Novel renin inhibiting peptides having a gamma lactam pseudo dipeptide insert

Claim 1

A renin inhibitory peptide of the formula X--A 6 --B 7 --C 8 --D 9 --E 10 --F 11 --G 12 --H 13 --I 14 --Z, wherein X is (a) hydrogen, (b) C 1 -C 5 alkyl (c) R 5 --O--CH 2 --C(O)--, (d) R 5 --CH 2 --O--C(O)--, (e) R 5 --O--C(O)--, (f) R 5 --(CH 2 ) n --C(O)--, (g) R 4 N(R 4 )--(CH 2 ) n --C(O)--, (h) R 5 --SO 2 --(CH 2 ) q --C(O)--, (i) R 5 --SO 2 --(CH 2 ) q --O--C(O)--, or (j) R 6 --(CH 2 ) i --C(O)--; wherein A 6 is absent or a divalent moiety of the formula XL 1 , XL 2 , or XL 2a ##STR5## wherein B 7 is absent or a divalent moiety of the formula XL b ##STR6## wherein C 8 --D 9 is XL 3 or XL 3a , or ##STR7## wherein C 8 --D 9 is a monovalent moiety of the formula XL 3b when X, A 6 , and B 7 are absent; ##STR8## wherein E 10 --F 11 is a divalent moiety of the formula XL 6 , XL 6a , XL 6b , XL 6c , XL 6d or XL 6e ; ##STR9## wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G 12 is absent or a divalent moiety of the formula XL 4 or XL 4a ; ##STR10## wherein H 13 is absent or a divalent moiety of the formula XL 4 ; ##STR11## wherein I 14 is absent or a divalent moiety of the formula XL 5 ; ##STR12## wherein Z is (a) --O--R 10 , (b) --N(R 4 )R 14 , or (c) C 4 -C 8 cyclic amino; wherein R is (a) isopropyl, (b) isobutyl, (c) phenylmethyl, or (d) C 3 -C 7 cycloalkyl; wherein R 1 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) aryl, (d) C 3 -C 7 cycloalkyl, (e) --Het, (f) C 1 -C 3 alkoxy, or (g) C 1 -C 3 alkylthio; wherein R 2 is (a) hydrogen, or (b) --CH(R 3 )R 4 ; wherein R 3 is (a) hydrogen, (b) hydroxy, (c) C 1 -C 5 alkyl, (d) C 3 -C 7 cycloalkyl, (e) aryl, (f) --Het, (g) C 1 -C 3 alkoxy, or (h) C 1 -C 3 alkylthio; wherein R 4 at each occurrence is the same or different and is (a) hydrogen, or (b) C 1 -C 5 alkyl; wherein R 5 is (a) C 1 -C 6 alkyl, (b) C 3 -C 7 cycloalkyl, (c) aryl, (d) --Het, or (e) 5-oxo-2-pyrrolidinyl; wherein R 6 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) --(CH 2 ) p --aryl, (d) --(CH 2 ) p --Het, (e) --(CH 2 ) p --C 3 -C 7 cycloalkyl, (f) 1- or 2-adamantyl, (g) --S--aryl, (h) --S--C 3 -C 7 cycloalkyl, or (i) --S--C 1 -C 6 --alkyl; wherein R 7 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) hydroxy, (d) amino C 1 -C 4 alkyl--, (e) guanidinyl C 1 -C 3 alkyl--, (f) aryl, (g) --Het, (h) methylthio, (i) --(CH 2 ) p --C 3 -C 7 cycloalkyl, or (j) amino; wherein R 8 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) hydroxy, (d) aryl, (e) --Het, (f) guanidinyl C 1 -C 3 alkyl--, or (g) --(CH 2 ) p --C 3 -C 7 cycloalkyl; wherein R 9 is (a) hydrogen, (b) hydroxy, (c) amino C 1 -C 4 alkyl--, or (d) guanidinyl C 1 -C 3 alkyl--; wherein R 10 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) --(CH 2 ) n R 16 , (d) --(CH 2 ) n R 17 , (e) C 3 -C 7 cycloalkyl, (f) a pharmaceutically acceptable cation, (g) --CH(R 25 )--CH 2 --R 15 , or (h) --CH 2 --CH(R 12 )--R 15 ; wherein R 11 is --R or --R 2 ; wherein R 12 is --(CH 2 ) n --R 13 ; wherein R 13 is (a) aryl, (b) amino, (c) mono-, di or tri-C 1 -C 3 alkylamino, (d) --Het, (e) C 1 -C 5 alkyl (f) C 3 -C 7 cycloalkyl, (g) C 2 -C 5 alkenyl, (h) C 3 -C 7 cycloalkenyl, (i) hydroxy, (j) C 1 -C 3 alkoxy, (k) C 1 -C 3 alkanoyloxy, (l) mercapto, (m) C 1 -C 3 alkylthio, (n) --COOH, (o) --CO--O--C 1 -C 6 alkyl, (p) --CO--O--CH 2 --(C 1 -C 3 alkyl)--N(C 1 -C 3 alkyl) 2 , (q) --CO--NR 22 R 26 ; (r) C 4 -C 7 cyclic amino, (s) C 4 -C 7 cycloalkylamino, (t) guanidyl, (u) cyano, (v) N-cyanoguanidyl, (w) cyanoamino, (x) (hydroxy C 2 -C 4 alkyl)amino, or (y) di-(hydroxyC 2 -C 4 alkyl)amino; wherein R 14 is (a) hydrogen, (b) C 1 -C 10 alkyl, (c) --(CH 2 ) n --R 18 , (d) --(CH 2 ) n --R 19 , (e) --CH(R 25 )--CH 2 --R 15 , (f) --CH 2 --CH(R 12 )--R 15 , (g) (hydroxy C 1 -C 8 alkyl), or (h) (C 1 -C 3 alkoxy)C 1 -C 8 alkyl; wherein