter fit algorithm.
  • 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 , 01 % BSA, 3 M KC1, 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 ⁇ l/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 .
  • 100 ⁇ L of Microscint-20 (Packard cat# 6013621) was added to each well.
  • the plates were then sealed, placed on a shaker for 30 seconds, and counted on a Topcount microplate scintillation counter (Packard).
  • Control wells containing DMSO alone were used to determine the level of VCAM-Ig binding corresponding to 0% inhibition.
  • Wells in which cells were omitted were used to determine the level of binding corresponding to 100% inhibition. Percent inhibition was then calculated for each test well and the IC 50 was determined from a ten point titration using a validated four parameter fit algorithm.

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Abstract

Des composés de formule (I) sont des antagonistes de VLA-4 et/ou de α4β7 et sont, en tant que tels, utiles pour inhiber ou empêcher l'adhésion cellulaire et pour lutter contre des pathologies induites par l'adhésion cellulaire. Ces composés peuvent être formulés sous forme de compositions pharmaceutiques et sont adaptés pour être utilisés dans le traitement de l'asthme, des allergies, des inflammations, de la sclérose en plaques et d'autres maladies inflammatoires et auto-immunes.
EP98926122A 1997-05-29 1998-05-29 Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire Ceased EP1001764A4 (fr)

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US4801797P 1997-05-29 1997-05-29
US48017P 1997-05-29
GB9714314 1997-07-07
GBGB9714314.3A GB9714314D0 (en) 1997-07-07 1997-07-07 Heterocyclic amide compounds as cell adhesion inhibitors
US6652597P 1997-11-25 1997-11-25
US66525P 1997-11-25
GB9800686 1998-01-14
GBGB9800686.9A GB9800686D0 (en) 1998-01-14 1998-01-14 Hetrocyclic amide compounds as cell adhesion inhibitors
PCT/US1998/010940 WO1998053814A1 (fr) 1997-05-29 1998-05-29 Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire

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Families Citing this family (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291511B1 (en) 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
DE69833654T2 (de) * 1997-05-29 2006-12-14 Merck & Co., Inc. (A New Jersey Corp.) Biarylalkansäuren in der verwendung als zelladhäsionsinhibitoren
WO1998054207A1 (fr) * 1997-05-30 1998-12-03 Celltech Therapeutics Limited Derives anti-inflammatoires de tyrosine
DK0991619T3 (da) 1997-06-23 2003-12-29 Tanabe Seiyaku Co Inhibitorer af alfa 4-beta 1-medieret celleadhæsion
US6559127B1 (en) 1997-07-31 2003-05-06 Athena Neurosciences, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6489300B1 (en) 1997-07-31 2002-12-03 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6291453B1 (en) 1997-07-31 2001-09-18 Athena Neurosciences, Inc. 4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6423688B1 (en) 1997-07-31 2002-07-23 Athena Neurosciences, Inc. Dipeptide and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6362341B1 (en) 1997-07-31 2002-03-26 Athena Neurosciences, Inc. Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492421B1 (en) 1997-07-31 2002-12-10 Athena Neurosciences, Inc. Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6583139B1 (en) 1997-07-31 2003-06-24 Eugene D. Thorsett Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7030114B1 (en) 1997-07-31 2006-04-18 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
US6645939B1 (en) 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
ES2221227T3 (es) * 1997-11-24 2004-12-16 MERCK & CO., INC. Derivados sustituidos de beta-alanina como inhibidores de la adhesion celular.
