WO2000005223A2 - Composes chimiques - Google Patents

Composes chimiques Download PDF

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Publication number
WO2000005223A2
WO2000005223A2 PCT/GB1999/002330 GB9902330W WO0005223A2 WO 2000005223 A2 WO2000005223 A2 WO 2000005223A2 GB 9902330 W GB9902330 W GB 9902330W WO 0005223 A2 WO0005223 A2 WO 0005223A2
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alkyl
hydrogen
group
formula
optionally substituted
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PCT/GB1999/002330
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WO2000005223A3 (fr
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David Robert Brittain
Craig Johnstone
Gareth Morse Davies
Michael Stewart Large
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Astrazeneca Ab
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Priority claimed from GBGB9815970.0A external-priority patent/GB9815970D0/en
Priority claimed from GBGB9815972.6A external-priority patent/GB9815972D0/en
Priority claimed from GBGB9914441.2A external-priority patent/GB9914441D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to JP2000561179A priority Critical patent/JP2002521375A/ja
Priority to AU50521/99A priority patent/AU5052199A/en
Priority to EP99934885A priority patent/EP1133484A2/fr
Publication of WO2000005223A2 publication Critical patent/WO2000005223A2/fr
Publication of WO2000005223A3 publication Critical patent/WO2000005223A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
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    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
    • C04B41/009—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone characterised by the material treated
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    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
    • C04B41/45—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements
    • C04B41/4572—Partial coating or impregnation of the surface of the substrate
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    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
    • C04B41/80—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone of only ceramics
    • C04B41/81—Coating or impregnation
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to compounds which are inhibitors of the interaction between the integrin ⁇ 4 ⁇ , also known as Very Late Antigen-4 (VLA-4) or CD49d/CD29, and its protein ligands, for example Vascular Cell Adhesion Molecule- 1 (VCAM-1) and fibronectin.
  • VLA-4 Very Late Antigen-4
  • VCAM-1 Vascular Cell Adhesion Molecule- 1
  • fibronectin fibronectin.
  • This invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic application.
  • ⁇ 4 ⁇ is a member of the integrin family of heterodimeric cell surface receptors that are composed of noncovalently associated glycoprotein subunits ( ⁇ and ⁇ ) and are involved in cell adhesion to other cells or to extracellular matrix.
  • Integrins can be subdivided based on their ⁇ subunit composition.
  • ⁇ 4 ⁇ is one of several ⁇ , integrins, also known as Very Late Antigens (VLA).
  • VLA Very Late Antigens
  • Ligands recognised by integrins include extracellular matrix proteins, such as collagen and fibronectin; plasma proteins, such as fibrinogen; and cell surface molecules, such as transmembrane proteins of the immunoglobulin superfamily and cell-bound complement.
  • the specificity of the interaction between integrin and ligand is governed by the ⁇ and ⁇ subunit composition. Integrin ⁇ 4 ⁇ , is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils [Hemler, M.E. et al (1987), J. Biol.
  • integrins that bind only to cell-extracellular matrix proteins ⁇ 4 ⁇ , binds to VCAM-1, an immunoglobulin superfamily member expressed on the cell surface, for example on vascular endothelial cells, and to fibronectin containing the alternatively spliced type III connecting segment (CS-1 fibronectin) [Elices, MJ. et al (1990), Cell, 60, 577-584; Wayner, E.A. et al (1989). J. Cell Biol., 109, 1321-1330].
  • ⁇ 4 ⁇ is believed to have an important role in the recruitment of lymphocytes, monocytes and eosinophils during inflammation.
  • ⁇ 4 ⁇ , /ligand binding has also been implicated in T-cell proliferation, B-cell localisation to germinal centres, haemopoeitic progenitor cell localisation in the bone marrow, placental development, muscle development and tumour cell metastasis.
  • ⁇ 4 ⁇ The affinity of ⁇ 4 ⁇ , for its ligands is normally low but chemokines expressed by inflamed vascular endothelium act via receptors on the leukocyte surface to upregulate ⁇ 4 ⁇ , function [Weber, C. et al (1996), J. Cell Biol., 134, 1063-1073].
  • VCAM-1 expression is upregulated on endothelial cells in vitro by inflammatory cytokines [Osborn, L. et al (1989) Cell, 59, 1203-1211] and in human inflammatory diseases such as rheumatoid arthritis
  • Monoclonal antibodies directed against the ⁇ 4 integrin subunit have been shown to be effective in a number of animal models of human inflammatory diseases including multiple sclerosis, rheumatoid arthritis, allergic asthma, contact dermatitis, transplant rejection, insulin- dependent diabetes, inflammatory bowel disease, and glomerulonephritis.
  • Integrins recognise short peptide motifs in their ligands
  • the minimal ⁇ 4 ⁇ , binding epitope in CS-1 is the tripeptide leucine-aspartic acid-valine (Leu-Asp- Val) [ Komoriya, A., et al (1991). J. Biol. Chem., 266, 15075-15079] while VCAM-1 contains the similar sequence isoleucine-aspartic acid-serine [Clements, J.M., et al (1994). J. Cell Sci., 107, 2127-2135].
  • the 25-amino acid fibronectin fragment, CS-1 peptide, which contains the Leu Asp-Val motif, is a competitive inhibitor of ⁇ 4 ⁇ , binding to VCAM-1 [Makarem, R., et al (1994). J. Biol. Chem., 269, 4005-4011].
  • Small molecule ⁇ 4 ⁇ , inhibitors based on the Leu- Asp-Val sequence in CS-1 have been described, for example the linear molecule phenylacetic acid-Leu-Asp-Phe-D-Pro-amide [Molossi, S. et al (1995). J. Clin.
  • non- and semi-peptidic compounds which inhibit ⁇ 4 ⁇ ,/VCAM binding and which can be orally administered have been reported in for example, WO96/22966 and WO98/04247.
  • A is a bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 6 alkanoyl, C 2 . 6 alkenyl, C 2 . 5 alkynyl, C, -6 alkoxy, C 1-6 alkylamino, C,_ 6 alkylthio, C alkylsulphonyl, C 1 . 4 alkoxylC 1 . 6 alkyl, C ⁇ alkylaminoC ⁇ alkyl, carboxy, carbamoyl, C 2 . 6 alkenyloxy, C 2-6 alkynyloxy, di-[(C 1 . 6 )alkyl]amino, C 2.
  • W is -NHCH(R w )CO- or OC(R w )CHNH where R w is -CH 2 CH(CH 3 ) 2 -CH 2 CH 2 S(CH 3 ) or CH 2 CH 2 S(O 2 )(CH 3 ); q is 0 or 1 and when q is 0 Z is linked to the group Y by the formation of an amide bond between Z and Y, and when q is 1 Z is linked to the group W by the formation of an amide bond between Z and W and W is linked to the group Y by the formation of an amide bond between W and Y;
  • Y is a fragment derived from the C-terminus of a compound which inhibits the interaction between the integrin ⁇ IIb ⁇ 3 and its ligand fibrinogen ;
  • R 1 is hydrogen, C ] . 5 alkyl, C,. 3 alkanoyl or C,. 3 alkoxycarbonyl; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
  • the compound has the formula (II)
  • A, B, R a , R b and 'a' are as hereinbefore defined;
  • X is a direct bond, oxygen, sulphur, amino or C 1 . 4 alkylamino
  • R 3 is hydrogen or C,_ 5 alkyl
  • R 2 is selected from a group of formul ⁇ i (III) or (IV), where
  • R 4 is selected from C 1-6 alkyl, C,. 6 alkoxy(C,. 6 )alkyl, C,. 6 alkylS(C 1 . 6 )alkyl and C,. 6 alkylS(O 2 )(C 1 . 6 )alkyl;
  • R 5 is hydrogen or C,_ 5 alkyl;
  • R 6 is selected from C,. 6 alkyl, C 2 . 6 alkenyl, l,3-benzodioxol-5-yl, an ester group, and aryl optionally substituted by at least one substituent selected from C M alkoxy, C,_ 6 alkyl, cyano, halogeno, and trifluoromethyl; and R 7 is an acidic functional group;
  • U is selected from oxygen, sulphur, a direct bond or -CH 2 O-
  • V is selected from nitrogen, oxygen, sulphur or a direct bond
  • d is zero or a number from 1 to 4
  • T is selected from R c or, when V is nitrogen, R c R d , where R c and R d are independently selected from hydrogen, C M alkyl, C M alkoxy, C M alkoxy(C,. 6 )alkyl or aryl; or a heterocycle containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, optionally substituted with one or more substituents selected from C ⁇ alkyl, C 2 .
