Claims for Patent: 5,210,079

Summary for Patent: 5,210,079

Title:	Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists
Abstract:	Substituted imidazoles such as 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxy methyl)imidazole and 2-butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imi dazole and pharmaceutically acceptable salts thereof are useful for treating chronic renal failure, mediated by angiotensin-II.
Inventor(s):	Carini; David J. (Wilmington, DE), Duncia; John Jonas V. (Newark, DE), Wong; Pancras C. (Wilmington, DE)
Assignee:	E. I. Du Pont de Nemours and Company (Wilmington, DE)
Application Number:	07/832,638
Patent Claims:	1. A method of treating chronic renal failure mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I): ##STR37## wherein R.sup.1 is 4--CO.sub.2 H; 4--CO.sub.2 R.sup.9 ; ##STR38## R.sup.2 is H; Cl; Br; I; F; NO.sub.2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO.sub.2 H; CO.sub.2 R.sup.9 ; NHSO.sub.2 CH.sub.3 ; NHSO.sub.2 CF.sub.3 ; CONHOR.sup.12 ; SO.sub.2 NH.sub.2 ; ##STR39## aryl; or furyl; R.sup.3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ; R.sup.5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms; R.sup.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO.sub.2 R.sup.14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ; benzyl or benzyl substituted on the phenyl ring with 2 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6; C.sub.6 F.sub.5 ; CN; ##STR40## straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH.sub.3, CF.sub.3, and COOR, and R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R.sup.8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the alkenyl portion is 2 to 6 carbon atoms; --(CH.sub.2).sub.m -imidazol-1-yl; --(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms; --(CH.sub.2).sub.s -tetrazolyl; ##STR41## R.sup.9 is ##STR42## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ; R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.12 is H, methyl or benzyl; R.sup.13 is --CO.sub.2 H; --CO.sub.2 R.sup.9 ; --CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ; ##STR43## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ; R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR44## Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl; R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR45## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6; R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ; R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR46## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --; R.sup.31 is H, alkyl of 1 to 4 carbon atoms, --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sup.32 ; R.sup.32 is H, NO.sub.2, NH.sub.2, OH or OCH.sub.3 ; X is a carbon-carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, --NH--, ##STR47## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR48## Y is O or S; Z is O, NR.sup.11, or S; m is 1 to 5; n is 1 to 10; p is 0 to 3; q is 2 to 3; r is 0 to 2; s is 0 to 5; t is 0 or 1; and pharmaceutically acceptable salt of these compounds; provided that: (1) the R.sup.1 group is not in the ortho position; (2) when R.sup.1 is ##STR49## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR50## then R.sup.13 must be in the ortho or meta position; or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho; (3) when R.sup.1 is ##STR51## and X is other than a single bond, then R.sup.13 must be ortho except when X=NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta; (4) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl; (5) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H; (6) when R.sup.1 is ##STR52## X is --OCH.sub.2 --, and R.sup.13 is 2--CO.sub.2 H, and R.sup.7 is H then R.sup.6 is not C.sub.2 H.sub.5 S; (7) when R.sup.1 is ##STR53## and R.sup.6 is n-hexyl, then R.sup.7 and R.sup.8 are not both hydrogen; (8) when R.sup.1 is ##STR54## R.sup.6 is not methoxybenzyl; (9) the R.sup.6 group is not --CHFCH.sub.2 CH.sub.2 CH.sub.3 or CH.sub.2 OH; (10) when r=O, R.sup.1 is ##STR55## X is --NH--CO--, R.sup.13 is 2--NHSO.sub.2 CF.sub.3, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ; (11) when r=0, R.sup.1 is ##STR56## X is --NH--CO--, R.sup.13 is 2--COOH, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ; (12) when r=1, R.sup.1 = ##STR57## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl); (13) when r=1, R.sup.1 = ##STR58## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl). 