对羟基苯乙酮衍生物的合成及其调节血脂活性研究

目的设计合成一系列对羟基苯乙酮衍生物,并测定其体内调节血脂活性。方法α-溴代对羟基苯乙酮分子中的溴原子被不同亲核试剂取代得到目标化合物A1～A4;α-溴代对羟基苯乙酮经Delepine反应、酰化反应得到目标化合物A5～A8;化合物A5～A7经氢氧化钠水解得到目标化合物A9～A11;1-叔丁氧基哌嗪与新戊酰氯缩合后,经三氟乙酸脱保护,再与α-溴代对羟基苯乙酮反应生成目标化合物A12。以对羟基苯乙酮、辛伐他汀、吉非罗齐为阳性对照药物,考察所合成化合物的调节血脂活性。结果与结论共合成了12个化合物,其中8个化合物为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A5、A8的活性与阳性药相当,具有显著的同时降低低密度脂蛋白胆固醇和甘油三酯的活性,并且具有一定的升高高密度脂蛋白胆固醇的作用。

Synthesis and effects on lipid regulation of 1-(4-hydroxyphenyl)ethanone derivatives

1-(4-Hydroxyphenyl)ethanone(PHA) was found to have lipid-lowing activity in vivo, but it also has some adverse effects such as relatively toxicity because of the small molecular structure. Now the structure modification of it was made by esterification of hydroxyl with acyl chlorides and meanwhile modification of α-keto. The target compounds A1-A4 were prepared by substitution reaction from 2-bromo-1-(4-hydroxyphenyl)ethanone （2）. 2-Amino-1-(4-hydroxyphenyl)ethanone（3） synthesized from 2 via Delepine reaction was converted to the target compounds A5-A8 with the acyl chlorides which converted to compounds A9-A11 by sodium hydroxide. Starting from 1-Boc-piperazine via condensation, treated with trifluoroacetic acid and SN2 substitution of 2, the target compound A12 was obtained. All the novel compounds have been characterized by 1H-NMR and Mass spectra. Furthermore, the lipid regulation activities in the rats of these compounds were evaluated. The results showed that compound A5 exhibited good lipid-lowing activity. The pharmacology data suggest that both of TG and LDL-C in serum decreased by the compound A6 and the HDL-C increased by the compound A7. Preliminary analysis of the structure-activity relationship showed that enlarged the molecular structure of PHA was benefit for their activity and esterification of its hydroxyl could increase the activity of reducing triglyceride. This study provides several clues for designing new lipid regulation agents.