Renin inhibitory peptides having improved solubility

Claim 2

A peptide of the formula: ##STR44## wherein: A is hydrogen or ##STR45## where X is --O--; ##STR46## R a 5 and R b 5 may be the same or different and are hydrogen; Y--(CH 2 )p-- or Y--(CH 2 ) p' --CH=CH--(CH 2 ) p" , where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or 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; p is 0 to 5; and p' and p" are independently 0 to 2; except that where X is --O--, only one of R a 5 or R b 5 is present; B is absent; glycyl; sarcosyl; or ##STR47## where R 1 has the same meaning as set out further below; D is absent; or ##STR48## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is ##STR49## where Y is --NH-- or --O--; q is 1-5; q' is 0-5; R 6 is hydrogen; hydroxy; N(R) 2 , where R may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N.sup.⊕ (R) 3 A.sup.⊖, where R is as defined above, and A - is a counterion; provided that at least one R 6 is not hydrogen; R 7 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to three 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, amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; 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; R 8 is hydrogen; or carboxy, ester, or amide; R 12 is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 13 is carboxy, ester, or amide; or ##STR50## where Y is --NH-- or --O--; k is 0-4; k' is 0 or 1; k" is 0-4; k"' is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; 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, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, and halo; or indolyl; 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, and halo; R 4 is hydrogen; or ##STR51## 10 where R 10 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 1 to 4; m' 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 E 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: ##STR52##

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: ##STR53## wherein: A is hydrogen; or ##STR54## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH--; and R a 5 and R b 5 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y'(CH 2 ) p' --CH=CH--(CH 2 ) p" , where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or 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; p is 0 to 5; and p' and p" are independently 0 to 2; except that where X is --O--, only one of R a 5 or R b 5 is present; B is absent; glycyl; sarcosyl; or ##STR55## where R 1 has the same meaning as set out further below; D is absent; or ##STR56## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is ##STR57## where Y is --NH-- or --O--; q is 1-5; q' is 0-5; R 6 is hydrogen; hydroxy; N(R) 2 , where R may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N.sup.⊕ (r) 3 A.sup.⊕ where R is as defined above, and A.sup.⊖ is a counterion; provided that at least one R 6 is not hydrogen; R 7 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to three 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, amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 -alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 16 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 8 is hydrogen; or carboxy, ester, or amide; R 12 is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl, ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 13 is carboxy, ester, or amide; or ##STR58## where Y is --NH-- or --O--; k is 0-4; k' is 0 or 1; K" is 0-4; k"' is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; 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, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, and halo; or indolyl; 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, and halo; R 4 is hydrogen; or ##STR59## where R 10 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 1 to 4; m' 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 E 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: ##STR53## wherein: A is hydrogen; or ##STR54## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH--; and R a 5 and R b 5 may be the same or different and are hydrogen; Y--(CH 2 ) p -- or Y'(CH 2 ) p' --CH=CH--(CH 2 ) p" , where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or 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; p is 0 to 5; and p' and p" are independently 0 to 2; except that where X is --O--, only one of R a 5 or R b 5 is present; B is absent; glycyl; sarcosyl; or ##STR55## where R 1 has the same meaning as set out further below; D is absent; or ##STR56## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is ##STR57## where Y is --NH-- or --O--; q is 1-5; q' is 0-5; R 6 is hydrogen; hydroxy; N(R) 2 , where R may be the same or different and is hydrogen or C 1-4 alkyl; guanidyl; or N.sup.⊕ (r) 3 A.sup.⊕ where R is as defined above, and A.sup.⊖ is a counterion; provided that at least one R 6 is not hydrogen; R 7 is C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to three 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, amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 -alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 -alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; carboxy, ester or amide; sulfo; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 16 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; R 8 is hydrogen; or carboxy, ester, or amide; R 12 is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C 1-4 alkyl, mono-, di-, or tri-C 1-4 alkylamino-C 1-4 alkyl, halo, carboxy, carboxy ester or amide, carboxy-C 1-4 alkoxy, carboxy-C 1-4 alkoxy ester or amide, α-aminocarboxy-C 1-4 alkyl, α-aminocarboxy-C 1-4 alkyl, ester or amide, carboxy-C 1-4 alkyl, carboxy-C 1-4 alkyl ester or amide, guanidyl, and guanidyl-C 1-4 alkyl; and R 13 is carboxy, ester, or amide; or ##STR58## where Y is --NH-- or --O--; k is 0-4; k' is 0 or 1; K" is 0-4; k"' is 0 or 1; R' is hydrogen or C 1-4 alkyl; and R" is hydrogen or C 1-4 alkyl; R 1 is hydrogen; C 1-4 alkyl; 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, and halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; 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, and halo; or indolyl; 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, and halo; R 4 is hydrogen; or ##STR59## where R 10 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 9 is hydrogen; C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; m is 1 to 4; m' 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 E 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: ##STR60##