Angiotensin II receptor blocking benzimidazoles

Claim 2

A compound of the formula ##STR74## where R 1 is --CO 2 H, --NHSO 2 CF 3 , ##STR75## R 2 is H, halogen, NO 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with a halogen atom, --OR 4 or up to two --CO 2 R 4 ; with the proviso that when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; R 4 is H, or alkyl of 1-4 carbon atoms; R 5 is H, alkyl of 1 to 5 carbon atoms, cycoalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 6 , or NR 7 R 8 ; R 6 H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; R 7 and R 8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR76## Q is NR 9 , O, or CH 2 ; R 9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 10 is alkyl of 1 to 6 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen, alkoxy of 1 to 6 carbon atoms; ##STR77## B is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH 2 --; n is 1 to 6; m is 0 to 3; p is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (1) when R 3 is methyl is must be substituted with --OR 4 or CO 2 R 4 ; (2) when R 3 is --CH═CH--CO 2 Et, then X is not --NHCO; (3) when R 3 is CH 2 OH, CH=CHCO 2 H or CH 2 CH 2 CO 2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond; (4) when R 1 is --CO 2 H, R 3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl; (5) when R 1 is --CO 2 H, R 3 is CH 2 OCH 3 and X is a carbon-carbon single bond, then A is not 5-CH 2 OH; (6) when R 1 is --CO 2 H, X is not --O--.

Claim 3

Compound of claim 1 wherein R 1 is --CO 2 H, --NHSO 2 CF 3 ; or ##STR78## R 2 is hydrogen; R 3 is alkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with --OR 4 or CO 2 R 4 ; R 5 is H, alkyl of 1 to 5 carbon atoms, OR 6 or NR 7 R 8 ; R 6 is H, alkyl of 1 to 5 carbon atoms; A is halogen, alkoxy of 1 to 6 carbon atoms; ##STR79## B is H; or a pharmaceutically acceptable salt thereof.

Claim 4

Compound of claim 2 wherein R 3 is alkyl of 3 to 5 carbon atoms, alkenyl or akynyl of 3 to 5 carbon atoms each of which may be unsubstituted or substituted with OH, OCH 3 , CO 2 H or CO 2 CH 3 ; ##STR80## n is 1-2; X is a carbon-carbon single bond, or --NHCO--; or a pharmaceutically acceptable salt thereof.

Claim 5

Compound of claim 1 which is 2-butyl-1[(2'-carboxybiphenyl-4-yl)methyl]-6-hydroxymethyl-benzimidazole, or a pharmaceutically suitable salt thereof.

Claim 6

Compound of claim 1 which is 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethyl-benzimidazole, or a pharmaceutically suitable salt thereof.

Claim 7

Compound of claim 1 which is 2-butyl-1-[2'-carboxybiphenyl-4-yl)methyl]-6-methoxybenzimidazole, or a pharmaceutically suitable salt thereof.

Claim 8

Compound of claim 1 which is 2-(1-butenyl)-1[(2'-carboxybiphenyl-4-yl)-methyl]-6-hydroxymethylbenzimidazole, or a pharmaceutically suitable salt thereof.

Claim 9

Compound of claim 1 which is 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-chlorobenzimidazole, or a pharmaceutically suitable salt thereof.

Claim 10

Pharmaceutical composition useful for treating hypertension or congestive heart failure in a warm-blooded animal comprising a suitable pharmaceutical carrier and a compound of any one of claims 1 through 8 in an amount effective to lower the animal's blood pressure or relieve the congestion.

Claim 11

Method of treating hypertension in a warm-blooded animal comprising administering to the animal in an amount effective to lower the animal's blood pressure a compound of any one of claims 1 through 8.

Claim 12

Method of treating congestive heart failure in a warm-blooded animal comprising administering to the animal a compound of any one of claims 1 through 8 in an amount effective to correct the hemodynamic burden on the heart to relieve the congestion.

Claim 13

Method of treating hypertension in a warm-blooded animal comprising administering to the animal in an amount effective to lower the animal's blood pressure a compound of the formula: ##STR81## where R 1 is --CO 2 H, --NHSO 2 CF 3 , ##STR82## R 2 is H, halogen, NO 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with a halogen atom, --OR 4 or up to two --CO 2 R 4 ; with the proviso that when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; R 4 is H, or alkyl of 1-4 carbon atoms; R 5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 6 , or NR 7 R 8 ; R 6 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; R 7 and R 8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR83## Q is NR 9 , O, or CH 2 ; R 9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 10 is alkyl of 1 to 6 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen, alkoxy of 1 to 6 carbon atoms; ##STR84## B is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH 2 --; n is 1 to 6; m is 0 to 3; p is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (1) when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; (2) when R 3 is --CH═CH--CO 2 Et, then X is not --NHCO; (3) when R 3 is CH 2 OH, CH=CHCO 2 H or CH 2 CH 2 CO 2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond; (4) when R 1 is --CO 2 H, R 3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl; (5) when R 1 is --CO 2 H, R 3 is CH 2 OCH 3 and X is a carbon-carbon single bond, then A is not 5-CH 2 OH.