  • Q is selected from a direct bond, methylene, oxygen, carbonyl, -C(OH)(H)- or Q together with the group (CH 2 ) S or CR 8 R 9 , when s is zero, form a C 2 alkenyl or C 2 alkynyl;
  • R 8 to R 10 are each independently selected from hydrogen, C,_ 6 alkyl, aryl and heterocycle, the aryl and heterocycle optionally substituted with one or more substituents independently selected from C,. 6 alkyl, C 2-6 alkenyl, C M alkanoyl, C 2 . 6 alkynyl, C,. 6 alkoxy, C,.
  • R u is selected from hydrogen, C ⁇ alkyl, C 2 . 6 alkenyl, l,3-benzodioxol-5-yl, an ester group, hydroxy, amido, heterocycle and aryl, the heterocycle, and aryl optionally substituted with one or more substituents independently selected from C 6 alkyl, C 2 . 6 alkenyl, C M alkanoyl, C 2 _ 6 alkynyl, C,. 6 alkoxy, C,. 6 alkylamino, C,.
  • - 'Bicyclic heteroaryl' means an aromatic 5,6- 6,5- or 6,6- fused ring system wherein one or both rings contain ring heteroatoms.
  • the ring system may contain up to three heteroatoms, independently selected from oxygen, nitrogen or sulphur and can be optionally substituted with one or more substituents selected from C,_ 6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C 1-6 alkoxy, C M alkanoyl, C,_ 6 alkylamino, C,. 4 alkoxylC,. 6 alkyl, C,.
  • bicyclic heteroaryl 's include quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, phthalazinyl and benzotriazolyl.
  • the term 'heterocycle' means an aromatic or non-aromatic saturated or partially saturated cyclic ring system containing up to five heteroatoms independently selected from nitrogen, oxygen and sulphur and which can be optionally substituted with one or more substituents selected from C, reconsider 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • Examples include 3 to 10 membered monocyclic or bicyclic rings with up to five heteroatoms selected from oxygen, nitrogen and sulphur, such as, for example, furanyl, pyrrolinyl, piperidinyl, piperazinyl, thienyl, pyridyl, imidazolyl, tetrazolyl, thiazolyl, pyrazolyl, pyrimidinyl, triazinyl, pyridazinyl, pyrazinyl, morpholinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl and tetrahydropyrimidiny
  • the 5 to 7 membered ring formed by substituents on ring B or substituents R 13 can be an, optionally substituted, saturated or unsaturated ring with up to three heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • 'acidic functional group' means a group which incorporates an acidic hydrogen and includes carboxylic acids, tetrazoles, acyl sulphonamides, sulphonic and sulphinic acids, and preferably is carboxy.
  • the term 'ester group' is an ester derived from a C 0 straight or branched alkyl, arylalkyl or C 5 . 7 cycloalkyl (optionally substituted with C M alkyl) alcohol.
  • Suitable ester groups are those of formula -COOR" where R" can be tert-butyl, 2,4-dimethyl-pent-3-yl, 4- methyl-tetrahydropyran-4-yl, 2,2-dimethyl aminoethyl or 2-methyl 3-phenyl prop-2-yl.
  • suitable specific groups for the substituents mentioned include :- for halogeno: fluoro, chloro, bro o and iodo for C ⁇ alkyl (this includes straight chained, branched structures and ring systems): methyl, ethyl, propyl, isopropyl, tert- butyl, cyclopropane and cyclohexane; for C 2.6 alkenyl: vinyl, allyl and but-2-enyl; for C,.
  • alkanoyl formyl, acetyl, propionyl or butyryl; for C 2 _ 6 alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for C ⁇ 6 alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for C 2.6 alkenyloxy: vinyloxy and allyloxy; for C 2 .
  • alkylcarbamoyl N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for C L galkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for C ⁇ alkoxyC ⁇ alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl, 2-methoxyethyl; for C,.
  • Y is derived from a compound which inhibits the interaction between the integrin ⁇ Ilb ⁇ 3 and its ligand fibrinogen.
  • Compounds which inhibit this interaction comprise a component containing an acid functional group that mimics the acidic amino acid-containing sequence in fibrinogen that is recognised by I]b ⁇ 3 .
  • ⁇ ⁇ b ⁇ 3 antagonists would be expected to inhibit fibrinogen binding to platelets and platelet aggregation in vitro.
  • Suitable compounds are described in the following patents/applications which are incorporated herein by reference: EP 608759 (Merck), WO95/18111 (Du Pont Merck), DE 4 241 632 (Thomae), EP 655 439 (Lilly), EP 540334 (Merck), US 5 334 596 (Merck), WO94/12181 (Merck), WO 94/18981 (Merck), DE 4405633 (Merck), EP 645376 (Merck), WO93/07867 (Monsanto), US 5 344 957 (Monsanto), US 5 314 902 (Monsanto), WO94/22820 (Searle), EP587134 (Thomae), EP503548 (Thomae), EP542363 (Glaxo), WO93/14077 (Glaxo), WO95/18619 (SmithKline Beecham), EP632020 (Zeneca),
  • EP727425 (Merck), WO94/08962(Merck), EP560730 (Sandoz), EP505868 (Hoffmann), EP381033 (Hoffman-La Roche), EP529858 (Takeda), WO94/12478 (Smith Kline Beecham), WO93/00095 (Smith Kline Beecham), WO94/29273 (Smith Kline Beecham), WO95/25091 (Ortho), EP632016 (Zeneca), WO96/22288 (Eli Lilly) and WO96/29309 (Fujisawa).
  • Other suitable compounds are disclosed in S A Mousa et al., (1997), Drug Discovery Today, 2 (5), 187-199.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention encompasses any such optically active or racemic form which can inhi bit the interaction between VCAM-1 and fibronectin with the integrin o ⁇ ,.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • R 1 , A, Z, W, q and Y are as hereinbefore defined;
  • B is a phenyl optionally substituted with up to five substituents independently selected from Cj. 6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C alkoxy, C M alkanoyl, C, .6 alkylamino, C, . 4 alkoxylC,. 6 alkyl, C,. 6 alkylaminoC t .
  • each R 13 is independently selected from C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C M alkoxy, C M alkanoyl, C,_ 6 alkylamino, C 1 _ 4 alkoxylC,.
  • D is a direct bond, oxygen, sulphur, amino or C M alkylamino; e is an integer from 1 to 4; f is zero or an integer from 1 to 5;
  • R 14 is selected from a group of formula (III), as hereinbefore defined where R 4 is C, .6 alkyl, C,. 6 alkoxy(C,. 6 )alkyl, and C 1 . 6 alkylS(C 1 . 6 )alkyl; or from a group of formula (VII) where
  • R 15 to R 18 are each independently hydrogen, C,. 6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C M alkoxy, C,. 4 alkanoyl, C,. 6 alkylamino, C,. 4 alkoxylC 1 . 6 alkyl, C,. 6 alkylaminoC ⁇ . 6 alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH 2 ) p OH where p is 1 or 2 - CO 2 R e , and - CONR e R f , where R e and R f are independently selected from hydrogen and C ⁇ alkyl;
  • R 19 to R 22 are each independently selected from hydrogen, C,. 6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with one or more substituents selected from nitro, C,. 6 alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C,_ 4 alkoxy, C ⁇ alkylamino, C 1 . 4 alkylC 1 . 6 alkyoxyl, C,.
