Patent ID: 6514952
Filing Date: 2003-02-04
Classification: A61P,C07K

Abstract:
A method for the prophylaxis of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, inflammatory disorders of the central nervous system, asthma, allergies, restenoses or diabetes comprising administering to a subject in need thereof an effective amount of a preparation comprising a VLA-4-antagonizing-effective amount of one or more compounds of the formula I in whichW is R1â€”Aâ€”C(R13) or R1â€”Aâ€”CH&boxH;C; Y is a carbonyl; Z is N(R0); A is a bivalent radical selected from the group consisting of (C1-C6)-alkylene, (C3-C12)-cycloalkylene, (C1-C6)-alkylene-(C3-C12)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alkylenephenyl, (C1-C6)-alkylenephenyl-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl and a bivalent radical of a 5- or 6-membered saturated or unsaturated ring which contains 0, 1 or 2 nitrogen atoms and is unsubstituted, mono- or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur; B is a bivalent radical selected from the group consisting of (C1-C6)-alkylene, (C2-C6)-alkenylene, phenylene, phenylene-(C1-C3)-alkyl, and (C1-C3)-alkylenephenyl, where the bivalent (C1-C6)-alkylene radical is unsubstituted or substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, unsubstituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl and heteroaryl-(C1-C6)-alkyl unsubstituted or substituted in the heteroaryl radical; D is C(R2)(R3), N(R3) or CH&boxH;C(R3); E is tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2 or R10CO; R is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, unsubstituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl or heteroaryl-(C1-C8)-alkyl unsubstituted or substituted in the heteroaryl radical, where alkyl radicals are unsubstituted, mono- or polysubstituted by fluorine; R0 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, unsubstituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl, heteroaryl-(C1-C8)-alkyl unsubstituted or substituted in the heteroaryl radical, CHO, (C1-C8)-alkyl-CO, (C3-C12)-cycloalkyl-CO, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-bicycloalkyl-CO, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-tricycloalkyl-CO, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-CO, unsubstituted or substituted (C6-C14)-aryl-CO, (C6-C14)-aryl-(C1-C8)-alkyl-CO unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl-CO, heteroaryl-(C1-C8)-alkyl-CO unsubstituted or substituted in the heteroaryl radical, (C1-C8)-alkyl-S(O)n, (C3-C12)-cycloalkyl-S(O)n, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12)-bicycloalkyl-S(O)n, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12)-tricycloalkyl-S(O)n, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-S(O)n, unsubstituted or substituted (C6-C14)-aryl-S(O)n, (C6-C14)-aryl-(C1-C8)-alkyl-S(O)n unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl-S(O)n or heteroaryl-(C1-C8)-alkyl-S(O)n unsubstituted or substituted in the heteroaryl radical, where n is 1 or 2; R1 is hydrogen, (C1-C10)-alkyl, which is unsubstituted, mono substituted or polysubstituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, unsubstituted or substituted R21-((C6-C14)-aryl), (R21-((C6-C14)-aryl))-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, the radical Het-, Het-(C1-C8)-alkyl or one of the radicals R21Oâ€”, R22Oâ€”NHâ€”, R21Oâ€”N(R23)â€”, R24NHâ€”, R25N(R25)â€”, HOâ€”((C1-C8)-alkyl)-N(R26)â€”, R27C(O)â€”NHâ€”, R21C(O)â€”N(R23)â€”, R21C(O)â€”, R21Oâ€”C(O)â€”, R28N(R21)â€”C(O)â€”, R21Oâ€”N&boxH;, O&boxH; and S&boxH;; R2 is hydrogen, (C1-C8)-alkyl, unsubstituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical or (C3-C8)-cycloalkyl; R3 is hydrogen, (C1-C8)-alkyl, unsubstituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C2-C8)-alkenylcarbonyl, (C2-C8)-alkynylcarbonyl, pyridyl, R11NH, R4CO, COOR4, CON(CH3)R4, CONHR4, CSNHR4, COOR15, CON(CH3)R15 or CONHR15; R4 is hydrogen or (C1-C28)-alkyl which is unsubstituted, mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3)-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarbonylamino-(C1-C3)-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarbonylamino-(C2-C18)-alkylaminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which is unsubstituted or substituted in the aryl radical, amino, mercapto, (C1-C18)-alkoxy, (C1-C18)-alkoxycarbonyl, unsubtituted or substituted (C3-C8)-cycloalkyl, HOS(O)2â€”(C1-C3)-alkyl, R9NHS(O)2â€”(C1-C3)-alkyl, (R8O)2P(O)â€”(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifluoromethyl and the radical R5; R5 is unsubtituted or substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring which is aromatic, partially hydrogenated or completely hydrogenated and which does not contain a heteroatom or contains one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, a radical R6 and a radical R6COâ€”, where the aryl radical and, independently thereof, the heterocyclic radical is unsubstituted, mono- or polysubstituted by identical or different radicals selected from the group consisting of (C1-C18)-alkyl, (C1-C18)-alkoxy, halogen, nitro, amino and trifluoromethyl; R6 is