Renin inhibitors containing homophe8 and a C-terminal amide cycle

Claim 2

A peptide of the formula: ##EQU3## wherein: A is hydrogen; or ##STR34## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH--; and R a 1 and R b 1 are independently hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is C 1-4 alkyl, hydrogen, or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, wherein the one or two substituents are independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; p is 0 to 5; and p' and p" are independently 0, 1 or 2; except that where X is --O--, only one of R a 1 and R b 1 is present; B is absent; glycyl, sarcosyl; or ##STR35## where R 2 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl, C 2-3 alkyl; methylthiomethyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, wherein the one or two substituents are independently selected from C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy and halo; D is absent; ##STR36## where Z is --(CH 2 ) 1 -- and 1 is 1 or 2; or --S--; E is ##STR37## where k is 2 to 4; and R 6 is hydrogen; C 1-4 alkyl; indolyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; F is absent or glycyl; R 3 is C 3-6 alkyl; or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR38## where R 7 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 6 is as defined above; R 5 is hydrogen; ##STR39## where R 6 and R 7 are as defined above; or --(CH 2 ) q --R 8 , where q is 0 or 1-4; and R 8 is an unsubstituted or mono- or disubstituted heterocycle, representing a 5- or 6-membered ring or benzofused 5- or 6-membered ring comprising one or two heteroatoms independently selected fron N, O and S, where the one or two substituents are independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, naphthyl-C 1 -C 4 -alkyl, amino, and mono- or di-C 1-4 alkylamino; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m is 1 to 4; n is 0 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 3

A peptide according to claim 1 wherein the peptide is a member selected from the group consisting essentially of: ##STR40##

Claim 4

A pharmaceutical composition for treating renin-associated hypertension or renin-associated a hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of the a peptide of the formula: ##EQU4## wherein: A is hydrogen; or ##STR41## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH--; and R a 1 and R b 1 are independently hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is C 1-4 alkyl, hydrogen, or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, wherein the one or two substituents are independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; p is 0 to 5; and p' and p" are independently 0, 1 or 2; except that where X is --O--, only one of R a 1 and R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR42## where R 2 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; methylthiomethyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, wherein the one or two substituents are independently selected from C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy and halo; D is absent; ##STR43## where X is --(CH 2 ) 1 -- and 1 is 1 or 2; or --S--; E is ##STR44## where k is 2 to 4; and R 6 is hydrogen; C 1-4 alkyl; indolyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or F is absent or glycyl; R 3 is C 3-6 alkyl; or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR45## where R 7 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 6 is as defined above; R 5 is hydrogen; ##STR46## where R 6 and R 7 are as defined above; or --(CH 2 ) q --R 8 , where q is 0 or 1-4; and R 8 is an unsubstituted or mono- or disubstituted heterocycle, representing a 5- or 6-membered ring or benzofused 5- or 6-membered ring comprising one or two heteroatoms independently selected from N, O and S, where the one or two substituents are independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, naphthyl-C 1 -C 4 -alkyl, amino, and mono- or di-C 1-4 alkylamino; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m is 1 to 4; n is 0 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 5

A pharmaceutical composition for treating renin-associated hypertension or renin-associated a hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of the a peptide of the formula: ##EQU4## wherein: A is hydrogen; or ##STR41## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH--; and R a 1 and R b 1 are independently hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is C 1-4 alkyl, hydrogen, or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, wherein the one or two substituents are independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; p is 0 to 5; and p' and p" are independently 0, 1 or 2; except that where X is --O--, only one of R a 1 and R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR42## where R 2 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; methylthiomethyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, wherein the one or two substituents are independently selected from C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy and halo; D is absent; ##STR43## where X is --(CH 2 ) 1 -- and 1 is 1 or 2; or --S--; E is ##STR44## where k is 2 to 4; and R 6 is hydrogen; C 1-4 alkyl; indolyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or F is absent or glycyl; R 3 is C 3-6 alkyl; or unsubstituted or mono- or disubstituted C 3-7 cycloalkyl, phenyl or naphthyl, where the one or two substituents are independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR45## where R 7 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 6 is as defined above; R 5 is hydrogen; ##STR46## where R 6 and R 7 are as defined above; or --(CH 2 ) q --R 8 , where q is 0 or 1-4; and R 8 is an unsubstituted or mono- or disubstituted heterocycle, representing a 5- or 6-membered ring or benzofused 5- or 6-membered ring comprising one or two heteroatoms independently selected from N, O and S, where the one or two substituents are independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, naphthyl-C 1 -C 4 -alkyl, amino, and mono- or di-C 1-4 alkylamino; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m is 1 to 4; n is 0 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 6

A composition according to claim 3 wherein the peptide is a member selected from the group consisting essentially of: ##STR47##