US6197794B1 (en) * 1998-01-08 2001-03-06 Celltech Therapeutics Limited Phenylalanine derivatives
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
EP1056714B1 (fr) 1998-02-26 2004-08-11 Celltech Therapeutics Limited Derives de phenylalanine en tant qu'inhibiteurs d'integrines alpha 4
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
GB9811159D0 (en) * 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9811969D0 (en) * 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
US6685617B1 (en) 1998-06-23 2004-02-03 Pharmacia & Upjohn Company Inhibitors of α4β1 mediated cell adhesion
GB9814414D0 (en) 1998-07-03 1998-09-02 Celltech Therapeutics Ltd Chemical compounds
US6323180B1 (en) 1998-08-10 2001-11-27 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders
GB9821061D0 (en) 1998-09-28 1998-11-18 Celltech Therapeutics Ltd Chemical compounds
GB9821222D0 (en) 1998-09-30 1998-11-25 Celltech Therapeutics Ltd Chemical compounds
GB9825652D0 (en) 1998-11-23 1999-01-13 Celltech Therapeutics Ltd Chemical compounds
GB9826174D0 (en) 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
GB9828074D0 (en) 1998-12-18 1999-02-17 Glaxo Group Ltd Therapeutically useful compounds
ES2339738T3 (es) * 1999-01-22 2010-05-25 Elan Pharmaceuticals, Inc. Derivados de acilo los cuales tratan trastornos relacionados con vla-4.
WO2000043415A1 (fr) * 1999-01-25 2000-07-27 Elan Pharmaceuticals, Inc. Composes inhibant l'adhesion des leucocytaire provoquee par vla-4
US6407066B1 (en) 1999-01-26 2002-06-18 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
PL349463A1 (en) 1999-02-18 2002-07-29 Hoffmann La Roche Phenylalaninol derivatives
CZ20012980A3 (cs) 1999-02-18 2002-04-17 F. Hoffmann-La Roche Ag Thioamidové deriváty
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
IL146288A0 (en) * 1999-06-30 2002-07-25 Daiichi Seiyaku Co Vla-4 inhibitor compounds
US6756378B2 (en) 1999-06-30 2004-06-29 Pharmacopeia Drug Discovery, Inc. VLA-4 inhibitor compounds
JP2003506491A (ja) 1999-08-13 2003-02-18 バイオジェン インコーポレイテッド 細胞接着インヒビター
US6420418B1 (en) 1999-08-16 2002-07-16 Merck & Co., Inc. Heterocycle amides as cell adhesion inhibitors
EP1088821A1 (fr) * 1999-09-28 2001-04-04 Applied Research Systems ARS Holding N.V. Derives des sulfamides pharmaceutiquement actifs
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
DK1237878T3 (da) * 1999-12-06 2007-07-30 Hoffmann La Roche 4-pyrimidinyl-N-acyl-L-phenylanin
YU40502A (sh) * 1999-12-06 2005-03-15 F.Hoffmann-La Roche Ag. 4-piridinil-n-acil-l-fenilalanini
US6380387B1 (en) 1999-12-06 2002-04-30 Hoffmann-La Roche Inc. 4-Pyrimidinyl-n-acyl-l phenylalanines
US6388084B1 (en) 1999-12-06 2002-05-14 Hoffmann-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
EP1242118B1 (fr) 1999-12-16 2009-11-11 Biogen Idec MA Inc. Methodes de traitement de lesion ischemique ou hemorragique du systeme nerveux central au moyen d'antagonistes anti-integrine alpha4
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
BR0016818A (pt) 1999-12-28 2002-10-01 Pfizer Prod Inc Inibidores não-peptidila de adesão celular dependente de vla-4 úteis no tratamento de doenças inflamatórias, auto-imunes e respiratórias
WO2001054690A1 (fr) * 2000-01-28 2001-08-02 Biogen, Inc. Compositions pharmaceutiques contenant des composes d'integrine anti-beta 1 et utilisations correspondantes
WO2001068586A2 (fr) * 2000-03-14 2001-09-20 Novartis Ag INHIBITEURS D'INTEGRINES α4β1 ET α4β¿7?
