新型哌嗪或3-氨基哌啶类化合物的合成及其DPP-4抑制作用  

Synthesis of Novel Piperazine or 3-Aminopiperidine Analogues as Potential DPP-4 Inhibitors

作　　者：孟祥国[1] 蔡正艳[1] 张伟[1] 周伟澄[1] 

机构地区：[1]中国医药工业研究总院上海医药工业研究院,创新药物与制药工艺国家重点实验室,上海市抗感染药物重点实验室,上海200437

出　　处：《中国医药工业杂志》2013年第1期6-12,共7页Chinese Journal of Pharmaceuticals

基　　金：国家科技部973项目(2010CB735601、2012CB724501)

摘　　要：2,3,4-三氟硝基苯与哌嗪发生亲核取代反应、三光气氯甲酰化,最后与胺类化合物缩合制得哌嗪衍生物8a～8e。另用2,3,4-三氟硝基苯与4-乙氧羰基哌啶-3-酮盐酸盐发生亲核取代、烯氨化、还原、氨基酰化、酯水解后与胺类化合物缩合制得17,再经脱保护、成盐或经硝基还原再脱保护、成盐生成3-氨基哌啶衍生物9a～9r。23个新化合物的结构经1H NMR和MS确证,并测定了它们的体外DPP-4抑制活性,其中8b和9m对DPP-4酶具有一定的抑制作用。Piperazine derivatives 8a - 8e were synthesized by nucleophilic substitution of 2,3,4-trifluoronitro- benzene with piperazine followed by chloroformylation with bis （trichloromethyl）carbonate and condensation with various amines. Meanwhile 3-aminopiperidine derivatives 9a - 9r were prepared from 2,3,4-trifluoronitrobenzene via nucleophilic substitution with 4-ethoxycarbonylpiperidin-3-one hydrochloride, enamination, reduction, acylation, hydrolysis and condensation with various amines to obtain the intermediates 17, followed by reduction of nitro group and/ or deprotection. The structures of 23 new targets were confirmed by JH NMR and MS. The inhibitory activities of above 23 compounds on DPP-4 were evaluated in vitro, and compounds 8b and 9m showed moderate inhibitory activities.

关 键 词：降血糖药 DPP-4抑制剂 哌嗪衍生物 3-氨基哌啶衍生物 合成 

分 类 号：R977.15[医药卫生—药品]