2. Method of claim 1 wherein, in the compound of formula I is a compound of formula II: ##STR59## wherein R.sup.1 is --CO.sub.2 H; --NHSO.sub.2 CF.sub.3 ; ##STR60## R.sup.6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro; R.sup.8 is ##STR61## phenylalkenyl wherein the alkenyl portion is 2 to 4 carbon atoms; --(CH.sub.2).sub.m -imidazol-1-yl; or --(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from --CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms; R.sup.13 is --CO.sub.2 H, --CO.sub.2 R.sup.9, NHSO.sub.2 CF.sub.3 ; SO.sub.3 H; or ##STR62## R.sup.16 is H, alkyl of 1 to 5 carbon atoms, OR.sup.17, or NR.sup.18 R.sup.19 ; X is carbon-carbon single bond, --CO--, --CH.sub.2 CH.sub.2 --, ##STR63## --OCH.sub.2 --, --CH.sub.2 O--, --O--, --SCH.sub.2 --, --CH.sub.2 S--, --NH--CH.sub.2 --, --CH.sub.2 NH-- or --CH.dbd.CH--; or a pharmaceutically acceptable salt thereof. 3. Method of claim 2 wherein the compound of formula II is a compound wherein: R.sup.2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; R.sup.6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R.sup.7 is H, Cl, Br, I; C.sub.v F.sub.2v+1, where v=1-3; ##STR64## straight or branched chain alkyl of 1 to 6 carbon atoms; or phenyl; R.sup.8 is ##STR65## R.sup.10 is CF.sub.3, alkyl of 1 to 6 carbon atoms or phenyl; R.sup.11 is H, or alkyl of 1 to 4 carbon atoms; R.sup.13 is CO.sub.2 H; CO.sub.2 CH.sub.2 OCOC(CH.sub.3).sub.3 ; NHSO.sub.2 CF.sub.3 ; ##STR66## R.sup.14 is H, or alkyl of 1 to 4 carbon atoms; R.sup.15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R.sup.16 is H, alkyl of 1 to 5 carbon atoms; OR.sup.17 ; or ##STR67## m is 1 to 5; X=single bond, --O--; --CO--; --NHCO--; or --OCH.sub.2 --; or a pharmaceutically acceptable salt thereof. 4. Method of claim 3 wherein the compound of formula II is a compound wherein R.sup.1 is ##STR68## and X is a single bond; or a pharmaceutically suitable salt thereof. 5. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxy methyl)imidazole or a pharmaceutically acceptable salt thereof. 6. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imid azole or a pharmaceutically acceptable salt thereof. 7. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)a minomethyl]imidazole or a pharmaceutically acceptable salt thereof. 8. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)a minomethyl]imidazole or a pharmaceutically acceptable salt thereof. 9. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxalde hyde or a pharmaceutically acceptable salt thereof. 10. Method of claim 4 wherein the compound of formula II is 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof. 11. Method of claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymeth yl)imidazole or a pharmaceutically acceptable salt thereof. 12. Method of claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-car boxaldehyde or a pharmaceutically acceptable salt thereof. 13. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydrox ymethyl) imidazole or a pharmaceutically acceptable salt thereof. 14. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole- 5-carboxaldehyde or a pharmaceutically acceptable salt thereof. 15. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5- carboxaldehyde or a pharmaceutically acceptable salt thereof. 16. Method of claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-h ydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof. 17. Method of claim 4 wherein the compound of formula II is 2-(1E-Butenyl)-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imid azole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof. 18. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole- 5-carboxylic acid or a pharmaceutically acceptable salt thereof. 19. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole -5-carboxylic acid or a pharmaceutically acceptable salt thereof. 20. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 21. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- 5-(hydroxylmethyl)imidazole or a pharmaceutically acceptable salt thereof. 22. Method of claim 4 wherein the compound of formula II is 2-Butyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]im idazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 23. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-trifluoromethyl-1-[(2'-(carboxybiphenyl-4-yl)methyl]imidazole-5 -carboxaldehyde or a pharmaceutically acceptable salt thereof. 24. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] -5-(hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof. 25. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 26. Method of claim 4 wherein the compound of formula II is 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]im idazole-5-carboxaldehyde or a pharmaceutically acceptable salt thereof. 27. Method of claim 4 wherein the compound of formula II is 1-[(2'-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl]-4-phenyl-2-propylimidazole- 5-carboxaldehyde or a pharmaceutically acceptable salt thereof. 28. Method of claim 4 wherein the compound of formula II is 1-[(2'-Carboxybiphenyl-4-yl)methyl]-4-phenyl-2-propylimidazole-5-carboxald ehyde or a pharmaceutically acceptable salt thereof. 29. A method of treating chronic renal failure mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I): ##STR69## wherein R.sup.1 is 4--CO.sub.2 H; 4--CO.sub.2 R.sup.9 ; ##STR70## R.sup.2 is H; Cl; Br; I; F; NO.sub.2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO.sub.2 H; CO.sub.2 R.sup.9 ; NHSO.sub.2 CH.sub.3 ; NHSO.sub.2 CF.sub.3 ; CONHOR.sup.12 ; SO.sub.2 NH.sub.2 ; ##STR71## aryl; or furyl; R.sup.3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ; R.sup.5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms; R.sup.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO.sub.2 R.sup.14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6; C.sub.6 F.sub.5 ; CN; ##STR72## straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH.sub.3, CF.sub.3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R.sup.8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the alkenyl portion is 2 to 6 carbon atoms; --(CH.sub.2).sub.m -imidazol-1-yl; --(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms; --(CH.sub.2).sub.s -tetrazolyl; ##STR73## R.sup.9 is ##STR74## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ; R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.12 is H, methyl or benzyl; R.sup.13 is --CO.sub.2 H; --CO.sub.2 R.sup.9 ; --CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ; ##STR75## --PO.sub.3 H.sub.2 ; --C(CF.sub.3).sub.2 OH; --NHSO.sub.2 CH.sub.3 ; --NHSO.sub.2 CF.sub.3 ; --NHCOCF.sub.3 ; --CONHOR.sup.12 ; --SO.sub.2 NH.sub.2 ; ##STR76## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ; R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR77## Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl; R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR78## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6; R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ; R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR79## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --; R.sup.31 is H, alkyl of 1 to 4 carbon atoms; --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sup.32 ; R.sup.32 is H, NO.sub.2, NH.sub.2, OH or OCH.sub.3 ; X is a carbon-carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, --NH--, ##STR80## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR81## Y is O or S; Z is O, NR.sup.11, or S; m is 1 to 5; n is 1 to 10; p is 0 to 3; q is 2 to 3; r is 0 to 2; s is 0 to 5; t is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (1) the R.sup.1 group is not in the ortho position; (2) when R.sup.1 is ##STR82## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR83## then R.sup.13 must be in the ortho or meta position; or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho; (3) when R.sup.1 is ##STR84## and X is other than a single bond, then R.sup.13 must be ortho except when X=NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta; (4) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl; (5) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H; (6) when R.sup.1 is ##STR85## X is --OCH.sub.2 --, and R.sup.13 is 2--CO.sub.2 H, and R.sup.7 is H then R.sup.6 is not C.sub.2 H.sub.5 S; (7) when R.sup.1 is ##STR86## and R.sup.6 is n-hexyl, then R.sup.7 and R.sup.8 are not both hydrogen; (8) when R.sup.1 is ##STR87## R.sup.6 is not methoxybenzyl; (9) the R.sup.6 group is not --CHFCH.sub.2 CH.sub.2 CH.sub.3 or CH.sub.2 OH; (10) when r=O, R.sup.1 is ##STR88## X is --NH--CO--, R.sup.13 is 2--NHSO.sub.2 CF.sub.3, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ; (11) when r=0, R.sup.1 is ##STR89## X is NH--CO--, R.sup.13 is 2--COOH, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ; (12) when r=1, R.sup.1 = ##STR90## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl); (13) when r=1, R.sup.1 = ##STR91## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl). 