Method of protecting against and/or treating ulcerative gastrointestinal conditions using a thromboxane A.sub.2 receptor antagonist and combination useful in preventing and/or treating ulcers and/or inflammation
AssigneeE. R. Squibb & Sons, Inc.
InventorsBernard Rubin, Martin L. Ogletree, Eugene H. O'Keefe, A. K. Gunnar Aberg
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Abstract
A method is provided for protecting against and/or treating ulcerative gastrointestinal conditions, including anti-inflammatory drug-induced gastrointestinal ulcers, using a thromboxane A.sub.2 receptor antagonist. In addition, a combination is provided which includes a thromboxane A.sub.2 receptor antagonist and an anti-inflammatory agent which combination may be used to treat inflammatory conditions, such as arthritis, while inhibiting formation of and/or treating gastrointestinal ulcers.
Claims10
A method for preventing or treating ulcerative conditions of the gastrointestinal tract, in a mammalian species, which comprises administering to a mammalian species in need of such treatment an effective amount of a thromboxane A.sub.2 receptor antagonist, which is a 7-oxabicycloheptane substituted diamide prostaglandin analog, or an interphenylene 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analog, said 7-oxabicycloheptane substituted diamide prostaglandin having the formula ##STR8## including all stereoisomers thereof, wherein m is 0 to 4;
- A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --;
- n is 1 to 5;
- O is --CH.dbd.CH--, --CH.sub.2 --, ##STR9## or a single bond;
- R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR10## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy;
- p is 1 to 4;
- R.sup.1 is H or lower alkyl;
- q is 1 to 12;
- R.sup.2 is H or lower alkyl;
- and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, arylalkyloxy, aryloxy, amino, alkylamino, arylalkylamino, arylamino, ##STR11## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl, and said interphenylene 7-oxabicycloheptane substituted heterocyclic amide prostaglandin analog having the formula ##STR12## and including all stereoisomers thereof, wherein m is 1, 2 or 3;
- n is 0, 1, 2, 3 or 4;
- Y is O or a single bond, with the proviso that when n is 0, Y is a single bond;
- R is CO.sub.2 H, CO.sub.2 lower alkyl, CO.sub.2 alkali metal, CONHSO.sub.2 R.sup.3 or 5-tetrazolyl, with the proviso that when R is 5-tetrazolyl, n cannot be 0;
- X is O, S or NH;
- R.sup.1 is lower alkyl, aryl, cycloalkyl, saturated heterocycle or aromatic heterocycle, each optionally substituted with an alkyl, aryl, cycloalkyl, or cycloalkylalkyl;
- R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl;
- or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring;
- and
- R.sup.3 is lower alkyl, aryl or aralkyl.
A method for preventing or treating an inflammatory condition without causing gastrointestinal ulcers, in a mammalian species, which comprises administering to a mammalian species in need of such treatment an effective amount of a thromboxane A.sub.2 receptor antagonist in combination with an anti-inflammatory agent, the thromboxane A.sub.2 receptor antagonist being a a 7-oxabicycloheptane substituted diamide prostaglandin analog, or an interphenylene 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analog, the thromboxane A.sub.2 receptor antagonist being employed in a weight ratio to the anti-inflammatory agent of within the range of from about 0.01:1 to about 100:1, said 7-oxabicycloheptane substituted diamide prostaglandin having the formula ##STR14## including all stereoisomers thereof, wherein m is 0 to 4;
- A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --;
- n is 1 to 5;
- O is --CH.dbd.CH--, --CH.sub.2 --, ##STR15## or a single bond;
- R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR16## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy;
- p is 1 to 4;
- R.sup.1 is H or lower alkyl;
- q is 1 to 12;
- R.sup.2 is H or lower alkyl;
- and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, arylalkyloxy, aryloxy, amino, alkylamino, arylalkylamino, arylamino, ##STR17## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl, and said interphenylene 7-oxabicycloheptane substituted heterocyclic amide prostaglandin analog having the formula ##STR18## and including all stereoisomers thereof, wherein m is 1, 2 or 3;
- n is 0, 1, 2, 3 or 4;
- Y is O or a single bond, with the proviso that when n is 0, Y is a single bond;
- R is CO.sub.2 H, CO.sub.2 lower alkyl, CO.sub.2 alkali metal CONHSO.sub.2 R.sup.3 or 5-tetrazolyl, with the proviso that when R is 5-tetrazolyl, n cannot be 0;
- X is O, S or NH;
- R.sup.1 is lower alkyl, aryl, cycloalkyl, saturated heterocycle or aromatic heterocycle, each optionally substituted with an alkyl, aryl, cycloalkyl, or cycloalkylalkyl;
- R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl;
- or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring;
- and
- R.sup.3 is lower alkyl, aryl or aralkyl.
Dependencies are inferred from the claim text.