氟哌啶醇季铵盐衍生物的合成及其扩血管活性

Studies on synthesis of quaternary ammonium salt derivatives of haloperidol and their vasodilative activities

目的合成氟哌啶醇季铵盐衍生物及其还原物并研究它们的扩血管活性。方法以氟哌啶醇、氟哌啶醇经四氢硼钠还原后得到的氢化氟哌啶醇为反应物,分别与取代氯苄回流下反应得到相应的氟哌啶醇季铵盐衍生物和氢化氟哌啶醇季铵盐衍生物;所有目的化合物结构均经IR,1H-NMR,MS和元素分析确证,并测定其对KCI诱导鼠、兔胸主动脉条收缩的抑制作用。结果合成了2个系列11个新化合物(ⅠF8-13,ⅡFB8-11和FB13)。初步生物活性实验表明,多数化合物具有不同程度的扩张血管作用,其中化合物F11的血管收缩抑制活性最强。结论F11扩张血管活性明显强于先导化合物,初步构效关系表明,N-取代苄基氟哌啶醇季铵盐衍生物中苄基苯环上取代基的电性效应和取代位置可能为影响扩血管活性的重要因素。氟哌啶醇母体上羰基被还原为羟基一般对其扩血管活性影响不大。

OBJECTIVE: To study the synthesis of quaternary ammonium salt derivatives of haloperidol and their vasodilative activities. METHODS: Haloperidol or hydrohaloperidol was reacted with different substituted benzyl chlorides in reflux condition to synthesize the corresponding quaternary ammonium salt derivatives. The chemical structures were determined by IR, 1H-NMR, MS and elemental analysis. Using the spiral strips of isolated rat and rabbit aorta, the vasodilative activities of these compounds were tested. RESULTS: Two series of eleven N-substituted benzyl haloperidol chlorides were synthesized. Preliminary pharmacological studies in vitro showed that most of these compounds exhibited vasodilative activities. Compound F11 showed the strongest effect. CONCLUSION: F11 demonstrated potential vasodilative activity and was superior to the lead compound. Preliminary structure-activity relationship indicated that electrical property and the place of substitute on benzyl effected the vasodilative activity. The reduction of the carbonyl group on haloperidol to hydroxyl group has almost no effect on its vasodilative activity.