The Synthesis Of A New Hypoglycemic Drug, Mitiglinide, And Its Analogues

The pathogenic mechanism and therapeutic agents of diabetes were reviewed in this thesis, and the new hypoglycemic drug, mitiglinide, was discussed in detail. Mitiglinide, which could close the K⁺-ATP channel located in the islet β cell and increase the concentration of intracellular Ca²⁺, so as to make the extracellular vascular excystate, was developed by Kisses and currently under phase III clinical evaluation as a therapeutic drug for diabetes.The aim of our study was to improve the synthetic procedure of Mitiglinide and develop convenient methods for the preparation of Mitiglinide analogues. Utilizing dimethy succinate and benzoic aldehyde as starting materials, Mitiglinide was synthesized with a high optical purity (>99%) in the overall yield 10.7% via a ten-step route including Stobbe condensation, hydrolyzation, catalytic hydrogenation and resolution. A key intermediate, cis-perhydroisoindole, was prepared from cis-1,2-cyclohexane-dicarboxylic anhydride in 48% yield through a two-step procedure. The structure of Mitiglinide was characterized by the application of ¹H-NMR, IR and MS. Five Mitiglinide analogues was designed, synthesized and tested for their anti-hyperglycemic activity.