Onofrio Migliara

Synthesis and pharmacological evaluation of 1-methyl-5- [substituted-4(3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.

Pyrazolobenzotriazinone Derivatives as COX Inhibitors: Synthesis, Biological Activity, and Molecular-Modeling Studies

Pyrazolylbenzotriazinones are endowed with a structural analogy with the COX‐2 selective inhibitor celecoxib. Considering that our research group has long been interested in the 3‐pyrazolyl‐substituted benzotriazinones as anti‐inflammatory agents, six new pyrazolylbenzotriazinone derivatives 16a–c and 18a–c have been prepared by reacting the opportune ethyl 5‐(2‐aminobenzamido)‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carboxylate or 5‐(2‐aminobenzamido)‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carboxyic acid with sodium nitrite in glacial acetic acid. The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5‐(4‐oxo‐1,2,3‐benzotriazin‐3(4H)‐yl)‐1‐pyridin‐2‐yl‐1H‐pyrazole‐4‐carboxylate, a good COX‐1/COX‐2 selectivity. Molecular modeling studies confirmed the obtained biological results.

Oxidative reactions of polyarylpyrroles. Part 3. Oxidative trimerization of 2,5-diphenylpyrrole

As in the oxidative reaction of 2,3,5-triphenylpyrrole previously studied, the oxidation of 2,5-diphenylpyrrole with potassium dichromate gave the dimer 2,2′,5,5′-tetraphenyl-3,3′-bipyrrole (2) and the related hydroxy-derivative 3-(2,5-diphenylpyrrol-3-yl)-2,5-diphenyl-2H-pyrrol-2-ol (6), together with the tetracyclic compound 1,6a-dihydro-2,5,6a-triphenylbenzo[g]pyrrolo[3.2-e]indole (3), whose formation involves the α-position of the pyrrole nucleus and the α′-phenyl group of the other pyrrole ring. In addition, large amounts of both the trimer 2,3-bis-(2,5-diphenylpyrrol-3-yl)-2,5-diphenyl-2H-pyrrole (4) and the tetracyclic compound 6a,6b-dihydro-1,3,5,6a,6b,8-hexaphenyl-2H-benzo[1,2-c:4,3-b′:5,6-b″]tripyrrole (5) were obtained. The formation of the various products of the oxidation is demonstrated in terms of the intermediate (2).