Angiotensin II receptor blocking imidazoles and combinations thereof with diuretics and NSaids

Claim 2

A pharmaceutical composition comprising a diuretic or a non-steroidal antiinflammatory drug, a pharmaceutically suitable carrier and an antihypertensive selected from compounds of the formula: wherein R' is 4-CO2H; 4-CO 2 R 9 ; 4-NHSO 2 CH 3 ; 4-NHSO 2 CF 3 ; -CONHOR 12 ; or R 2 is H; Cl; Br; I; F; NO 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; C0 2 H; CO 2 R 9 ; NHSO 2 CH 3 ; NHSO 2 CF 3 ; CONHOR 12 ; SO 2 NH 2 ; aryl; or furyl; R 3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is CN, N0 2 or CO 2 R 11 ; R 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 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 2 R 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 2 ) s Z(CH 2 ) m R 5 optionally substituted with F or CO 2 R 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 7 is H, F, Cl, Br, I, NO 2 C v F 2v+1 , where v = 1-6 C 6 Fs; CN; 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 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 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 aliphatic portion is 2 to 6 carbon atoms; -(CH 2 ) m -imidazol-1-yl; -(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2 CH 3 or alkyl of 1 to 4 carbon atoms; -(CH 2 ) s -tetrazolyl; -(CH 2 ) n NR 11 -{CH 2 ) n NR 11 SO 2 R 10 ; -(CH 2 ) n NR 11 -(CH 2 ) m ONO 2 ; -CH 2 N 3 ; R 9 is R 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 2 ) p C 6 H 5 ; R 11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 12 is H, methyl or benzyl; R 13 is -C0 2 H; -CO 2 R 9 ; -CH 2 CO 2 H, -CH 2 CO 2 R 9 ; -PO 3 H; -C(CF 3 ) 2 OH; -NHSO 2 CH 3 ; -NHSOzCF 3 ; -NHCOCF 3 ; -CONHOR 12 ; -SO 2 NH 2 ; R 14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 1s 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 16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) p C 6 H 5 , OR 17 , or NR 18 R 19 ; R 17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 18 and R 19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl, or taken together with the nitrogen form a ring of the formula Q is NR 20 , O or CH 2 ; R 20 is H, alkyl of 1-4 carbon atoms, or phenyl; R 21 is alkyl of 1 to 6 carbon atoms, -NR 22 R 23 , or R 22 and R 23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u where u is 3-6; R 24 is H, CH3 or -C 6 H 5 ; R2 5 is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 , R 25 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R 27 and R 28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R 29 and R 30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH 2 ) q -; R 31 is H, alkyl of 1 to 4 carbon atoms, -CH 2 CH=CH 2 or -CH 2 C 6 H 4 R 32 ; R 32 is H, N0 2 , NH 2 , OH or OCH 3 ; X is a carbon-carbon single bond, -CO-,-CH 2 , -0-, -S-, -NH-, -OCH 2 -, -CH 2 0-, -SCH 2 -, -CH 2 S-, NHC(R 27 )(R 28 ), -NR 23 SO 2 -, -SO 2 NR 23 -, -C(R 27 )(R 28 )NH-, -CH=CH-, -CF=CF-, -CH=CF-, CF=CH-, -CH 2 CH 2 -, -CF 2 CF 2 -, Y is 0 or S; Z is 0, NR 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 salts of these compounds; provided that: (1) the R 1 group is not in the ortho position; (2) when R 1 is X is a single bond, and R 13 is CO 2 H, or then R 13 must be in the ortho or meta position; or when R 1 and X are as above and R 13 is NHSO 2 CF 3 or NHSO 2 CH 3 , R 13 must be ortho; (3) when R 1 is and X is other than a single bond, then R 13 must be ortho except when X = NR 23 CO and R 13 is NHSO 2 CF 3 or NHSO 2 CH 3 , then R 13 must be ortho or meta; (4) when R 1 is 4-C0 2 H or a salt thereof, R 6 cannot be S-alkyl; (5) when R 1 is 4-CO 2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH 2 0H, CH 2 OCOCH 3 , or CH 2 CO 2 H; (6) when R 1 is X is -OCH 2 ., and R 13 is 2-CO 2 H, and R 7 is H then R 6 is not C 2 H s S; (7) when R 1 is and R 6 is n-hexyl then R 7 and R 8 are not both hydrogen; (8) when R 1 is R 6 is not methoxybenzyl; (9) the R 6 group is not - (10) when r= 0 , R 1 is X is R 13 is 2-NHSO 2 CF 3 , and R 6 is n-propyl, then R 7 and R 8 are not -CO 2 CH 3 ; (11) when r=0, R 1 is X is R 13 is 2-COOH, and R 6 is n-propyl, then R 7 and R 8 are not -CO 2 CH 3 ; (12) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 3-(tetrazol-5-yl); (13) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 4-(tetrazol-5-yl).

Claim 3

Composition of Claim 1 wherein the antihypertensive compound is selected from compounds of the formula: wherein R 1 is -CO 2 H; -NHSO 2 CF 3 ; or R 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 8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, °(CH 2 ) m -imidazol-1-yl, -(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from C0 2 CH 3 or alkyl of 1 to 4 carbon atoms, (CH 2 ) m -tetrasolyl, -(CH 2 ) n OR 11 ; -(CH 2 ) m F; or R 13 is -CO 2 H, -CO 2 R 9 , NHSO 2 CF 3 ; SO 3 H; of R 16 is H, alkyl of 1 to 5 carbon atoms, OR 17 , or NR 18 R 19 ; X is carbon-carbon single bond, -CO-, -OCH 2 -, -CH 2 O-, -0-, SCH 2 -, -CH 2 S-, -NHCH 2 -, -CH 2 NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.

