Patent DE-19962998-A1 (DE)
Title: New integrin receptor ligands, especially  integrin-alphavbeta3 ligands, useful for treating e.g. atherosclerosis, rheumatoid arthritis, restenosis, angioplasty and acute kidney failure
Inventor: ZECHEL JOHANN-CHRISTIAN
IPC: C07D405/14
Filed: 1999-12-24
Abstract: Integrin receptor ligands (I), their salts, prodrugs, their enantiomers or diastereomers and tautomeres are new. Integrin receptor ligands of formula (I), their salts, prodrugs, their enantiomers or diastereomers and tautomeres are new. L = U-T; T = COOH or a group hydrolyzable to COOH; U = (CRL1RL2)a-(VL)b-(CRL3RL4)c-(WL)d-(CRL5RL6)e-(XL)f(CRL7RL8)g; a, c, e, g = 0-3; b, d, f = 0 or 1; RL1-RL8 = e.g. H, halo or OH; (CH2)w-(YL)y-RL9; 3-7C cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl (all optionally substituted); or RL1+RL2, RL3+RL4, RL5+RL6, RL7+RL8 = 3-7-membered ring optionally substituted and optionally saturated carbo- or heterocyclyl, which may contain up to 3 N, O or S; w = 0- 4,  YL = CO, CON(RY1), N(RY1)CO, N(RY1)-C(O)N(RY1 asterisk ), N(RY1)-COO, O, S, SO2, SO2N(RY1), SO2O, COO, OCO, OCON(RY1), N(RY1) or N(RY1')SO2; RY1, RY1 asterisk = e.g. H, optionally substituted 1-6C alkyl or SO2-1-6C alkyl or optionally substituted, CO-aryl, SO2-ary-, hetaryl, CO-hetaryl or SO2-alkylene-aryl; RL9 = e.g. H, OH, CN, halo,optionally substituted 1-6C alkyl, Cl substituted 1-4C-alkyl or aryl substituted alkynyl or alkenyl, optionally substituted 6-12C-bicycloalkyl; or  RL9+RY1, RL9+RY1 asterisk = optionally unsaturated 3-7-heterocyclyl optionally containing up to 3 O, S or N;  WL = optionally substituted 4-11-membered mono- or polycyclic aliphatic or aromatic hydrocarbyl, having up to 6 double bonds and up to 6 N, O, S; VL, XL = CO, CONRL10, NRL10CO, SO, SO2, SO2NRL10, NRL10SO2, CS, CSNRL10, NRL10CS, CSO, OCS, COO, OCO, O, ethynylene, CHRL11OCHRL12, C(=CRLI1RL12), CRL11=CRL12, CRL11(ORL13)-CHRL12, CHRL11-CRL12(ORL13), CH(NRL14SO2RL15) , -CH(NRL14CORL15), CH(NRL14COORL16), CH(NRL14CONRL14'CRL15), CH(CORL15), CH(COORL16) or CH(CONRL14RL15); RL10 = e.g. H, optionally substituted 1-6C-alkyl, 1-6C-alkoxyalkyl, 2-6C alkenyl, 3-12C alkynyl; or  RL10 and RL1, RL 2, RL 3, RL 4, RL5, RL6, RL7 or RL8 together form an optionally substituted 4-8 membered heterocyclyl, containing up to 5 O, N or S; RL11, RL12 = e.g. H, OH, 1-6C alkyl or alkylene-cycloalkyl or optionally substituted 3-7C cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl; RL13 = e.g. H, optionally substituted 1-6C alkyl or alkylene-cycloalkyl or optionally substituted 3-7C-cycloalkyl or hetarylalkyl; RL14, RL14' = e.g. H, optionally substituted 1-6C alkyl, 1-6C alkoxyalkyl, 2-6C alkenyl, 3-12C alkynyl, CO-1-6C alkyl, CO-O-1-6C-alkyl-, 1-6C-alkylene-3-7C-cycloalkyl or SO2-1-6C-alkyl or optionally substituted 3-7C cycloalkyl; RL15 = optionally substituted 1-6C-alkyl, alkoxyalkyl, 1-6C-alkylene-3-7C-cycloalkyl, 6-12C-bicycloalkyl, 1-6C-alkylene-6-12C-bicycloalkyl, 7-20C tricycloalkyl or 1-6C alkylene-7-20C tricycloalkyl, up to 3 substituted 3-7C cycloalkyl, aryl, arylalkyl, hetarylalkyl or 3-8-membered optionally saturated or aromatic heterocyclyl; or RL15+RL14, RL15+RL14 asterisk = an optionally saturated 3-7C heterocyclyl, optionally containing up to 2 O, S or N; RL16 = optionally substituted 1-6C-alkyl, alkoxyalkyl or 1-6C-alkylene-3-7C cycloalkyl or optionally substituted 3-7C cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl,  G = a group of formula (a);  the incorporation of G can be any of the 2 orientations; ZG = O, S or NRG3; RG1, RG2 = H, CN, NO2, halo, optionally substituted 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl, optionally substituted 1-4C alkylene-ORG4, 1-4C-alkylene-CO-ORG4, 1-4C-alkylene-CO-RG4, 1-4C-alkylene-SO2-NRG5RG6, 1-4C -alkylene-CO-NRG5RG6, 1-4C-alkylene-NRG5RG6 or 1-4C-alkylene-SRG4, optionally substituted 3-7C-cycloalkyl, 1-4C-alkylene-3-7C cycloalkyl, 1-4C alkylene-3-7C-heterocycloalkyl or 1-4C-alkylene-3-7C heterocycloalkenyl, optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl, SRG4, ORG4, SORG4, SO2-RG4, COORG4, OCORG4, O-CO-NRG5RG6, SO2NRG5RG6, CONRG5RG6, NRG5RG6 or CORG4; or RG1+RG2 = optionally substituted optionally saturated or aromatic 3-9-membered carbocyclyl, carbopolycyclyl, heterocyclyl or heteropolycyclyl, containing up to 4 O, N or S; RG3 = H, OH, CN, optionally substituted 1-6C alkyl or 1-4C-alkoxy or optionally substituted 3-7C-cycloalkyl, O-3-7C-cycloalkyl, aryl, -O-aryl, arylalkyl-or O-alkylene-aryl; RG4 = e.g. H, optionally substituted 1-8C alkyl or optionally substituted aryl or heterocycloalkyl; RG5, RG6 = e.g. H, optionally substituted 1-8C alkyl or SO2RG4, COORG4, CONRG4RG4 asterisk or CORG4; RG4 asterisk = as for RG4; B = a structural element containing at least one atom which can act as a hydrogen acceptor under physiological conditions, where at least one hydrogen acceptor atom along the shortest possible path on the structural element frame is at a distance of 4-13 atomic bonds to the structural element G. The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for the following: (1) use of structural elements of formula -G-L for the preparation of compounds which bind to integrin receptors; (2) pharmaceuticals containing -G-L; (3) use of (I) in the manufacture of medicaments for treating diseases, especially diseases involving excessive or reduced interaction between integrins (particularly  alpha v beta 3-integrin) and their natural ligands; (4) pharmaceutical composition containing (I), optionally auxiliary substances and at least a further compound selected from other active substances, and the use of these compositions for treating specific diseases.