Synthesis of new 4-[2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines:: A search for novel nitric oxide donor anti-inflammatory agents

A group of 4-[2-(4-methyl(amino) sulfonylphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines (11-14) possessing a variety of substituents (Me, CO2Et, H, N = O) attached to the 1,2,3,6-tetrahydropyridyl N-1-nitrogen atom were synthesized and evaluated as anti-inflammatory agents. Structure-activity relationship data showed that the N-methyl-1,2,3,6-tetrahydropyridylmoiety is a suitable bioisosteric replacement for the tolyl moiety in celecoxib. The most potent compound 4-[5-(1-methyl- 1,2,3,6-tetrahydropyridin-4-yl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonamide (11b; ED50 = 61.2 mg/kg po) exhibited an anti-inflammatory activity between that of the reference drugs celecoxib (ED50 = 10.8 mg/kg po) and aspirin (ED50 = 128.7 mg/kg po). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 4-[2-(4-methyl(amino) sulfonylphenyl)-5-trifluoromethyl-2H- pyrazol-3-yl]-1,2,3,6-tetrahydropyridines (5) requires further investigation since the reaction of 1,2,3,6-tetrahydropyridines with nitric oxide furnished the undesired N-nitroso-1,2,3,6-tetrahydrohydropyridyl product rather than the desired N-diazen-1-ium-1,2-diolate-1,2,3,6-tetrahydropyridyl product. (C) 2008 Elsevier Ltd. All rights reserved.