Claim 4

Composition of Claim 2 wherein, in the antihypertensive compound of formula II: R 2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; R 6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R 7 is H, Cl, Br, I; C v F 2v+1 ,where v=1-3; R 8 is R 10 is CF 3 , alkyl of 1 to 6 carbon atoms or phenyl; R 11 is H, or alkyl of 1 to 4 carbon atoms; R 13 is C0 2 H; CO 2 CH 2 OCOC(CH 3 ) 3 ; NHSO 2 CF 3 and R 14 is H, or alkyl of 1 to 4 carbon atoms; R 15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R 16 is H, alkyl of 1 to 5 carbon atoms; OR 17 ; or m is 1 to 5; X = single bond, -0-; -CO-; -NHCO-; or -OCH 2 -; and pharmaceutically acceptable salts.

Claim 5

Composition of Claim 3 wherein, in the antihypertensive compound of formula II, R 1 is and X is a single bond, and pharmaceutically suitable salts thereof.

Claim 6

Composition of Claim 4 wherein the antihypertensive compound of formula II is selected from • 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Butyl-4-chloro-1-[(2-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Butyl-4-chloro-1-[(2-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)aminomethyl]imidazole. • 2-Butyl-4-chloro-1-[(2'-carboxybiphenyt-4-yl)methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole. • 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-(1 E-Butenyl)-4-chloro-1-[(2-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-(1 E-Butenyl)-4-chloro-1-[(2-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Propyl-4-chloro-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Propyl-4-chloro-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-(1 E-Butenyl)-4-chloro-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole. • 2-(1 E-Butenyl)-4-chloro-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Butyl-4-chloro-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. • 2-Propyl-4-chloro-1-[(2-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. • 2-Propyl-4-trifluoromethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. • 2-Propyl-4-trifluoromethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)imidazole. • 2-Butyl-4-trifluoromethyl-1-[(2-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboyxlic acid. • 2-Propyl-4-trifluoromethyl-1-[(2'-(carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. • 2-Propyl-4-pentafluoroethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Propyl-4-pentafluoroethyl-1-[(2-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. •2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, and pharmaceutically acceptable salts thereof.

Claim 7

Composition of Claim 4 wherein the antihypertensive compound of formula II is selected from 2-propyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-4,5-dicarboxylic acid, and pharmaceutically acceptable salts thereof.

Claim 12

An antihypertensive compound of the formula: wherein R 1 is 4-CO z H; 4-CO 2 R 9 ; 4-NHSO 2 CH 3 ; 4-NHSO 2 CF 3 ; -CONHOR 12 ; -SO 2 NH 2 ; or R 2 is H; Cl; Br; I; F; N0 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO 2 H; CO 2 R 9 ; NHSO 2 CH 3 ; NHSO 2 CF 3 ; CONHOR 12 ; SO 2 NH 2 ; aryl; or furyl; R 3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is CN, NO2 or CO 2 R 11 ; R 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 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 2 R 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 2 ) s Z(CH 2 ) m R 5 optionally substituted with F or CO 2 R 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 7 is H, F, Cl, Br, I, NO z , C v F 2v+1 , where v = 1-6, 0 C 6 F 5 ; CN; - C -R 16 ; 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 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 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 aliphatic portion is 2 to 6 carbon atoms; -(CH z ) m -imidazol-1-yl; -(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2 CH 3 or alkyl of.1 to 4 carbon atoms; -(CH 2 ) s -tetrazolyl; R9 is R 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 2 ) p C 6 H 5 ; R 11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 12 is H, methyl or benzyl; R 13 is -C0 2 H; -CO 2 R 9 ; -CH 2 CO 2 H; -CH 2 CO 2 R 9 ; -PO3H; -C(CF 3 ) 2 OH; -NHSO 2 CH 3 ; -NHHO 2 CF 3 ; -NHCOCF 3 ; -CONHOR 12 ; -SO 2 NH 2 ; R 14 is H, alkyl of perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 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 16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) P C 6 H 5 , OR 17 , or NR 18 R 19 ; R 17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 18 and R 19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl, or taken together with the nitrogen form a ring of the formula Q is NR 20 , 0 or CH 2 ; R 20 is H, alkyl of 1-4 carbon atoms, or phenyl; R 21 is alkyl of 1 to 6 carbon atoms, -NR 22 R 23 , or R 22 and R 23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u where u is 3-6; R24 is H, CH 3 or -C 6 H 5 ; R2 5 is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 , R 26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R 27 and R 28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R 29 and R 30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH 2 )q-; R 31 is H, alkyl of 1 to 4 carbon atoms, -CH 2 CH = CH 2 or -CH 2 C 6 H 4 R 32 ; R 32 is H, NO 2 . NH 2 , OH or OCH 3 ; X is a carbon-carbon single bond, -CO-, -CH 2 , -0-, -S-, -NH-, -OCH 2 -, -CH 2 0-, -SCH 2 -, -CH 2 S-, -NHC(R 27 )(R 28 ), -NR 23 SO 2 -, -SO 2 NR 23 -, -C(R 27 )(R 28 )NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH 2 CH 2 -, -CF 2 CF 2 -, Y is O or S; Z is 0, NR 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 salts of these compounds; provided that: (1) the R 1 group is not in the ortho position; (2) when R 1 is X is a single bond, and R 13 is CO 2 H, or then R 13 must be in the ortho or meta position; or when R 1 and X are as above and R 13 is NHS0 2 CF 3 or NHSO 2 CH 3 , R 13 must be ortho; (3) when R 1 is and X is other than a single bond, then R 13 must be ortho except when X = NR 23 CO and R 13 is NHSO 2 CF 3 or NHSO 2 CH 3 , then R 13 must be ortho or meta; (4) when R 1 is 4-CO 2 H or a salt thereof, R 6 cannot be S-alkyl; (5) when R 1 is 4-CO 2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH 2 OH, CH 2 0COCH 3 , or CH 2 CO 2 H; (6) when R 1 is X is -OCH 2 -, and R 13 is 2-CO 2 H, and R 7 is H then R 6 is not C 2 H 5 S; (7) when R 1 is and R 6 is n-hexyl then R 7 and R 8 are not both hydrogen; (8) when R 1 is R 6 is not methoxybenzyl; (9) the R 6 group is not- or CH 2 OH; (10) when r=0, R' is X is R 13 is 2-NHSO 2 CF 3 , and R 6 is n-propyl, then R 7 and R 8 are not -C0 2 CH 3 ; (11) when r=0, R 1 is X is R 13 is 2-COOH, and R 6 is n-propyl, then R 7 and R 8 are not -CO 2 CH 3 ; (12) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 3-(tetrazol-5-yl); (13) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 4-(tetrazol-5-yl). (14) at least one of R 1 , R 2 , R 7 , and R 8 is selected from the following: R 1 is R 2 is CN; R 7 is C v F 2v+1 , where v = 2-6; C 6 Fs; or phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms, and the phenyl or phenylalkyl is optionally substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, OH, OCH 3 and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 8 is tetrazolyl; -(CH 2 ) n-1 CHR 11 OR 17 where R 11 ≠ H; -CH=N-NR 11 R 17 ;

