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有机化学
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有机化学 ›› 2008, Vol. 28 ›› Issue (2): 234-239. 上一篇    下一篇

研究论文

3-(4-取代-哌嗪-1-甲基)-1,2,3,9-四氢咔唑-4-酮衍生物的合成与止吐活性研究

徐启贵a，刘天渝a，田睿a，马德银b，李勤耕*,a   

  1. (a重庆医科大学药学院 重庆 400016)
    (b西南合成制药股份有限公司 重庆 401147)
  • 收稿日期:2006-03-30 修回日期:2007-08-08 发布日期:2008-02-01
  • 通讯作者: 李勤耕

Synthesis and Antiemetic Activity of 3-(4-Substituted-piperazin-1- yl-methyl)-1,2,3,9-tetrahydrocarbazol-4-one Derivatives

XU Qi-Guia,LIU Tian-Yua,TIAN Ruia,MA De-Yinb,LI Qin-Geng*,a   

  1. (a School of Pharmacy, Chongqing Medical University, Chongqing 400016)
    (b Southwest Synthetic Pharmaceutical Corporation Limited, Chongqing 401147)
  • Received:2006-03-30 Revised:2007-08-08 Published:2008-02-01
  • Contact: LI Qin-Geng

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以1,3-环己二酮(1)为起始原料, 一个羰基与盐酸苯肼发生缩合反应生成1,3-环己二酮单苯腙(2), 2在ZnCl2催化下通过分子内环合、重排反应得到1,2,3,9-四氢咔唑-4-酮(3), 3的甲基化物4在冰醋酸中经Mannich反应获得其3-二甲胺甲基物5, 5与哌嗪类化合物通过亲核取代反应合成了9个未见文献报道的3-(4-取代-哌嗪-1-甲基)-1,2,3,9-四氢咔唑-4-酮衍生物6a～6i. 所有合成的新化合物均经元素分析、红外光谱、质谱和核磁共振光谱证明其结构; 初步药理试验采用顺铂诱导的大鼠干呕模型研究了新化合物的止吐活性, 结果表明部分新化合物活性与昂丹司琼相当.

关键词: 5-HT3受体拮抗剂, 1,2,3,9-四氢咔唑-4-酮, Mannich反应, 止吐

One of the two carbonyl groups of starting material 1,3-cyclohexandione (1) was condensed with phenylhydrazine hydrochloride to form monophenylhydrazone (2). 1,2,3,9-tetrahydro-carbazol-4-one (3) was prepared from 2 through cyclization and rearrangement in the presence of ZnCl2. Through methylation reaction, compound 3 is converted to 9-methyl-1,2,3,9-tetrahydro-carbazol-4-one (4). 3-Dimethylaminomethyl- substituted compound (5) was synthesized from 4 by Mannich reaction in glacial acetic acid. Nine novel 3-(4-substituted-piperazin-1-ylmethyl)-1,2,3,9-tetrahydro-carbazol-4-one derivatives 6a～6i were synthesized via nucleophilic substitution reaction of 5 with piperazines. The struc-tures of all the target compounds were determined by elemental analysis, IR, MS, 1H NMR and 13C NMR spectra. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control ondansetron.

Key words: 1,2,3,9-tetrahydro-carbazol-4-one, 5-HT3 receptor antagonist, Mannich reaction, an-tiemetic