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US 4,880,804 AGranted
Angiotensin II receptor blocking benzimidazoles
AssigneeE. I. Du Pont de Nemours and Company
InventorsDavid J. Carini, John Jonas V. Duncia, Sung-Eun Yoo
Life of this patent
Estimating the term…
Abstract
Substituted benzimidazoles such as ##STR1## and pharmaceutically suitable salts thereof are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
Claims13
A compound of the formula ##STR74## where R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, ##STR75## R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms;
- R.sup.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.sup.4 or up to two --CO.sub.2 R.sup.4 ;
- with the proviso that when R.sup.3 is methyl it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ;
- R.sup.4 is H, or alkyl of 1-4 carbon atoms;
- R.sup.5 is H, alkyl of 1 to 5 carbon atoms, cycoalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.6, or NR.sup.7 R.sup.8 ;
- R.sup.6 H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl;
- R.sup.7 and R.sup.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.sup.9, O, or CH.sub.2 ;
- R.sup.9 is H, alkyl of 1 to 4 carbon atoms, or phenyl;
- R.sup.10 is alkyl of 1 to 6 carbon atoms;
- A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms;
- ##STR77## B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms;
- X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.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.sup.3 is methyl is must be substituted with --OR.sup.4 or CO.sub.2 R.sup.4 ;
- (2) when R.sup.3 is --CH.dbd.CH--CO.sub.2 Et, then X is not --NHCO;
- (3) when R.sup.3 is CH.sub.2 OH, CH=CHCO.sub.2 H or CH.sub.2 CH.sub.2 CO.sub.2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond;
- (4) when R.sup.1 is --CO.sub.2 H, R.sup.3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl;
- (5) when R.sup.1 is --CO.sub.2 H, R.sup.3 is CH.sub.2 OCH.sub.3 and X is a carbon-carbon single bond, then A is not 5-CH.sub.2 OH;
- (6) when R.sup.1 is --CO.sub.2 H, X is not --O--.
19 more elements
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.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, ##STR82## R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms;
- R.sup.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.sup.4 or up to two --CO.sub.2 R.sup.4 ;
- with the proviso that when R.sup.3 is methyl it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ;
- R.sup.4 is H, or alkyl of 1-4 carbon atoms;
- R.sup.5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.6, or NR.sup.7 R.sup.8 ;
- R.sup.6 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl;
- R.sup.7 and R.sup.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.sup.9, O, or CH.sub.2 ;
- R.sup.9 is H, alkyl of 1 to 4 carbon atoms, or phenyl;
- R.sup.10 is alkyl of 1 to 6 carbon atoms;
- A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms;
- ##STR84## B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms;
- X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.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.sup.3 is methyl it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ;
- (2) when R.sup.3 is --CH.dbd.CH--CO.sub.2 Et, then X is not --NHCO;
- (3) when R.sup.3 is CH.sub.2 OH, CH=CHCO.sub.2 H or CH.sub.2 CH.sub.2 CO.sub.2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond;
- (4) when R.sup.1 is --CO.sub.2 H, R.sup.3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl;
- (5) when R.sup.1 is --CO.sub.2 H, R.sup.3 is CH.sub.2 OCH.sub.3 and X is a carbon-carbon single bond, then A is not 5-CH.sub.2 OH.
19 more elements
Method of treating congestive heart failure in warm-blooded animals comprising administering to the animal a compound of the formula:
- ##STR85## where R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, ##STR86## R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms;
- R.sup.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.sup.4 or up to two --CO.sub.2 R.sup.4 ;
- with the proviso that when R.sup.3 is methyl it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ;
- R.sup.4 is H, or alkyl of 1-4 carbon atoms;
- R.sup.5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.6, or NR.sup.7 R.sup.8 ;
- R.sup.6 H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl;
- R.sup.7 and R.sup.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.sup.9, O, or CH.sub.2 ;
- R.sup.9 is H, alkyl of 1 to 4 carbon atoms, or phenyl;
- R.sup.10 is alkyl of 1 to 6 carbon atoms;
- A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms;
- ##STR88## B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms;
- X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.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.sup.3 is methyl it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ;
- (2) when R.sup.3 is --CH=CH--CO.sub.2 Et, then X is not --NHCO;
- (3) when R.sup.3 is CH.sub.2 OH, CH=CHCO.sub.2 H or CH.sub.2 CH.sub.2 CO.sub.2 H and A and B are hydrogen, then X cannot be a carbon-carbon single bond;
- (4) when R.sup.1 is --CO.sub.2 H, R.sup.3 is butyl, and X is a carbon-carbon single bond, then A is not 5-Cl;
- (5) when R.sup.1 is --CO.sub.2 H, R.sup.3 is CH.sub.2 OCH.sub.3 and X is a carbon-carbon single bond, then A is not 5-CH.sub.2 OH.
19 more elements
Dependencies are inferred from the claim text.