Studies on Anti-inflammatory Agents. V. Synthesis and Pharmacological Properties of 3-(Difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole and Related Compounds

A series of novel 1, 5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30=0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50=21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.