Synthesis and pharmacological profile of 6-methyl-3-isopropyl-2 H-1,2-benzothiazin-4(3 H)-one 1,1-dioxide derivatives: non-steroidal anti-inflammatory agents with reduced ulcerogenic effects in the rat

Abstract

The new anti-inflammatory agents 6-methyl-3-isopropyl-2 H-1,2-benzothiazin-4(3 H)-one 1,1-dioxide 6a and its analogues 6b– f were synthesized from l-valine. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 6a– f (5–20 mg/kg, i.p.) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay in albino rats, and their effects are comparable to that of piroxicam (5 mg/kg, i.p.), used as a reference drug. The nature of the substituents on the sulfonamide nitrogen and those on position three had a pronounced effect on the anti-inflammatory activity. Studies of structure–activity relationships have led to selection of compound 2,6-dimethyl-3-isopropyl-1,2-benzothiazin-3,4-diol 1,1-dioxide 6f which exhibited the most potent activity (61.7% inhibition at 5 mg/kg, i.p. and ED 50=4.5 mg/kg, i.p.). Comparison of the gastrointestinal safety of compounds 6a– f with that of piroxicam showed a far better tolerability for our products. This comparison was based on the ulcer index and the pH of gastric content.