Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents

We report here the synthesis of a series of 5-[4-[2-[substituted phthalazin ones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3 -benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and the ir plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPAR gamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in thi s series, showed better in vitro PPAR gamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showe d better plasma glucose and triglyceride lowering activity than the standar d drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatm ent-related adverse effect. (C) 2001 Editions scientifiques et medicales El sevier SAS.