  • alkylaminoC L galkyl cyano, halogeno, trifluoromethyl, hydroxy, (CH 2 ) p OH where p is 1 or 2, - CO 2 R e , and -CONR e R f , where R e and R f are independently selected from hydrogen and C ⁇ or two of R 19 to R 22 can be taken together to form phenyl or 3 to 7 membered heterocycle;
  • R is an acidic functional group; and g and h are each independently 0 or 1 ; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
  • the compound is of formula (VIII)
  • R 1 ,R 13 and f are as hereinbefore defined;
  • R 24 to R 26 are each independently selected from hydrogen, C M alkyl, C M alkanoyl or halogeno;
  • R 27 is -CH 2 CH(CH 3 )(CH 3 ) or -CH 2 CH 2 SCH 3 ;
  • R 28 is hydrogen or C 5 alkyl; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
  • the compound is of formula (IX)
  • each R 29 is independently selected from C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C,. 6 alkoxy, C, .4 alkanoyl, C 1-6 alkylamino, C 1 . 4 alkoxylC,. 6 alkyl, C ⁇ . 6 alkylaminoC ⁇ .
  • R 30 is hydrogen, C,- 5 alkyl, C r3 alkanoyl or C,- 3 alkoxycarbonyl; E is a bicyclic heteroaryl optionally substituted with one or more substituents selected from C M alkyl, C,. 4 alkanoyl, C 1-6 alkyl, C 2 . 6 alkenyl, C 2 .
  • R 31 is selected from a group of formula (X) or (XI) ,0 G)— (CH 2 ) n ⁇ ⁇ (CR 32 R 33 )— CR 34 R 35 — (CH 2 ) ⁇ COOH
  • R 41 is a group of formula U - (CH 2 ) d - V -T as hereinbefore defined:
  • G is aryl, a monocyclic heteroaryl linked through ring carbon atoms, a bicyclic heteroaryl linked to nitrogen by a ring carbon in one ring and to the group (CH 2 ) n or oxygen by a ring carbon in the second ring, the aryl and mono and bicyclic heteroaryl optionally substituted with one or more substituents independently selected from C,. 6 alkyl, C 3 . 6 cycloalkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C M alkoxy, C M alkanoyl, C 6 alkylamino, C M alkoxylC ] .
  • R 32 to R 34 are each independently selected from hydrogen, C, ⁇ alkyl, aryl and heterocycle, the aryl and heterocycle optionally substituted with one or more substituents independently selected from nitro, C 1-6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C,. 4 alkoxy, C ⁇ alkylamino, C M alkylC 1 . 6 alkyoxyl, C 1-6 alkylan ⁇ inoC,.
  • R 35 is selected from hydrogen, hydroxy, C j _ 6 alkyl, C 2 . 6 alkenyl, l,3-benzodioxol-5-yl, an ester group, amido, heterocycle and aryl, the heterocycle, and aryl optionally substituted with one or more substituents independently selected from nitro, C,_ 6 alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C,. 4 alkoxy, C,. 6 alkylamino, C,. 4 alkylC,_ 6 alkyoxyl, C,. 6 alkylaminoC,.
  • R 36 to R 38 are each independently hydrogen, C,_ 6 alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C M alkoxy, C M alkanoyl, C,_ 6 alkylamino, C,. 4 alkoxylC,. 6 alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH 2 ) p OH where p is 1 or 2 - CO 2 R e , and - CONR e R f , where R e and R f are independently selected from hydrogen and C,. 6 alkyl;
  • R 39 is an acidic functional group; h and n are zero or 1 ; m is zero, 1 or 2; k is zero or a number from 1 to 3; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
  • X is a direct bond or oxygen, preferably a direct bond
  • R 1 is hydrogen or C,_ 2 alkyl, preferably hydrogen and
  • R 3 is hydrogen
  • R 2 is a group of formula (III) where R 4 is C,. 6 alkyl, C,. 6 alkylS(C, alkyl or C,. 6 alkylS(O 2 )(C ⁇ .
  • R 5 is hydrogen, R 6 is l,3-benzodioxol-5-yl, R 7 is carboxy;
  • R 3 is methyl, and R 2 is a group of formula (III) where R 4 is C, .6 alkyl, R 5 is hydrogen, R 6 is l,3-benzodioxol-5-yl and R 7 is carboxy; or (iii) R 3 is hydrogen, and R 2 is a group of formula (III) where R 4 is C 1-6 alkyl, C, . 6 alkylS(C,. 6 )alkyl or C 1 . 6 alkylS(O 2 )(C 1 . 6 )alkyl, R 5 is hydrogen, R 6 is C, profession 6 alkyl and R 7 is carboxy;
  • R 3 is hydrogen, and R 2 is a group of formula (III) where R 4 is C, .6 alkyl, R 5 is hydrogen, R 6 is -COOR", where R" is 2,4-dimethyl-pent-3-yl or 2,2-dimethylaminoethyl, isopropoxyphenyl; -C 2 H 4 N(CH 3 ) 2 and R 7 is carboxy;
  • R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R ⁇ are as hereinbefore defined, and preferably R 8 to R 11 are all hydrogen or R 8 to R 10 are all hydrogen and R u is C alkyl, hydroxy or phenyl optionally substituted with C,. 4 alkyl ;
  • R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl substituted with one or more substituents selected from methoxy, cyano, halogeno, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R 11 are as hereinbefore defined and preferably R 8 to R 10 are all hydrogen and R u is C,. 4 alkyl;
  • R 3 is hydrogen and R 2 is a group of formula (IV), where C is phenyl, Q is oxygen, R 8 to R 10 are all hydrogen, R 11 is l,3-benzodioxol-5-yl or a C 2 . 3 alkenyl, preferably l,3-benzodioxol-5-yl, R 12 is carboxy, r and s are both zero and t is 1;
  • R 3 is hydrogen and R 2 is a group of formula (IV), where C is phenyl substituted with a C,. 4 alkoxy, C M alkyl, halogeno, or trifluoromethyl, preferably C,. 4 alkoxy, Q is oxygen, R 8 to R 10 are all hydrogen, R 11 is l,3-benzodioxol-5-yl or a C 2 alkenyl, preferably l,3-benzodioxol-5-yl, R 12 is carboxy, r and s are both zero and t is 1;
  • R 3 is hydrogen and R 2 is a group of formula (IV), where C is phenyl optionally substituted with C M alkoxyl, Q is oxygen, R 8 to R 10 are all hydrogen, R" is a nitrogen containing heterocycle, preferably piperidinyl or morpholinyl, R 12 is carboxy, r and s are both zero and t is 1 ;
  • R 3 is hydrogen and R 2 is a group of formula (IV), where C is phenyl, optionally substituted with C alkoxyl, Q is oxygen, R 8 to R 10 are all hydrogen, R 11 is phenyl substituted with a C 3 alkoxy, R 12 is carboxy, r and s are both zero and t is 1;
  • R 3 is methyl and R 2 is a group of formula (IV) where C is phenyl, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R 11 are as hereinbefore defined, and preferably R 8 to R 11 are all hydrogen or R 8 to R 10 are all hydrogen and R u is C M alkyl, hydroxy or phenyl optionally substituted with C, .4 alkyl; or
  • R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl, Q is oxygen, R 12 is carboxy, r is zero, s and t are both one and R 8 to R ⁇ are all hydrogen
  • X is a direct bond and R 1 is hydrogen or C,. 2 alkyl and
  • R 3 is hydrogen, and R 2 is a group of formula (III), where R 4 is C 1-6 alkyl, R 5 is hydrogen, R 6 is l,3-benzodioxol-5-yl and R 7 is carboxy; or
  • R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R" are as hereinbefore defined, preferably R 8 to R 11 are all hydrogen.
