Design, synthesis and hypoglycemic activity of 3-methyl-1-phenyl-4-{4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzylene(benzyl)}-2-pyrazol-5-one

Abstract

Based on the SAR (structure activity relationship) of TZDs (thiazolidinediones), 3-methyl-1-phenyl-2-pyrazoline-5-one was selected as a substitute for TZD. Compounds of 3-methyl-1-phenyl-4-{4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzylene(benzyl)}-2-pyrazol-5-one were designed and synthesized to find some more hypoglycemic active agents and further investigate the SAR of this class of compounds. Butanedione monoxime reacted with (substituted) benzaldehyde via cyclization and chlorination to give 4-(chloromethyl)-5-methyl-2-phenyloxazole derivatives, which condensed with 4-hydroxybenzaldehyde or vanillin, and was followed by the Knoevenagel reaction with 3-methyl-1-phenyl-2-pyrazol-5-one to give compounds Ia–Ih. Compounds Ia–Ih were hydrogenated with Pd–C to give IIa–IIh, and their hypoglycemic activity was evaluated with a glucose oxidase kit and insulin load test on normal mice. Sixteen new target compounds were synthesized. All the compounds were characterized by ¹H NMR, IR, MS and elemental analysis. The preliminary pharmacological tests show that the compounds have good hypoglycemic activity and can enhance the action of insulin, especially Ib, Id and If.

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