Z,E型-α-氯代桂皮酰胺类化合物的合成与抗惊活性的研究

Synthesis and Structure-Activity Relationship of (Z), (E)-α-Chlorocinnamamides

由E,Z型-α-氯代桂皮酸经酰氯、胺解及层析分离制得10对Z,E型异构体。其中Z型-对溴-α-氯代桂皮酰另丁胺的抗惊作用(MES)较强。药理实验表明这些异构体的构型、酰胺氮上的取代基对其生物活性有重大影响。

The (Z), (E)-or-chlorocinnamic acid with different substituents on the aromatic ring could be obtained by the alkaline elimination of α,β-dichlorophen-ylpropionic acids. The position of the substituents on the benzene ring showed important influence on the ratio of the (Z) and (E) isomers.The substituted (Z), (E) -α-chlorocinnamic acids were converted into corresponding (Z), (E)-α-chlorocinnamamides by means of acid chlorides and amin-olysis. After chromatography, we isolated ten pairs of geometric isomers including (z) and (E)-m-chloro-α-chloro-N-sec-butyl-cinnamamides.The configurations of α-chlorocinnamamides were assigned based on UV λmax, εmax and chemical shifts of amide and olefinic protons. The values of UV λmax, εmax and of chemical shifts (ppm) were greater for (Z) form and less for (E) form. The configurations were also confirmed by X-ray diffraction.Among ten pairs of isomers, (Z)-p-bromo-α-chlorocinnamoyl sec-butyl -amine was found to be more potent in anticonvulsive activity than others. The pharmacological evaluation showed that the configuration and the substituents at amide group displayed important effect on the biological activity.