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US4478826A
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Renin inhibitory peptides
Assignee: Merck and Co Inc
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Filing: 1982-09-03
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Granted: 1984-10-23
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Expires: 2002-09-03
Abstract
Abstract Renin inhibitory peptides of the formula ##STR1## and analogs thereof inhibit renin and are useful for treating various forms of renin-associated hypertension and hyperaldosteronism.
Inventors
- 👤 Daniel F. Veber
- 👤 Joshua S. Boger
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 13:53
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/02; C07K5/0227; C07K7/00; C07K7/02; A; A61; A61K; A61K38/00; Y; Y10; Y10S; Y10S530/00; Y10S530/80; Y10S530/86
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
247 words
A peptide of the formula: ##STR13## wherein: A is hydrogen; ##STR14## 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 ##STR15## D is absent; or ##STR16## 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 and R a 4 are independently hydrogen; or ##STR17## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 2
Dependent Claim
247 words
A peptide of the formula: ##STR13## wherein: A is hydrogen; ##STR14## 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 ##STR15## D is absent; or ##STR16## 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 and R a 4 are independently hydrogen; or ##STR17## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 3
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is His-Pro-Phe-His-Sta-Leu-Phe-NH 2 .
Claim 4
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is iso-valeryl-His-Pro-Phe-His-Sta-Leu-Phe-NH 2 .
Claim 5
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is acetyl-Pro-Phe-His-Sta-Leu-Phe-NH 2 .
Claim 6
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is acetyl-Phe-His-Sta-Leu-Phe-NH 2 .
Claim 7
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is tert-butyloxycarbonyl-Phe-His-Sta-Leu-Phe-NH 2 .
Claim 8
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is tert-butyloxycarbonyl-His-Pro-Phe-Phe-Sta-Leu-Phe-NH 2 .
Claim 9
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is iso-butyryl-His-Pro-Phe-His-Sta-Ala-Phe-NH 2 .
Claim 10
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is iso-butyryl-His-Pro-Phe-His-Sta-Cyclo-hexyl-Ala-Phe-NH 2 .
Claim 11
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is tert-butyloxycarbonyl-His-Pro-Phe-His-Sta-Leu-Leu-OCH 3 .
Claim 12
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is tert-butyloxycarbonyl-His-Pro-Phe-His-Sta-Leu-Tyr-NH 2 .
Claim 13
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is iso-butyryl-His-Pro-Phe-His-Sta-Leu-Phe-Lys-NH 2 .
Claim 14
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is tert-butyloxycarbonyl-His-Pro-Phe-p-I-Phe-Sta-Leu-Phe-NH 2 .
Claim 15
Dependent Claim
13 words
A peptide according to claim 1 wherein the peptide is iso-valeryl-His-Pro-Phe-His-Sta-Leu-Val-Phe-NH 2 .
Claim 16
Dependent Claim
264 words
A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: ##STR18## wherein: A is hydrogen; ##STR19## 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 ##STR20## D is absent; or ##STR21## 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 and R a 4 are independently hydrogen; or ##STR22## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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
Dependent Claim
264 words
A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: ##STR18## wherein: A is hydrogen; ##STR19## 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 ##STR20## D is absent; or ##STR21## 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 and R a 4 are independently hydrogen; or ##STR22## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 18
Independent Claim
268 words
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: ##STR23## wherein: A is hydrogen; ##STR24## 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 ##STR25## D is absent; or ##STR26## 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 and R a 4 are independently hydrogen; or ##STR27## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 19
Independent Claim
268 words
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: ##STR23## wherein: A is hydrogen; ##STR24## 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 ##STR25## D is absent; or ##STR26## 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 and R a 4 are independently hydrogen; or ##STR27## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 20
Dependent Claim
264 words
A pharmaceutical composition for treating renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula ##STR28## wherein: A is hydrogen; ##STR29## 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 ##STR30## D is absent; or ##STR31## 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 and R a 4 are independently hydrogen; or ##STR32## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 21
Dependent Claim
264 words
A pharmaceutical composition for treating renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula ##STR28## wherein: A is hydrogen; ##STR29## 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 ##STR30## D is absent; or ##STR31## 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 and R a 4 are independently hydrogen; or ##STR32## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 22
Independent Claim
268 words
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: ##STR33## wherein: A is hydrogen; ##STR34## 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 ##STR35## D is absent; or ##STR36## 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 and R a 4 are independently hydrogen; or ##STR37## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 23
Independent Claim
268 words
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: ##STR33## wherein: A is hydrogen; ##STR34## 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 ##STR35## D is absent; or ##STR36## 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 and R a 4 are independently hydrogen; or ##STR37## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 24
Independent Claim
283 words
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: ##STR38## wherein: A is hydrogen; ##STR39## 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 ##STR40## D is absent; or ##STR41## 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 and R a 4 are independently hydrogen; or ##STR42## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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 25
Independent Claim
283 words
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: ##STR38## wherein: A is hydrogen; ##STR39## 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 ##STR40## D is absent; or ##STR41## 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 and R a 4 are independently hydrogen; or ##STR42## where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; 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.
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