ATE375330T1 (de) 2000-04-17 2007-10-15 Ucb Pharma Sa Enamin-derivate als zell-adhäsionsmoleküle
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
EP1296949A2 (fr) 2000-06-21 2003-04-02 Bristol-Myers Squibb Pharma Company Amides de piperidine utilises comme modulateurs de l'activite des recepteurs des chimiokines
US6960597B2 (en) * 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
WO2002004426A1 (fr) 2000-07-07 2002-01-17 Celltech R & D Limited Derives d'acide squarique contenant un noyau heteroaromatique bicyclique comme antagonistes d'integrine
EP1305291A1 (fr) 2000-08-02 2003-05-02 Celltech R&D Limited Derives d'isoquinoline-1-yl substitues en 3
MY129000A (en) 2000-08-31 2007-03-30 Tanabe Seiyaku Co INHIBITORS OF a4 MEDIATED CELL ADHESION
EP1193267A1 (fr) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Composés de sulfonamides hydrophiles pharmaceutiquement actifs
EP1193268A1 (fr) 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Dérivés de sulfonamide pharmaceutiquement actifs comportant des groupes lipophiles ainsi que ionisables comme inhibiteurs de protéine junkinases
EP1323711B1 (fr) 2000-09-29 2006-11-15 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
JP2004526733A (ja) * 2001-03-20 2004-09-02 メルク　エンド　カムパニー　インコーポレーテッド 強力な細胞接着阻害剤としての置換ｎ−アリールスルホニル−プロリン誘導体
US6559174B2 (en) 2001-03-20 2003-05-06 Merck & Co., Inc. N-arylsulfonyl aryl aza-bicyclic derivatives as potent cell adhesion inhibitors
US6855708B2 (en) 2001-03-20 2005-02-15 Merck & Co., Inc. N-arylsulfonyl aza-bicyclic derivatives as potent cell adhesion inhibitors
KR20040068240A (ko) 2001-12-14 2004-07-30 노보 노르디스크 에이/에스 호르몬 민감성 리파아제의 활성을 감소시키기 위한 화합물및 그들의 사용
MY140707A (en) 2002-02-28 2010-01-15 Mitsubishi Tanabe Pharma Corp Process for preparing a phenylalanine derivative and intermediates thereof
ES2197003B1 (es) * 2002-04-08 2005-03-16 J. URIACH & CIA S.A. Nuevos compuestos antagonistas de integrinas alfa.
TW200307671A (en) 2002-05-24 2003-12-16 Elan Pharm Inc Heteroaryl compounds which inhibit leukocyte adhesion mediated by α 4 integrins
TWI281470B (en) 2002-05-24 2007-05-21 Elan Pharm Inc Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
MXPA05000200A (es) 2002-07-02 2005-06-06 Schering Corp Nuevos antagonistas del receptor neuropeptido y y5.
AU2002345266B2 (en) * 2002-07-08 2009-07-02 Ranbaxy Laboratories Limited 3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonists
EP1558250A4 (fr) 2002-10-30 2006-11-02 Merck & Co Inc Modulateurs gamma-aminoamides de l'activite de recepteur de chimiokine
CA2514117A1 (fr) 2003-01-24 2004-08-12 Elan Pharmaceuticals, Inc. Composition et methode destinees a traiter les maladies de demyelinisation et la paralysie par administration d'agents de remyelinisation
WO2004089898A1 (fr) 2003-04-09 2004-10-21 Ranbaxy Laboratories Limited Derives d'azabicyclo hexane substitues en tant qu'antagonistes de recepteurs muscariniques
US20070021487A1 (en) 2003-04-11 2007-01-25 Mohammad Salman Azabicyclo derivatives as muscarinic receptor antagonists
BRPI0410456B8 (pt) 2003-05-21 2021-05-25 Boehringer Ingelheim Int compostos inibidores de hepatite c, composição farmacêutica, uso dos mesmos, bem como artigo de fabricação
CA2528723A1 (fr) * 2003-06-25 2005-01-06 Elan Pharmaceuticals, Inc. Methodes et compositions de traitement de la polyarthrite rhumatoide
AU2004274051A1 (en) 2003-09-22 2005-03-31 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US20050176755A1 (en) * 2003-10-31 2005-08-11 Dyatkin Alexey B. Aza-bridged-bicyclic amino acid derivatives as alpha4 integrin antagonists
CA2549851C (fr) 2004-01-21 2012-09-11 Boehringer Ingelheim International Gmbh Peptides macrocycliques actifs contre le virus de l'hepatite c
