Renin inhibitors containing a C-terminal disulfide cycle

A pharmaceutical composition for treating renin-associated hypertension or hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula:

• ##STR38## wherein:
• A is hydrogen;
• or ##STR39## where X is --O--;
• ##STR40## and R.sub.a.sup.1 and R.sub.b.sup.1 may be the same or different and are hydrogen;
• Y--(CH.sub.2).sub.p -- or Y--(CH.sub.2).sub.p, --CH.dbd.CH--(CH.sub.2).sub.p", where Y is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• C.sub.3-7 cycloalkyl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.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.sub.a.sup.1 or R.sub.b.sup.1 is present;
• B is absent;
• glycyl;
• sarcosyl;
• or ##STR41## where R.sup.2 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy C.sub.1-4 alkyl;
• aryl;
• aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• indolyl;
• 4-imidazolyl;
• amino C.sub.2-4 alkyl;
• guanidyl C.sub.2-3 alkyl;
• or methylthiomethyl;
• D is absent;
• or ##STR42## where Z is --(CH.sub.2).sub.q -- and q is 1 or 2;
• or --S--;
• E is absent;
• or ##STR43## where R.sup.6 is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• aryl C.sub.1-4 alkyl;
• or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• or indolyl;
• F is hydrogen;
• ##STR44## where R and R' are independently hydrogen or C.sub.1-4 alkyl;
• R.sup.3 is C.sub.3-6 alkyl;
• C.sub.3-7 cycloalkyl;
• aryl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• R.sup.4 is hydrogen;
• or ##STR45## where R.sup.7 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy;
• or C.sub.3-7 cycloalkyl;
• and R.sup.6 is as defined above;
• R.sup.5 is hydrogen;
• ##STR46## where R.sup.6 and R.sup.7 are as defined above;
• or --(CH.sub.2).sub.r --R.sup.8, where r is 0 or 1-4;
• and R.sup.8 is heterocyclic;
• heterocyclic substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, trifluoromethyl;
• C.sub.1-4 alkoxy, halo, aryl, aryl C.sub.1-4 alkyl, amino, and mono- or di-C.sub.1-4 alkylamino;
• guanidyl C.sub.2-3 alkyl;
• or amino C.sub.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.

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.sub.a.sup.1 and R.sub.b.sup.1 may be the same or different and are hydrogen;
• Y--(CH.sub.2).sub.p -- or Y--(CH.sub.2).sub.p' --CH.dbd.CH--(CH.sub.2).sub.p", where Y is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• C.sub.3-7 cycloalkyl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.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.sub.a.sup.1 or R.sub.b.sup.1 is present;
• B is absent;
• glycyl;
• sarcosyl;
• or ##STR50## where R.sup.2 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy C.sub.1-4 alkyl;
• aryl;
• aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• indolyl;
• 4-imidazolyl;
• amino C.sub.2-4 alkyl;
• guanidyl C.sub.2-3 alkyl;
• or methylthiomethyl;
• D is absent;
• or ##STR51## where Z is --(CH.sub.2).sub.q -- and q is 1 or 2;
• or --S--;
• E is absent;
• or ##STR52## where R.sup.6 is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• aryl C.sub.1-4 alkyl;
• or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• or indolyl;
• F is hydrogen;
• ##STR53## where R and R' are independently hydrogen or C.sub.1-4 alkyl;
• R.sup.3 is C.sub.3-6 alkyl;
• C.sub.3-7 cycloalkyl;
• aryl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• R.sup.4 is hydrogen;
• or ##STR54## where R.sup.7 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy;
• or C.sub.3-7 cycloalkyl;
• and R.sup.6 is as defined above;
• R.sup.5 is hydrogen;
• ##STR55## where R.sup.6 and R.sup.7 are as defined above;
• or --(CH.sub.2).sub.r --R.sup.8, where r is 0 or 1-4;
• and R.sup.8 is heterocyclic;
• heterocyclic substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, trifluoromethyl, C.sub.1-4 alkoxy, halo, aryl, aryl C.sub.1-4 alkyl, amino, and mono- or di-C.sub.1-4 alkylamino;
• guanidyl C.sub.2-3 alkyl;
• or amino C.sub.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.