  • R 3 is hydrogen
  • R 2 is a group of formula (III), where R 4 is C,_ 6 alkyl, R 5 is hydrogen, R 6 is l,3-benzodioxol-5-yl and R 7 is carboxy or
  • R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R 11 are as hereinbefore defined, preferably R 8 to R u are all hydrogen.
  • R a and R b are both hydrogen, a is 1, A is benzoxazolyl, optionally substituted as hereinbefore defined especially where R is C 1-4 methoxy, B is phenyl, optionally substituted as hereinbefore defined, but preferably phenyl, A and B are linked together as shown in figure (1), R 1 is hydrogen or C,_ 2 alkyl, X is a direct bond or oxygen, preferably a direct bond, R 3 is hydrogen and R 2 is a group of formula (IV) where C is phenyl, r and s are both zero i) R 8 to R 10 are all hydrogen, R 11 is l,3-benzodioxol-5-yl, R 12 is carboxy, t is 1 and Q is -C(OH)(H)-, carbonyl, methylene; ii) R 11 is l,3-benzodioxol-5-yl, R 12 is carboxy, t is 1
  • CR 8 R 9 form a C 2 alkenyl or C 2 alkynyl; or iii) R 11 is hydrogen, R 12 is carboxy, t is 1 and Q together with the group CR 8 R 9 form a C 2 alkenyl or C 2 alkynyl.
  • R 3 is hydrogen
  • R 2 is a group of formula (IV) where C is phenyl, optionally substituted as hereinbefore defined, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R u are all hydrogen.
  • X is a direct bond or oxygen, preferably a direct bond
  • R 1 is hydrogen or C,. 2 alkyl
  • R 3 is hydrogen
  • R 2 is a group of formula (III), where R 4 is C,. 6 alkyl, R 5 is hydrogen, R 6 is l,3-benzodioxol-5-yl and R 7 is carboxy; or (ii) R 3 is hydrogen, and R 2 is a group of formula (IV) where C is phenyl, optionally substituted as hereinbefore defined, Q is oxygen, R 12 is carboxy, r and s are both zero, t is one and R 8 to R u are all hydrogen.
  • R 34 and R 35 are both hydrogen
  • R 41 is the group O-(CH 2 ) d -T where d is from 1 to 4, preferably 2 or 3 and T is a nitrogen containing heterocycle linked to oxygen through a ring nitrogen or ring carbon and preferably is selected from piperidinyl, morpholinyl, piperazinyl, methylpiperazinyl, pyrrolidinyl, imidazolyl and pyridyl; iii) h and k are both 1, R 34 and R 35 are both hydrogen and R 41 is the group
  • R c and R d are each independently (CH 2 ) 2 OCH 3 C l- 4 alkyl or hydrogen; iv) h and k are both 1 , R 34 is hydrogen, R 35 is a C,_ 4 alkyl, preferably methyl, or l,3-benzodioxol-5-yl, and R 41 is the group -O-(CH 2 ) d -T where d is from 1 to 4, preferably 2 or 3 and T is a nitrogen containing heterocycle linked to oxygen through a ring nitrogen and preferably is selected from piperidinyl, morpholinyl, imidazolyl, pyrrolidinyl and pyridyl; or v) h and k are both 1, R 34 and R 35 are both hydrogen and R 41 is the group -(CH 2 ) d -T where d is 1 and T is morpholiny
  • a particular advantage of compounds of formula (IX), where R 31 is a group of formula (XII), is that they show reduced non specific protein binding.
  • Pharmaceutically acceptable salts include acid addition salts such as salts formed with mineral acids, for example, hydrogen halides such as hydrogen chloride and hydrogen bromide, sulphonic and phosphonic acids; and salts formed with organic acids, especially citric, maleic, acetic, oxalic, tartaric, mandelic, p-toluenesulphonic, methanesulphonic acids and the like.
  • suitable salts are base salts such as alkali metals salts, for example, sodium and potassium; alkaline earth metal salts such as magnesium and calcium; aluminium and ammonium salts; and salts with organic bases such as ethanolamine, methylamine, diethylamine, isopropylamine, trimethylamine and the like.
  • base salts such as alkali metals salts, for example, sodium and potassium; alkaline earth metal salts such as magnesium and calcium; aluminium and ammonium salts; and salts with organic bases such as ethanolamine, methylamine, diethylamine, isopropylamine, trimethylamine and the like.
  • Such salts may be prepared by any suitable method known in the art.
  • In vivo hydrolysable derivatives include, in particular, pharmaceutically acceptable derivatives that may be oxidised or reduced in the human body to produce the parent compound or esters that hydrolyse in hte human body to produce the parent compound.
  • esters can be identified by administering, for example, intravenously to the test animal, the compound under test and subsequently examining the test animal's body fluids.
  • Suitable in vivo hydrolysable esters for hydroxy include acetyl and for carboxyl include, for example, alkyl esters, dialkylaminoalkoxy esters, esters of formula -C(O)-O-CH 2 C(O)NR a R b where R a and R b are, for example, selected from hydrogen and C 4 alkyl, and C ⁇ alkoxy methyl esters for example methoxymethyl, C,. 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 .
  • _ 6 alkyl esters for example 1-cyclohexylcarbonyloxy ethyl
  • l,3-dioxolan-2-ylmethyl esters for example 5-methyl-l,3- dioxolan-2-ylmethyl
  • C,_ 6 alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyloxyethyl.
  • the activities of the compounds of this invention to inhibit the interaction between VCAM-1 and fibronectin with integrin ⁇ 4 ⁇ may be determined using a number of in vitro and in vivo screens.
  • compounds of formulae (I), (II), (VI), (VIII) and (IX) preferably have an IC 50 of ⁇ 10 ⁇ M, more preferably ⁇ l ⁇ M in the MOLT-4 cell/Fibronectin assay hereinafter described.
  • a compound of formulae (I), (II), (VI), (VIII) and (IX) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof is typically formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • a pharmaceutical composition which comprises a compound of formulae (I), (II), (VI), (VIII) and (IX)or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof and a pharmaceutically acceptable carrier.
  • compositions of this invention may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension, or a depot formulation with drug incorporated in a biodegradable polymer.
  • parenteral use including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • parenteral use including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile aqueous or oily solution or suspension for example a depot formulation with drug incorporated in
  • compositions of this invention may be in a form suitable for topical administration such as for example creams, ointments and gels. Skin patches are also contemplated.
  • compositions of this invention may be formulated by means known in the art, such as for example, as described in general terms, in Chapter 25.2 of Comprehensive Medicinal Chemistry, Volume 5, Editor Hansch et al, Pergamon Press 1990.
  • the pharmaceutical composition of the present invention may contain one or more additional pharmacological agents suitable for treating one or more disease conditions referred to hereinabove, in addition to the compounds of the present invention.
  • the additional pharmacological agent or agents may be co-administered, either simultaneously or sequentially, with the pharmaceutical compositions of the invention.
  • composition of the invention will normally be administered to humans such that the daily dose will be 0.01 to 75mg/kg body weight and preferably 0.1 to 15mg/kg body weight.
  • a preferred composition of the invention is one suitable for oral administration in unit dosage form for example a tablet or capsule which contains from 1 to lOOOmg and preferably 10 to 500mg of a compound according to the present invention in each unit dose.
  • the present invention provides a method of treating a disease mediated by the interaction between VCAM-1 and/or fibronectin and the integrin receptor ⁇ 4 ⁇ , in need of such treatment which comprises administering to said warm-blooded mammals an effective amount of a compound of formulae (I), (II), (VI), (VIII) and (IX) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof.
