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  

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

作　　者：罗杰[1] 赵桂龙[2] 王玉丽[2] 邵华[2] 曲宝涵[1] 汤立达[3] 

机构地区：[1]青岛农业大学化学与药学院,山东青岛266109 [2]天津药物研究院天津市分子设计与药物发现重点实验室,天津300193 [3]天津药物研究院药代动力学与药效学省部共建国家重点实验室,天津300193

出　　处：《中国药物化学杂志》2010年第6期496-500,516,共6页Chinese Journal of Medicinal Chemistry

基　　金：天津市应用基础及前沿技术研究计划(09JCZDJC21700);国家重大新药创新专项(2009ZX09301-008-N-11)

摘　　要：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(7f、7h)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。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.

关 键 词：4-甲基噻唑 二肽基肽酶Ⅳ 合成 口服葡萄糖耐受量法 糖尿病 

分 类 号：R91[医药卫生—药学]