Renin inhibitors containing a C-terminal disulfide cycle

Claim 1

A peptide of the formula: ##STR28## wherein: A is hydrogen; or ##STR29## where X is --O--; ##STR30## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p , --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR31## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR32## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR33## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR34## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR35## 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; ##STR36## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 7

A method of treating renin-associated hypertension comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR48## wherein: A is hydrogen; or ##STR49## where X is --O--; --O--CH--; --CH--O--; or --CH--; and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR50## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR51## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR52## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR53## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR54## 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; ##STR55## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 8

A method of treating renin-associated hypertension comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR48## wherein: A is hydrogen; or ##STR49## where X is --O--; --O--CH--; --CH--O--; or --CH--; and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR50## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR51## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR52## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR53## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR54## 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; ##STR55## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 10

A method of treating renin-associated hyperaldosteronism, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR57## wherein: A is hydrogen; or ##STR58## where X is --O--; ##STR59## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR60## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR61## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR62## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR63## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR64## 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; ##STR65## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 11

A method of treating renin-associated hyperaldosteronism, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR57## wherein: A is hydrogen; or ##STR58## where X is --O--; ##STR59## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR60## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR61## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR62## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR63## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR64## 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; ##STR65## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 12

A method of determining the presence of renin-associated hypertension in a patient, comprising administering to such a patient, at a hypotensive dosage level and as a single dose, a peptide of the formula: ##STR66## wherein: A is hydrogen; or ##STR67## where X is --O--; ##STR68## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR69## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR70## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR71## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR72## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR73## 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; ##STR74## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.

Claim 13

A method of determining the presence of renin-associated hypertension in a patient, comprising administering to such a patient, at a hypotensive dosage level and as a single dose, a peptide of the formula: ##STR66## wherein: A is hydrogen; or ##STR67## where X is --O--; ##STR68## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y--(CH 2 ) p' --CH═CH--(CH 2 ) p" , where Y is hydrogen; C 1-4 alkyl; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members 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 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR69## where R 2 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; guanidyl C 2-3 alkyl; or methylthiomethyl; D is absent; or ##STR70## where Z is --(CH 2 ) q -- and q is 1 or 2; or --S--; E is absent; or ##STR71## where R 6 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; or aryl C 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; F is hydrogen; ##STR72## where R and R' are independently hydrogen or C 1-4 alkyl; 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 ##STR73## 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; ##STR74## where R 6 and R 7 are as defined above; or --(CH 2 ) r --R 8 , where r is 0 or 1-4; and R 8 is heterocyclic; 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; guanidyl C 2-3 alkyl; or amino C 1-4 alkyl; m and m' are independently 1 or 2; n 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 F substituents, and at the junction of F, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.