No abstract

A variety of new 3-carbamoyl-4-hydroxy-2//-l,2-benzothiazine 1,1-dioxides of structure II was prepared and evaluated an antiinflammatory agents. Three synthetic methods were employed. Method A, consisting of base-catalyzed carbamoylation of ketone I by isocyanates, and method B, involving aminolysis of j3-keto ester III, are modifications of previously described processes. In the completely new method C, the enamine IV, derived from ketone I, is reacted with phosgene to give the acid chloride V. The latter reacts with an amine to give enamine-amide VI which can be hydrolyzed to II. The prototype compound 2 has the same order of activity as phenylbutazone when evaluated against adjuvant-induced polyarthritis as well as carrageenin-induced edema. Its acute toxicity is less than that of phenylbutazone. The structural modifications described herein all resulted in decreased or complete loss of activity in the carrageenin test.Our continuing studies1 in 1,2-benzothiazine chemistry as

No abstract

A novel series of antiinflammatory agents, N-isoxazolyl-3-carboxamides of 4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide, was synthesized and evaluated as antiinflammatory agents in the carrageenin-induced rat paw edema (CIRPE) assay and adjuvant-induced polyarthritis (AIP) assay. Several analogues were found to be equipotent or more potent than aspirin and phenylbutazone. Structure-activity relationships are discussed. One of the compounds, 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine 3-carboxamide 1,1-dioxide (3a; isoxicam), was found to be 3 times as potent as phenylbutazone in the CIRPE and in the therapeutic AIP assays. Isoxicam (3a) is presently undergoing phase III clinical trial as an antiarthritic drug.

No abstract