Renin inhibitory peptides having PHE13 delection

Claim 1

A peptide of the formula: ##STR45## wherein: A is hydrogen; ##STR46## 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 ##STR47## D is absent; or ##STR48## where Z is (CH 2 ) n and n is 1 or 2; or --S--; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or C 3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ##STR49## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and E is --Y--(CH.sub.2).sub.n --R.sup.6 ( 1) where Y is --NH-- or --O--; n 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; ##STR50## where Y is as defined above; n is 0 or 1; k is 0 or 1; 1is 1 to 4; m 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 ##STR51## where R 7 is hydrogen or C 1-3 alkyl; or ##STR52## where Y is as defined above; n is 0 or 1; and Z is ##STR53## where n is 0 or 1; and R 7 is as defined above; or ##STR54## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, 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: ##STR65## wherein: A is hydrogen; ##STR66## 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 ##STR67## D is absent; or ##STR68## where Z is (CH 2 ) n and n is 1 or 2; or --S--; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or C 3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ##STR69## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and E is --Y--(CH.sub.2).sub.n --R.sup.6 ( 1) where Y is --NH-- or --O--; n 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; ##STR70## where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m 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 ##STR71## where R 7 is hydrogen or C 1-3 alkyl; or ##STR72## where Y is as defined above; n is 0 or 1; and Z is ##STR73## where n is 0 or 1; and R 7 is as defined above; or ##STR74## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, 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: ##STR65## wherein: A is hydrogen; ##STR66## 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 ##STR67## D is absent; or ##STR68## where Z is (CH 2 ) n and n is 1 or 2; or --S--; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or C 3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ##STR69## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and E is --Y--(CH.sub.2).sub.n --R.sup.6 ( 1) where Y is --NH-- or --O--; n 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; ##STR70## where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m 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 ##STR71## where R 7 is hydrogen or C 1-3 alkyl; or ##STR72## where Y is as defined above; n is 0 or 1; and Z is ##STR73## where n is 0 or 1; and R 7 is as defined above; or ##STR74## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, 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: ##STR75##

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: ##STR75##

Claim 14

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: ##STR85## wherein: A is hydrogen; ##STR86## 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 ##STR87## D is absent; or ##STR88## where Z is (CH 2 ) n and n is 1 or 2; or --S--; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or C 3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ##STR89## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and E is --Y--(CH.sub.2).sub.n --R.sup.6 ( 1) where Y is --NH-- or --O--; n 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; ##STR90## where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m 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 ##STR91## where R 7 is hydrogen or C 1-3 alkyl; or ##STR92## where Y is as defined above; n is 0 or 1; and Z is ##STR93## where n is 0 or 1; and R 7 is as defined above; or ##STR94## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.

Claim 15

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: ##STR85## wherein: A is hydrogen; ##STR86## 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 ##STR87## D is absent; or ##STR88## where Z is (CH 2 ) n and n is 1 or 2; or --S--; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or C 3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ##STR89## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and E is --Y--(CH.sub.2).sub.n --R.sup.6 ( 1) where Y is --NH-- or --O--; n 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; ##STR90## where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m 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 ##STR91## where R 7 is hydrogen or C 1-3 alkyl; or ##STR92## where Y is as defined above; n is 0 or 1; and Z is ##STR93## where n is 0 or 1; and R 7 is as defined above; or ##STR94## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.