Renin inhibitory tripeptides

Claim 2

A peptide of the formula: wherein: A is hydrogen; or where X is -O-; -O-CH-; -CH-O-; -CH-; -NH-CH-; or -S- CH -; and and may be the same or different and are hydrogen; Y-(CH 2 ) n - or Y-(CH 2 ) m -CH=CH-(CH 2 ) p , where Y is hydrogen; aryl; 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; n is 0 to 5; m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of or R2 is present; R 1 is hydrogen; C 1-4 alkyl, provided, that where R 1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl; 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; fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or , where R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 3-4 altcyl, trifluoromethyl, hydroxy; C 1-4 alkoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and B is (1) -Y-(CH 2 ) n -R 6 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; where Y is as defined above; n is 0 or 1; k is 0 or 1; 1 is 1 to 4; m is 1 to 4; and R 6 and R 6 may be the same or different and have the same meaning as R 6 above and R6 may additionally be where R 7 is hydrogen or C 1-3 alkyl; where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; or D is absent; glycyl; sarcosyl; or ; and E is absent; OR; NHR; or N(R) 2 , where 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 for those in the A, B,and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 3

A peptide according to Claim 1 wherein the peptide is a member selected from the group consisting essentially of: His-Sta-Leu-Phe-methyl ester; His-Sta-Phe-Phe-methyl ester; His-Sta-Ala-Phe-methyl ester; BOC-His-Sta-Leu-Phe-amide; POA-His-Sta-Leu-Phe-methyl ester; POA-His-Sta-Leu-Phe-amide; POA-His-Sta-Phe-Phe-amide; 3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-methyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-ethyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2,3-diphenylpropionyl-His-Sta-Leu-benzylamide; 2-benzyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenethyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenylpropyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenylbutyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenethenyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-(4,4-dimethyl-l-butenyl)-3-phenylpropionyl-His-Sta-Leu-benzylamide; 10,11-dihydro-SH-dibenzo- [2,d]cycloheptenylcarbonyl-His-Sta-Leu-benzylamide; BOC -His-AHPPA-Leu-benzylamide; 3-phenylpropionyl-His-AHPPA-Leu-benzylamide; POA-His-AHPPA-Leu-benzylamide; 2-benzyl-3-phenylpropionyl-His-AHPPA-Leu-benzylamide. POA-His-ACHPA-Leu-Phe-amide; POA-His-ACHPA-Ile-benzylamide; POA-His-ACHPA-Ile-2-pyridyl- methylamide; 2-phenylpropyl-3-phenylpropionyl-His-AHPPA-Leu-benzylamide.

Claim 4

A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen; or where X is -O-; -O-CH-; -CH-O-; -CH-; -NH-CH-; or -S-CH-; and and may be the same or different and are hydrogen; Y-(CH 2 ) n - or Y-(CH 2 ) m -CH=CH-(CH 2 ) P , where Y is hydrogen; aryl; 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; n is 0 to 5; m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of R2 or R2 is present; R is hydrogen; C 1-4 alkyl, provided, that where R 1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl; 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; fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or- , where R 2 is hydrogen; 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, fluoro, chloro, bromo, and iodo; or indolyl; R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and B is (1) -Y-(CH 2 )n-R 6 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-Cl-4alkylamino; 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; where Y is as defined above; n is 0 or 1; k is 0 or 1; 1 is 1 to 4; m is 1 to 4; and R 6 and may be the same or different and have the same meaning as R 6 above and R 6 may additionally be where R 7 is hydrogen or C 1-3 alkyl; where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; or D is absent; glycyl; sarcosyl; or ; and E is absent; OR; NHR; or N(R) 2 , where 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 for those in the A,-B,and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 5

A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula: wherein: A is hydrogen; or where X is -O-; -O-CH-; -CH-O-; -CH-; -NH-CH-; or -S-CH-; and and may be the same or different and are hydrogen; Y-(CH 2 ) n - or Y-(CH 2 ) m -CH=CH-(CH 2 ) P , where Y is hydrogen; aryl; 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; n is 0 to 5; m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of R2 or R2 is present; R is hydrogen; C 1-4 alkyl, provided, that where R 1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl; 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; fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or- , where R 2 is hydrogen; 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, fluoro, chloro, bromo, and iodo; or indolyl; R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and B is (1) -Y-(CH 2 )n-R 6 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-Cl-4alkylamino; 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; where Y is as defined above; n is 0 or 1; k is 0 or 1; 1 is 1 to 4; m is 1 to 4; and R 6 and may be the same or different and have the same meaning as R 6 above and R 6 may additionally be where R 7 is hydrogen or C 1-3 alkyl; where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; or D is absent; glycyl; sarcosyl; or ; and E is absent; OR; NHR; or N(R) 2 , where 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 for those in the A,-B,and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 6

