含噻唑环的新型二肽基肽酶Ⅳ抑制剂的设计合成及其降血糖作用  

Design,synthesis and anti-diabetic activities of thiazole-bearing compounds as novel dipeptidyl peptidase Ⅳ inhibitors

作　　者：战付旭[1] 赵桂龙[2] 王玉丽[2] 徐为人[2] 汤立达[3] 王建武[1] 

机构地区：[1]山东大学化学与化工学院,山东济南250100 [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》2009年第5期334-339,共6页Chinese Journal of Medicinal Chemistry

基　　金：科技部支撑项目(2007BAI40B01)

摘　　要：目的合成一类新型的以噻唑环为母体的二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂,并测试它们在治疗糖尿病方面的活性。方法通过Hantzsch噻唑合成反应制备各种2-氨基噻唑,用氯乙酰氯和三乙胺进行氯乙酰化,乙酰化产物经芳基甲胺处理得到相应的仲胺,仲胺在干燥的乙醚中用氯化氢乙醚溶液处理即可得到目标化合物。利用小鼠体内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20个结构新颖的化合物,其结构经过1H-NMR、13C-NMR和ESI-MS谱确证。结论活性测试结果显示,有3个化合物具有明显的降血糖作用,其中化合物6l的活性与阳性对照药格列齐特和格列喹酮相当,另外两化合物6d、6n的降血糖作用比阳性对照药强,显示出在治疗糖尿病方面的价值。Aim To find novel dipeptidyl peptidase Ⅳ inhibitors with thiazole rings and to test their anti-diabetic activities.Methods Several 2-aminothiazoles were prepared by Hantzsch-Thiazole synthetic method,and they were treated with ClCH2COCl and Et3N.The resulting chloroacetamides were treated with aryl-methylamines to give the desired compounds,which were converted to the corresponding hydrochlorides in dried ether with a solution of HCl in ether.Bioactivity was performed through by oral glucose tolerance test（OGTT） in mouse in vivo.Results Twenty novel target compounds were synthesized and characterized by ^1H-NMR,^13C-NMR,and ESI-MS.Conclusion Preliminary pharmacological test showed that three target compounds could significantly decrease blood glucose.Compound 6l was comparable with that of gliclazide and gliquidon,and compounds 6d,6n were more potent than controls,which indicated that these three compounds are promising in the treatment of diabetes.

关 键 词：噻唑 二肽基肽酶Ⅳ 化学合成 口服葡萄糖耐受量法 糖尿病 

分 类 号：R91[医药卫生—药学] R96