  • the present invention also provides the use of a compound of formulae (I), (II), (VI), (VIII) and (IX) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof in the production of a medicament for use in the treatment of a disease or medical condition mediated by the interaction between fibronectin and/or VCAM-1 (especially VCAM-1) and the integrin receptor ⁇ 4 ⁇ j
  • the mammal in need of treatment is suffering from multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease, psoriasis, atherosclerosis, transplant rejection, inflammatory bowel disease, insulin-dependent diabetes and glomerulonephritis.
  • An alternative route for the preparation of anilinobenzoxazoles and which avoids the need to use toxic mercuric oxide involves reacting o-hydroxyureas using Mitsunobu reaction conditions, i.e a trisubstituted triphosphine, for example tributylphosphine or triphenylphosphine and an azodicarbonyl compound, for example 1,1'-
  • T, NH 2 by known methods e.g. the Curtius Reaction.
  • the anilinobenzoxazoles acids prepared as above may be coupled with amines to form compounds of formula (I) according to the invention.
  • Suitable amines are those based on ⁇ ⁇ b ⁇ 3 antagonists such as those described in S A Mousa et al., (1997), Drug Discovery Today, 2 (5), 187-199, US 5256812 and EP 560730 and include:
  • anilinobenzoxazoles amines prepared as above may be coupled with carboxylic acids to prepare compounds of formula (I) according to the invention.
  • a suitable acid based on m, ⁇ 3 antagonists such as those described in S A Mousa et al., (1997), Drug Discovery Today, 2 (5), 187-199 includes:
  • Suitable amines and acids can be derived from compounds which inhibit the interaction between the integrin ⁇ IIb ⁇ 3 and its ligand fibrinogen as hereinbefore defined.
  • the reactions to couple the above acids to the above amines are to couple a compound of formula (XII) to an appropriate amine are performed under standard coupling conditions for forming peptide bonds. They can be performed either on a solid support (Solid Phase Peptide Synthesis) or in solution using normal techniques used in the synthesis of organic compounds. With the exception of the solid support, all the other protecting groups, coupling agents, deblocking reagents and purification techniques are similar in both the solid phase and solution phase peptide synthesis techniques. During the reaction, amino acid functional groups may, if necessary, be protected by protecting groups, for example BOC (tert-butoxycarbonyl). Such groups can be cleaved when necessary using standard techniques such as acid or base treatment.
  • protecting groups for example BOC (tert-butoxycarbonyl).
  • Suitable protecting groups for the protection of the carboxyl groups include esters.
  • Coupling reagents for forming peptide bonds include the commonly used azide, symmetrical anhydride, mixed anhydride and various active esters and carbodiimides.
  • additives such as 1 -hydroxybenzotriazole and N-hydroxysuccinimide may also be added.
  • Coupled reagents include lH-benzotriazole-1-yl-oxy-tris- pyrrolidinophosphonium hexafluorophosphate (PyBOP), (2-(lH-benzotriazole-l-yl)-l,l,3,3- tetramethyluronium tetrafluoroborate (TBTU), (2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU)] and O-(7-azabenzotriazol- 1 -yl)- 1,1,3,3- tetramethyluronium hexafluorophosphate (HATU).
  • PyBOP lH-benzotriazole-1-yl-oxy-tris- pyrrolidinophosphonium hexafluorophosphate
  • TBTU 2,3,3- tetramethyluronium tetrafluorobo
  • the coupling reactions can be performed at temperatures between -20°C to 40°C.
  • the time of the reaction can vary such as between 10 minutes and 24 hours.
  • Suitable purification methods for the intermediates and final products include chromatographic techniques such as high pressure liquid chromatography (HPLC) along with many other standard techniques used in organic chemistry (e.g. solvent extraction and crystallisation).
  • HPLC high pressure liquid chromatography
  • step b) The malonic ester from step b) (3g) was heated at 100°C in a mixture of acetic acid (20ml) and cone, hydrochloric acid (10ml) for 2 hrs. and then evaporated to dryness. The residue was triturated with a mixture of diethyl ether and hexane to give 3-hydroxy-4-nitrophenylacetic acid as a yellow solid (1.4g) isolated by filtration.
  • the organic layer was separated, washed with aqueous acetic acid, brine, aqueous sodium bicarbonate (2 times), dried and evaporated to dryness.
  • the residue was purified by purified by chromatography on silica using an increasingly polar mixture of ethyl acetate/dichloromethane and the appropriate fraction yielded, after evaporation to dryness, a solid which was triturated with a mixture of diethylether/hexane to give the product (0.08g) as a purple-pink solid.
  • ⁇ nmr (DMSOd ⁇ /Acetic d4): l.Od, (d), 3H; 2.1-2.5d, (m), 3H; 3.5d (s), 3H; 3.65d, (s), 2H; 3.7d, (s), 3H; 3.75d, (m), 2H; 6.85d, (d), IH; 7.0d, (t), IH; 7.1d, (d), IH; 7.15d (d), IH; 7.35d, (m), 4H; 7.4d, (s), IH; 7.7d, (d), 2H.
  • Methyl 3-amino-3-(3,4-methylenedioxyphenyl) propionate(185mg) was dissolved in DMF (5ml) and triethylamine (140 ⁇ l) and the resultant solution added to the solution of the N-(t- butoxycarbonyl)leucine activated ester followed by diisopropylethylamine (lOO ⁇ l). The mixture was sti ⁇ ed overnight at ambient temperature.
  • Methyl 3-(l ,3-benzodioxol-5-yl)-3-( ⁇ 2-[tert-butoxycarbonyl)amino]4- methylpentanoyl ⁇ amino)propanoate (lOg) was treated with 90% TFA in water(l ⁇ ml). The mixture was sti ⁇ ed for 30 min and the TFA and water were then removed by evaporation. The residue was purified by preparative HPLC on a C18 silica column eluting with acetonitrile/water/0.1% TFA to give a gummy solid on evaporation of appropriate fractions.
  • Example 6 Preparation of 3-(l,3-benzodioxoI-5-yI)-3- ⁇ [4-methyl-2-( ⁇ 2-[2-toluidino)-l,3- benzoxazol-6-yl]acetyl ⁇ amino)pentanoyl]amino ⁇ propanoic acid This was prepared by hydrolysis of the methyl ester using the process described in Example 2.
  • IH nmr (DMSO do): 1.9d, (m), 2H; 2.3d, (t), 2H; 3.7d, (s), 2H; 3.9d, (m), 2H; 6.8d, (d), IH; 7.0d, (t), IH; 7.1d, (m), 3H; 7.3d (m), 4H; 7.45d, (s) IH; 7.75d, (d), 2H; lO.ld, (bs) ,1H; and 10.55d, (bs), IH.
  • IH nmr (DMSO d6): 1.9d, (m), 2H; 2.4d, (t), 2H; 3.6d, (s), 3H ; 3.7d, (s), 2H; 3.95d, (t), 2H;
  • Example 8 Preparation of 3-[(2- ⁇ [2-(2-anilino-l,3-benzoxazol-6-yl)acetyl]amino ⁇ -4- methylpentanoyl)amino]-4-(l-isopropyl-2-methylpropoxy)-4-oxobutanoic acid.
  • 1H nmr (DMSO d6): 0.85-0.95d, (m), 18H; 1.45d, (m), 2H; 1.55d, (m),lH; 1.8d, (m), 2H; 2.5- 2.75d, (m), 2H; 3.5d, (q), 2H; 4.35d, (m), IH; 4.45d, (m), IH; 4.65d,(m), IH; 7.0d, (t), IH; 7.1d, (d), IH; 7.3-7.4d (m), 4H;7.75d, (d) 2H; 8.2d, (d), IH; 8.45d, (d), IH; 10.7d, (bs) ,1H.
