OCYCLYLAMINO)ALKOXY]BENZYL]-2,4-THIAZOLIDINEDIONES AS POTENT ANTIHYPERGLYCEMIC AGENTS

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and cyclylam ino)alkoxy]-benzyl]-2,4-thiazolidinediones was synthesized from the co rresponding aldehydes. Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of t he type such as pioglitazone and troglitazone (CS-045). The benzoxazol e 49, a cyclic analogue of 16, was a very potent enhancer of insulin s ensitivity, and by modification of the aromatic heterocycle, an aminop yridine, 37, was identified as a lead compound from SAR studies. Evalu ation of antihyperglycemic activity together with effects on blood hem oglobin content, to determine the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 Bl/6 ob/o b mice. From these studies, BRL 49653 (37) has been selected, on the b asis of antihyperglycemic potency combined with enhanced selectivity a gainst reductions in blood hemoglobin content, for further evaluation.