30. A method of treating chronic renal failure mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I): ##STR92## wherein R.sup.1 is 4--CO.sub.2 H; 4--CO.sub.2 R.sup.9 ; ##STR93## -- NHSO.sub.2 CH.sub.3 ; --4--NHSO.sub.2 CF.sub.3 ; --CONHOR.sup.12 ; ##STR94## R.sup.2 is H; Cl; Br; I; F; NO.sub.2 ; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO.sub.2 H; CO.sub.2 R.sup.9 ; NHSO.sub.2 CH.sub.3 ; NHSO.sub.2 CF.sub.3 ; CONHOR.sup.12 ; SO.sub.2 NH.sub.2 ; aryl; or furyl; or ##STR95## R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6; C.sub.6 F.sub.5 ; CN; R.sup.8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the alkenyl portion is 2 to 6 carbon atoms; --(CH.sub.2).sub.m -imidazol-1-yl; --(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms; --(CH.sub.2).sub.m -tetrazolyl; ##STR96## X is a carbon-carbon single bond, --CO--, --O--, --S--, --NH--, --NR.sup.26 --, --CONR.sup.23 --, --NR.sup.23 CO--, --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, SO.sub.2 NR.sup.23 --, C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR97## or pharmaceutically suitable salt thereof. 31. A method of treating chronic renal failure mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I): ##STR98## wherein R.sup.1 is 4--CO.sub.2 H; 4--CO.sub.2 R.sup.9 ; ##STR99## -- NHSO.sub.2 CH.sub.3 ; --4--NHSO.sub.2 CF.sub.3 ; --CONHOR.sup.12 ; ##STR100## R.sup.2 is H; Cl; Br; I; F; NO.sub.2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO.sub.2 H; CO.sub.2 R.sup.9 ; NHSO.sub.2 CH.sub.3 ; NHSO.sub.2 CF.sub.3 ; CONHOR.sup.12 ; SO.sub.2 NH.sub.2 ; ##STR101## aryl; or furyl; R.sup.3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ; R.sup.5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms; R.sup.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO.sub.2 R.sup.14 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; (CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6; C.sub.6 F.sub.5 ; CN; ##STR102## straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH.sub.3, CF.sub.3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R.sup.8 is ##STR103## R.sup.9 is ##STR104## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ; R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.12 is H, methyl or benzyl; R.sup.13 is --CO.sub.2 H; --CO.sub.2 R.sup.9 ; --CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ; ##STR105## --PO.sub.3 H.sub.2 ; --C(CF.sub.3).sub.2 OH; --NHSO.sub.2 CH.sub.3 ; --NHSO.sub.2 CF.sub.3 ; --NHCOCF.sub.3 ; --CONHOR.sup.12 ; --SO.sub.2 NH.sub.2 ; ##STR106## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, or benzyl; R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ; R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR107## Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl; R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR108## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6; R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ; R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR109## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --; R.sup.31 is H, alkyl of 1 to 4 carbon atoms, --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.r R.sup.32 ; R.sup.32 is H, NO.sub.2, NH.sub.2, OH or OCH.sub.3 ; X is a carbon-carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, --NH--, ##STR110## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR111## Y is O or S; Z is O, NR.sup.11, or S; m is 1 to 5; n is 1 to 10; p is 0 to 3; q is 2 to 3; r is 0 to 2; s is 0 to 5; t is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (1) the R.sup.1 group is not in the ortho position; (2) when R.sup.1 is ##STR112## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR113## then R.sup.13 must be in the ortho or meta position; or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho; (3) when R.sup.1 is ##STR114## and X is other than a single bond, then R.sup.13 must be ortho except when X=NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta; (4) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl; (5) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H; (6) when R.sup.1 is ##STR115## R.sup.6 is not methoxybenzyl; (7) the R.sup.6 group is not ##STR116## or CH.sub.2 OH.