Claim 13

An antihypertensive compound of the formula: wherein R 1 is 4-CO z H; 4-CO 2 R 9 ; 4-NHSO 2 CH 3 ; 4-NHSO 2 CF 3 ; -CONHOR 12 ; -SO 2 NH 2 ; or R 2 is H; Cl; Br; I; F; N0 2 ; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO 2 H; CO 2 R 9 ; NHSO 2 CH 3 ; NHSO 2 CF 3 ; CONHOR 12 ; SO 2 NH 2 ; aryl; or furyl; R 3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is CN, NO2 or CO 2 R 11 ; R 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 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 2 R 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 2 ) s Z(CH 2 ) m R 5 optionally substituted with F or CO 2 R 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 7 is H, F, Cl, Br, I, NO z , C v F 2v+1 , where v = 1-6, 0 C 6 F 5 ; CN; - C -R 16 ; 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 3 , CF 3 , and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 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 aliphatic portion is 2 to 6 carbon atoms; -(CH z ) m -imidazol-1-yl; -(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2 CH 3 or alkyl of.1 to 4 carbon atoms; -(CH 2 ) s -tetrazolyl; R9 is R 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 2 ) p C 6 H 5 ; R 11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 12 is H, methyl or benzyl; R 13 is -C0 2 H; -CO 2 R 9 ; -CH 2 CO 2 H; -CH 2 CO 2 R 9 ; -PO3H; -C(CF 3 ) 2 OH; -NHSO 2 CH 3 ; -NHHO 2 CF 3 ; -NHCOCF 3 ; -CONHOR 12 ; -SO 2 NH 2 ; R 14 is H, alkyl of perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 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 16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) P C 6 H 5 , OR 17 , or NR 18 R 19 ; R 17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R 18 and R 19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl, or taken together with the nitrogen form a ring of the formula Q is NR 20 , 0 or CH 2 ; R 20 is H, alkyl of 1-4 carbon atoms, or phenyl; R 21 is alkyl of 1 to 6 carbon atoms, -NR 22 R 23 , or R 22 and R 23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH 2 ) u where u is 3-6; R24 is H, CH 3 or -C 6 H 5 ; R2 5 is NR 27 R 28 , OR 28 , NHCONH 2 , NHCSNH 2 , R 26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R 27 and R 28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R 29 and R 30 are independently alkyl of 1-4 carbon atoms or taken together are -(CH 2 )q-; R 31 is H, alkyl of 1 to 4 carbon atoms, -CH 2 CH = CH 2 or -CH 2 C 6 H 4 R 32 ; R 32 is H, NO 2 . NH 2 , OH or OCH 3 ; X is a carbon-carbon single bond, -CO-, -CH 2 , -0-, -S-, -NH-, -OCH 2 -, -CH 2 0-, -SCH 2 -, -CH 2 S-, -NHC(R 27 )(R 28 ), -NR 23 SO 2 -, -SO 2 NR 23 -, -C(R 27 )(R 28 )NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH 2 CH 2 -, -CF 2 CF 2 -, Y is O or S; Z is 0, NR 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 salts of these compounds; provided that: (1) the R 1 group is not in the ortho position; (2) when R 1 is X is a single bond, and R 13 is CO 2 H, or then R 13 must be in the ortho or meta position; or when R 1 and X are as above and R 13 is NHS0 2 CF 3 or NHSO 2 CH 3 , R 13 must be ortho; (3) when R 1 is and X is other than a single bond, then R 13 must be ortho except when X = NR 23 CO and R 13 is NHSO 2 CF 3 or NHSO 2 CH 3 , then R 13 must be ortho or meta; (4) when R 1 is 4-CO 2 H or a salt thereof, R 6 cannot be S-alkyl; (5) when R 1 is 4-CO 2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH 2 OH, CH 2 0COCH 3 , or CH 2 CO 2 H; (6) when R 1 is X is -OCH 2 -, and R 13 is 2-CO 2 H, and R 7 is H then R 6 is not C 2 H 5 S; (7) when R 1 is and R 6 is n-hexyl then R 7 and R 8 are not both hydrogen; (8) when R 1 is R 6 is not methoxybenzyl; (9) the R 6 group is not- or CH 2 OH; (10) when r=0, R' is X is R 13 is 2-NHSO 2 CF 3 , and R 6 is n-propyl, then R 7 and R 8 are not -C0 2 CH 3 ; (11) when r=0, R 1 is X is R 13 is 2-COOH, and R 6 is n-propyl, then R 7 and R 8 are not -CO 2 CH 3 ; (12) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 3-(tetrazol-5-yl); (13) when r =1, R 1 = X is a single bond, R 7 is Cl, and R 8 is -CHO, then R 13 is not 4-(tetrazol-5-yl). (14) at least one of R 1 , R 2 , R 7 , and R 8 is selected from the following: R 1 is R 2 is CN; R 7 is C v F 2v+1 , where v = 2-6; C 6 Fs; or phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms, and the phenyl or phenylalkyl is optionally substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, OH, OCH 3 and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 8 is tetrazolyl; -(CH 2 ) n-1 CHR 11 OR 17 where R 11 ≠ H; -CH=N-NR 11 R 17 ;

