Pyrimidines derivatives as antagonists of the vitronectin receptors

摘要

4-substituted amino-pyrimidine derivatives (I), as pure or mixed stereoisomers and/or pure or mixed E and Z isomers, and their acid addition salts, solvates, prodrugs and metabolites, are new. 4-substituted amino-pyrimidine derivatives of formula (I) as pure or mixed stereoisomers and/or pure or mixed E and Z isomers, and their acid addition salts, solvates, prodrugs and metabolites, are new. R : e.g. -X-alk-Het or 4-G-piperidino; X : e.g. O or S; alk : 1-4C alkylene; Het, G : optionally substituted heterocycle; R 1> : hydrogen, 5-14C aryl, 5-14C aryl(1-4C)alkyl or amino (optionally substituted by 1-2 1-4C alkyl and/or acyl); R 2> : hydrogen, halo, nitro, 1-4C alkyl, amino (optionally substituted by 1-2 1-4C alkyl or acyl), (CH 2) 0-2-COOR 5> or (CH 2) 0-2-OR 5>; R 3> : hydrogen, COOR 5>, SO 2R 5> or a mono- or poly-cyclic system, where each ring contains 4-10 members (aromatic or not), containing 1-4 heteroatoms (N, O or S), optionally substituted by one or more R 0>; R 4> : e.g. hydroxy, 1-8C alkoxy, 5-14C aryloxy or 3-12C cycloalkoxy; R 5> : 1-8C alkyl, 5-14C aryl, 5-14C aryl-(1-4C)alkyl, 3-12C cycloalkyl, 3-12C cycloalkyl-(1-4C)alkyl, bi- or tri-cycloalkyl(1-4C)alkyl (all optionally substituted by one or more R 0>); R 0> : halo, amino, hydroxy, 1-4C alkoxy, 1-4C alkylthio, carboxy, 1-4C alkoxycarbonyl, or 1-8C alkyl (optionally substituted by one or more halo, 5-14C aryl or 5-14C aryl-1-4C alkyl). The full definitions are given in the DEFINITIONS (Full Definitions) field. An independent claim is also included for preparation of (I). [Image] ACTIVITY : Osteopathic; Cytostatic; Antiinflammatory; Cardiant; Vasotropic; Antiarteriosclerotic; Nephrotropic; Ophthalmological. At a dose of 1-10 mg/kg (subcutaneously) (I) inhibited bone resorption induced by parathyroid hormone in rats lacking both thyroid and parathyroid glands. MECHANISM OF ACTION : Vitronectin receptor antagonist. (I) thus inhibits cellular adhesion, so inhibiting bone resorption mediated by osteoclasts. (I) also induces apoptosis in angiogenic cells. In an enzyme-linked immunosorption assay, (I) has IC 50 2-10 4> nM for inhibition of interaction between vitronectin and its ligand (kistrin); no results are given for individual compounds.