Claim 14

Method of treating hypertension in a warm-blooded animal comprising administering to the animal in an amount effective to lower the animal's blood pressure a compound of the formula: ##STR81## where R 1 is --CO 2 H, --NHSO 2 CF 3 , ##STR82## R 2 is H, halogen, NO 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with a halogen atom, --OR 4 or up to two --CO 2 R 4 ; with the proviso that when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; R 4 is H, or alkyl of 1-4 carbon atoms; R 5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 6 , or NR 7 R 8 ; R 6 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; R 7 and R 8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR83## Q is NR 9 , O, or CH 2 ; R 9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 10 is alkyl of 1 to 6 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen, alkoxy of 1 to 6 carbon atoms; ##STR84## B is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH 2 --; n is 1 to 6; m is 0 to 3; p is 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (1) when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; (2) when R 3 is --CH═CH--CO 2 Et, then X is not --NHCO; (3) when R 3 is CH 2 OH, CH=CHCO 2 H or CH 2 CH 2 CO 2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond; (4) when R 1 is --CO 2 H, R 3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl; (5) when R 1 is --CO 2 H, R 3 is CH 2 OCH 3 and X is a carbon-carbon single bond, then A is not 5-CH 2 OH.

Claim 15

Method of treating congestive heart failure in warm-blooded animals comprising administering to the animal a compound of the formula: ##STR85## where R 1 is --CO 2 H, --NHSO 2 CF 3 , ##STR86## R 2 is H, halogen, NO 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with a halogen atom, --OR 4 or up to two --CO 2 R 4 ; with the proviso that when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; R 4 is H, or alkyl of 1-4 carbon atoms; R 5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 6 , or NR 7 R 8 ; R 6 H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; R 7 and R 8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR87## Q is NR 9 , O, or CH 2 ; R 9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 10 is alkyl of 1 to 6 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen, alkoxy of 1 to 6 carbon atoms; ##STR88## B is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH 2 --; n is 1 to 6; m is 0 to 3; p is 0 or 1; or a pharmaceutically acceptable salt thereof in an amount effective to correct the hemodynamic burden on the heart to relieve the congestion; provided that: (1) when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; (2) when R 3 is --CH=CH--CO 2 Et, then X is not --NHCO; (3) when R 3 is CH 2 OH, CH=CHCO 2 H or CH 2 CH 2 CO 2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond; (4) when R 1 is --CO 2 H, R 3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl; (5) when R 1 is --CO 2 H, R 3 is CH 2 OCH 3 and X is a carbon-carbon single bond, then A is not 5-CH 2 OH.

Claim 16

Method of treating congestive heart failure in warm-blooded animals comprising administering to the animal a compound of the formula: ##STR85## where R 1 is --CO 2 H, --NHSO 2 CF 3 , ##STR86## R 2 is H, halogen, NO 2 , methoxy, or alkyl of 1 to 4 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be unsubstituted or substituted with a halogen atom, --OR 4 or up to two --CO 2 R 4 ; with the proviso that when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; R 4 is H, or alkyl of 1-4 carbon atoms; R 5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) m C 6 H 5 , OR 6 , or NR 7 R 8 ; R 6 H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; R 7 and R 8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR87## Q is NR 9 , O, or CH 2 ; R 9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; R 10 is alkyl of 1 to 6 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen, alkoxy of 1 to 6 carbon atoms; ##STR88## B is H, alkyl of 1 to 10 carbon atoms, C r F 2r+1 where r=1-6, C 6 F 5 , halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH 2 --; n is 1 to 6; m is 0 to 3; p is 0 or 1; or a pharmaceutically acceptable salt thereof in an amount effective to correct the hemodynamic burden on the heart to relieve the congestion; provided that: (1) when R 3 is methyl it must be substituted with --OR 4 or --CO 2 R 4 ; (2) when R 3 is --CH=CH--CO 2 Et, then X is not --NHCO; (3) when R 3 is CH 2 OH, CH=CHCO 2 H or CH 2 CH 2 CO 2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond; (4) when R 1 is --CO 2 H, R 3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl; (5) when R 1 is --CO 2 H, R 3 is CH 2 OCH 3 and X is a carbon-carbon single bond, then A is not 5-CH 2 OH.