EP0253310A2 — Angiotensin II receptor blocking imidazoles

Claim 1

Independent Claim 1066 words

An antihypertensive compound of the formula: wherein R 1 is -4-CO 2 H; -4-CO 2 R 9 : -SO 3 H, R 2 is H; Cl: Br; I; F: NO 2 ; 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. NO 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 , CF 3 or CN: 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: -(CH2)m-tetrazolyl: -(CH 2 ) m F: -(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 )pC 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 1 2 is H. methyl or benzyl: R 13 is -CO 2 H; -CO 2 R 9 ; -CH 2 CO 2 H, -CH 2 CO 2 R 9 ; R 14 is H , alkyl or 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, α-methylbenzyl, or taken together 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, CH 3 or -C 6 H 5 ; R 25 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 R 32 is H, NO 2 , NH 2 , OH or OCH 3 ; X is a carbon-carbon single bond, -CO-. -O-, -S-, Y is O or S: Z is O, 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 C O 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 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 OCOCH 3 , or CH 2 CO 2 H; (6) when R 1 is X is -OCH 2 -, R 13 is 2-CO 2 H, and R 7 is H then R 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 or CH 2 OH.

Claim 2

Dependent Claim 1066 words

An antihypertensive compound of the formula: wherein R 1 is -4-CO 2 H; -4-CO 2 R 9 : -SO 3 H, R 2 is H; Cl: Br; I; F: NO 2 ; 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. NO 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 , CF 3 or CN: 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: -(CH2)m-tetrazolyl: -(CH 2 ) m F: -(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 )pC 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 1 2 is H. methyl or benzyl: R 13 is -CO 2 H; -CO 2 R 9 ; -CH 2 CO 2 H, -CH 2 CO 2 R 9 ; R 14 is H , alkyl or 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, α-methylbenzyl, or taken together 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, CH 3 or -C 6 H 5 ; R 25 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 R 32 is H, NO 2 , NH 2 , OH or OCH 3 ; X is a carbon-carbon single bond, -CO-. -O-, -S-, Y is O or S: Z is O, 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 C O 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 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 OCOCH 3 , or CH 2 CO 2 H; (6) when R 1 is X is -OCH 2 -, R 13 is 2-CO 2 H, and R 7 is H then R 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 or CH 2 OH.

Claim 3

Dependent Claim 190 words

A compound of claim 1 having 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 CO 2 CH 3 or alkyl of 1 to 4 carbon atoms, (CH 2 ) m -tetrazolyl, -(CH 2 ) n OR 11 ; R 13 is -C0 2 H, -CO 2 R 9 , NHSO 2 CF 3 ; and 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-, and pharmaceutically acceptable salts of these compounds.

Claim 4

Dependent Claim 174 words

A compound of claim 2 wherein: 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 or CF 3 ; R 8 is -(CH 2 ) m OR 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 CO 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. -O-; -CO-: -NHCO-: or -OCH 2 -: and pharmaceutically acceptable salts.

Claim 5

Dependent Claim 107 words

The compounds of claims 1 to 3, selected from 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole. or a pharmaceutically acceptable salt thereof. 2-Butyl-4-chloro-l-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)-aminomethyl]imidazole, or a pharmaceutically acceptable salt thereof. 2-Butyl-4-chloro-l-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)-aminomethyl]imidazole, or a pharmaceutically acceptable salt thereof. 2-Butyl-4-chloro-l-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. or a pharmaceutically acceptable salt thereof. 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. or a pharmaceutically acceptable salt thereof. 2-(lE - Butenyl)-4-chloro-l-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof. 2-(lE-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof. 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof; 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde. or a pharmaceutically acceptable salt thereof. 2-butyl-4-chloro-1-[2 1- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof. 2-(lE-butenyl)-4-chloro-l-[2 1- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof. and 2-(lE-butenyl)-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde. or a pharmaceutically acceptable salt thereof.

Claim 6

Dependent Claim 18 words

A pharmaceutical composition comprising a pharmaceutically suitable carrier and at least one compound of Claims 1 to 4.

Claim 7

Dependent Claim 151 words

A process for the preparation of a compound of claims 1 to 4 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 , R 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 8

Dependent Claim 70 words

Process of claim 6 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 9

Dependent Claim 155 words

Process of claim 6 wherein: R 1 is X is a carbon-carbon single bond. -CO-. -O-, -S-, or -NH-; R 2 and R 3 are each independently H, Cl. Br, I, CO 2 R 14 , F, NO 2 , alkyl of 1 to 4 carbon atoms. alkoxy of 1 to 4 carbon atoms, aryl or furyl; Rand R 7 are as defined in claim 20; 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: -(CH2) OR 11 ; -(CH 2 ) n SR 15 ; or -(CH 2 ) n CN; R 11 is as defined in Claim 20; R 13 is CO 2 R 14 , CN, NO 2 , trialkyltin tetrazole. or trityltetrazole; and R 14 and R 15 are as defined in Claim 20.

Claim 10

Dependent Claim 89 words

Process of Claim 8 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 2 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 -C0 2 H.

Claim 11

Dependent Claim 32 words

Process of Claim 9 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 12

Dependent Claim 20 words

Process of Claim 9 wherein R 14 is t-butyl and the reaction is conducted in CF 3 CO 2 H.

Claim 13

Dependent Claim 97 words

Process of Claim 8 wherein R13 is - CN and the product of Formula 3 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 - 9 6 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 -CO 2 H.

Claim 14

Dependent Claim 28 words

Process of Claim 12 wherein at least one of R 2 , R 3 or R13 is -CO 2 R 14 and is converted to -CO 2 H.

