Synthesis and pharmacological profile of 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide derivatives: non-steroidal anti-inflammatory agents with reduced ulcerogenic effects in the rat.
The new anti-inflammatory agents 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-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 6 f 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.
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, Faculté des Sciences, Avenue de l'Environnement, 5000, Monastir, Tunisia.
Yakdhane
Y
Kacem
Jamil
J
Kraiem
Emna
E
Kerkeni
Abderrahman
A
Bouraoui
Béchir
B
Ben Hassine
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002351:Carrageenan; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005745:Gastric Acidity Determination; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D014633:Valine / Q000737:chemistry
C473018:2,6-dimethyl-3-isopropyl-1,2-benzothiazin-3,4-diol 1,1-dioxide; C473017:6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003499:Cyclic S-Oxides; D016861:Cyclooxygenase Inhibitors; D013843:Thiazines; D002351:Carrageenan; D014633:Valine