CA2554188A1 (fr) * 2004-01-23 2005-08-04 Elan Pharmaceuticals, Inc. Conjugues a base de polyethylene glycol d'acides heterocycloalkyl carboxamido propanoiques
RU2369604C2 (ru) 2004-04-13 2009-10-10 Инсайт Корпорейшн Производные пиперазинилпиперидина в качестве антагонистов хемокинового рецептора
JP2007533749A (ja) * 2004-04-20 2007-11-22 アムゲン インコーポレイティッド アリールスルホンアミドおよびそれに関連する使用方法
ATE546430T1 (de) * 2004-06-29 2012-03-15 Aventis Pharma Inc Fkbp bindende zusammensetzung und deren pharmazeutische verwendung
US7777042B2 (en) 2004-06-29 2010-08-17 Aventis Pharmaceuticals Inc. N-sulfonylpipecolic acid derivative FKBP binding composition and pharmaceutical use thereof
NZ588839A (en) * 2004-07-08 2012-09-28 Elan Pharm Inc Multivalent vla-4 antagonists comprising polyethylene glycol moieties
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
CA2573346C (fr) 2004-07-20 2011-09-20 Boehringer Ingelheim International Gmbh Analogues peptidiques inhibiteurs de l'hepatite c
UY29016A1 (es) 2004-07-20 2006-02-24 Boehringer Ingelheim Int Analogos de dipeptidos inhibidores de la hepatitis c
WO2006052962A2 (fr) 2004-11-10 2006-05-18 Janssen Pharmaceutica, N.V. Composes de triazole bicycliques inhibiteurs de l'integrine $g(a)4
CA2851103A1 (fr) 2005-09-29 2007-04-12 Elan Pharmaceuticals, Inc. Composes de pyrimidinyl amide qui inhibent l'adherence leucocytaire a mediation par vla-4
NZ567270A (en) 2005-09-29 2011-06-30 Elan Pharm Inc Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by VLA-4
MEP1008A (xx) 2005-12-21 2010-02-10 Incyte Corp 3-aminociklopentankarboksamidi kao modulatori receptora hemokina
KR20080100271A (ko) 2006-02-27 2008-11-14 엘란 파마슈티칼스, 인크. Ｖｌａ-4에 의해 매개되는 백혈구 부착을 억제하는 피리미디닐 술폰아미드 화합물
AU2008219007A1 (en) 2007-02-20 2008-08-28 Merrimack Pharmaceuticals, Inc. Methods of treating multiple sclerosis by administration of alpha-fetoprotein in combination with an integrin antagonist
CA2721093A1 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de serum humain, et ses conjugues
DK2370442T5 (da) 2008-11-26 2013-09-23 Pfizer 3-aminocyclopentancarboxamider som chemokinreceptor modulatorer
JP2012517426A (ja) 2009-02-09 2012-08-02 アステックス ファーマシューティカルズ インコーポレイテッド ピロロピリミジニルａｘｌキナーゼ阻害剤
EP3052515A4 (fr) * 2013-09-30 2017-03-15 The Regents of the University of California Composés d'intégrine anti-aphavbêta1 et méthodes correspondantes
CN107405331A (zh) * 2014-12-12 2017-11-28 联邦科学和工业研究组织 使用α9整联蛋白拮抗剂从骨髓干细胞龛迁移和释放HSC
EP3268369A4 (fr) 2015-03-10 2018-08-08 The Regents of The University of California Inhibiteurs anti-intégrine alphavbeta1 et méthodes d'utilisation associées
US10836720B2 (en) 2016-04-01 2020-11-17 The Regents Of The University Of California Inhibitors of integrin alpha 5 beta 1 and methods of use
WO2018140510A1 (fr) 2017-01-25 2018-08-02 Biogen Ma Inc. Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc
CN109111435B (zh) * 2017-06-26 2022-03-18 南京柯菲平盛辉制药有限公司 一类吡咯烷磺酰基衍生物RORγ调节剂及其用途
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
CA3114240C (fr) 2018-10-30 2023-09-05 Gilead Sciences, Inc. Derives d'imidazopyridine utilises en tant qu'inhibiteurs de l'integrine alpha4beta7
WO2020092401A1 (fr) 2018-10-30 2020-05-07 Gilead Sciences, Inc. COMPOSÉS POUR INHIBITION DE L'INTÉGRINE ALPHA 4β7
EP3873884A1 (fr) 2018-10-30 2021-09-08 Gilead Sciences, Inc. Dérivés de quinoléine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
JP7491996B2 (ja) 2019-08-14 2024-05-28 ギリアード サイエンシーズ， インコーポレイテッド α４β７インテグリンの阻害のための化合物
EP4165037A1 (fr) 2020-06-10 2023-04-19 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
