Renin inhibitors containing homophe8

Claim 2

A peptide of the formula: ##STR30## wherein: A is hydrogen; ##STR31## where n is 0 to 5 and R 3 has the same meaning as set out further below, and may additionally be hydrogen; B is absent; glycyl; sarcosyl; or ##STR32## where R 1 has the same meaning as set out further below; D is absent; or ##STR33## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is (1) --Y--(CH 2 ) q --R 6 where Y is --NH-- or --O--; q is 0 to 5; and R 6 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR34## where Y is as defined above; r is 0 or 1; r' is 0 or 1; r" is 1 to 4; r"' is 1 to 4; and R 6 and R a 6 may be the same or different and have the same meaning as R 6 above and R a 6 may additionally be ##STR35## where R 7 is hydrogen or C 1-3 alkyl; ##STR36## where Y is as defined above; s is 0 or 1; and Z is ##STR37## where s is 0 or 1; and R 7 is as defined above; or ##STR38## where s is 0 or 1; ##STR39## (5) absent; F is absent; OR; NHR; or N(R)2, where R may be the same or different and is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; quanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR40## where R 8 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; arylC 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 2 to 4; m' is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in A, B, D, and E 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: ______________________________________ IVA HisProHphHisStaLeuPheNH.sub.2 IVA HisProHphHisACHPALeuPheNH.sub.2 IVA HisProHphHisStaIleHisNH.sub.2 IVA ##STR41## ##STR42## IVA ##STR43## ##STR44## ##STR45## ##STR46## ______________________________________

Claim 4

A pharmaceutical composition for treating renin-associated hypertension or renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: ##STR47## wherein: A is hydrogen; ##STR48## where n is 0 to 5 and R 3 has the same meaning as set out further below, and may additionally be hydrogen; B is absent; glycyl; sarcosyl; or ##STR49## where R 1 has the same meaning as set out further below; D is absent; or ##STR50## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is (1) --Y--(CH 2 ) q --R 6 where Y is --NH-- or --O--; q is 0 to 5; and R 6 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR51## where Y is as defined above; r is 0 or 1; r' is 0 or 1; r" is 1 to 4; r"' is 1 to 4; and R 6 and R a 6 may be the same or different and have the same meaning as R 6 above and R a 6 may additionally be ##STR52## where R 7 is hydrogen or C 1-3 alkyl; ##STR53## where Y is as defined above; s is 0 or 1; and Z is ##STR54## where s is 0 or 1; and R 7 is as defined above; or ##STR55## where s is 0 or 1; ##STR56## (5) absent; F is absent; OR; NHR; or N(R)2, where R may be the same or different and is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; quanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR57## where R 8 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; arylC 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 2 to 4; m' is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, and E 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 hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: ##STR47## wherein: A is hydrogen; ##STR48## where n is 0 to 5 and R 3 has the same meaning as set out further below, and may additionally be hydrogen; B is absent; glycyl; sarcosyl; or ##STR49## where R 1 has the same meaning as set out further below; D is absent; or ##STR50## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is (1) --Y--(CH 2 ) q --R 6 where Y is --NH-- or --O--; q is 0 to 5; and R 6 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR51## where Y is as defined above; r is 0 or 1; r' is 0 or 1; r" is 1 to 4; r"' is 1 to 4; and R 6 and R a 6 may be the same or different and have the same meaning as R 6 above and R a 6 may additionally be ##STR52## where R 7 is hydrogen or C 1-3 alkyl; ##STR53## where Y is as defined above; s is 0 or 1; and Z is ##STR54## where s is 0 or 1; and R 7 is as defined above; or ##STR55## where s is 0 or 1; ##STR56## (5) absent; F is absent; OR; NHR; or N(R)2, where R may be the same or different and is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; quanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR57## where R 8 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; arylC 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 2 to 4; m' is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, and E 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: ______________________________________ IVA HisProHphHisStaLeuPheNH.sub.2 IVA HisProHphHisACHPALeuPheNH.sub.2 IVA HisProHphHisStaIleHisNH.sub.2 IVA ##STR58## ##STR59## IVA ##STR60## ##STR61## ##STR62## ##STR63## ______________________________________