Claim 14

A compound of Claim 9 having the formula: Wherein R 1 is -C0 2 H; -NHSO 2 CF 3 ; or R 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 8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH 2 ) m -imidazol-1-yl, -(CH 2 ) m -1,2,3-triazolyl optionally substituted with one or two groups selected from C0 2 CH 3 or alkyl of 1 to 4 carbon atoms, -(CH2)n -(CH 2 ) n NH -(CH 2 ) n NHSO s R 10 ; -(CH 2 ) m F; or R 13 is -CO 2 H, -CO 2 R 9 , NHSO 2 CF 3 ; S0 3 H; or R 16 is H, alkyl of 1 to 5 carbon atoms, OR 17 , or NR 18 R 19 ; X is carbon-carbon single bond, -CO-, -CH 2 S-, -NHCH 2 -, -CH 2 NH- or -CH=CH-; and pharmaceutically acceptable salts of these compounds.

Claim 15

A compound of claim 10 wherein , in the antihypertensive compound of formula II: R 2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; R 6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R 7 is H, Cl, Br, I; C v F 2v+1 , where v= 1-3; or R 8 is -(CH 2 ) m OR 11 ; or -COR 11 ; R 10 is CF 3 , alkyl of 1 to 6 carbon atoms or phenyl; R 11 is H, or alkyl of 1 to 4 carbon atoms; R 13 is C0 2 H; C0 2 CH 2 0COC(CH 3 ) 3 ; NHS0 2 CF 3 and R 14 is H, or alkyl of 1 to 4 carbon atoms; R 15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R 16 is H, alkyl of 1 to 5 carbon atoms; OR 17 ; or m is 1 to 5; X = single bond, -0-; -CO-; -NHCO-; or OCH 2 -; and pharmaceutically acceptable salts.

Claim 16

A compound of Claim 11 wherein , in the antihypertensive compound of formula II, R' is and X is a single bond, and pharmaceutically suitable salts thereof.

Claim 17

An antihypertensive compound of Claim 9 wherein R 7 is C v F 2v+ 1 where v = 2 to 6, or C 6 F 5 , and pharmaceutically acceptable salts thereof.

Claim 18

An antihypertensive compound of claim 13 selected from • 2-Propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. • 2-Propyl-1-[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-4,5-dicarboxylic acid. • 2-Propyt-4-pentafluoroethyl-1-[(2-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic acid. • 2-Propyl-4-pentafluoroethyl-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, and pharmaceutically acceptable salts thereof.

Claim 19

An antihypertensive compound of Claim 9 wherein R 1 is

Claim 20

An antihypertensive compound of Claim 9 wherein R 2 is CN.

Claim 21

An antihypertensive compound of Claim 9 wherein R 7 is -n -R 16 . B

Claim 22

An antihypertensive compound of Claim 9 wherein R 7 is phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms, and the phenyl or phenylalkyl is optionally substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, OH, OCH 3 and COOR, where R is H, alkyl of 1 to 4 carbon atoms,or phenyl.

Claim 23

An antihypertensive compound of Claim 9 wherein R 8 is tetrazolyl; -(CH 2 ) n-1 ,CHR 11 OR 17 where R 11 ≠H;-CH-N-NR 11 R 17 :

Claim 24

A process for the preparation of a compound of Claim 9 wherein r is 1 which comprises contacting an imidazole derivative of Formula 1 with a benzyl derivative of Formula 2 in a solvent in the presence of a base for about 1 to about 10 hours at a temperature in the range of about 20 C to the reflux temperature of the solvent to form a benzylimidazole of Formula 3 : wherein each of R 1 , R 2 , R 3 , R 6 , R 7 and R 8 is stable under the reaction conditions and is a group as defined in Claim 1 or an intermediate or protected form thereof which can be transformed to such a group and wherein X 1 is halogen, p-toluenesulfonyloxy or methylsulfonyloxy; and thereafter as necessary transforming said intermediate or protected forms of the R groups to R groups as defined in Claim 1.

Claim 25

Process of Claim 20 wherein compounds 1 and 2 are contacted in the presence of a base selected from the group consisting of a metal hydride, MH, a metal alkoxide, MOR, sodium carbonate, potassium carbonate, triethylamine and pyridine, in a dipolar aprotic solvent or, where the base is MOR, the solvent can be an alcohol, ROH, where M is lithium, sodium or potassium and R is methyl, ethyl or t-butyl.

Claim 26

Process of Claim 20 wherein a two-phase solvent system, one an organic phase such. as methylene chloride and the other an aqueous phase, is used in the presence of a phase transfer catalyst such as tricaprylmethylammonium chloride.

