Design And Synthesis Of Dipeptidyl Peptidase Ⅳ Inhibitors As Novel Drugs For The Treatment Of Type 2 Diabetes

Objective Dipeptidyl peptidase-Ⅳ(DPP-Ⅳ) is an important enzyme related to diabetes. After inhibited by DPP-Ⅳinhibitors, it can completely protect endogenous and exogenous glucagon-like peptide-1(GLP-1) from degradation,stimulate regeneration of pancreaticβ-cell, improve the impaired glucosu tolerance(IGT), and increase the sensitivity of insulin, without inducing hypoglycaemia or obesity. Today, design and synthesis of novel DPP-Ⅳinhibitors for the treatment of diabetes have become a hot research topic. In this report, we synthesized pyrrolidine derivatives of DPP-Ⅳinhibitors, in which we expected to find the leading compounds with high selectivity and high antidiabetes activity. Methods Firstly, we synthesized the key intermediates, C-C adducts, through L-proline-catalyzed asymmetric Mannich reaction. Then we got the expected compounds through a series of chemical reactions under mild conditions. All the structures of target compounds were identified by IR, 1HNMR and 13CNMR. Results We have synthesized six pyrrolidine derivatives of DPP-Ⅳinhibitors, and three of the intermediates are new compounds which have never been reported in literature. Conclusion All the compounds we got were identified as the target compounds by 1HNMR, 13CNMR and IR.