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WO1998053818A1 - Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire - Google Patents

Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire Download PDF

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Publication number
WO1998053818A1
WO1998053818A1 PCT/US1998/010952 US9810952W WO9853818A1 WO 1998053818 A1 WO1998053818 A1 WO 1998053818A1 US 9810952 W US9810952 W US 9810952W WO 9853818 A1 WO9853818 A1 WO 9853818A1
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Prior art keywords
aryl
optionally substituted
independently selected
ioalkyl
alkyl
Prior art date
Application number
PCT/US1998/010952
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English (en)
Inventor
Philippe L. Durette
William K. Hagmann
Malcolm Maccoss
Sander G. Mills
Richard A. Mumford
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 GBGB9714335.8A external-priority patent/GB9714335D0/en
Priority claimed from GBGB9800684.4A external-priority patent/GB9800684D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002291708A priority Critical patent/CA2291708A1/fr
Priority to EP98924989A priority patent/EP0998282A4/fr
Priority to AU77032/98A priority patent/AU728435B2/en
Priority to JP50093999A priority patent/JP2002501537A/ja
Priority to US09/424,823 priority patent/US6221888B1/en
Publication of WO1998053818A1 publication Critical patent/WO1998053818A1/fr

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    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • 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

Definitions

  • the compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen- 4"; CD49d/CD29; or c-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 c-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 c-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 c-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, rhe
  • the present invention relates to sulfonamide 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, 61, 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 ⁇ -i ⁇ l) 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 c ⁇ 4 ⁇ (VLA-
  • ⁇ 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, r ⁇ , 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, o-4 ⁇ 7.
  • Neutralizing anti-0.4 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 0.4 ⁇ i integrin.” Nature. 356, (_3 (1993) and E. Keszthelyi et al., "Evidence for a prolonged role of 0.4 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:
  • Rl is 1) Ci-ioalkyl
  • R2 and R3 are independently selected from
  • R is 1) hydrogen
  • heteroaryl-Ci_io a lkyl 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 ⁇ ; or
  • R3, R4 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 S;
  • B is 1) hydrogen, 2) Ci-io alkyl,
  • R is 1) hydrogen
  • R7 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
  • R a is 1) Cy, or 2) a group selected from Rx; wherein Cy is optionally substituted with one to four substituents independently selected from R c ;
  • Rk 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
  • Rd and R e are independently selected from hydrogen, Ci-ioalkyl, C2-10alkenyl, C2-10alkynyl, Cy and Cy Ci-ioalkyl, 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;
  • W and Rg are independently selected from hydrogen, Ci-ioalkyl, Cy and Cy Ci-ioalkyl; or R* 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
  • 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 is 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
  • heterocyclyl wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rx;
  • 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
  • compounds of formula I are those wherein R ⁇ is Cy.
  • Rl Cy is preferably aryl optionally substituted with one to four substituents selected from R D . More preferred R* is phenyl with a substituent on the
  • compounds of Formula I are those wherein R ⁇ is H or Ci-6alkyl.
  • R ⁇ is H or Ci-3alkyl, more preferably H or methyl.
  • compounds of Formula I are those wherein one of R3 and R4 is other than hydrogen.
  • R3 and R4 are hydrogen and the other is Cy, Cy-C]-. ⁇ oalkyl, or C-j_.iQa_ls.yl, each of which is optionally substituted as provided under Formula I.
  • R3/R4 Cy is preferably aryl or heteroaryl each optionally substituted with one to four substituents selected from R D ; and alkyl is optionally substituted with one to four substituents independently selected from R a .
  • R /R i s selected from phenyl; Cy-C ⁇ _3alkyl wherein Cy is thienyl, pyridyl or phenyl optionally substituted with one or two groups selected from phenyl, hydroxy, halogen, cyano, and nitro; and C ⁇ .galkyl optionally substituted with CO2H or CO H2.
  • compounds of Formula I are those wherein one of R6 and R? is other than hydrogen.
  • one of R ⁇ and R? is hydrogen and the other is aryl, aryl-Ci-l ⁇ alkyl, or Ci-ioalkyl, wherein aryl is optionally substituted with one to four substituents independently selected from Ry, and alkyl is optionally substituted with one to four substituents selected from Rx.
  • compounds of Formula I are those wherein X is -C(O)ORd.
  • the cell adhesion is mediated by VLA-4, and the compounds are of Formula la as described hereinbelow.
  • R2 is 1) hydrogen, or
  • Ci- ⁇ alk l one of R and R4 is hydrogen and the other is 1) aryl, 2) heteroaryl,
  • Ci.ioalkyl wherein aryl and heteroaryl are each optionally substituted with one to four substituents selected from R"; and alkyl is optionally substituted with one to four substituents independently selected from R a ; or R3, R4 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 S; one of R6 and R ⁇ is hydrogen and the other is
  • Ci.ioalkyl wherein aryl is optionally substituted with one to four substituents independently selected from Ry, and alkyl is optionally substituted with one to four substituents selected from R x ;
  • R a , R D , R x and Ry are as defined above under Formula I.
  • Rb is selected from Ci-ioalkoxy, halogen, cyano, and trifluoromethyl;
  • R2 is H or methyl; one of R3 and R4 is hydrogen and the other is phenyl, Cy-C ⁇ _3alkyl (wherein Cy is thienyl, pyridyl or phenyl optionally substiuted with one or two groups selected from phenyl, hydroxy, halogen, cyano, and nitro); and Ci. alkyl optionally substituted with CO2H or CONH2; one of R6 and R? is hydrogen and the other is aryl-C ⁇ _
  • the present compounds are generally composed of three domains: 1) a sulfonyl moiety, 2) amino acid 1, and 3) amino acid 2, and are named in a manner similar to that used to name oligopeptides.
  • 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 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 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.
  • Optical Isomers Diastereomers - Geometric Isomers - Tautomers
  • 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.
  • 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: (a) other VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO9640781, W096/22966, WO96/20216,
  • 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.
  • Compounds of the present invention may be prepared by procedures illustrated in the accompanying schemes.
  • 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- diisopropylethylamine (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- diisopropylethylamine (DIEA) in DMF
  • the Fmoc group is removed with piperidine in DMF to yield the free amine F.
  • a sulfonyl chloride derivative is reacted with F in the presence of DIEA to yield G.
  • the final product is removed from the resin with strong
  • 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
  • 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 sulfonylation) of the terminal amino group.
  • the desired N-terminal capping reagent (sulfonylchloride or acylchloride) (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.
  • 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.
  • Jurkat cells obtained from the American Type Culture Collection (Rockville, MD; cat # ATCC TIB-152) were grown and maintained in RPMI-1640 culture medium containing 10% fetal calf serum (FCS), 50 units/ml penicillin, 50 ⁇ g/ml streptomycin and 2 mM 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.
  • FCS fetal calf serum
  • 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% C ⁇ 2/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.
  • VCAM-Ig The signal peptide as well as domains 1 and 2 of human
  • VCAM (GenBank Accession no. M30257) were amplified by PCR using the human VCAM cDNA (R & D Systems) as template and the following primer sequences: 3'-PCR primer:5'-AATTATAATTTGATCAACTTAC
  • 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 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).
  • 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 2 Preparation of 1 0 I-VCAM-Ig VCAM-Ig was labeled to a specific radioactivity greater that
  • the labeled protein was separated from unincorporated isotope by means of a calibrated HPLC gel filtration column (G2000SW; 7.5 x 600 mm; Tosoh, Japan) using uv and radiometric detection.
  • 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 M HEPES, 150 M NaCl, 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.
  • Step 1 ⁇ 4 ⁇ 7 Cell line.
  • RPMI-8866 cells (a human B cell line ⁇ ⁇ j / ⁇ /; 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 M Hepes, 150 mM NaCl , 0.1 % BSA, 3 mM KC1, 2 mM Glucose, pH 7.4).
  • binding buffer 25 M Hepes, 150 mM NaCl , 0.1 % BSA, 3 mM KC1, 2 mM Glucose, pH 7.4
  • 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