  • IH nmr (DMSO d6): 0.85-0.95d, (m), 18H; 1.45d, (m), 2H; 1.55d, (m),lH; 1.8d, (m), 2H; 2.7d, (dd), IH; 2.9d, (dd), IH; 3.5d, (q), 2H; 4.35d, (m), IH; 4.45d, (m), IH; 4.7d,(m), IH; 5.05d, (s), 2H; 7.0d, (t), IH; 7.1d, (d), IH; 7.2-7.4d (m), 9H;7.75d, (d) 2H; 8.2d, (d), IH; 8.5d, (d), IH; 10.53d, (bs) ,1H. [m/e685 (MH) + ]
  • Fluorophenylisothiocyanate(46mg) was added and the mixture kept at room temperature for 2 hours .
  • the mixture was treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(l 15mg) and the mixture was sti ⁇ ed at room temperature for 48 hours and evaporated to dryness.
  • the residue was partitioned between ethyl acetate and water and the organic phase was dried and evaporated to dryness.
  • the residue was purified by flash chromatography on silica using an increasingly polar mixture of dichloromethane and ethyl acetate and the appropriate fractions combined and evaporated to dryness to give product (53 mg) as an off white solid.
  • IH nmr (DMSO d6): 1.9d, (m), 2H; 2.45d, (t), 2H; 3.6d, (s), 3H ; 3.7d, (s), 2H; 3.95d, (t), 2H; 6.6d, (d), IH; 6.9-7.2d, (m), 4H; 7.25-7,45d, (m), 5H; 7.75d, (d), 2H; lO.ld, (s) ,1H; and
  • Example 11 Preparation of 3-[(2- ⁇ [2-(2-anilino-l,3-benzoxazol-5-yl)acetyl]amino ⁇ -4- methylpentanoyl)amino]-3-(l,3-benzodioxol-5-yl) propanoic acid This was prepared by hydrolysis of the methyl ester using the process described in Example 2.
  • Examples 12 to 128 are described by reference to Table 1.
  • This table describes the route for making the examples by reference to methods for i) the final stage, i.e. removal of the acid protecting group ii) the penultimate stage i.e. forming final product but with acid protecting group; iii) preparing the benzoheterocyclic acid or the precursor to the benzoheterocycle; and iv) preparing the appropriate amine for coupling to the benzoheterocyclic acid or preparing an o-hydroxyurea with the amide bonds intact for processes in which the benzoheterocycle, typically a benzoxazole, is formed in the penultimate stage, i.e. formation of the benzoheterocycle mediated by mercuric oxide or the Mitsunobu reaction conditions, all of which are described below.
  • Trimethylsilyltriflate(299ul) was added to a solution of 2-anilino-6-(3-[2-(s)-allyl-3- ⁇ carboxy-t-butoxy ⁇ propoxy]anilinocarbonylmethyl)benzoxazole(170mg) in dry dioxan containing triethylamine(236ul). The solution was warmed to 60°C for 30 min and the solvents were removed by evaporation under reduced pressure. The residue was then triturated with water to give product as an off white solid which was recovered by filtration.
  • ⁇ MNR (DMSO, 300MHz): ⁇ 0.74 (3H,d); 0.80 (3H,d); 1.29 (2H,m); 1.40 (lH,m); 2.69 (2H,m); 3.28 (2H,m); 3.49 (3H,s); 4.24 (lH,q); 5.07 (lH,q); 5.95 (2H,s); 6.41 (lH,d); 6.47 (lH,d); 6.55 (lH,s); 6.68 (lH,d); 6.79 (lH,d); 6.84 (lH,s); 7.82 (lH,d); 8.23 (lH,d).
  • Phenylacetic acid (6.81g) was added to a stirred suspension of sodium hydride (2.20g) in THF(200mL) and diisopropylamine (7.0mL) under argon. The mixture was heated briefly to reflux, stirred for 30min at ambient temperature then cooled to 0°C. A solution of n- butyl lithium (1.6m in hexane) (32. OmL) was added slowly while maintaining the temperature of the mixture below 5°C. The mixture was warmed to 30°C till a solution was formed, then cooled to 10°C and t-butyl bromoacetate (8.1 OmL) was added and the resultant solution stirred overnight at ambient temperature.
  • Diethylazodicarboxylate(0.66mL) was added to a solution of 3-(phenyl)-4- hydroxybutyric acid t-butyl ester(l .00g), 3-nitrophenol(0.58g) and triphenylphosphine(l . lOg) in THF (lOmL) at 0°C under argon over a period of 30 min.
  • the resultant solution was allowed to warm to ambient temperature, stirred overnight and then evaporated under reduced pressure.
  • the residual oil was taken up in toluene, filtered and purified using a Biotage system, eluting with toluene to give the product (1.14g).
  • the oil was purified by chromatography (Varian Megabondelut silica column) using a gradient of 100% dichloromethane to 20% ethyl acetate/ dichloromethane to give the product as an oil (0. lg. 29%) ms 265(M+)
  • Tin (II) chloride dihydrate(1.5g) was added to a solution of t-butyl (3S)-3-allyl,4-(3- nitro ⁇ henoxy)butyrate (425mg) in ethanol (4mL) and heated to 60°C for 40 min. After cooling to ambient temperature, water (20mL) was added, the mixture was basifed with 2N sodium hydroxide and then extracted with ethyl acetate (3x30mL). The combined ethyl acetate extracts were washed with brine(2xl0mL), dried (MgSO 4 ) and evaporated under reduced pressure to give the product (380mg) as a brown oil which was used without further purification in the next step.
  • the silver salt of the methyl 3- methylglutarate (49g; 184mmol) was suspended in carbon tetrachloride (245mL) and bromine (9.5mL) slowly added. The reaction mixture warmed to «30°C during this process and effervescence was seen. The reaction mixture was maintained at this temperature by the rate of addition of bromine. After the final addition of bromine the viscous mixture was sti ⁇ ed for 0.5h before being heated at reflux for lh. After cooling, the pale yellow precipitate was removed by filtration and the filtrate washed with IM aqueous sodium thiosulphate , brine, dried (phase separation paper) and concentrated under reduced pressure.
  • Methyl 2-methoxycarbonyl-3-(benzo[l,3]dioxyol-5-yl)-2-propenoate was prepared using the procedure described by Lehnert in Tetrahedron Letters 54 pp 4723-4724 1970, starting from piperonal and dimethyl malonate.
  • Di-t-butyl malonate(18g) was added dropwise to a stirred suspension of sodium hydride[60% dispersion in mineral oil](3.3g) in N-methyl py ⁇ olidinone(lOOmL) under an atmosphere of argon and the mixture was sti ⁇ ed until effervescence ceased.
  • 3,5 Difluoro-2- nitro-anisole(6.4g) was added and the mixture was sti ⁇ ed at 80°C for 2h. The mixture was cooled to room temperature then partitioned between water and ether and then the ether extract was dried and evaporated to dryness.
  • step 3 is step c) of example 1.
  • Di-t-butyl malonate(1.72g) was added dropwise to a stirred suspension of sodium hydride[60% dispersion in mineral oil](0.3g) in N-methyl pyrrolidinone(lOmL) under an atmosphere of argon and the mixture was sti ⁇ ed until effervescence ceased.
  • 2-benzyloxy-4,6- difluoronitrobenzene(0.85g) was added and the mixture was sti ⁇ ed at 80°C for 2h.
  • the mixture was cooled to room temperature then partitioned between water and ether.
  • the ether extract was dried and evaporated to dryness.
  • the residue was subjected to flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(0.4g) [m/e460,MH-].
  • Method 12c Preparation of methyl-2-(3-benzyloxy-4-nitrophenyl)propionate and dimethyl-2-(3-benzyloxy-4-nitrophenyl)-2-methylmalonate a) Preparation of dimethyI-2-(3-benzyloxy-4-nitrophenyI)-2-methylmalonate A mixture of dimethyl-(3-benzyloxy-4-nitrophenyl)malonate(2.3g), N- methylpyrrolidinone( 15mL) and a 60%> dispersion of sodium hydride in mineral oil(0.31 g) was sti ⁇ ed under an argon atmosphere at 0°C for 0.5h.
