Synthesis of new 4-[2-(4-methyl(amino)sulfonylphenyl)-5-trifluoromethyl-2 H-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-2 H-pyrazol-3-yl]-1,2,3,6-tetrahydropyridines ( 11– 14) possessing a variety of substituents (Me, CO 2Et, 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-tetrahydropyridyl moiety 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; ED 50 = 61.2 mg/kg po) exhibited an anti-inflammatory activity between that of the reference drugs celecoxib (ED 50 = 10.8 mg/kg po) and aspirin (ED 50 = 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-2 H-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.