Liguzinediol甲基替代衍生物的合成及其正性肌力活性研究  

Synthesis and positive inotropic effect of methyl-substituted derivatives of liguzinediol

作　　者：刘贞兴 李伟[1] 陈龙[1] 陈磊[1] 文红梅[1] 朱晓雯[1] 

机构地区：[1]南京中医药大学,江苏南京210023

出　　处：《中国新药与临床杂志》2014年第5期357-363,共7页Chinese Journal of New Drugs and Clinical Remedies

基　　金：国家自然科学基金项目(81072542);高等学校博士学科点专项科研基金(20123237110010);江苏省自然科学基金项目(BK2011077)

摘　　要：目的设计合成liguzinediol甲基替代衍生物,并分析其对正常大鼠离体心脏的正性肌力作用。方法分别以2,5-二甲基吡嗪和吡嗪为原料,通过与醛进行自由基取代得烷基酰化产物,经还原、氧化、BOEKELHEIDE重排等反应,硅胶柱层析分离纯化得到目标化合物;采用1H-NMR、ESI-MS对其结构进行了表征;采用Langendorff离体灌流装置观察化合物对大鼠离体心脏心功能的影响。结果合成了五个liguzinediol甲基替代衍生物,正性肌力活性实验结果显示,2,5-二羟甲基-3,6-二乙基吡嗪、2,5-二羟甲基-3,6-二丙基吡嗪、2,5-二羟甲基-3,6-二丁基吡嗪对正常大鼠离体心脏产生正性肌力作用;2,5-二羟甲基吡嗪、2,5-二羟甲基-3,6-二异丁基吡嗪对正常大鼠离体心脏无正性肌力作用。结论当liguzinediol的二个甲基被H和异丁基取代时,无正性肌力活性,而被乙基、丙基及丁基取代时表现出一定的正性肌力活性,且随着碳链的延长,正性肌力活性显著下降。AIM To synthesize methyl- substituted derivatives of liguzinediol and to investigate their inotropic effects on the normal isolated rat hearts. METHODS The desired products were obtained through reduction, oxidation, and BOEKELHEIDE rearrangement of alkyl acylation products which were prepared from 2,5- dimethylpyrazine or pyrazine reacting with aldehydes via radical substitution reaction. The compounds were seperated and purified by silica gel column chromatography. The structures were identified by 1H-NMR and ESI- MS. The left ventricular inotropic effects of these compounds were observed on the normal isolated rat hearts perfused by the Langeudorff technique. RESULTS Five methyl- substituted derivatives of liguzinediol were synthesized. The results showed that 2, 5- dihydroxymethyl- 3, 6- diethylpyrazine, 2, 5- dihydroxymethyl- 3, 6- dipropylpyrazine, 2, 5- dihydroxymethyl- 3, 6- dibutylpyrazine displayed positive inotropic effects. But unfortunately, 2, 5- dihydroxymethyl pyrazine, 2, 5- dihydroxymethyl- 3, 6- diisobutylpyrazine had no significantly positive inotropic effects on normal isolated hearts. CONCLUSION The derivatives whose dimethyl groups are substituted with H from liguzinediol have no positive inotropic activity. The compounds with ethyl, propyl butyl or isobutyl present positive inotropic activity and derivatives with more substituted alkyls show lessened positive inotropic effect.

关 键 词：LIGUZINEDIOL 结构修饰 甲基替代衍生物 化学 药物 强心药 心肌收缩 

分 类 号：R914[医药卫生—药物化学] R962[医药卫生—药学]