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.

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The preparation of 2‐indolyl alkyl ketones by reductive cleavage of a β‐keto sulfone or by the reaction of 1‐chloro‐2‐propanone (chloroacetone) with a 2‐aminobenzoic acid derivative is described. The β‐keto sulfone intermediates are prepared by condensation of the carbanion of dimethyl sulfone and indole‐2‐carboxylic acid esters. Lack of reactivity of several 2‐aminobenzoic acids in the 1‐chloro‐2‐propanone process is related to the presence of electron‐withdrawing substituents in the aromatic ring.

Several methods for the synthesis of bemarinone, 5,6‐dimethoxy‐4‐methyl‐2(1H)‐quinazolinone, were explored with the most successful being a directed metalation route. Details of the lithiation and the subsequent reaction with electrophiles of 3′,4′‐dimethoxy‐2,2‐dimethylpropioanilide and other derivatives of 3,4‐dimethoxyaniline are given.