Angiotensin converting enzyme inhibitors

Claim 1

An angiotensin converting enzyme inhibitor having the formula wherein, R is hydrogen, formyl, acetyl, propanoyl, butanoyl, phenylacetyl, phenylpropanoyl, benzoyl, cyclopentanecarbonyl, tert-butyloxycarbonyl, cyclopentanecarbonyl-L-lysyl, pyro-L-glutamyl-L-lysyl, L-arginyl, L-lysyl or pyro-L-glutamyl; A is proline, 3,4-dehydroproline, a-methyl proline, thiazolidine-4-carboxylic acid, cycloleucine, pyroglutamic acid, 1-amino-1-cyclopropane carboxylic acid, 1-amino-1-cyclobutane carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, substituted proline wherein the substituent is halo or hydroxy, phenylglycine, R-benzyl aspartic acid, y-benzyl glutamic acid, S-benzyl cysteine, O-benzyl serine, 0-benzyl tyrosine, O-benzyl threonine, β-phenyl serine, thyronine, β-2-thienylserine, β-2-thienylalanine, a-methyl histidine, α-methyl tyrosine, α-methyl phenylalanine, a-methyl tryptophan, substituted tyrosine wherein the substituent is halo, nitro, methoxy or hydroxy, substituted phenylalanine wherein the substituent is halo, nitro, amino, or methoxy or substituted trytophan wherein the substituent is fluoro, methyl or methoxy, methionine, cysteine, arginine, ω-nitro-arginine, lysine, ornithine, aspartic acid, asparagine, glutamic acid, glutamine, homocysteine, penicillamine, norleucine, serine, β-alanine, ethionine, homoserine, isoserine, norvaline, threonine, α-aminobutyric acid, α-aminoisobutyric acid, β-cyclohexanyl-alanine, 0-phosphothreonine, S-ethylcysteine, vinyl glycine, the a-methyl derivative of valine, leucine, isoleucine, cysteine, methionine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine or arginine, or phenylalanyl, glycyl, alanyl, tryptophyl, tryosyl, isoleucyl, leucyl, histidyl, or valyl, the α-amino group or imino group thereof or β-amino group of (β-alanine being in amide or imide linkage respectively with R, and the carboxyl group thereof being in thioester linkage with S; S is a sulfur atom in thioester linkage with A and Z; Z is R i is hydrogen or halogen; R 1 ' is hydrogen or halogen; R 2 is hydrogen, lower alkyl or trifluoromethyl; R 3 is hydrogen, lower alkyl or trifluoromethyl, not more than one of R 2 and R 3 being trifluoromethyl, and at least one of R 1 , R 1 ', R 2 or R 3 is a halogen or trifluoromethyl substituent represented by the named symbol above; R 4 is hydrogen, lower alkyl or phenyl-lower alkylene; R 5 is hydrogen, lower alkyl or phenyl-lower alkylene; R 6 is hydrogen or hydroxy or when n = 2, R 6 can also be halogen; R 7 is hydrogen, lower alkanoyl or amino(imino)methyl; R 8 is hydrogen, lower alkyl or hydroxy-lower alkylene; R 9 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, mercapto-lower alkylene, lower alkyl-thio-lower alkylene, imidazolyl-lower alkylene, indolyl-lower alkylene, carbamoyl-lower alkylene or carboxy-lower alkylene; or R 8 and Rg together form a (CH 2 ) v bridge which completes a ring of 5 or 6 atoms with the nitrogen and carbon to which they are attached, one carbon optionally bearing a hydroxy group when v = 4, one carbon optionally bearing a hydroxy group or halogen group when v = 3; R 10 is hydrogen or lower alkyl; R 11 is hydrogen, lower alkyl or lower alkanoyl; R 12 is carboxy, alkoxycarbonyl, carbamoyl, N-substituted carbamoyl or cyano; R 15 is hydrogen, lower alkyl, phenyl or phenyl-lower alkylene; R 16 is hydrogen, lower alkyl, phenyl or phenyl-lower alkylene; R 17 is hydrogen, hydroxy or lower alkyl or when s = 2, R 17 can also be halogen; R 18 is hydrogen or lower alkyl; R 19 is lower alkyl; R 20 is lower alkyl; R 21 is hydrogen or lower alkyl; or R 19 and R 20 together form a (CH 2 ) w bridge which completes a ring of 5 atoms with the carbon to which they are attached; or R 19 and R 21 together form a (CH 2 ) x bridge which completes a ring of 5 atoms with the nitrogen and carbon to which they are attached; R 23 is hydrogen or lower alkyl; R 24 is hydroxy, amino or lower alkoxy; R 25 is hydrogen or when m = 1, p = 0, R 4 = H and R 7 lower alkanoyl, then R 25 is hydrogen or lower alkyl; X is 0 or S; m and t each is 0 or 1; n and s each is 1, 2 or 3; p is 0, 1, 2, 3 or 4; q and r each is 0, 1 or 2; v is 3 or 4; w is 4; x is 3; and z is 2 or 3; with the further proviso that where A is phenylalanyl, glycyl, alanyl, tryptophyl, tyrosyl, isoleucyl, leucyl, histidyl, or valyl, r is not 0 when R Z4 is hydroxy, s is 2, R 17 is hydrogen or hydroxy and R 16 is methyl; r is not 1 when R 24 is hydroxy, s is 2, R 15 is hydrogen, R 17 is hydrogen or hydroxy and R 16 is hydrogen or methyl; and in formula IV, at least one of m and p is other than 0.