Renin inhibitory peptides having His13

Claim 1

A peptide of the formula: ##STR15## wherein: A is hydrogen; ##STR16## 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 ##STR17## D is absent; or ##STR18## 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 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 ##STR19## where R' is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3-, or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR"; NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof.

Claim 11

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: ##STR25## wherein: A is hydrogen; ##STR26## 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 ##STR27## D is absent; or ##STR28## 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 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 ##STR29## where R' is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3-, or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR", NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof.

Claim 12

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: ##STR25## wherein: A is hydrogen; ##STR26## 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 ##STR27## D is absent; or ##STR28## 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 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 ##STR29## where R' is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3-, or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR", NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof.

Claim 15

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: ##STR35## wherein: A is hydrogen; ##STR36## 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 ##STR37## D is absent; or ##STR38## 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 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 ##STR39## where R" is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3-, or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR"; NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof.

Claim 16

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: ##STR35## wherein: A is hydrogen; ##STR36## 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 ##STR37## D is absent; or ##STR38## 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 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 ##STR39## where R" is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3-, or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR"; NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof.

Claim 17

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: ##STR40## wherein: A is hydrogen; ##STR41## 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 ##STR42## D is absent; or ##STR43## 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 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 ##STR44## where R' is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3- , or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR"; NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.

Claim 18

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: ##STR40## wherein: A is hydrogen; ##STR41## 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 ##STR42## D is absent; or ##STR43## 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 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 ##STR44## where R' is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; R 5 is 4-imidazolyl; amino C 2-4 alkyl; 2-, 3- , or 4-pyridyl; or guanidyl C 2-3 alkyl; and E is OR"; NHR", or N(R") 2 , where each R" may be the same or different and is hydrogen or C 1-4 alkyl; wherein all of the asymmetric carbon atoms have an S configuration, except those of substituents B and D, which may also have the R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.