Substituted Isoquinolin-3-carboxyamides, their preparation and medical use

摘要

N-(Carboxymethyl or 2-hydroxyethyl)-4-hydroxy-isoquinoline-3-carboxamide derivatives (I) are new. N-(Carboxymethyl or 2-hydroxyethyl)-4-hydroxy-isoquinoline-3-carboxamide derivatives of formula (I) and their salts are new. [Image] A : COOH or CH 2OH; R 1>H or Cl; R 2>H, 1-8C alkyl, 1-8C alkoxy, Cl, CF 3, OH, benzyloxy (optionally substituted by 1-5C alkyl or 1-5C alkoxy) or fluoroalkoxy of formula -O(CH 2) x-Q; x : 0 or 1; Q : 1-5C alkyl, substituted by 1-11 F; R 3>F, CN or as for R 2>; and R 4>, R 5>H, 1-5C alkyl, F, Cl, Br, CF 3, CN, 1-5C alkoxy or -O(CH 2) x-Q. Independent claims are included for the preparation of (I). ACTIVITY : Antiinflammatory; Hepatotropic; Nephrotropic; Dermatological; Vulnerary; Antiarteriosclerotic. In a carbon tetrachloride-induced liver fibrosis model in the rat, N-((1-chloro-4-hydroxy-isoquinolin-3-yl)-carbonyl)-glycine (Ia) at a dose of 2 x 20 mg/kg i.p. per day for 2 weeks inhibited the production of hydroxyproline (as a indicator of collagen production) in the liver by 67%. (Ia) caused no steatosis of the liver when administered to rats at 2 x 25 mg/kg i.p. for 6 weeks. MECHANISM OF ACTION : Prolyl-4-hydroxylase inhibitor; Collagen biosynthesis inhibitor.