摘要
目的为筛选活性更好的抗血小板聚集药物,制得两个系列(series 1和series 2)共10个未见文献报道的化合物。方法以2,4-二甲基苯酚为原料,经Williamson反应、氧化和氯代制得中间体4-甲氧基-1,3-苯二甲酰氯(Ⅰ);以苯甲醚为原料,经氯磺化反应得到中间体4-甲氧基-1,3-苯二磺酰氯(Ⅱ);将两个中间体分别与不同的三取代苯胺化合物反应制得目标化合物1f-1k、2c-2f。以吡考他胺和阿司匹林为阳性对照药,采用Born比浊法对目标化合物进行体外抗血小板聚集活性筛选。结果与结论药理实验筛选结果表明,有5个化合物抗血小板聚集活性优于阳性对照药吡考他胺,其中化合物1i和2c的活性最高且优于对照药阿司匹林。构效关系研究表明,4-位上进行Cl和Br取代时有较高的抗血小板聚集活性;甲酰胺系列与磺酰胺系列化合物的抗血小板聚集活性的相差较大。在化合物1c的4位引入氯原子,制得的侧链苯环具有2,4,6-三氯取代结构的化合物1i的活性最高。目标化合物的结构经IR、MS和1H-NM R谱确证。
To screen out the drugs of antiplatelet aggregation with high activity, ten target compounds （ series 1 and series 2 ） were synthesized, which were not reported before. Their intermediate 4-methoxy-1,3- benzenedicarboxylic acid chloride（ Ⅰ ） was synthesized from 2,4-dimethylphenol by Williamson oxidation and chlorination reaction. 4-Methoxy-1,3-benzene-disulfonyl chloride （ Ⅱ） was synthesized by sulfonation and chlorination using anisole as starting materials. Two intermediates were reacted with different haloanilines to produce the target compounds 1f - 1k and 2c -2f. The antiplatelet aggregation activities in vitro of the target compounds were screened out by Born＇s test,in which picotamide and aspirin were used as the positive control drugs. Pharmacological experiments results showed that the antiplatelet aggregation activities of the five compounds 1f, 1g, 1i, 1j ,2c were superior to picotamide, of which two compounds li and 2e showed better activities compared to aspirin; structure-activity relationships （SAR） showed that it had higher activity when atom Cl or Br was on the 4-position. To introduce chlorine on the 4-position of lc gave compound li, that is 2,4,6-trichloro-substituted structure on the side chain benzene, which had the best activity. The structures of each target compounds were confirmed by IR, MS and ^1H-NMR spectra.
出处
《中国药物化学杂志》
CAS
CSCD
2017年第6期440-445,共6页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(21342014)
天津市自然科学基金重点项目(15JCZDJC33100)