Claim 27

Process of Claim 21 wherein: R 1 is X is a carbon-carbon single bond, -CO-, -0-, -S-, or -NH-; R 2 and R 3 are each independently H, Cl, Br, I, CO 2 R 14 , F, NO z , alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl or furyl; R 6 and R 7 are as defined in Claim 1; R 8 is alkyl of 1 to 10 carbon atoms or alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; -(CH 2 ) n OR 11 ; -(CH 2 ) n SR 15 ; or --(CH 2 )( n CN; R 11 is as defined in Claim 1; R 13 is CO 2 R 14 , CN, N0 2 , trialkyltin tetrazole, or trityltetrazole; and R 14 and R 15 are as defined in Claim 1.

Claim 28

Process of Claim 23 wherein R 13 is -CO 2 R 14 and the product of Formula 3 is contacted with an alkali in an aqueous alcoholic solvent or with CF 3 CO z H at a temperature in the range of about 20° C to the reflux temperature of the solvent for about 1-24 hours, followed by adjustment of the pH of the mixture to a value in the range of 3 to 7, to convert the product to the corresponding product wherein R 13 is -CO z H.

Claim 29

Process of Claim 24 wherein at least one of R 2 , R 3 or R 13 in Formula 1 is -CO 2 R 14 and is converted to -CO 2 H.

Claim 30

Process of Claim 24 wherein R 14 is t-butyl and the reaction is conducted in CF 3 CO z H.

Claim 31

Process of Claim 23 wherein R 13 is -CN and the product of Formula , is contacted with (i) a strong acid at reflux temperature of the solvent for about 2-96 hours or (ii) a strong alkali in an alcohol solvent at a temperature in the range of about 20° C and the reflux temperature of the solvent for about 2-96 hours followed by adjustment of the pH to about 3-7, or (iii) sulfuric acid followed by acid or alkali, to convert the product to the corresponding compound wherein R 13 is -C0 2 H.

Claim 32

Process of Claim 41 wherein at least one of R 2 , R 3 or R 13 is -CO 2 R 14 and is converted to -C0 2 H.

Claim 33

Process of Claim 27 wherein R 8 is -(CH 2 ) n CN and is converted to -(CH 2 ) n CO 2 H, or is -(CH 2 ) n OR 11 and is converted to (CH 2 ) n OH when R 13 is converted to -C0 2 H.

Claim 34

Process of Claim 23 wherein R 13 is -CN and the product of Formula is contacted with a mixture of equimolar amounts of sodium azide and ammonium chloride in a polar aprotic solvent at a temperature in the range of about 30° C to the reflux temperature of the solvent, for about 1 hour to 10 days, to convert the product to the corresponding compound wherein R 13 is 5-tetrazolyl.

Claim 35

Process of Claim 30 wherein R 8 is -(CH 2 )CN and is converted to -(CH z ) m -tetrazolyl when R 13 is converted to 5-tetrazolyl.

Claim 36

Process of Claim 23 wherein R 13 is -CN and the product of Formula is reacted with trialkyltin azide or triaryltin azide followed by acidic or basic hydrolysis to convert the product to the corresponding compound wherein R 13 is 5-tetrazolyl.

Claim 37

Process of Claim 23 wherein R 13 is -CN and the product of Formula 3 is reacted with trialkyltin azide or triaryltin azide to produce a compound of Formula wherein R 13 is trialkyl or triaryl stannyl tetrazol-5-yl, the latter compound is reacted with triphenylmethyl chloride to produce a compound of Formula , wherein R 13 is triphenylmethyl-tetrazol-5-yl, and the latter compound is hydrolyzed to produce a compound of Formula , wherein R 13 is 5-tetrazolyl.

Claim 38

Process of Claim 32 wherein R 8 is -(CH 2 ) n CN and is converted to -(CH 2 ) m -tetrazolyl when R 13 is converted to 5-tetrazolyl.

Claim 39

Process of Claim 31 wherein R 13 is -NO z and the product of Formula , is contacted with a reducing agent to form a second intermediate of Formula 3 in which R' 3 is NH 2 , and the latter is contacted with an anhydride (CH 3 SO 2 ) 2 O or (CF 3 S0 2 ) 2 0 or a chloride CH 3 SO 2 Cl or CF 3 SO 2 Cl of sulfonic acid in a solvent to produce a compound in which R 13 is -NHSO 2 CH 3 or -NHS0 2 CF 3 .

Claim 40

Process of Claim 38 wherein at least one of R 2 , R 3 , or R 13 is -NO 2 and is converted to -NHSO 2 CH 3 or -NHSO 2 CF 3 .

Claim 41

Process of Claim 24 or 27 wherein the compound of Formula 3 with R 13 =CO 2 H either (a) is contacted with about 1-4 equivalents of thionyl chloride in excess thionyl chloride or another solvent at a temperature in the range of about 20 °C to the reflux temperature of the solvent for a period of about 5 minutes to about 2 hours to form an intermediate of Formula 3 wherein R 13 is CDCI, and the latter is contacted with about 2-10 equivalents of hydroxylamine derivative H 2 NOR 12 in excess hydroxylamine derivative H 2 NOR 12 or other solvent, at a temperature in the range of about 25-80° for about 2-18 hours, or (b) is contacted the hydroxylamine derivative H 2 NOR 12 , dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in a solvent at a temperature in the range of about 0-30° C for about 1-24 hours; to provide a compound in which R 13 is CONHOR 12 .

Claim 42

Process of Claim 20 wherein: R 1 is X is a carbon-carbon single bond, -CO-, -0-, -S-, or -NH-; R 2 , R 3 , R 6 and R 7 are as defined in Claim 1; and R 8 is (CH 2 ) n OR 11 (CH 2 ) n OCOR 14 , (CH 2 ) n CH(OH)R 16 , (CH 2 ) n COR 16 (CH 2 ) n Cl, (CH 2 ) n CN, CHO.

