Addition salts of inhibitors of the angiotensin-conversing enzyme with NO-donor acids, method for their preparation and pharmaceutical compositions containing them

摘要

Compounds e.g. perindopril-ethoxycarbonyl-butyl-amino-propionyl-octahydro-indole-2-carboxylic acid (I) are new. Compounds e.g. perindopril-ethoxycarbonyl-butyl-amino-propionyl-octahydro-indole-2-carboxylic acid of formula (A) m(B1) n(I) are new. A : angiotensin converting enzyme inhibitor moiety comprising at least one basic functional group; B1 : a moiety comprising at least one acid functional group and at least one NO donor group; m : number of acid functional group of B1; and n : number of basic functional groups of A, where A and B1 are ionic type. Independent claims are included for: (1) alkyl compounds of formula X-(AK 1) x-(Y 1) y-(Ak 2) z-Z (III); and (2) preparation of (I). X : CO 2H, SO 3H or P(O)(OH) 2; Ak 1, Ak 2 : 1-8C alkylene (optionally branched and optionally saturated, where one or more C atom is replaced by O, S, N or SO 2, and optionally substituted by carboxy, OH or amino); x, y, z : 0 or 1; Y 1 : CO or CONH; Z : 4-benzenesulfonyl-5-oxy-furazan-3-oxo moiety of formula (a) or (b); and R 4, R1a 4 : H, halo, 1-6C alkyl, CF 3or -OCF 3. [Image] ACTIVITY : Cardiovascular-Gen.; Hypotensive; Nephrotropic; Vasotropic; Cardiant; Antiarteriosclerotic; Prevention: Anticoagulant; Thrombolytic; Antimicrobial; Cerebroprotective; Antidiabetic; Antiinflammatory; Tranquilizer; Metabolic; Anorectic. MECHANISM OF ACTION : Angiotensin converting enzyme inhibitor. The effect of (I) to inhibit angiotensin converting enzyme was tested in rats. The result showed that (2S)-2-[(3-{[5-oxido-4-(phenylsulfonyl)-1,2,5-oxadiazol-3-yl]-oxy}-propionyl)-amino]-succinic acid-(2S,3as,7aS)-1-[(2S)-2-{[(1S)-1-(ethoxycarbonyl)-butyl]-amino}-propionyl]-octahydro-1H-indole-2-carboxylic acid exhibited 80-85% of inhibition.