Anti-inflammatory 1-heteroaryl-oxindole-3-carboxamides

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514418, 548181, 548465, 548467, C07D40714, C07D40914, C07D41714, A61K 31125

Patent

active

051283522

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to new and useful nonsteroidal anti-inflammatory agents. More particularly, it relates to certain N-(substituted)-1-heteroaryloxindole-3-carboxamides which are potent inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) and which are of value as anti-inflammatory agents in mammals.
2. Description of Related Art
U.S. Pat. No. 3,634,453, issued Jan. 11, 1972, describes a series of anti-inflammatory N-(substituted)oxindole-3-carboxamides, the 1-position of which may be substituted by, inter alia, C.sub.1-6 alkyl or phenylalkyl; and the carboxamide moiety of which carries a phenyl, substituted phenyl or naphthyl group.
Oxindole-3-(N-2-thiazolyl)carboxamides, the 1-position of which is unsubstituted or bears an alkyl, aryl or aralkyl group, and their use as antipyretic, analgesic and anti-inflammatory agents are disclosed in U.S. Pat. No. 3,749,731, issued July 31, 1973. Each of U.S. Pat. No. 4,644,005 and 4,686,224 describes N-(substituted)-1-phenyl oxindole-3-carboxamides wherein a monoor bicyclic ring system is fused to the 5,6-positions of the oxindole and wherein the N-substituent can be pyridyl or 2-thiazolyl. The compounds are anti-inflammatory agents.
Tricyclic oxindole 3-carboxamides, the 1-position of which is substituted with a phenyl group, and the carboxamide moiety of which bears a phenyl, substituted phenyl or heterocyclyl moiety, and their use as anti-inflammatory agents are disclosed in U.S. Pat. No. 4,695,571.
U.S. Pat. No. 4,730,004 discloses anti-inflammatory 1-acyloxindole-3-carboxamides, the carboxamide moiety of which is substituted by a heterocyclic (thienyl, furyl, thiazolyl, etc.), furylmethyl, thenyl or substituted phenyl group.
A variety of anti-inflammatory oxindoles, the 1,3-positions of which are substituted by carboxamide or substituted carboxamide groups; or the 1-position of which bears a carboxamide group and the 3-position an acyl group, or vice versa, are known. However, said oxindoles are structurally different from the oxindoles of this invention and are merely mentioned to indicate the rather extensive and intensive efforts to develop non-steroidal anti-inflammatory agents.


SUMMARY OF THE INVENTION

It has been found that certain N-(substituted)-1-heteroaryl-2-oxindole-3-carboxamides of formula (I) ##STR1## or a pharmaceutically acceptable base salt thereof wherein
R.sup.1 is thienyl, furyl or 2-thiazolyl;
R.sup.2 is thienyl, furyl or ##STR2## wherein
X is hydrogen, fluoro, chloro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, nitro or trifluoromethyl;
Y is hydrogen, fluoro or chloro;
and each of R.sup.3 and R.sup.4, which may be alike or different, is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, nitro or trifluoromethyl are potent inhibitors of CO and LO enzymes, and are of value as anti-inflammatory agents for treating an inflammatory disease in a mammal. They are especially useful for treatment of rheumatoid arthritis in mammals.
A favored group of compounds are those wherein R.sup.2 is phenyl or substituted phenyl. Within this group of compounds those wherein each of R.sup.3 and R.sup.4 is hydrogen; and one or both of X and Y are hydrogen, fluoro or chloro are preferred compounds. Especially preferred in this latter group are those compounds wherein each of X and Y is hydrogen, chloro or fluoro; and R.sup.1 is 2- or 3-thienyl.
Included within this invention are pharmaceutical compositions, useful as anti-inflammatory agents in a mammal, comprising a pharmaceutically acceptable carrier and an anti-inflammatory disease treating amount of a compound of formula (I).
Additionally, the present invention includes a method of treating an anti-inflammatory disease in a mammal which comprises administering to said mammal an anti-inflammatory disease treating amount of a compound of formula (I).


DETAILED DESCRIPTION OF THE INVENTION

The comp

REFERENCES:
patent: 4791129 (1988-12-01), Kadin

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