Les composés correspondant à la formule (I) sont des antagonistes de VLA-4 et/ou de α4β7 et sont, en tant que tels, utiles pour inhiber ou empêcher l'adhérence cellulaire et des pathologies induites par l'adhérence cellulaire. Ces composés peuvent être formulés sous forme de compositions pharmaceutiques et peuvent 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.
PCT/US1998/010952 1997-05-29 1998-05-29 Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire WO1998053818A1 (fr)

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CA002291708A CA2291708A1 (fr) 1997-05-29 1998-05-29 Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire
EP98924989A EP0998282A4 (fr) 1997-05-29 1998-05-29 Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire
AU77032/98A AU728435B2 (en) 1997-05-29 1998-05-29 Sulfonamides as cell adhesion inhibitors
JP50093999A JP2002501537A (ja) 1997-05-29 1998-05-29 細胞接着阻害薬としてのスルホンアミド類
US09/424,823 US6221888B1 (en) 1997-05-29 1998-05-29 Sulfonamides as cell adhesion inhibitors

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US4795497P 1997-05-29 1997-05-29
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GB9714335.8 1997-07-07
GBGB9714335.8A GB9714335D0 (en) 1997-07-07 1997-07-07 Sulfonamides as cell adhesion inhibitors
US6678797P 1997-11-25 1997-11-25
US60/066,787 1997-11-25
GB9800684.4 1998-01-14
GBGB9800684.4A GB9800684D0 (en) 1998-01-14 1998-01-14 Sulfonamides as cell adhesion inhibitors

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Publication number Publication date
CA2291708A1 (fr) 1998-12-03
AU728435B2 (en) 2001-01-11
EP0998282A4 (fr) 2000-08-30
AU7703298A (en) 1998-12-30
EP0998282A1 (fr) 2000-05-10
JP2002501537A (ja) 2002-01-15

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