N-甲基-N-(2-噻吩甲基)-N′-(4-甲基-2-噻唑)甘氨酰胺的合成、降血糖活性及药动学研究  

Synthesis,hypoglycemic activity,and pharmacokinetics of N-methyl-N-(2thiophenylmethyl)-N'-(4-methyl-2-thiazolyl) glycinamide

作　　者：魏群超[1] 王玉丽[1] 徐为人[1] 汤立达[1] 赵桂龙[1,2] 

机构地区：[1]天津药物研究院天津市药物设计与发现重点实验室,天津300193 [2]山东轻工业学院化学与制药工程学院,山东济南250353

出　　处：《现代药物与临床》2013年第1期7-10,共4页Drugs & Clinic

基　　金：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)

摘　　要：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.

关 键 词：N-甲基-N-(2-噻吩甲基)-N′-(4-甲基-2-噻唑)甘氨酰胺 DPP-IV抑制剂 降血糖活性 药动学 

分 类 号：R914.2[医药卫生—药物化学]