piroxicam and Stomach-Ulcer

An efficient method for trapping isocyanate 4, generated from the Curtius rearrangement, with ethyl alcohol to afford the carbamate 5 is reported. 5-Nitrobenzo[b]thiophene-2-carboxylic acid 1 is converted to the corresponding hydrazide 2 by the reaction with hydrazine hydrate and then to the azide 3 with nitrous acid, followed by thermal rearrangement, cooling, and trapping in one pot reaction. The carbamate 5 is treated with hydrazine hydrate to afford the desired, Zileuton analogue, 4-(5-nitrobenzo[b]thiophene-2-yl)semicarbazide 6. Also the reactivity of hydrazide 2 towards some carboxyaldehydes and phenylisothiocyanate afforded the corresponding carbohydrazides 7, 8 and phenylthiosemicarbazide 9, respectively. Compounds 9, 2 and 6, respectively, were more potent as anti-inflammatory and anti-nociceptive agents.

Topics: Acetic Acid; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Carrageenan; Edema; Liver; Mice; Pain; Pain Threshold; Piroxicam; Rats; Stomach Ulcer; Structure-Activity Relationship; Thiophenes

A series of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones was synthesized and evaluated as candidate antiinflammatory/analgesic agents as well as dual inhibitors of prostaglandin and leukotriene synthesis. Some compounds that showed dual inhibitory activity were found to possess equipotent antiinflammatory activities to indomethacin, with reduced ulcerogenic effects. One of the compounds, N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-o ne, was found to have a wider safety margin than indomethacin or piroxicam, and was selected for detailed evaluation as a candidate drug for clinical application.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzylidene Compounds; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Male; Prostaglandins E; Pyrrolidinones; Rats; Rats, Inbred Strains; Stomach Ulcer

The synthesis of tenoxicam, 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxami de 1,1-dioxide (1e), and of the analogues with various residues on the ring nitrogen and the amide nitrogen is described. This new class of "oxicams" has pronounced antiinflammatory and analgesic properties. The very specific structure-activity relationship of isomeric and isosteric groups at the amide nitrogen has been evaluated. The substituent in position 2 also has a great influence on the pharmacological properties. Tenoxicam is presently undergoing clinical trials.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Piroxicam; Rats; Stomach Ulcer; Structure-Activity Relationship