Imidazole angiotensin II antagonists incorporating a substituted benzyl element

Claim 1

A compound of Formula 1 which is ##STR44## or a pharmaceutically acceptable salt thereof wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below, ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) COOR 2 , vii) N[((C 1 -C 4 )-alkyl)] 2 , viii) NHSO 2 R 2 , ix) CF 3 , x) COOR 2 , or xi) SO 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: i) Cl, Br, F, I, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 v) CF 3 vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C 3 -C 10 )-alkenyl; and E is: (a) a single bond, (b) --S(O) x (CH 2 ) s --, or (c) --O--; and x is 0 to 2, s is 0 to 5; m is 1 to 5; p is 0 to 3; n is 1 to 10; R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl, and R 2a is: (a) R 2 , (b) CH 2 -aryl, or (c) aryl; and R 3 is: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl, (c) Cl, Br, I, F, (d) NO 2 (e) (C 1 -C 8 )-perfluoroalkyl, (f) C 6 F 5 , (g) CN, (h) NH 2 , (i) NH[(C 1 -C 4 )-alkyl], (j) N[(C 1 -C 4 )-alkyl] 2 , (k) NH[CO(C 1 -C 4 )-alkyl], (l) N[(C 1 -C 4 )-alkyl)-(CO(C 1 -C 4 )-alkyl)], (m) N(C 1 -C 4 )-alkyl-COaryl, (n) N(C 1 -C 4 )alkyl-SO 2 aryl, (o) CO 2 H, (p) CO 2 R 2a , (q) phenyl, (r) phenyl-(C 1 -C 3 )-alkyl, (s) phenyl and phenyl-(C 1 -C 3 )-alkyl substituted on the phenyl ring with one or two substituents selected from: i) (C 1 -C 4 )-alkyl, ii) (C 1 -C 4 )-alkoxyl, iii) F, Cl, Br, I, iv) hydroxyl, v) methoxyl, vi) CF 3 , vii) CO 2 R 2a , or viii) NO 2 ; and R 4 is: (a) H, (b) CN, (c) (C 1 -C 8 )-alkyl, (d) (C 3 -C 6 )-alkenyl, (e) (C 1 -C 8 )-perfluoroalkyl, (f) (C 1 -C 8 )-perfluoroalkenyl, (g) NH 2 , (h) NH(C 1 -C 4 )-alkyl, (i) N[(C 1 -C 4 )-alkyl] 2 , (j) NH(C 1 -C 4 )-acyl, (k) N[((C 1 -C 4 )-acyl)((C 1 -C 4 )-alkyl)], (l) CO 2 H, (m) CO 2 R 24 , (n) phenyl, (o) phenyl-(C 2 -C 6 )-alkenyl, ##STR45## (z) (CH 2 ) n NHSO 2 R 16 , (aa) (CH 2 ) n F, (ab) (CH 2 ) m -imidazol-1-yl, (ac) tetrazol-5-yl, (ad) --CONH--SO 2 -aryl, (ae) --CONH--SO 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (af) --CONH--SO 2 --(C 1 -C 4 )-perfluoroalkyl, (ag) --CONHSO 2 NR 2a R 2a ; and ##STR46## R 5 is: (a) CN, (b) NO 2 , or (c) CO 2 R 2a ; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form an phenyl ring, (h) (C 1 -C 6 )-perfluoroalkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j) aryl, (k) (C 1 -C 6 )-alkyl-S(O) x --(CH 2 ) n --, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2 R 21 , (q) --[(C 1 -C 6 )-alkyl]NR 2 R 21 , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , (t) --NR 2 CO--(C 1 -C 4 )-alkyl, or (u) --CON(R 2 ) 2 ; and X is: (a) --O--, (b) --S(O) x --, (c) --NR 13 -- (d) --CH 2 O--, (e) --CH 2 S(O) x , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) x CH 2 --, (j) --CH 2 --, (k) --(CH 2 ) 2 --, (l) single bond, or (m) --CH═, wherein Y and R 12 are absent forming a --C═C-- bridge to the carbon bearing Z and R 11 ; and Y is: (a) single bond, (b) --O--, (c) --S(O) x --, (d) --NR 13 --, or (e) --CH 2 --; and except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO 2 ); R 11 and R 12 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 21 , (iv) OH, (v) CO 2 R 2a , or (vi) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substitutents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl-S(O) x --(CH 2 ) x --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 21 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 ) 2 , (xiii) --G--[(C 1 -C 6 )-alkyl]--R 23 , (xiv) --P(O)[O--(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl; G is: a single bond, O, S(O) x or NR 23 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl--(C═O)--, (e) (C 1 -C 6 )-alkyl--(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) aryl-CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 24 , (c) --tetrazol-5-yl, (d) --CO--NH(tetrazol-5-yl) (e) --CONH--SO 2 -aryl, (f) --CONH--SO 2 --(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (g) --CONHSO 2 --(C 1 -C 4 )-perfluoroalkyl, (i) --CONHSO 2 NR 2a R 2a ; and (j) --SO 2 NHCO-aryl, (k) --SO 2 NHCO--(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (l) --SO 2 NHCO--(C 1 -C 4 )-perfluoroalkyl, (n) --SO 2 NHCONR 2a R 2a ; (o) --PO(OH) 2 , (p) --PO(OR 2 ) 2 , or (q) --PO(OH)(OR 2 ); and R 14 is: (a) H, (b) (C 1 -C 8 )-alkyl, (c) (C 1 -C 8 )-perfluoroalkyl, (d) (C 3 -C 6 )-cycloalkyl, (e) phenyl, or (f) benzyl; and R 15 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) (C 3 -C 6 )-cycloalkyl, (d) (CH 2 ) p -phenyl, (e) OR 17 , (f) NR 18 R 19 ; and R 16 is: (a) (C 1 -C 8 )-alkyl, (b) (C 1 -C 8 )-perfluoroalkyl, (c) 1-adamantyl, (d) 1-naphthyl, (e) (1-naphthyl)ethyl, or (f) --(CH 2 ) p -phenyl; and R 17 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) (C 3 -C 6 )-cycloalkyl, (d) phenyl, or (e) benzyl; and R 18 and R 19 are independently: (a) H, (b) (C 1 -C 4 )-alkyl, (c) phenyl, (d) benzyl, or (e) α-methylbenzyl; and R 21 is: (a) H, or (b) (C 1 -C 4 )-alkyl, is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 22 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazole can be substituted with (C 1 -C 4 )-alkyl; and R 23 is: (a) OH, (b) NR 2 R 21 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) x --(C 1 -C 4 )-alkyl, R 24 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 25 --O--COR 26 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (e) aryl, or --CH 2 -aryl, where aryl is as defined above or optionally substituted with --CO 2 --(C 1 -C 4 )-alkyl, ##STR47## R 25 and R 26 independently are (C 1 -C 6 )-alkyl or phenyl.