Claim 43

Process of Claim 38 wherein R 8 is (CH 2 ) n OH and the product of Formula 3 is contacted with an alcohol R 11 OH in the anhydrous state in the presence of a strong acid or a Lewis acid, followed by saponification of any CO 2 R 14 groups concomitantly formed or present in intermediate 3, to form the corresponding compound of Formula 3, wherein R 8 is (CH 2 ) n OR 11 and R 11 is not H.

Claim 44

Process of Claim 38 wherein R 8 is (CH 2 ) n OR 11 and R" is not H and the product of Formula is contacted with an aqueous acidic medium at a temperature in the range of about 25 C and the reflux temperature of the solvent for a period of about 0.5-24 hours to form the corresponding compound of Formula 3 wherein R 8 is (CH 2 ) n OH.

Claim 45

Process of Claim 38 wherein R 8 is (CH 2 ) n OH and the product of Formula is contacted with (a) a carboxylic acid anhydride (R 14 CO) 2 O or chloride R 14 COCl in a solvent in presence of a base at a temperature in the range of about 0° C and the reflux temperature of the solvent for about 0.5-24 hours or (b) a carboxylic acid R 14 CO 2 H under anhydrous conditions in presence of a strong acid or Lewis acid at about 0°-100°C for about 0.5 to 24 hours, to form the corresponding compound in which R 8 is (CH 2 )- n OCOR 14 .

Claim 46

Process of Claim 38 wherein R 8 is (CH 2 ) n OCOR 14 and the product of Formula 3 is contacted with aqueous acid or alkali to form the corresponding compound wherein R 8 is (CH 2 ) n OH.

Claim 47

Process of Claim 38 wherein R 8 is (CH 2 ) n OH and the product of Formula 3 is contacted with an oxidizing agent at a temperature of about 25-45 C for about 1-200 hours to produce a corresponding compound of Formula in which R 8 is (CH 2 ) n-1 COR 16 and R 16 is H.

Claim 48

Process of Claim 38 wherein R 8 is (CH 2 ) n COR 16 and R 16 is H and the product of Formula 3 is contacted with an organometallic compound R 16 P in which P is MgBr or Li in a solvent at a temperature in the range of about -78° C to 100° C for about 0.5-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n CH(OH)R 16 and R 16 is not H.

Claim 49

Process of Claim 38 wherein R 8 is (CH 2 ) n CH(OH)R 16 and R 16 is not H and the product of Formula 3, is contacted with an oxidizing agent in a solvent to form a corresponding compound of Formula 3 in which R 8 is (CH 2 ) n COR 16 and R 16 is not H.

Claim 50

Process of Claim 38 wherein R 8 is (CH 2 ) n COR 16 and R 16 is OH and the compound of Formula 3 is contacted with an oxidizing agent in a solvent to form a corresponding compound of Formula 3 in which R 8 is (CH 2 ) n COR 16 and R 16 is OH.

Claim 51

Process of Claim 38 wherein R 8 is (CH 2 ) n COR 16 and R 16 is OH and the compound of Formula 3 is contacted with thionyl chloride in excess or in another solvent at a temperature in the range of about 0 C to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 in which R 8 is (CH 2 ) n COCl followed by contact of the latter with an amine NHR 18 R 19 in excess or in a solvent at temperatures in the range of about 0° C and reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 in which R8 is (CH 2 ) n CONR 18 R 19 .

Claim 52

Process of Claim 38 wherein R 8 is (CH 2 ) n OR 11 and R" is H and the product of Formula 3 is contacted with thionyl chloride in excess or in a solvent at a temperature in the range of about 20 °C to the reflux temperature of the solvent for about 0.5-24 hours to form an intermediate compound Formula 3 in which R 8 is (CH 2 ) n Cl.

Claim 53

Process of Claim 48 in which the compound of Formula 3 wherein R 8 is (CH 2 ) m Cl is contacted with imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or phthalimide in the presennce of base in a solvent at temperatures in the range of about 55° C to the reflux temperature of the solvent for about 1-24 hours to produce a corresponding compound of Formula 3 in which R 8 is (CH 2 ) m -imidazole, (CH 2 ) m -triazole, (CH 2 )- m -tetrazole or (CHz)m-phthalimide.

Claim 54

Process of Claim 48 wherein the compound of Formula 3 in which R 8 is (CH 2 ) n Cl is contacted with sodium or potassium salt of a mercaptan R 15 SH in a solvent at a temperature in the range of about 25-100° C for about 1-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n SR 15 .

Claim 55

Process of Claim 38 wherein the compound of Formula 3 in which R 8 is (CH 2 ) n Cl is contacted with an alkali metal cyanide in a solvent at a temperature in the range of about 20-100 °C for about 1-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n CN and the latter compound is hydrolyzed to the corresponding compound of Formula 3 in which R 8 is (CH 2 ) n COR 16 and R' 6 is OH.

Claim 56

Process of Claim 38 wherein the compound of Formula 3 in which R 8 is (CH 2 ) n-1 Cl is contacted with the sodium or potassium salt of a dialkyl malonate in a solvent at a temperature in the range of about 20-100 °C afor about 0.5-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n CH(CO 2 alkyl) 2 followed by saponification of the latter with aqueous alkali at a temperature in the range of about 25° C to the reflux temperature of the solvent followed by acidification with mineral acid to form a compound of Formula 3 in which R 8 is (CH 2 ) n CH(CO 2 H) 2 followed by heating the latter to about 120°C or in dilute mineral acid at reflux temperature to form a product of Formula 3 in which R 8 is (CH 2 ) n COR 16 and R 16 is OH.

