Synthesis of 4-alkyl-1,2-diphenyl-3,5-dioxopyrazolidines possessing aryl methylsulfonyl and sulfonamide pharmacophores for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors

A group of, 1,2-diphenyl-3,5-dioxopyrazolidines possessing a methylsulfonyl (11) or sulfonamide (15) substituent at the pari position of the N-1-phenyl ring, in conjunction with a hydrogen, methyl or fluoro substituent at-the para position of the N-2-phenyl ring, and a C-4 n-butyl, methyl or spiro-cyclopropyl substituent were synthesized for. evaluation as potential cyclooxygenase-2 (COX-2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four-step and a three-step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative (6, 12) gave the corresponding azobenzene product (8, 13) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene (9, 14). Base-catalyzed condensation of 9 and 14 with a-malonyl dichloride (10) afforded the target 3,5-dioxopyrazolidine product (11, 15). 4-n-Butyl-1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioiopyrazolidine (11a) was a selective COX-I inhibitor (COX-1 IC50 = 8.48 muM): In contrast, 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyrazolidine (11b, COX-2 IC50 = 11:45 muM) and 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-dioxopyrazolidine (11c, COX-2 IC50 = 9.86 muM) were about 46-fold and 20-fold less selective COX-2 inhibitors respectively, relative to the reference drug celecoxib.