KR20240035513A (ko) 2021-07-09 2024-03-15 알리고스 테라퓨틱스 인코포레이티드 항바이러스 화합물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350698A (en) * 1981-09-25 1982-09-21 Smithkline Corporation Antiallergic imidosulfamides
EP0443132A1 (fr) * 1989-12-22 1991-08-28 Fujisawa Pharmaceutical Co., Ltd. Peptides ayant une activité antagoniste de tachykinine, leur préparation et médicaments les renfermant
EP0696593A2 (fr) * 1994-08-11 1996-02-14 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl protéine transférase
WO1996040641A1 (fr) * 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. Derives de sulfonamides servant a moduler l'adherence cellulaire
WO1997021690A1 (fr) * 1995-11-28 1997-06-19 Cephalon, Inc. Inhibiteurs de cysteine et serine proteases derives d'acide d-amine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229381A (en) * 1983-12-01 1993-07-20 Merck & Co., Inc. Substituted azetidinones as anti-inflammatory and antidegenerative agents
IT1244873B (it) * 1990-09-12 1994-09-12 Depha Team Srl Derivati dell'acido 5-aminosalicilico (5-asa) per la terapia delle infiammazioni croniche intestinali
SE9300012D0 (sv) * 1993-01-05 1993-01-05 Astra Ab New peptides
CA2118985A1 (fr) * 1993-04-02 1994-10-03 Dinesh V. Patel Inhibiteurs heterocycliques de la farnesyl proteine transferase
US5424329A (en) * 1993-08-18 1995-06-13 Warner-Lambert Company Indole-2-carboxamides as inhibitors of cell adhesion

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350698A (en) * 1981-09-25 1982-09-21 Smithkline Corporation Antiallergic imidosulfamides
EP0443132A1 (fr) * 1989-12-22 1991-08-28 Fujisawa Pharmaceutical Co., Ltd. Peptides ayant une activité antagoniste de tachykinine, leur préparation et médicaments les renfermant
EP0696593A2 (fr) * 1994-08-11 1996-02-14 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl protéine transférase
WO1996040641A1 (fr) * 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. Derives de sulfonamides servant a moduler l'adherence cellulaire
WO1997021690A1 (fr) * 1995-11-28 1997-06-19 Cephalon, Inc. Inhibiteurs de cysteine et serine proteases derives d'acide d-amine

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BYK G ET AL: "Local constrained shifty pseudopeptides inhibitors of ras-farnesyl transferase" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 5, no. 22, 16 November 1995 (1995-11-16), pages 2677-2682, XP004135213 ISSN: 0960-894X *
CALCAGNI A ET AL: "Peptides containing the sulfonamide junction: Synthesis, structure, and conformation of Z-Tau-Pro-Phe-NHiPr" BIOPOLYMERS 1997 UNITED STATES, vol. 41, no. 5, 1997, pages 555-567, XP002332346 ISSN: 0006-3525 *
HAGMANN W K ET AL: "The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists" BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS 22 OCT 2001 UNITED KINGDOM, vol. 11, no. 20, 22 October 2001 (2001-10-22), pages 2709-2713, XP002332349 ISSN: 0960-894X *
LIN L S ET AL: "Specific and dual antagonists of [alpha]4[beta]1 and [alpha]4[beta]7 integrins" BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS 21 JAN 2002 UNITED KINGDOM, vol. 12, no. 2, 21 January 2002 (2002-01-21), pages 133-136, XP002332347 ISSN: 0960-894X *
LIN L S ET AL: "The discovery of acylated [beta]-amino acids as potent and orally bioavailable VLA-4 antagonists" BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS 25 FEB 2002 UNITED KINGDOM, vol. 12, no. 4, 25 February 2002 (2002-02-25), pages 611-614, XP002332348 ISSN: 0960-894X *
See also references of WO9853814A1 *

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JP2002512625A (ja) 2002-04-23
EP1001764A4 (fr) 2005-08-24
CA2291778A1 (fr) 1998-12-03

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