Chin. J. Org. Chem. ›› 2016, Vol. 36 ›› Issue (3): 604-612.DOI: 10.6023/cjoc201508003 Previous Articles     Next Articles



史永恒a, 周春梅a, 张盼龙a, 刘继平a, 赵桂龙b, 王玉丽b   

  1. a 陕西中医药大学药学院 咸阳 712046;
    b 天津药物研究院有限公司 天津市新药设计与发现重点实验室 天津 300193
  • 收稿日期:2015-08-05 修回日期:2015-11-01 发布日期:2015-11-06
  • 通讯作者: 史永恒
  • 基金资助:

    陕西省教育厅专项科研(No. 15JK1203)、国家自然科学基金(No. 21302141)和山东省自然科学基金(No. ZR2015BM028)资助项目.

Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

Shi Yonghenga, Zhou Chunmeia, Zhang Panlonga, Liu Jipinga, Zhao Guilongb, Wang Yulib   

  1. a College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046;
    b Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193
  • Received:2015-08-05 Revised:2015-11-01 Published:2015-11-06
  • Supported by:

    Project supported by the Scientific Research Projects of Shaanxi Education Department (No. 15JK1203), the National Natural Science Fundation of China (No. 21302141) and the Natural Science Foundation of Shandong Province (No. ZR2015BM028).

A novel series of cyclopropane-bearing C-glucosides were designed and synthesized as sodium-glucose cotransporter 2 (SGLT2) inhibitors starting from the substituted bromobenzoic acids. The reaction condition for the construction of the cyclopropane moiety was studied, and a more economical synthetic route was established. All the synthesized compounds were characterized by 1H NMR and HR-MS. In vivo evaluation of these compounds by rat urinary glucose excretion (UGE) test revealed that all the synthesized seven cyclopropane-bearing C-glucosides 1a~1g exhibited potent hypoglycemic activity, among which (1S)-1-deoxy-1-{4-chloro-3-[1-(4-ethoxyphenyl)cyclopropyl-1-yl]-phenyl}-D-glucopyranose (1e) was the most potent one but still exhibited lower hypoglycemic activity to dapagliflozin, demonstrating that the cyclopropane moiety can not be well tolerated in dapagliflozin molecule and the position of the Cl atom in dapagliflozin is the best among the analogues.

Key words: cyclopropane, C-glucoside, SGLT2 inhibitor, synthesis, hypoglycemic activity