  • 2-Anilino-5-methoxycarbonylmethylbenzimidazole was hydrolysed by the process described in Method la to give 2-Anilino-5-carboxymethylbenzimidazole[m/e266,MH-] which was then used in the process described in method A(i) to give coupled products.
  • Dimethyl malonate(45.7g) was added dropwise to a stirred mixture of sodium hydride [60%dispersion in oil], (13.8g) and dimethylsulphoxide(300mL) and then the mixture was treated with 2,4-difluoronitrobenzene(25g).
  • the mixture was sti ⁇ ed at 100°C for lh, then poured onto saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate.
  • the extract was washed with water, dried and evaporated to dryness and the residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(5g).
  • 2-anilino-6-methoxycarbonylmethyl benzothiazole was hydrolysed by the process described in Method la to give 2-anilino-6-carboxymethylbenzothiazole [m/e283,MH-] which was used in the process described in example A(i) to give, after hydrolysis in each case, 2- anilino-6- ⁇ 3-[3-carboxypropoxy]anilinocarbonylmethyl ⁇ benzothiazole and 2-anilino-6-[2- carboxy-l-(benzo[l,3]dioxoly-5-yl)ethylaminocarbonyl(S)-(2-methylpropyl) methylaminocarbonylmethyljbenzofhiazole (example 33).
  • nitrobenzene derivative (8.39mmol), iron powder (2.8g; 50.3mmol) and ammonium chloride (0.3g; 5.87mmol) were heated at reflux in ethanol (56mL) and water (18mL) for lh. The iron was filtered off and the filtrate concentrated under reduced pressure. The residue was taken up in dichloromethane (DCM) washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure to give the aniline as a brown oil.
  • DCM dichloromethane
  • the propoxychloride ester (0.22mmol) and nitrogenous nucleophile (selected from piperidine; bis(2methoxyefhyl)amine; piperazine; N-methylpiperazine; morpholine;
  • Phenol (16.7mmol), appropriate electrophile (selected from methyl 4-bromobutyrate; methyl 3-methyl-4-bromobutyrate; ethyl S-3-methyl-4-bromobutyrate; 18.4mmol) and potassium carbonate (6.9g; 50. lmmol) were heated together in DMF (25 mL) at 80°C over night. A small amount of water was added to dissolve the solid and the DMF removed under reduced pressure. The residue was taken-up in ethyl acetate and washed with brine (3 times), dried (MgSO 4 ) and concentrated under reduced pressure to give desired ester.
  • the above phenol can also be alkylated according to Method 4a (Mitsunobu Reaction). iii) De-benzylation/hydrogenation and Boc protection
  • N-Boc-anilino phenol (0.62mmol) and appropriate electrophile (selected from 2-chloroethyl methyl ether; N-(2-chloro ethyl) piperidine hydrochloride; N-(2-chloroethyl) mo holine hydrochloride; 2-chloromethylpyridine hydrochloride; 3-chloromethylpyridine hydrochloride; 4-chloro methyl pyridine hydrochloride; N-(2-chloroethyl)py ⁇ olidine hydrochloride; 2- dimethylamino ethyl hydrochloride; and l-(2-chloroethyl)-imidazole hydrochloride (0.74mmol)) were dissolved in DMF (2mL) and potassium carbonate (254mg; 1.84mmol) was added.
  • the reaction mixture was heated at 80°C for 4h. After cooling, the reaction mixture was diluted with ethyl acetate and washed with brine (x3), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was chromatographed (DCM - l%>MeOH/DCM - 2%MeOH/DCM) to give the desired N-Boc-anilino phenol ether.
  • the N-Boc-anilino phenol ether (0.34mmol) was dissolved in 4M hydrogen chloride in dioxane (5mL) and the mixture stirred at room temperature for 0.5h. The reaction mixture was concentrated under reduced pressure and the residue dissolved in DCM, washed with saturated, aqueous sodium hydrogen carbonate, dried (MgSO 4 ) and concentrated under reduced pressure to give aniline.
  • Nitro phenol (0.62mmol) and electrophile selected from l-(2-chloroethyl)-imidazole hydrochloride, N-(2-chloroethyl) piperidine hydrochloride, N-(2-chloroethyl)py ⁇ olidine hydrochloride, 4-chloromethylpyridine hydrochloride and 2-chloroethyl-bis-(2-methoxy- ethyl)-amine (0.74mmol)
  • DMF dimethylpyridine
  • potassium carbonate 254mg; 1.84mmol
  • HOBT 255mg was added to a solution of N-(t-butoxycarbonyl)leucine (297mg) in DMF (5mL), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (273mg) and the solution sti ⁇ ed for 15 min.
  • Methyl 3-amino-3-(3,4-methylenedioxyphenyl) propionate (prepared according to the method described in WO96/22966 (Biogen) at pages 52 to 55 and incorporated herein by reference) was dissolved in DMF (5mL) and triethylamine (140 ⁇ l).
  • the compounds of the invention or pharmaceutically acceptable salts thereof may be formulated into tablets together with, for example, lactose Ph.Eur, Croscarmellose sodium, maize starch paste (5% w/v paste) and magnesium stearate for therapeutic or prophylactic use in humans.
  • the tablets may be prepared by conventional procedures well known in the pharmaceutical art and may be film coated with typical coating materials such as 0 hydroxypropylmefhylcellulose.
  • MOLT-4 cells human T-lymphoblastic leukaemia cells (European Collection of Animal Cell 5 Cultures, Porton Down)
  • Fibronectin - purified from human plasma by gelatin-sepharose affinity chromatography according to the methods described in E.Nengvall, E.Ruoslahti, Int. J. Cancer, 1977, 20, pages
  • RPMI 1640 - cell culture medium (Life technologies, Paisley UK). 0 PBS - Dulbecco's phosphate buffered saline (Life Technologies).
  • BSA - Bovine serum albumin, fraction V (ICN, Thame, UK).
  • the MOLT-4 cell /fibronectin adhesion assay was used to investigate the interaction of the integrin ⁇ 4 - ⁇ , expressed on the MOLT-4 cell membrane with fibronectin.
  • Polystyrene 30 96 well plates were coated overnight at 4°C with fibronectin, 100 ⁇ l of 10 ⁇ g/ml in PBS.
  • Non-specific adhesion sites were blocked by adding 100 ⁇ l BSA, 20 mg/ml. After incubating for 1 h at room temperature, the solutions were aspirated. MOLT-4 cells suspended in serum- free RPMI-1640 medium 2E6 cells/ml (50 ⁇ l) and solutions of compound diluted in the same medium (50 ⁇ l) were added to each well. After incubation for 2 h at 37°C in a humidified atmosphere of 5%> (v/v) CO 2 , non-adherent cells were removed by gentle shaking followed by vacuum aspiration. Adherent cells were quantified by a colorimetric acid phosphatase assay.
  • mice (20-25g) are immunised on the flank with an 1 : 1 (v/v) emulsion of ovalbumin (2 mg/ml) with CFA. Seven days later the mice are challenged by subplantar injection of 1% heat aggregated ovalbumin in saline (30 ⁇ l) into the right hind foot pad. Swelling of the foot develops over a 24 hour period following which foot pad thickness is measured and compared with the thickness of the contralateral uninjected foot. The percentage increase in foot pad thickness is calculated. Compounds are dosed orally by gavage to groups of 5 mice at doses ranging from 0.001 mg/kg to 100 mg/kg. Inhibition of the inflammatory response is calculated comparing vehicle treated animals and compound treated groups.
