Novel thiazolinyl, thiazolidinonyl, thiadiazolyl and oxadiazolyl-benzotriazole derivatives with potential antiinflammatory activity and minimum ulcerogenic effect

Four novel series of 1H-benzotriazole derivatives; containing thiazolin, thiazolidin, thiadiazole and oxadiazole moieties; namely 1-[(3,4-disubstituted thiazolin-2-ylidene)hydrazinocarbonyl]methyl-1H-benzotriazoles 3a-1; 1-[3-substituted 5-ethoxycarbonyl-4-methyl thiazolin-2-ylidene)hydrazinocarbonyl]methyl-1H-benzotriazoles 4a-c; 1-[(3-substituted-4-oxothiazolidin-2-ylidene)hydrazinocarbonyl]methyl-1H- benzotriazoles 5a-d; 1-[(5-substituted aminothiadiazol-2-yl)methyl]-1H-benzotriazoles 6a-c have been synthesized by cyclization of the key intermediates 1-[(substituted thiocarbamoylhydrazinocarbonyl)methyl]-1H-benzotriazoles 2a-d. Furthermore 1-[(5-substituted aminooxadiazol-2-yl)methyl]-1H-benzotriazoles 7a, b were obtained by one-pot synthesis starting from 1H-benzotriazol-1-acetic acid hydrazide. The antiinflammatory activity of representative compounds was evaluated in vivo against indomethacin as a standard using the sponge implantation model of inflammation in rats. Both non-immunological parameters such as exudate volume, total leucocyte count (TLC), and differential leucocyte count (DLC), and immunological parameters, for example neutrophil phagocytic function by reduced cytochrome C levels, and the assay of interleukin-1 beta (IL-1 beta) levels in drug-pre-treated rats, were determined. The ulcerogenic activity of compounds showing marked antiinflammatory activity was also studied. Compounds 3e, 5b and 5c showed antiinflammatory activity comparable to indomethacin, and they also demonstrated minimum ulcerogenic activity.