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有机化学
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有机化学 ›› 2011, Vol. 31 ›› Issue (06): 836-842. 上一篇    下一篇

研究论文

含反式环己烷结构的C-葡萄糖苷类SGLT2抑制剂的设计、合成与降血糖活性研究

邵华1，高云龙1,2，楼袁媛3，王玉丽1，刘巍1，徐为人1，王建武2，赵桂龙*,1，汤立达*,1   

  1. (1天津药物研究院药物设计与发现天津市重点实验室 天津 300193)
    (2山东大学化学与化工学院 济南 250100)
    (3青岛科技大学化学与分子工程学院 青岛 266042)
  • 收稿日期:2010-12-06 修回日期:2010-12-30 发布日期:2011-01-24
  • 通讯作者: 赵桂龙 E-mail:zhao_guilong@126.com

Design, Synthesis and Anti-hyperglycemic Activity of trans- Cyclohexane-Bearing C-Glucosides as SGLT2 Inhibitors

Shao Hua1 Gao Yunlong1,2 Lou Yuanyuan3 Wang Yuli1 Liu Wei1 Xu Weiren1 Wang Jianwu2 Zhao Guilong*,1 Tang Lida*,1   

  1. (1 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceu-tical Research, Tianjin 300193)
    (2 School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100)
    (3 College of Chemistry and Molecular Engineer-ing, Qingdao University of Science and Technology, Qingdao 266042)
  • Received:2010-12-06 Revised:2010-12-30 Published:2011-01-24

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设计并合成了一系列含有反式环己烷结构的C-葡萄糖苷类SGLT2抑制剂, 关键步骤是对溴苯甲醚与反式环己烷甲酰氯在无水AlCl3催化下的区域选择性Friedel-Crafts酰基化. 所有化合物的结构经过了1H NMR和HRMS的表征. 小鼠口服糖耐量实验(OGTT)显示, 化合物11a～11d均显示较强的降血糖活性, 且11c的活性超过了阳性对照药dapagliflozin, 具有良好的开发前景.

关键词: 环己烷, C-葡萄糖苷, SGLT2抑制剂, 合成, 降血糖活性, 糖尿病

A series of trans-cyclohexane-bearing C-glucosides were designed and synthesized as SGLT2 inhibitors, with the key step being the region-selective Friedel-Crafts alkylation of trans-cyclohexanecar- bonyl chloride and 4-bromoanisole mediated by anhydrous aluminum chlo-ride. All the synthesized compounds were characterized by 1H NMR and HRMS techniques. Evaluation of these compounds by mice oral glucose tolerance test (OGTT) revealed that all the synthesized compounds 11a～11d exhibited potent antihyperglycemic activity, with 11c being more potent than the positive control dapagliflozin, which is a promising agent for the treatment of type 2 diabetes.

Key words: cyclohexane, C-glucoside, SGLT2 inhibitor, synthesis, anti-hyperglycemic activity, diabetes