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.sub.a.sup.1 and R.sub.b.sup.1 may be the same or different and are hydrogen;
• Y--(CH.sub.2).sub.p -- or Y--(CH.sub.2).sub.p' --CH.dbd.CH--(CH.sub.2).sub.p", where Y is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• C.sub.3-7 cycloalkyl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.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.sub.a.sup.1 or R.sub.b.sup.1 is present;
• B is absent;
• glycyl;
• sarcosyl;
• or ##STR60## where R.sup.2 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy C.sub.1-4 alkyl;
• aryl;
• aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• indolyl;
• 4-imidazolyl;
• amino C.sub.2-4 alkyl;
• guanidyl C.sub.2-3 alkyl;
• or methylthiomethyl;
• D is absent;
• or ##STR61## where Z is --(CH.sub.2).sub.q -- and q is 1 or 2;
• or --S--;
• E is absent;
• or ##STR62## where R.sup.6 is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• aryl C.sub.1-4 alkyl;
• or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• or indolyl;
• F is hydrogen;
• ##STR63## where R and R' are independently hydrogen or C.sub.1-4 alkyl;
• R.sup.3 is C.sub.3-6 alkyl;
• C.sub.3-7 cycloalkyl;
• aryl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• R.sup.4 is hydrogen;
• or ##STR64## where R.sup.7 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy;
• or C.sub.3-7 cycloalkyl;
• and R.sup.6 is as defined above;
• R.sup.5 is hydrogen;
• ##STR65## where R.sup.6 and R.sup.7 are as defined above;
• or --(CH.sub.2).sub.r --R.sup.8, where r is 0 or 1-4;
• and R.sup.8 is heterocyclic;
• heterocyclic substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, trifluoromethyl, C.sub.1-4 alkoxy, halo, aryl, aryl C.sub.1-4 alkyl, amino, and mono- or di-C.sub.1-4 alkylamino;
• guanidyl C.sub.2-3 alkyl;
• or amino C.sub.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.

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.sub.a.sup.1 and R.sub.b.sup.1 may be the same or different and are hydrogen;
• Y--(CH.sub.2).sub.p -- or Y--(CH.sub.2).sub.p' --CH.dbd.CH--(CH.sub.2).sub.p", where Y is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• C.sub.3-7 cycloalkyl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.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.sub.a.sup.1 or R.sub.b.sup.1 is present;
• B is absent;
• glycyl;
• sarcosyl;
• or ##STR69## where R.sup.2 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy C.sub.1-4 alkyl;
• aryl;
• aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• indolyl;
• 4-imidazolyl;
• amino C.sub.2-4 alkyl;
• guanidyl C.sub.2-3 alkyl;
• or methylthiomethyl;
• D is absent;
• or ##STR70## where Z is --(CH.sub.2).sub.q -- and q is 1 or 2;
• or --S--;
• E is absent;
• or ##STR71## where R.sup.6 is hydrogen;
• C.sub.1-4 alkyl;
• aryl;
• aryl C.sub.1-4 alkyl;
• or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• or indolyl;
• F is hydrogen;
• ##STR72## where R and R' are independently hydrogen or C.sub.1-4 alkyl;
• R.sup.3 is C.sub.3-6 alkyl;
• C.sub.3-7 cycloalkyl;
• aryl;
• or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
• R.sup.4 is hydrogen;
• or ##STR73## where R.sup.7 is hydrogen;
• C.sub.1-4 alkyl;
• hydroxy;
• or C.sub.3-7 cycloalkyl;
• and R.sup.6 is as defined above;
• R.sup.5 is hydrogen;
• ##STR74## where R.sup.6 and R.sup.7 are as defined above;
• or --(CH.sub.2).sub.r --R.sup.8, where r is 0 or 1-4;
• and R.sup.8 is heterocyclic;
• heterocyclic substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, trifluoromethyl, C.sub.1-4 alkoxy, halo, aryl, aryl C.sub.1-4 alkyl, amino, and mono- or di-C.sub.1-4 alkylamino;
• guanidyl C.sub.2-3 alkyl;
• or amino C.sub.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.