New antagonist derivatives of the vitronectin receptor, method for their preparation, their application as medicine and pharmaceutical compositions containing them

摘要

4-(N-(2-Amino-2-carboxyethyl)-amino)-6-(4-substituted 1-piperidinyl)-4-pyrimidine derivatives (I) are new. Pyrimidine derivatives of formula (I) (including isomers and isomer mixtures) and their salts are new. [Image] G : R 7>R 8>N-C(=NR 6>)-NHCO-, Het-NHCO-, Het-NHCH 2- or Het-; Het : mono- or polycyclic ring system, in which each ring is 4-10 membered and aromatic or non-aromatic and at least one ring contains 1-4 N heteroatoms, optionally substituted (os) by one or more groups R 9>; R 1>H, aryl, arylalkyl or amino (os by 1 or 2 of alkyl and/or 1-4C acyl); R 2>H, halo, NO 2, alkyl, amino (os by 1 or 2 of alkyl and/or 1-4C acyl), -Q-COOR 5> or -Q-OR 5>; Q : direct bond, CH 2 or CH 2CH 2; R 3>COOR 5> or SO 2R 5>; or a mono- or polycyclic ring system, in which each ring is 4-10 membered and aromatic or non-aromatic and at least one ring contains 1-4 N, O and/or S heteroatoms, os by one or more groups R 9>; R 4>OH, 1-8C alkoxy, 5-14C aryloxy, arylalkoxy, cycloalkoxy, cycloalkylalkoxy, (1-8C) alkylcarbonyloxyalkoxy, aryl-(1-8C) alkylcarbonyloxyalkoxy, di-(1-8C alkyl)-aminocarbonylmethoxy or aryl-dialkylaminocarbonylmethoxy; amino (os by 1 or 2 of alkyl, aryl, arylalkyl and/or 1-5C acyl); or a D- or L-aminoacid residue; R 5>1-8C alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, bicycloalkylalkyl or cycloalkylalkyl, where aryl, alkyl, cycloalkyl, bicycloalkylalkyl and tricycloalkyl moieties are os by one or more groups R 9>; R 6>H, OH, NO 2, (1-6C) alkoxycarbonyl or (1-6C) alkoxycarbonyloxy; R 7>, R 8>H or 1-6C alkyl (os by R 9>); R 9>halo, NH 2, NO 2, OH, alkoxy, alkylthio, COOH, alkoxycarbonyl, or 1-8C alkyl (os by one or more of halo, aryl or arylalkyl); unless specified otherwise alkyl moieties have 1-4C, aryl moieties 5-14C and cycloalkyl moieties 5-14C. Independent claims are also included for the preparation of (I). ACTIVITY : Osteopathic; Cytostatic; Antiinflammatory; Cardiant; Vasotropic; Antiarteriosclerotic; Nephrotropic; Ophthalmological; Antiarthritic; Antirheumatic. MECHANISM OF ACTION : Vitronectin receptor antagonist. 3-((5-Ethyl-6-(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl)-4-pyrimidinyl)-amino)-N-((phenylmethoxy)-carbonyl)-alanine (Ia) had IC 5 0 3 nM in a vitronectin (alpha vbeta 3) receptor binding assay in vitro.