A composition according to Claim 3 wherein the peptide is a member selected from the group consisting essentially of: His-Sta-Leu-Phe-methyl ester; His-Sta-Phe-Phe-methyl ester; His-Sta-Ala-Phe-methyl ester, BOC-His-Sta-Leu-Phe-amide; POA-His-Sta-Leu-Phe-methyl ester; POA-His-Sta-Leu-Phe-amide; POA-His-Sta-Phe-Phe-amide; 3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-methyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-ethyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2,3-diphenylpropionyl-His-Sta-Leu-benzylamide; 2-benzyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenethyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenylpropyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenylbutyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-phenethenyl-3-phenylpropionyl-His-Sta-Leu-benzylamide; 2-(4,4-dimethyl-l-butenyl)-3-phenylpropionyl-His-Sta-Leu-benzylamide; 10,11-dihydro-5H-dibenzo- [2,d]cycloheptenylcarbonyl-His-Sta-Leu-benzylamide; BOC -His-AHPPA-Leu-benzylamide; 3-phenylpropionyl-His-AHPPA-Leu-benzylamide; POA-His-AHPPA-Leu-benzylamide; 2-benzyl-3-phenylpropionyl-His-AHPPA-Leu-benzylamide; POA-His-ACHPA-Leu-Phe-amide; POA-His-ACHPA-Ile-benzylamide; POA-His-ACHPA-Ile-2-pyridyl- methylamide; 2-phenylpropyl-3-phenylpropionyl-His-AHPPA-Leu-benzylamide.

Claim 7

A pharmaceutical composition for treating renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula wherein: A is hydrogen; o where X is -0-; -0-CH-; -CH-O-; -CH-; -NH-CH-; ;or -S-CH-; and and may be the same or different and are hydrogen; Y-(CH 2 ) n - or Y-(CH 2 ) m -CH=CH-(CH 2 ) P , where Y is hydrogen; aryl; 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; n is 0 to 5; m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of or R2 is present; R is hydrogen; C 1-4 alkyl, provided, that where R 1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl; 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; fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ' , where R 2 is hydrogen; 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, fluoro, chloro, bromo, and iodo; or indolyl; R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C3-7 cycloalkyl; and B is (1) -Y-(CH 2 ) n -R 6 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 l-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; where Y is as defined above; n is 0 or 1; k is 0 or 1; 1 is 1 to 4; m is 1 to 4; and R 6 and R 6 may be the same or different and have the same meaning as R 6 above and may additionally be where R 7 is hydrogen or C 1-3 alkyl; where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; or D is absent; glycyl; sarcosyl; or ; and E is absent; OR; NHR; or N(R) 2 , where 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 for those in the A, B,and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 8

A pharmaceutical composition for treating renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of the formula wherein: A is hydrogen; o where X is -0-; -0-CH-; -CH-O-; -CH-; -NH-CH-; ;or -S-CH-; and and may be the same or different and are hydrogen; Y-(CH 2 ) n - or Y-(CH 2 ) m -CH=CH-(CH 2 ) P , where Y is hydrogen; aryl; 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; n is 0 to 5; m is 0 to 2; and p is 0 to 2; except that where X is -O-, only one of or R2 is present; R is hydrogen; C 1-4 alkyl, provided, that where R 1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl; 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; fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or ' , where R 2 is hydrogen; 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, fluoro, chloro, bromo, and iodo; or indolyl; R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C3-7 cycloalkyl; and B is (1) -Y-(CH 2 ) n -R 6 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 l-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; where Y is as defined above; n is 0 or 1; k is 0 or 1; 1 is 1 to 4; m is 1 to 4; and R 6 and R 6 may be the same or different and have the same meaning as R 6 above and may additionally be where R 7 is hydrogen or C 1-3 alkyl; where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; or D is absent; glycyl; sarcosyl; or ; and E is absent; OR; NHR; or N(R) 2 , where 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 for those in the A, B,and D substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.