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

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.

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

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.