目的 在前期发现的DPP-IV抑制剂N-(2-噻吩甲基)-N′-(4-甲基-2-噻唑)甘氨酰胺（1）基础上，设计并合成N-甲基- N-(2-噻吩甲基)-N′-(4-甲基-2-噻唑)甘氨酰胺（2），以延长半衰期，并保证其降血糖活性。方法 尝试了两种方法合成化合物2，一是对化合物1用氨化–还原法甲基化，二是用N-甲基-2-噻吩甲胺（3）与2-氯-N-(4-甲基-2-噻唑)乙酰胺（4）反应制得化合物2。葡萄糖耐量实验降血糖模型研究化合物2的降血糖活性，并研究其药动学。结果 两种方法合成了化合物2，其中方法二收率较高。化合物2的降血糖活性与化合物1相当，但是半衰期延长。结论 获得了合成化合物2的较优方法，保证化合物2降血糖活性前提下，延长了半衰期。

Objective To design and synthesize N-methyl-N-(2-thiophenylmethyl)-N′-(4-methyl-2-thiazolyl) glycinamide (2) based on a previous discovered dipeptidyl peptidase IV (DPP-IV) inhibitor N-(2-thiophenylmethyl)-N′-(4-methyl-2-thiazoyl) glycinamide (1) in order to prolong its half-life and keep its hypoglycemic activity. Methods The synthesis of compound 2 was attempted with two methods: methylation of compound 1 via reductive ammoniation and synthesis by reaction of N-methyl-2-thiophenyl methanamine (3) and 2-chloro-N-(4-methyl-2-thiazolyl) acetamide (4). Hypoglycemic activity of compound 2 was investigated by ig administraation using glucose tolerance test and its pharmacokinetics was researched. Results Compound 2 was synthesized with the above-mentioned two methods, and the second one was better with higher yield. It was tested by ig administration using glucose tolerance test. The hypoglycemic activity of compound 2 was the same as that of compound 1, while the half-life of compound 2 was prolonged. Conclusion The optimal method to synthesize compound 2 is obtained. The half-life of compound 2 is prolonged under the guarantee of hypoglycemic activity of compound 2.

国家重大新药创制科技重大专项（2011ZX09401-009）；天津市科技支撑计划重点项目（10ZCKFSH01300）