Claim 57

Process of Claim 38 wherein R 8 is (CH 2 ) n CN and the compound of Formula 3 is contacted with sodium azide and ammonium chloride in a solvent at a temperature in the range of about 30 °C and the reflux terrfperature of the solvent for about 1 hour to about 10 days to form a compound of the invention in which R 8 is (CH 2 ) n -tetrazole.

Claim 58

Process of Claim 38 wherein R 8 is -CHO and the compound of Formula 3 is contacted with a methylene phosphorane (C 6 H 5 ) 3 P=CH(CH 2 ) s CHR 14 OR 15 or (C 6 H 5 ) 3 P=CH(CH 2 ) s CO 16 in a solvent at a temperature in the range of about 25 C to the reflux temperature of the solvent for about 1-24 hours to form a compound of Formula 3 in which R 8 is -CH=CH(CH 2 ) s CHR 14 OR 15 or -CH=CH(CH 2 )SCOR 16 , except where R 1s is H and R 16 is OH, and optionally then contacting the compound of Formula 3 in which R 8 is -CH=CH(CH 2 ) s COR 16 with a reducing agent in a solvent at a temperature of about 0°-25°C for about 0.5-24 hours to form a product of Formula 3 in which R 8 is -CH=CH(CH 2 ) s CHR 14 OH.

Claim 59

Process of Claim 38 wherein R 8 is (CH 2 ) m OH and the compound of Formula 3 is contacted with a fluorinating agent in a solvent at a temperature in the range of about -30 °C to 25 °C for a period of about 0.5- 24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) m F.

Claim 60

Process of Claim 38 wherein the compound of Formula 3 in which R 8 is (CH 2 ) m Cl is contacted with silver nitrate in a dipolar aprotic solvent at a temperature in the range of about 25-80 C for about 1-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) m ONO 2 .

Claim 61

Process of Claim 38 wherein R 8 is (CH 2 ) n OH and the compound of Formula 3 is contacted with an isocyanate of Formula R 10 NCO in a solvent at a temperature in the range of about 25 °C to the reflux temperature of the solvent for a period of about 5 minutes to about 24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n OCONHR 10 .

Claim 62

Process of Claim 38 wherein the compound in which R 8 is (CH 2 ) n Cl is contacted with an amine R 11 NH 2 in excess amine or another solvent for a period of about 1-24 hours at a temperature in the range of about 0°C to the reflux temperature of the solvent to form an intermediate of Formula 3 in which R 8 is (CH 2 ) n NHR 11 .

Claim 63

Process of Claim 38 in which R 8 is (CH 2 ) n Cl and the compound of Formula 3 is contacted with an alkali metal azide in an aprotic solvent at a temperature in the range of about 25-80° C for about 1-24 hours to form a compound of Formula 3 in which R 8 is (CH 2 ) n N 3 and the latter is contacted with a reducing agent to form an intermediate of Formula 3 in which R 8 is (CH 2 ) n NH 2 .

Claim 64

Process of Claim 58 or 59 in which R 8 is (CH 2 ) n NHR 11 or (CH 2 ) n NH 2 and the compound of Formula 3 is contacted with a chloroformate of Formula R 10 OCOCl or a sulfonyl derivative of Formula R 10 SO 2 Cl, or (R 10 SO 2 )O in a solvent in the presence of a base at a temperature in the range of about 0° C to the reflux temperature of a solvent for about 5 minutes to about 24 hours to form a compound of Formula 3 in whch R 8 is -(CH 2 ) n NR 11 CO 2 R 10 or -(CH 2 ) n NR 11 SO 2 R 10 .

Claim 65

Process of Claim 58 or 59 in which the compound of Formula 3 with R 8 equal to -(CH 2 ) n NHR 11 or (CH 2 ) n NH 2 is contacted with an isocyanate or isothiocyanate R 10 NCY in a solvent at a temperature in the range of about 25° C to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a compound of the Formula 3 in which R 8 is -(CH 2 ) n NR 11 CYNHR 10 .

Claim 66

Process of Claim 20 wherein R 1 is NO2 and R 2 , R 3 , R 6 , R 7 , and R 8 are as defined in Claim 34 in which the compound of Formula 3 wherein R 1 is NO2 is reduced by means of iron and acetic acid, stannous chloride or hydrogen and palladium to a compound of Formula 3 wherein R 1 is NH 2 and the latter is reacted with an appropriate acid anhydride such as phthalic anhydride or a substituted phthalic anhydride in a solvent or with an appropriate acid chloride such as substituted anthranilic acid chloride in the presence of aqueous alkali or a base or with an appropriately substituted phthalic or anthranilic acid in the presence of dicyclohexylcarbodiimide in a solvent to produce a compound of the Formula 3 in which R 1 is and X is NHCO.

Claim 67

Process of Claim 20 wherein R 1 is OCH 2 C 6 H 5 , R 2 and R 3 are H and R s , R 7 , and R 8 are as defined in Claim 34 and the resulting compound of Formula 3 with R 1 equal to OCH 2 C 6 H 5 is contacted with trifluoroacetic acid at reflux temperature for a period of about 0.2-1 hour or with hydrogen and palladium to form the corresponding compound of Formula 3 in which R 1 is OH and the latter is contacted with a base at about 25 C and a suitable benzyl halide of the formula: to produce the corresponding compound of Formula 3 wherein R 1 is and X is -OCH 2 -.

Claim 68

Process of Claim 20 wherein R 8 is -CHO, whereby the benzyl derivative of Formula 2 attaches to the imidazole derivative of Formula preferentially at the nitrogen atom adjacent the carbon atom of the imidazole ring to which R 8 is attached.

