【摘要】 设计合成具有血管舒张活性的苯基哌嗪类系列化合物。以naftopidil活性代谢产物为先导化合物,根据已报道的苯基哌嗪类α1-受体拮抗剂构效关系研究结论对先导化合物进行结构优化,设计并合成一系列新的苯基哌嗪类化合物,确定其结构,并通过测定其对苯肾上腺素引起家兔胸主动脉条收缩的抑制作用评价其血管舒张活性。发现其中5个化合物显示出不同程度的活性,其中化合物16的血管舒张活性较强,其在0.01和1μmol.L-1条件下血管收缩抑制率分别达到7.03%和22.72%,化合物16拟采用自发性高血压大鼠降压试验等进行进一步抗高血压活性研究。以上研究提示已报道苯基哌嗪类化合物的构效关系研究结论可适合于naftopidil的结构修饰。更多还原

【Abstract】 According to the results of activity-structure relationship （SAR） studies of α₁-adrenoceptor antagonists hydantoin-phenylpiperazine and benzimidazo-arypiperazine derivatves, to design and synthesize a series of novel phenylpiperazine α₁-adrenoceptor antagonists with more potent vasorelaxant activity, active metabolites of naftopidil were used as lead compounds. Ten novel R,S-1-substituted phenyl-4-[3-（naphthal-yl-oxy）-2-hydroxy propyl]-piperazine were designed and synthesized, their vasorelaxant activity was evaluated by calculating inhibition rate of phenylephrine-induced vasocontration of rabbit artery trips. Five compounds exhibited vasorelaxant activity, and compound 16 showed significant vasorelaxant activity in vitro. At 0.01 and 1 μmol·L -1 , its inhibition rates were 7.03% and 22.72%, respectively. This compound possessed ideal vasorelaxant activity in vitro, and would be selected for further anti-hypertension evaluation in vivo. Moreover, by analyzing the primary activity and structure relationship of these compounds, it could be concluded that the SAR results of the reported phenylpiperazine α₁-adrenoceptor antagonists could be used for reference in designing novel derivatives of naftopidil with optimal pharmacological properties.更多还原