ISOXAZOLIDINE-3,5-DIONE AND NONCYCLIC 1,3-DICARBONYL COMPOUNDS AS HYPOGLYCEMIC AGENTS

Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid de rivatives, was found to decrease blood glucose at an oral dose of 38 m g/kg/day in KKA(y) mice and is currently undergoing evaluation in phas e II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was import ant for insulin-sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding t hiazolidine-2,4-dione 1.