Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones

Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hy droxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazoli dinedione and substituted benzofuran pharmacophores showed considerable imp rovement in their euglycemic activity. Further improvement has been observe d when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N- [3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl] -(2S)-pyrrolidin-2-ylmethoxy]phenylene]-thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glu cose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.