摘要
以替诺福韦(PMPA)为原料,经氨基保护,酰化,缩合,脱保护和成盐反应合成了8个替诺福韦前药(Ⅲa~Ⅲh),收率为16.1%~40.7%。探讨了不同碱性试剂对化合物Ⅰ、乙酸用量对化合物Ⅱ转化率的影响,并考察了乙酸与前药母体成盐比例。得到最优的实验条件为:碱性试剂选用三乙胺、n(Ⅱ)∶n(乙酸)=1∶5,乙酸与前药母体成盐物质的量之比为0.74~0.93∶1。采用ESI-MS、1HNMR对化合物进行了结构表征。通过初步活性研究筛选出一个潜在化合物Ⅲh(替诺福韦二羟丙酮乙二醇缩酮酯),与富马酸替诺福韦二吡呋酯(TDF)相比,化合物Ⅲh在体外大鼠和人血浆中稳定性分别提高了2倍和2.5倍。化合物Ⅲh在小鼠体内肝脏和肾脏中PMPA药时曲线下面积AUC(0-t)分别为(47 314.75±10 128.11)(μg·h)/L和(21 670.64±8 964.98)(μg·h)/L,而TDF在肝脏和肾脏中PMPA药时曲线下面积AUC(0-t)分别为(213 269.79±10 750.47)(μg·h)/L和(46 379.24±3 944.65)(μg·h)/L。
Eight tenofovir prodrugs（ Ⅲ a ~ Ⅲ h） were synthesized from tenofovir（ PMPA） through amino protection,acylation,condensation,deprotection and salification,and their yields were between16. 1% and 40. 7%. The effects of different alkaline reagents and acetic acid amount on the conversion rate of compound Ⅰ and Ⅲ were investigated,respectively. In addition,the proportion of acetic acid to prodrug parent was discussed. The optimal conditions were obtained as following： triethylamine was selected as alkaline reagent,the molar ratio of acetic acid to prodrug parent was 0. 74 ~ 0. 93∶1. These compounds were confirmed by ESI-MS and1 HNMR. A potential compound Ⅲ h（ tenofovir dihydroxyacetone ethylene ketal） was screened by preliminary activity study. Compared with that of tenofovir dipivoxil fumarate（ TDF）,the in vitro stability of compound Ⅲh in rat and human plasma was increased by 2-fold and 2. 5-fold,respectively. The area under the curve [AUC（ 0-t）] of PMMA concentration in the liver and kidney of mice in vivo for compound Ⅲh was（ 47 314. 75 ± 10 128. 11）（ μg·h）/L and（ 21 670. 64 ± 8 964. 98）（ μg·h）/L,respectively,while the corresponding value for TDF was（ 213 269. 79 ± 10 750. 47）（ μg·h）/L and（ 46 379. 24 ± 3 944. 65）（ μg·h）/L.
出处
《精细化工》
EI
CAS
CSCD
北大核心
2017年第4期437-443,共7页
Fine Chemicals
关键词
替诺福韦
前药
代谢
医药与日化原料
tenofovir
prodrug
metabolism
drug and cosmetic materials
