3,4-二氢喹啉-2(1H)-酮衍生物(±)-SIPI6360及其光学异构体的合成和药理学评价(英文)

Synthesis and Pharmacological Evaluation of a 3,4-Dihydroquinolin-2(1H)-ketone Derivative(±)-SIPI6360 and Its Optical Isomers

7-[3-[4-(6-氟苯并[d]异(口恶)唑-3-基)哌啶-1-基]丙氧基]-3-甲基-3,4-二氢喹啉-2(1H)-酮[(±)-SIPI6360]为本课题组发现的多靶点抗精神分裂症候选新药,其化学结构中存在一个手性中心。本试验报道了(±)-SIPI6360及其2个光学异构体的制备和体内外药理性能的比较研究。结果显示,(±)-SIPI6360及其光学异构体的体内外药效、大鼠体内药动学特性及毒性方面无显著性差别。基于原料制备成本,确定(±)-SIPI6360消旋体作为抗精神分裂症候选新药的更优结构。

7-[3-[4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]propoxy]-3-methyl-3,4-dihydroquinolin-2(1 H)-one[(±)-SIPI6360] is a multireceptor antipsychotic candidate discovered by our research group. It has two optical isomers because of a chiral carbon atom at the 3,4-dihydroquinoline segment. The synthesis, in vitro and in vivo pharmacology, pharmacokinetics in rats, and repeat-dose toxicity(14 days) in rats of(±)-SIPI6360 and its two optical isomers were reported. No significant differences among(±)-SIPI6360 and its two optical isomers were found regarding to the efficacy, metabolic parameters and toxic effects. Thus,(±)-SIPI6360 was chosen as the candidate for potential psychotic treatment based upon preparation cost.