羟基法舒地尔前药衍生物的设计合成及初步体外药动学评价

Design,synthesis and preliminary pharmacokinetic evaluation of 1-OH-fasudil prodrug derivatives

目的设计合成系列羟基法舒地尔前药并测试其体外水解代谢率。方法以异喹啉-5-磺酸为起始原料,经过磺酰化、亲核取代、氨基保护、氧化反应,在相转移催化剂的存在下,于二氯甲烷和水的两相体系中与苯甲酰氯和水反应,合成关键中间体4,4与不同的卤代物反应、脱保护得到目标化合物。体外水解代谢率以肝微粒体体外温孵法进行初步评价。结果与结论共合成了19个羟基法舒地尔前药,其中16个是未见报道的新化合物,其结构均经~1H-NM R,^(13)C-NM R及HRM S谱确证。其中,目标化合物Ⅰa、Ⅰh、Ⅰi、Ⅱd的24 h大鼠肝微粒体体外水解率分别为87%、93%、98%、95%。

Fasudil listed in Japan in 1995 can only clinical be intravenous injected for prevention of cerebral ischemia and improvement of the symptoms of cerebral vasospasm after subarachnoid hemorrhage. Study found that the main metabolism of fasudil after oral administration 1-OH-fasudil possessed stronger activity and better selectivity, but there were some disadvantages like short half-life and low brain penetration. Therefore,we designed ether prodrugs and acetal prodrugs of 1-OH-fasudil in order to get the oral long- acting compound with low side effects according to prodrug principle. The key intermediate 4（ N-Cbz-I-OH- fasudil） was synthesized through these reactions of sulfonylation, nucleophilic substitution, amino protection,oxidation and then reacting with benzoyl chloride and water in two-phase system of dichloromethane and water in the presence of a phase transfer catalyst. Target compounds land II were obtained by reaction of in- termediate 4 and different halides, and then reaction of amino deprotection. The Result was that a total of 19 compounds were synthesized,including 3 known and 16 novel compounds. Their structures were confirmed by 1H-NMR, 13C-NMR and HRMS spectra. The rates of hydrolysis metabolism of target compounds were preliminarily evaluated by external liver microsome incubation method. Among them, the 24 hours＇ hydrolysis rates of target compounds Ia, Ih, Ii and H d were 87% ,93% ,98% and 95% ,respectively.