Anti-hypertensive agents

A new compound having the general formula I. R--A--S--Z, and the physiologically acceptable salts thereof, wherein:

• R is selected from hydrogen, formyl, acetyl, propanoyl, butanoyl, phenylacetyl, phenylpropanoyl, benzoyl, cyclopentanecarbonyl, tert-butyloxycarbonyl, cyclopentanecarbonylL-lysyl, pyro-L-glutamyl-L-lysyl, L-arginyl, L-lysyl and pyro-L-glutamyl,
• A is selected from phenylalanyl, glycyl, alanyl, tryptophyl, tyrosyl, isoleucyl, leucyl, histidyl and valyl and the -amino group of A is in amide linkage with R when R is an acyl group and forms a primary amino group with R when R is hydrogen;
• S is a sulfur atom joined to A in a thioester linkage;
• and
• Z is selected from the following:
• ##STR60## wherein (i) R.sub.1 and R.sub.1 ' are each hydrogen or halogen, and R.sub.2 and R.sub.3 are each hydrogen, lower alkyl or trifluoromethyl provided that only one of R.sub.2 and R.sub.3 may be trifluoromethyl and further provided that at least one of R.sub.1, R.sub.1 ', R.sub.2 and R.sub.3 must be halogen or trifluoromethyl;
• (ii) R.sub.23 is hydrogen or lower alkyl and
• (iii) m is 0 or 1;
• ##STR61## wherein (i) R.sub.4 and R.sub.5 are each hydrogen, lower alkyl or phenyl-lower alkylene;
• (ii) n is 1, 2 or 3;
• (iii) R.sub.6 is hydrogen or hydroxy or when n is 2, R.sub.6 may also be halogen, and
• (iv) m and R.sub.23 are as stated in II. above;
• ##STR62## wherein (i) R.sub.7 is hydrogen, lower alkanoyl or amino (imino)-methyl;
• (ii) p is 0 or an integer of from 1 to 4;
• (iii) R.sub.25 is hydrogen but when m is 1, p is 0, R.sub.4 is hydrogen and R.sub.7 is lower alkanoyl, R.sub.25 may also be lower alkyl;
• (iv) R.sub.8 is selected from hydrogen, lower alkyl and hydroxy lower alkylene
• when R.sub.9 is selected from 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 and carboxy-lower alkylene but R.sub.8 and R.sub.9 may together constitute a (CH.sub.2).sub.v bridge wherein v is 3 or 4, thus forming a 5 or 6-membered ring with the N and C to which R.sub.8 and R.sub.9 are respectively attached and in such instance when v is 3 one hydrogen of (CH.sub.2).sub.v may be replaced by OH or halogen and when v is 4, one such hydrogen may be replaced by OH;
• (v) m and R.sub.23 are each as defined in II. above;
• and
• (iv) R.sub.4 is as defined in III. above, provided further, however, that m and p may not both be 0. ##STR63## wherein (i) r.sub.10 is hydrogen or lower alkyl;
• (ii) R.sub.11 is hydrogen, lower alkyl or lower alkanoyl;
• (iii) X is 0 or S;
• (iv) m and R.sub.23 are as stated in II. above, and
• (v) R.sub.8, R.sub.9 and p are as stated in IV. above;
• ##STR64## wherein (i) R.sub.12 is selected from carboxy, lower alkoxycarbonyl, carbamoyl, N-substituted carbamoyl and cyano;
• (ii) m and R.sub.23 are as stated in II. above;
• and
• (iii) R.sub.8, R.sub.9 and p are as stated in IV. above;
• ##STR65## wherein (i) R.sub.13 is hydrogen, lower alkyl or phenyl-lower alkylene;
• (ii) R.sub.14 is selected from hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, imidazolyl-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-thio-lower alkylene, carbamoyl-lower alkylene and carboxy-lower alkylene;
• (iii) R.sub.4 and R.sub.5 are as stated in III. above;
• and
• (iv) q is 0, 1 or 2 ##STR66## wherein (i) R.sub.15 and R.sub.16 are each hydrogen, lower alkyl, phenyl or phenyl-lower alkylene;
• (ii) r is 0, 1 or 2;
• (iii) s is 1, 2, or 3;
• (iv) R.sub.17 is hydrogen, hydroxy or lower alkyl and when s is 2, R.sub.17 may also be halogen;
• and
• (v) R.sub.24 is hydroxy, amino or lower alkoxy;
• provided that when R.sub.24 is OH, s is 2, and R.sub.17 is H or OH:
• (a) if r is 0, R.sub.16 may not be methyl or H, and
• (b) if r is 1, R.sub.15 and R.sub.16 may not both be H and R.sub.16 may not be methyl if R.sub.15 is H ##STR67## wherein (i) R.sub.18 is hydrogen or lower alkyl;
• (ii) R.sub.19 and R.sub.20 are each lower alkyl and may together constitute a (CH.sub.2).sub.w bridge wherein w is 4, to form a ring of 5-carbons with the carbon to which they are each attached;
• (iii) R.sub.21 is hydrogen or lower alkyl and may constitute with R.sub.19 a (CH.sub.2).sub.x bridge wherein x is 3, to form a five-membered ring with the N and C to which they are respectively attached;
• provided, however, that when R.sub.19 and R.sub.21 constitute (CH.sub.2).sub.x, R.sub.18 may not be hydrogen or methyl ##STR68## wherein (i) R.sub.22 is hydrogen or lower alkyl;
• (ii) t and u are each 0 or 1;
• (iii) R.sub.23 is as stated in II. above;
• provided, however, that u may not be zero when R.sub.23 is H;
• and ##STR69## wherein (i) z is 2 or 3;
• (ii) R.sub.10 is as stated in V. above, and
• (iii) R.sub.23 is as stated in II above.