R7R8N, R7O or R7S or an amino acid side chain, a natural or unnatural amino acid, imino acid, azaamino acid, Nâ€”(C1-C8)-alkylated or Nâ€”((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which is unsubstituted or substituted in the aryl radical, or a dipeptide radical, or a dipeptide radical reduced in the peptide bond to â€”NHâ€”CH2â€”, or an ester or amide thereof, where functional groups are present in free form or are replaced with hydrogen or hydroxymethyl; R7 is hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18)-alkylcarbonyl, (C1-C18)-alkoxycarbonyl, (C6-C14)-arylcarbonyl, (C6-C14)-aryl-(C1-C8)-alkylcarbonyl or (C6-C14)-aryl-(C1-C18)-alkyloxycarbonyl, where the alkyl groups are unsubstituted or substituted by an amino group, and where the aryl radicals are unsubstituted, mono- or polysubstituted by identical or different radicals selected from the group consisting of (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino and trifluoromethyl, or is a natural or unnatural amino acid, imino acid, azaamino acid, Nâ€”(C1-C8)-alkylated or Nâ€”((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which is unsubstituted or substituted in the aryl radical, or a dipeptide radical, or a dipepetide radical reduced in the peptide bond to â€”NHâ€”CH2â€”; R8 is hydrogen, (C1-C18)-alkyl, unsubstituted or substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl which is unsubstituted or substituted in the aryl radical; R9 is hydrogen, aminocarbonyl, (C1-C18)-alkylaminocarbonyl, (C3-C8)-cycloalkylaminocarbonyl, unsubstituted or substituted (C6-C14)-arylaminocarbonyl, (C1-C18)-alkyl, unsubstituted or substituted (C6-C14)-aryl or (C3-C8)-cycloalkyl; R10 is hydroxyl, (C1-C18)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which is unsubstituted or substituted in the aryl radical, unsubstituted or substituted (C6-C14)-aryloxy, amino or mono- or di-((C1-C18)-alkyl)amino; R11 is hydrogen, (C1-C18)-alkyl, R12CO, R12aCS, unsubstituted or substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical, R9NHS(O)2 or the radical R15; R12 is hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, unsubstituted or substituted (C6-C14)-aryl, (C1-C18)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which is unsubstituted or substituted in the aryl radical, unsubstituted or substituted (C6-C14)-aryloxy, the radical R15, the radical R15â€”Oâ€”, amino, mono- or di-((C1-C18)-alkyl)amino, (C2-C8)-alkenylamino, (C2-C8)-alkynylamino, (C3-C12)-cycloalkylamino, (C3-C12)-cycloalkyl-(C1-C8)-alkylamino, the radical R15â€”NHâ€”, unsubstituted or substituted (C6-C14)-aryl-NH, (C6-C14)-aryl-(C1-C8)-alkyl-NH, which is unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl-NH or heteroaryl-(C1-C8)-alkyl-NH unsubstituted or substituted in the heteroaryl radical; R12a is amino, mono- or di-((C1-C18)-alkyl)-amino, (C2-C8)-alkenylamino, (C2-C8)-alkynylamino, (C3-C12)-cycloalkylamino, (C3-C12)-cycloalkyl-(C1-C8)-alkylamino, the radical R15â€”NHâ€”, unsubstituted or substituted (C6-C14)-aryl-NH, (C6-C14)-aryl-(C1-C8)-alkyl-NH, which is unsubstituted or substituted in the aryl radical, unsubstituted or substituted heteroaryl-NH or heteroaryl-(C1-C8)-alkyl-NH unsubstituted or substituted in the heteroaryl radical; R13 is hydrogen, (C1-C6)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl unsubstituted or substituted in the aryl radical or (C3-C8)-cycloalkyl; R15 is R16â€”(C1-C6)-alkyl or R16; R16 is a 6- to 24-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which does not contain a heteroatom or contains one to four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of (C1-C4)-alkyl and oxo; R21 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine and the radicals R21 are identical or different if they occur several times; R22 is (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine; R23 is (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine; R24 (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine; R25 has the meanings of R23, where the radicals R25 are identical or different; R26 has the meanings of R21 or HOâ€”((C1-C8)-alkyl), where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine; R27 is hydrogen, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals are unsubstituted, monosubstituted or polysubstituted by fluorine; R28 is one of the radicals R21â€”, R21Oâ€”, R26N(R26)â€”, R21C(O)â€”, R21Oâ€”C(O)â€”, ((C1-C18)-alkyl-Oâ€”C(O)â€”((C1-C6)-alkyl)-Oâ€”C(O)â€”, R21N(R21)â€”C(O)â€”, R21N(R21)â€”C(&boxH;N(R21))â€” or R21C(O)â€”N(R21)â€”; Het is a mono- or polycyclic, 4- to 14-membered, aromatic or nonaromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms selected from the group consisting of N, O and S as ring members and are unsubstituted or substituted by one or more, identical or different substituents; b, c, d and f independently of one another are 0 or 1, but are not simultaneously 0; e, g and h independently of one another are 0, 1, 2, 3, 4, 5 or 6; in all their stereoisomeric forms or mixtures thereof in any ratio, or their physiologically tolerable salts together with one or more physiologically tolerable carriers or additives.