Claim 69

Process of Claim 20 wherein R 7 is I and the product of Formula 3 is contacted with a perfluoroalkyl copper reagent, CF 3 (CF 2 ) n Cu. (wherein n=0-5), or pentafluorophenyl copper in a polar solvent such as dimethylformamide or dimethylsulfoxide alone or in the presence of a palladium (0) catalyst, at 25-100° C for 1-24 hours to form the corresponding compound of Formula wherein R 7 is (CF 2 ) n CF 3 (where n=0-5) or C 6 F 5 .

Claim 70

A process for the preparation of a compound of Claim 9 wherein r is 0 which comprises contacting an imidazole derivative of Formula or its metallic salt with 4-fluoro-1-nitrobenzene in a solvent, in the presence of a base if the free imidazole is used, for 1-10 days at a temperature of 25-150° C to form an N-phenylimidazole followed by elaboration to compounds wherein X=NHCO by the process described in Claim 62.

Claim 71

A process of Claim 38 wherein R 8 is CHO and the product of Formula 3 is contacted with a hydrazine derivative or hydrazine itself in the presence or absence of a solvent such as alcohol or water at room temperature to form the corresponding compound of Formula 3, wherein R 8 is -CH =N-NR 11 R 17 ;

Claim 72

A process of Claim 38 wherein R 8 is CHO, and X is a carbon-carbon single bond, and the product of Formula 3 is contacted with an organometallic reagent such as R 11 MgBr or R 11 Li in the presence of an anhydrous nonhydroxylic solvent such as ether, THF or dimethoxyethane at -78 to 25 C followed by aqueous work-up followed by acid hydrolysis of any CO 2 R 14 groups where R 14 is t-butyl or hydolysis of any trityl-protected tetrazole groups to form the corresponding compound of Forumula 3 wherein R 8 is where R 11 ≠H.

Claim 73

Process of Claim 20 wherein r= 1, R 1 is X is a carbon-carbon single bond R 2, R 3 are H R 7 and R 8 are each CO 2 R 17 R1 7 is alkyl R 13 is CO 2 R 17 , or N-trityltetrazole.

Claim 74

A process of Claim 69 wherein the product of Formula where R 13 is CO 2 R 17 is contacted with an alkali in an aqueous/organic mixture such as aqueous tetrahydrofuran or aqueous methanol at a temperature in the range of 20°C to the reflux temperature of the solvent for 1-24 hours followed by adjustment of the pH of the mixture to a value in the range of 3 to 7 to convert the product to the corresponding product wherein R 7 , R 8 and R 13 are COOH.

Claim 75

A process of Claim 69 wherein the product of Formula 3 wherein R 13 is trityltetrazole is contacted with an aqueous acid such as HCI or CF 3 COOH at 0°-100°C for 1 hour to 5 days to yield product of Forumula 3 wherein R 7 and R 8 are COOH and R 13 is tetrazole.

Claim 76

A process of Claim 69 wherein the product of Formula 3, wherein R 13 is N-trityltetrazole is refluxed in R 17 0H from 1 hour to 5 days, to yield a product wherein R 7 and R 8 are CO 2 R 17 and R 13 is tetrazole.

Claim 77

A process of Claim 69 wherein the product of Formula wherein R 13 is N-trityltetrazole is contacted with a sterically hindered hydride reducing agent such as lithium tri-t-butoxyaluminumhydride in an anhydrous solvent such as tetrahydrofuran, ether, or dioxane at -78° to the reflux temperature of the solvent followed by quenching with an alcohol followed by purification to yield compound of Formula 3 wherein R 7 is 4-CO 2 R 17 , R 8 is 5-CH z OH and R 13 is N-trityltetrazole followed by

Claim 78

(a) contacting with an alcohol R 17 OH at its reflux temperature for 1 hour to 5 days to yield a product wherein R 7 is 4-CO 2 R 17 , R 8 is CH 2 0H and R 13 is tetrazole or (b) contacting with aqueous acid such as HCI or H 2 SO 4 or CF 3 COOH at 0-100° C for 1 hour to 5 days to yield product of Formula wherein R 7 is 4-COOH, R 8 is CH 2 0H and R 13 is tetrazole.

Claim 79

(a) contacting with an alcohol R 17 OH at its reflux temperature for 1 hour to 5 days to yield a product wherein R 7 is 4-CO 2 R 17 , R 8 is CH 2 0H and R 13 is tetrazole or (b) contacting with aqueous acid such as HCI or H 2 SO 4 or CF 3 COOH at 0-100° C for 1 hour to 5 days to yield product of Formula wherein R 7 is 4-COOH, R 8 is CH 2 0H and R 13 is tetrazole.

Claim 80

Process of Claim 20 in which the compound of Formula 3 wherein R 8 is (CH 2 ) n Cl is contacted with (2-methoxyphenyl)piperazine in a solvent at temperature in the range of 25 °C to the reflux temperature of the solvent for 1-48 hours to produce a corresponding compound of Formula 3 in which R 8 is

Claim 81

A process of Claim 20 wherein R 8 is CO 2 R 17 , R 17 is alkyl, and the compound of Formula 3 is contacted with a metallic salt such as lithium or sodium salt of (2-methoxyphenyl)piperazine in an anhydrous solvent such as tetrahydrofuran, ether or dioxane to yield product of Formula 3 wherein R 8 is

Claim 82

A process of Claim 75 in which the product of Formula 3 is contacted with hydride reducing agents such as sodium bis(2-methoxyethoxy)aluminum hydride in non-hydroxylic solvents at 0°C to the reflux temperature of the solvent to yield a product of Formula 3 wherein R 8 is

Claim 83

A process of Claim 75 or 76 in which R 1 is and R 13 is N-trityltetrazole and the product Formula 3 is hydrolyzed to yield a compound of Formula 3 wherein R8 is or and R 13 is tetrazole.