  • mice are immunised with 0.1ml of an emulsion prepared from equal volumes of bovine collagen type II in 0.05M acetic acid (2 mg/ml) and CFA. This mixture is injected at the base of the tail. Twenty days later compounds are dosed orally by gavage at doses ranging from 0.001 mg/kg/day to 100 mg/kg/day. On the day following the first dose, each animal receives an intra-peritoneal booster injection of 0.1ml of collagen type II in acetic acid. The mice are assessed for the incidence and severity of arthritis in all four limbs for up to 28 days. Inhibition of arthritis is calculated by comparing vehicle treated and compound treated mice.

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Abstract

L'invention concerne un composé de la formule (I) dans laquelle: A représente un hétéroaryle bicyclique éventuellement substitué par un ou plusieurs substituants; B représente un aryle ou un hétéroaryle mono ou bicyclique, chacun pouvant être éventuellement substitué par un ou plusieurs substituants; Z représente -(CRaRb)aCO, -NH, -CO ou le groupe -X-(CH2)bCONH(CH2)cNH dans lequel X désigne de l'oxygène, du soufre, un amino, un alkylamino ou une liaison directe, Ra et Rb représentent indépendamment un hydrogène ou un alkyle en C¿1-6?, a désigne un entier de 1 à 4, b désigne 1 ou 2 et c est compris entre 2 et 5 et; W représente -HCH(R?w¿)CO- ou OC(Rw)CHNH, Rw représentant -H¿2?CH(CH3)2 -CH2CH2S(CH3) ou CH2CH2S(O2)(CH3); q désigne 0 ou 1 et lorsque q désigne 0, Z est lié au groupe Y par formation d'une liaison amide entre Z et Y, et lorsque q désigne 1, Z est lié au groupe W par formation d'une liaison amide entre Z et W et W est lié au groupe Y par formation d'une liaison amide entre W et Y; Y représente un fragment dérivé de l'extrémité C-terminale d'un composé qui inhibe l'interaction entre l'intégrine αIIbβ3 et son ligand fibrinogène; R?1¿ représente un hydrogène, un alkyle en C¿1-3?, un alcanoyle en C1-3 ou un alcoxycarbonyle en C1-3; ou alors, l'invention concerne un sel de ce composé acceptable du point de vue pharmaceutique ou un dérivé de ce composé pouvant être hydrolysé in vivo.
PCT/GB1999/002330 1998-07-23 1999-07-20 Composes chimiques WO2000005223A2 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000049005A1 (fr) * 1999-02-16 2000-08-24 Aventis Pharma Limited Composes bicycliques et leur utilisation comme ligands du recepteur de l'integrine
WO2001053295A1 (fr) * 2000-01-21 2001-07-26 Astrazeneca Ab Composes heteroaryles bicycliques utilises comme inhibiteurs de l'interaction entre le recepteur alpha4beta1 de l'integrine et vcam-1 et/ou la fibronectine
WO2001064659A2 (fr) * 2000-02-28 2001-09-07 Aventis Pharma Limited Derives d'indane
WO2002053534A1 (fr) * 2000-12-28 2002-07-11 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs de vla-4
WO2003010135A1 (fr) * 2001-07-26 2003-02-06 Ajinomoto Co., Inc. Nouveaux derives de l'acide phenylpropionique
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
WO2005070920A1 (fr) 2004-01-21 2005-08-04 Bristol-Myers Squibb Company Amino-benzazoles utilises comme inhibiteurs du recepteur p2y1
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
CN100396680C (zh) * 2000-12-28 2008-06-25 第一制药株式会社 极迟抗原-4抑制剂
US7524862B2 (en) 2004-04-14 2009-04-28 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US7592358B2 (en) 2004-04-14 2009-09-22 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US7691894B2 (en) 2003-07-24 2010-04-06 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0001348D0 (en) * 2000-01-21 2000-03-08 Astrazeneca Uk Ltd Chemical compounds
DE10360745A1 (de) * 2003-12-23 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Amid-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
DE102006021878A1 (de) * 2006-05-11 2007-11-15 Sanofi-Aventis Phenylamino-benzoxazol substituierte Carbonsäuren, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
WO1997036862A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. DERIVES DE PHENYLENE META-SUBSTITUES, UTILISES COMME ANTAGONISTES OU INHIBITEURS DE L'INTEGRINE ALPHAvBETA¿3?
WO1999024398A2 (fr) * 1997-11-12 1999-05-20 Astrazeneca Uk Limited Composes chimiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
WO1997036862A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. DERIVES DE PHENYLENE META-SUBSTITUES, UTILISES COMME ANTAGONISTES OU INHIBITEURS DE L'INTEGRINE ALPHAvBETA¿3?
WO1999024398A2 (fr) * 1997-11-12 1999-05-20 Astrazeneca Uk Limited Composes chimiques

Cited By (39)

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Publication number Priority date Publication date Assignee Title
WO2000049005A1 (fr) * 1999-02-16 2000-08-24 Aventis Pharma Limited Composes bicycliques et leur utilisation comme ligands du recepteur de l'integrine
US6593354B2 (en) 1999-02-16 2003-07-15 Aventis Pharma Limited Substituted benzoxazole compounds
US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
WO2001053295A1 (fr) * 2000-01-21 2001-07-26 Astrazeneca Ab Composes heteroaryles bicycliques utilises comme inhibiteurs de l'interaction entre le recepteur alpha4beta1 de l'integrine et vcam-1 et/ou la fibronectine
US6762199B2 (en) * 2000-02-28 2004-07-13 Aventis Pharma Limited Indane derivatives
WO2001064659A2 (fr) * 2000-02-28 2001-09-07 Aventis Pharma Limited Derives d'indane
WO2001064659A3 (fr) * 2000-02-28 2001-12-27 Aventis Pharma Ltd Derives d'indane
CN100471838C (zh) * 2000-12-28 2009-03-25 第一制药株式会社 Vla-4抑制剂
AU2002219555B2 (en) * 2000-12-28 2006-11-30 Daiichi Pharmaceutical Co., Ltd. VLA-4 Inhibitors
US7157487B2 (en) 2000-12-28 2007-01-02 Daiichi Pharmaceutical Co., Ltd. Vla-4 inhibitors
CN100396680C (zh) * 2000-12-28 2008-06-25 第一制药株式会社 极迟抗原-4抑制剂
WO2002053534A1 (fr) * 2000-12-28 2002-07-11 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs de vla-4
WO2003010135A1 (fr) * 2001-07-26 2003-02-06 Ajinomoto Co., Inc. Nouveaux derives de l'acide phenylpropionique
US7193108B2 (en) 2001-07-26 2007-03-20 Ajinomoto Co., Inc. Phenylpropionic acid derivatives
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
US7893279B2 (en) 2003-07-24 2011-02-22 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
US7691894B2 (en) 2003-07-24 2010-04-06 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US8053450B2 (en) 2004-01-21 2011-11-08 Bristol-Myers Squibb Company Amino-benzazoles as P2Y1 receptor inhibitors with pyridine ring and heterocyclic components
US7470712B2 (en) 2004-01-21 2008-12-30 Bristol-Myers Squibb Company Amino-benzazoles as P2Y1 receptor inhibitors
WO2005070920A1 (fr) 2004-01-21 2005-08-04 Bristol-Myers Squibb Company Amino-benzazoles utilises comme inhibiteurs du recepteur p2y1
US7592358B2 (en) 2004-04-14 2009-09-22 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US7524862B2 (en) 2004-04-14 2009-04-28 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US11130753B2 (en) 2010-02-18 2021-09-28 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US11649230B2 (en) 2010-02-18 2023-05-16 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10287284B2 (en) 2010-02-18 2019-05-14 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10570126B2 (en) 2010-02-18 2020-02-25 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10030011B2 (en) 2010-02-18 2018-07-24 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10463652B2 (en) 2014-12-01 2019-11-05 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10898475B2 (en) 2014-12-01 2021-01-26 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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