R 15 is (a) hydroxy, (b) C 3 -C 7 cycloalkyl, (c) aryl, (d) amino, (e) mono-, di-, or tri-C 1 -C 3 alkylamino, (f) mono- or di-[hydroxy C 2 -C 4 alkyl]amino, (g) --Het, (h) C 1 -C 3 alkoxy--, (i) C 1 -C 3 alkanoyloxy--, (j) mercapto, (k) C 1 -C 3 alkylthio--, (l) C 1 -C 5 alkyl, (m) C 4 -C 7 cyclic amino, (n) C 4 -C 7 cycloalkylamino, (o) C 1 -C 5 alkenyloxy, (p) C 3 -C 7 cycloalkenyl; wherein R 16 is (a) aryl, (b) amino, (c) mono- or di-C 1 -C 3 alkylamino, (d) hydroxy, (e) C 3 -C 7 cycloalkyl, (f) C 4 -C 7 cyclic amino, or (g) C 1 -C 3 alkanoyloxy; wherein R 17 is (a) --Het, (b) C 2 -C 5 alkenyl, (c) C 3 -C 7 cycloalkenyl, (d) C 1 -C 3 alkoxy, (e) mercapto, (f) C 1 -C 3 alkylthio, (g) --COOH, (h) --CO--O--C 1 -C 6 alkyl, (i) --CO--O--CH 2 --(C 1 -C 3 alkyl)--N(C 1 -C 3 alkyl) 2 , (j) --CO--NR 22 R 26 , (k) tri-C 1 -C 3 alkylamino, (l) guanidyl, (m) cyano, (n) N-cyanoguanidyl, (o) (hydroxy C 2 -C 4 alkyl)amino, (p) di-(hydroxy C 2 -C 4 alkyl)amino, or (q) cyanoamino; wherein R 18 is (a) amino, (b) mono-, or di-C 1 -C 3 alkylamino, (c) C 4 -C 7 cyclic amino; or (d) C 4 -C 7 cycloalkylamino; wherein R 19 is (a) aryl, (b) --Het, (c) tri-C 1 -C 3 alkylamino, (d) C 3 -C 7 cycloalkyl, (e) C 2 -C 5 alkenyl, (f) C 3 -C 7 cycloalkenyl, (g) hydroxy, (h) C 1 -C 3 alkoxy, (i) C 1 -C 3 alkanoyloxy, (j) mercapto, (k) C 1 -C 3 alkylthio, (l) --COOH, (m) --CO--O--C 1 -C 6 alkyl, (n) --CO--O--CH 2 --(C 1 -C 3 alkyl)--N(C 1 -C 3 alkyl) 2 , (o) --CO--NR 22 R 26 , (p) guanidyl, (q) cyano, (r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy C 2 -C 4 alkyl)amino, (u) di-(hydroxy C 2 -C 4 alkyl)amino; or (v) --SO 3 H; wherein R 20 is (a) hydrogen, (b) C 1 -C 5 alkyl, or (c) aryl--C 1 -C 5 alkyl; wherein R 21 is (a) --NH 2 , or (b) --OH; wherein R 22 is (a) hydrogen, or (b) C 1 -C 3 alkyl; wherein R 23 is (a) --(CH 2 ) n --OH, (b) --(CH 2 ) n --NH 2 , (c) aryl, or (d) C 1 -C 3 alkyl; wherein R 24 is (a) --R 1 , (b) --(CH 2 ) n --OH, or (c) --(CH 2 ) n --NH 2 ; wherein R 25 is (a) hydrogen, (b) C 1 -C 3 alkyl, or (c) phenyl--C 1 -C 3 alkyl; wherein R 26 is (a) hydrogen, (b) C 1 -C 3 alkyl, or (c) phenyl--C 1 -C 3 alkyl; wherein m is one or two; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein p is zero to 2 inclusive; wherein q is 1 to 5, inclusive; wherein Q is (a) --CH 2 --, (b) --CH(OH)--, (c) --O--, or (d) --S--; and wherein M is (a) --CO--, or (b) --CH 2 --; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: (a) C 1 -C 3 alkyl, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) halo, (e) amino, (f) mono- or di-C 1 -C 3 alkylamino, (g) --CHO, (h) --COOH, (i) COOR 26 , (j) CONHR 26 , (k) nitro, (l) mercapto, (m) C 1 -C 3 alkylthio, (n) C 1 -C 3 alkylsulfinyl, (o) C 1 -C 3 alkylsulfonyl, (p) --N(R 4 )--C 1 -C 3 alkylsulfonyl, (q) SO 3 H, (r) SO 2 NH 2 , (s) --CN, or (t) --CH 2 NH 2 ; wherein --Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) C 1 -C 6 alkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C 1 -C 4 alkoxy, (v) halo, (vi) aryl, (vii) aryl C 1 -C 4 alkyl--, (viii) amino, (ix) mono- or di-C 1 -C 4 alkylamino, and (x) C 1 -C 5 alkanoyl; with the overall provisos that (1) R 18 or R 19 is hydroxy, mercapto, or amino, or a mono-substituted nitrogen containing group bonded through the nitrogen only when n is not one; (2) R 12 is --(CH 2 ) n --R 13 and n is zero and both R 13 and R 15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen; (3) R 17 or R 19 is --COOH only when n for that moiety is other than zero; (4) R 16 or R 17 is an amino-containing substituent, hydroxy, mercapto, or --Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive; (5) when R 12 is --(CH 2 ) n --R 13 and n is zero, then R 13 and R 15 cannot both be --COOH; and (6) R 17 or R 19 is --Het, only when --Het is other than cyclic amino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof.