Isoxicam and related 4-hydroxy-N-isoxazolyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxides. Potent nonsteroidal antiinflammatory agents

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.

A modified mouse air pouch model for evaluating the effects of compounds on granuloma induced cartilage degradation

“…BW755C also exhibits an effect in the rat paw oedema assay, even when administered 2h after the carrageenan (Holsapple & Yim, 1984). Employing the in vivo rat models associated with chronic inflammation, adjuvant polyarthritis (Goldberg & Godfrey, 1980;Zinnes et al, 1982) and type II collageninduced arthritis (Billingham et al, 1980;Probert et al, 1984) the NSAIDs including indomethacin were found to be protective. In addition granuloma formation induced by cotton pellets is inhibited, although the data are far from unequivocal, with the results depending on the actual NSAID employed (Di Rosa, 1979).…”

4-Hydroxy-2-[(4-iodobenzoyl)methyl]-3-(3-methoxybenzoyl)-2H-1,2-benzothiazine 1,1-dioxide

“…Benzothiazine nucleus occupies a significant position among heterocyclic compounds. Oxicams are benzothiazine derivatives which are in use for the treatment of various inflammatory diseases (Lombardino & Wiseman, 1972;Zinnes et al, 1982). Besides oxicams, numerous other benzothiazine compounds are found to possess antimicrobial (Zia-ur-Rehman et al, 2005), analgesic (Turck et al, 1996), antioxidant activities (Ahmad et al, 2010).…”

Synthesis, structure, and reactivity to nucleophiles of 3-benzylidene- and 3-ethylidene-2,3-dihydro-2-methyl-1,2-benzothiazin-4-one 1,1-dioxides

“…120-121 "C, whose m.p.s and spectroscopic data agree with those previously reported.' 1,2,3,3a,4,9b-Hexahydro-4-methyl-3-phenylpyrazolo[4,3-c]- [ 1,2]benzothiazin-9b-o1 5,5-Dioxide (5).-A solution of compound (4) (0.5 g, 1.7 mmol) in ethanol (10 ml) was treated with hydrazine hydrate (0.084 ml, 1.7 mmol) and was set aside at room temperature for 2 h. The precipitate was filtered off and washed with cold ethanol to give the title alcohol (5) (0. and OS~-sodium hydroxide (20 ml) was added the alcohol (5) (0.4 g, 1.2 mmol) and the solution was stirred at room temperature for 12 h. The solvent was evaporated off and the residue was extracted with chloroform. After drying and evaporation of the solvent the residue was crystallized from isopropyl alcohol to give the title compound (6) (0.6 g, W%), m.p.…”

“…General Procedure.-A solution of a ketone (4) (5 mmol) and compound (11) (10 mmol) in toluene (50 ml) was heated at 80°C for 12 h. The solvent was evaporated off to give the following products (12). [ 1,2) General Method for Deamination of Compounds (12) to Aikenes (13).-Hydrogen chloride gas was passed, for 6 h, into a stirred, refluxing solution of an amine (12) (3 mmol) in dioxane (20 ml). The solvent was evaporated off and the residue was treated with water and extracted with methylene dichloride.…”