含4-甲基噻唑环的新型二肽基肽酶IV抑制剂的设计、合成及降血糖活性测试

目的：合成一类新型的以4-噻唑环为母体的二肽基肽酶IV (DPP-IV)抑制剂，测试并研究它们的降血糖活性。方法：通过Hantzsch噻唑合成反应制备2-氨基4-甲基噻唑，然后用氯乙酰氯和三乙胺进行氯乙酰化，所得中间体氯乙酰胺经芳基甲胺处理得到目标物，最后，在干燥的乙醚中用氯化氢乙醚溶液处理即可得到目标物的盐酸盐。利用小鼠体内口服葡萄糖耐受量法测定目标化合物在治疗糖尿病方面的活性。结果：合成了21个结构新颖的化合物，结构经过1H-NMR和ESI-MS确认。结论：经过活性测试，发现其中的两个目标化合物具有明显的降血糖作用，其中化合物7f的活性与阳性对照药西他列汀相当，化合物7h的活性则超过阳性对照药，显示了在治疗糖尿病方面的前景。

Design, synthesis and anti-hyperglycemic activities of 4-methylthiazole derivatives as novel dipeptidyl peptidase IV inhibitors

Aim To prepare novel dipeptidyl peptidase Ⅳ inhibitors based on 4-methylthiazole ring and to investigate their anti-hyperglycemic activities.Methods 2-Amino-4-methylthiazole was prepared by Hantzsch method,and it was treated with ClCH2COCl in the presence of triethylamine.The resulting chloroacetamide was treated with arylmethylamines to give the desired compounds,which were converted to corresponding hydrochlorides in dried ether with a solution of HCl in ether.Bioactivity was performed through in vivo by oral glucose tolerance test（OGTT） in mice.Results Twenty-one novel target compounds were synthesized and characterized by 1H-NMR and ESI-MS.Conclusion Preliminary evaluation through mice OGTT showed that two of the twenty-one target compounds were found to be antihyperglycemic agents.7f was comparable with sitagliptin and compound 7h was more potent than that,which indicated that these two compounds are promising in the development for the treatment of type Ⅱ diabetes.