(Z)-4-烷基硫基-5-烷基硫基次甲基-1-芳基-3-羟基吡咯酮类化合物的合成及升高白细胞活性研究  

Synthesis and effects on leukocyte count of (Z)-4-alkylthio-5-alkylthiomethenyl-1-aryl-3-hydroxy pyrrolidone derivatives

作　　者：谭相端[1] 李春刚[1] 钱考胜[1] 于振鹏[1] 王国平[1] 孙海燕[2] 刘全海[2] 

机构地区：[1]上海医药工业研究院化学制药新技术中心,上海200437 [2]上海医药工业研究院药理室,上海200437

出　　处：《中国药物化学杂志》2012年第6期469-475,共7页Chinese Journal of Medicinal Chemistry

基　　金："重大新药创制"科技重大专项(2009ZX09313-006)

摘　　要：目的设计合成一系列(Z)-4-烷基硫基-5-烷基硫基次甲基-1-芳基-3-羟基吡咯酮类化合物,并测定其体内升高白细胞活性。方法以1,3-二氯丙酮为起始原料,与烷基硫醇发生取代反应,再与相应的芳香氨基化合物反应生成席夫碱,使用草酰氯关环,最后与酰氯衍生物酯化得到目标化合物。以赛格力(G-CSF)为阳性对照药物,考察所合成化合物的升高白细胞活性,活性数据以白细胞数和嗜中性粒细胞百分比为依据,同时以小鼠的状态作为初步判断毒性的依据。结果与结论共合成了18个未见文献报道的新化合物,其结构经1H-NMR、MS谱确证。活性测试结果表明,化合物Ⅰ5、Ⅰ16的活性与阳性药相当,具有显著升高白细胞活性。As one of the dithiolopyrrolones, ZL-004 was found to have anti-leukopenia activity in vivo, but it also has some adverse effects such as low solubility and relatively high toxicity. Now the structural modifica- tion of ZL-004 was made by cleavage of disulfide bond and replalement of 6-position nitrogen atom by oxy- gen atom. The target compounds（ I1- I 18 ） were prepared by＇ SN2 substitution,imine formation,cyclization and acylation starting from 1,3-dichloroacetone. All the target compounds have been characterized by 1H- NMR and Mass spectra. Furthermore, the raising leukocyte count activities in the normal mice of these com- pounds were evaluated. The results showed that some target compounds exhibited raising leukocyte count ac- tivity. Among them, the compound 1 5 and 1 16 exhibited potent raising leukocyte count activity. Preliminary analysis of the structure-activity relationship showed that introduction of p-toluenesulfonyl on oxygen atom at 3-position of pyrrolidone was benefit for their activity. This study provides several clues for designing new active anti-leukopenia agents.

关 键 词：(Z)-4-烷基硫基-5-烷基硫基次甲基-1-芳基-3-羟基吡咯酮 合成 升高白细胞活性 

分 类 号：R914[医药卫生—药物化学]