Renin inhibitors containing 2-substituted statine

Claim 1

a peptide of the formula: ##STR42## wherein: A is hydrogen; or ##STR43## where X is --O--; --O--CH--; --CH--O--; --CH--; --NH--CH--; or --S--CH-- and R a 2 and R b 2 may be the same or different and are hydrogen; W--(CH 2 ) n -- or W--(CH 2 ) m --CH═CH--(CH 2 ) p , where W is hydrogen; C 1-4 alkyl; phenyl; naphthyl; C 3-7 cycloalkyl; or mono- or disubstituted phenyl, naphthyl or C 3-7 cycloalkyl wherein the substituent(s) is/are 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 R a 2 or R b 2 is present; B is absent; glycyl; sarcosyl; or ##STR44## where R 1 is as defined further below; D is absent; or ##STR45## where Z is --(CH 2 ) 1 -- and 1 is 1 or 2; or --S--; E is absent; or ##STR46## where m is 1 to 4; and R 5 is hydrogen; C 1-4 alkyl; indolyl; phenyl; naphthyl; phenyl-C 1 -C 4 -alkyl; naphthyl-C 1 -C 4 -alkyl; or mono- or disubstituted phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl or naphthyl-C 1 -C 4 -alkyl, wherein the substituent(s) is/are selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; G is ##STR47## where q is 1 to 4; q' is 0 to 4; R 6 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; naphthyl; or mono- or disubstituted phenyl, naphthyl or C 3-7 cycloalkyl, wherein the substituent(s) is/are selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; and R 6a is C 1-8 alkyl; C 2-8 alkyl substituted with one or two members independently selected from the group consisting of hydroxy, carboxy, carboxy ester or amide, amino, mono-, di-, or tri-C 1-4 alkylamino, and guanidyl; wherein said substitution occurs on the last 1 or 2 carbon atoms of the alkyl chain; phenyl; naphthyl; C 3-7 cycloalkyl; or mono- or disubstituted phenyl, naphthyl or C 3-7 cycloalkyl, wherein the substituent(s) is/are selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; J is --Y--(CH.sub.2).sub.n --R.sup.7 ( 1) where Y is --NH-- or --O--; n is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; unsubstituted or mono- or disubstituted phenyl or naphthyl, wherein the substituent(s) is/are 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; or an unsubstituted or mono- or disubstituted heterocycle, representing a 5- or 6-membered ring or benzofused 5- or 6-membered ring comprising one or two heteroatoms independently selected from N, O and S, where the substituent(s) is/are 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; ##STR48## where Y is as defined above; n is 0 or 1; N' is 0 or 1; n" is 1 to 4; n'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR49## where R 8 is hydrogen or C 1-3 alkyl; ##STR50## where Y is as defined above; n is 0 or 1; and Z' is ##STR51## where n is 0 or 1; and R 8 is as defined above; or ##STR52## where n is 0 or 1; ##STR53## where R 5 is as defined above; and R 9 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; or ##STR54## where Y is --NH-- or --O--; q is 1-5; q' is 0-5; R 10 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 10 is not hydrogen; R 11 is C 1-4 alkyl; C 3-7 cycloalkyl; unsubstituted or mono- or disubstituted phenyl or naphthyl, wherein the substituents(s) is/are 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, αaminocarboxy-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; or an unsubstituted or mono- or disubstituted heterocycle, representing a 5- or 6-membered ring or benzofused 5- or 6-membered ring comprising one or two heteroatoms independently selected from N, O and S, where the substituent(s) is/are independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, phenyl-C 1 -C 4 -alkyl, naphthyl-C 1 -C 4 -alkyl, amino, and mono- or di-C 1-4 alkylamino; R 12 is hydrogen; or carboxy, ester or amide; R 13 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 14 is carboxy, ester or amide; or ##STR55## 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; L is absent; OR"; NHR"; or N(R") 2 , where R" may be the same or different and is hydrogen or C 1-4 alkyl; provided that, B and/or L are/is present only when J is ##STR56## where R 5 and R 9 are as defined above; R 1 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; mono- or disubstituted pheny or naphthyl, where the substituent(s) is/are 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; acyl-C 2-4 -alkyl wherein the acyl is ##STR57## and R 9 is as defined above; guanidyl C 2-3 -alkyl; or methylthiomethyl; R 4 is hydrogen; or ##STR58## where R 9 is as defined above; and R 3 is hydrogen; C 1-4 alkyl; indolyl; or unsubstituted or mono- or disubstituted phenyl, naphthyl, phenyl-C 1 -C 4 alkyl, or naphthyl-C 1 -C 4 alkyl, wherein the substituent(s) is/are selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B and D substituents, which may have an S or R configuration, and the G group, which must have a 2R,3S,4S configuration; and a pharmaceutically acceptable salt thereof.