脑靶向N-苯甲酰-他克林的合成及性质的初步研究

为了提高盐酸他克林 (THA)透过血脑屏障 (BBB)的能力 ,以 THA和苯甲酰氯反应制得其酰化前体药物 :N-苯甲酰 - THA和 N-二苯甲酰 - THA。考察了它们在不同 p H值和不同温度的缓冲液中 ,及小鼠血浆中的降解情况 ;测定了前体药物与原药的脂水分布系数 ;用生物分配胶团色谱法预测了前体药物的靶向性。结果表明 :合成产物经 1 H NMR、IR、MS、U V证实为目标前体药物。前体药物在不同的体外环境下比较稳定。与原药相比较 ,前体药物脂水分布系数、生物分配胶团色谱保留时间均显著增大。提示 N-苯甲酰 - THA前体药物有望成为脑内定向给药的有效途径

Studies on Synthesis and Properties of N-benzoyl-THA Targeting for Brain

It is the intent of these studies to synthesize acylated prodrugs of tacrine hydrochloride for improving the penetrating ability across the blood-brain barrier (BBB). Prodrugs of tacrine were prepared by benzoylation of the 9 amino group of THA. The structures of the synthesized prodrugs were determined by IR, 1H NMR, MS and UV. Their physical-chemical properties and stability under different conditions were investigated. The function of prodrugs targeting for brain were evaluated in vitro by biopartition micellar chromatography (BMC). The results showed that prodrugs were stable in different environments. Ethyl acetate/water partition coefficient indicated that the lipophicility of prodrugs was increased, compared with THA. BMC predicted that prodrugs could improve the infiltration ability across BBB of parent-drug. It was suggested that this kind of prodrugs be a promising brain-targeting delivery system.