Claim 15

Dependent Claim 50 words

Process of Claim 12 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 -CO 2 H.

Claim 16

Dependent Claim 71 words

Process of Claim 8 wherein R 13 is - CN and the product of Formula 3 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 17

Dependent Claim 27 words

Process of Claim 15 wherein R 8 is -(CH 2 )CN and is converted to -(CH 2 ) m -tetrazolyl when R 13 is converted to 5-tetrazolyl.

Claim 18

Dependent Claim 43 words

Method of Claim 8 wherein R 13 is - CN and the product of Formula 3 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 19

Dependent Claim 29 words

Process of Claim 17 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 20

Dependent Claim 99 words

Process of Claim 8 wherein R 13 is -NO 2 and the product of Formula 3 is contacted with a reducing agent to form a second intermediate of Formula 3 in which R 13 is NH 2 , and the latter is contacted with an anhydride (CH 3 SO 2 ) 2 O or (CF 3 SO 2 ) 2 O 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 -NHSO 2 CF 3'

Claim 21

Dependent Claim 36 words

Process of Claim 1 9 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 22

Dependent Claim 156 words

Process of Claim 9 or 12 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 COCl, and the latter is contacted with about 2-10 equivalents of hydroxylamine derivative H 2 NOR 12 in excess hydroxylamine derivative H2NOR12 or other solvent, at a temperature in the range of about 25-80°C 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 O-30°C for about 1-24 hours: to provide a compound in which R 13 is C ONHOR 12 .

Claim 23

Dependent Claim 77 words

22 . Process of Claim 6 wherein: R 1 is X is a carbon-carbon single bond, -CO-. -O-. -S-, or -NH-: R 2 . R 3 , R6 and R 7 are as defined in Claim 15; and R 8 is (CH 2 ) OR 11 , (CH 2 ) OCOR 14 . (CH 2 ) n CH(OH)R 16 . (CH 2 ) n COR 16 (CH 2 ) n Cl, (CH 2 ) n CN. CHO.

Claim 24

Dependent Claim 83 words

Process of Claim 22 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 25

Dependent Claim 73 words

Process of Claim 22 wherein R 8 is (CH 2 ) n OR 11 and R 11 is not H and the product of Formula 3 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 26

Dependent Claim 112 words

Process of Claim 22 wherein R 8 is (CH 2 ) n OH and the product of Formula 3 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 O°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 27

Dependent Claim 39 words

Process of Claim 22 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 )nOH.

Claim 28

Dependent Claim 58 words

Process of Claim 22 wherein R8 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 3 in which R 8 is (CH 2 ) n-1 COR 16 and R 16 is H.

Claim 29

Dependent Claim 83 words

Process of Claim 22 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 30

Dependent Claim 58 words

Process of Claim22 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 is not H.

Claim 31

Dependent Claim 59 words

Process of Claim 22 wherein R 8 is (CH 2 ) n COR 16 and R 16 is H 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 ) a COR 16 and R 16 is OH .

Claim 32

Dependent Claim 141 words

Process of Claim 22 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 O°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 R 8 is (CH 2 ) n CONR 18 R 19 .

Claim 33

Dependent Claim 74 words

Process of Claim 22 wherein R 8 is (CH 2 ) n OR 11 and R 11 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 of Formula 3 in which R 8 is ( CH2 ) nCl .

Claim 34

Dependent Claim 87 words

Process of Claim 32 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 presence 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 (CH 2 ) m -phthalimide.

Claim 35

Dependent Claim 68 words

Process of Claim 32 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 36

Dependent Claim 89 words

Process of Claim 32 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 16 is OH.

Claim 37

Dependent Claim 159 words

process of Claim 32 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 24-100°C for 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 38

Dependent Claim 71 words

Process of Claim 22 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 temperature 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 39

Dependent Claim 176 words

3 8. Process of Claim 22 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 COR 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 ) s COR 16 . except where R 15 is H and R 16 is OH. and except where R 15 H and 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 40

Dependent Claim 63 words

Process of Claim 22 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 41

Dependent Claim 62 words

Process of Claim 22 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 42

Dependent Claim 77 words

Process of Claim 22 Wherein R 8 is (CH 2 ) n OH and the compound of Formula 3 is contacted with an isocyanate of Formula R 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 43

Dependent Claim 74 words

Process of Claim 2 2 wherein the compound in which R8 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 44

Dependent Claim 91 words

Process of Claim 22 in which R 8 is (CH 2 ) n Cl and the compound of Formula 3 is n 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 45

Dependent Claim 124 words

Process of Claim 42 or 43 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 which R 8 is -(CH 2 ) n NR 11 CO 2 R 10 or -(CH 2 ) n NR 1 SO 2 R 10 .

Claim 46

Dependent Claim 90 words

Process of Claim 42 or 43 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 47

Dependent Claim 132 words

Process of Claim 6 wherein R 1 is NO 2 R 2 , R 3 , R 6 , R 7 , and R 8 are as defined in Claim 20 in which the compound of Formula 3 wherein R 1 is N0 2 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 to produce the corresponding compound of Formula 3 wherein R 1 is and X is -OCH 2 -.

Claim 48

Dependent Claim 77 words

Method of claim 6 wherein R 8 is -CHO, whereby the benzyl derivative of Formula 2 attaches to the imidazole derivative of Fornula 1 preferentially at the nitrogen atom adjacent the carbon atom of the imidazole ring to which R 8 is attached. 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 49

Dependent Claim 109 words

Process of Claim 6 wherein R 1 is OCH 2 C 6 H 5 , R 2 and R 3 are H and R 6 , R 7 , and R 8 are as defined in Claim 20 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:

Angiotensin II receptor blocking imidazoles

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