5-Substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxylpyrimidines-acyclic nucleoside phosphonate analogues with antiviral activity
5-Substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxylpyrimidines-acyclic nucleoside phosphonate analogues with antiviral activity
复制标题
DOI：
10.1021/jm030932o
复制
发表时间：
2003-11-06
影响因子：
7.3
通讯作者：
Balzarini, J
中科院分区：
文献类型：
--
作者：
Hocková, D;Holy, A;Balzarini, J
通过C5-烷基化或通过环化形成嘧啶环制备在5位被烯丙基、苄基、氰基甲基、乙氧基羰基甲基、苯基、环丙基或甲基取代的2，4-二氨基-6-羟基嘧啶。它们与2-[（二异丙氧基磷酰基）甲氧基]乙基甲苯磺酸酯的烷基化得到N1-和O 6-区域异构体，其通过用溴三甲基硅烷处理然后水解而分离并转化为游离膦酸。2，4-二氨基-6-{[（二异丙氧基磷酰基）甲氧基]乙氧基}嘧啶与元素溴、N-氯代或N-碘代琥珀酰亚胺反应，分别得到相应的磷保护的5-溴代、5-氯代和5-碘代衍生物。它们的脱保护得到2，4-二氨基-5-溴-和-5-氯-6-[2-（膦酰甲氧基）乙氧基]嘧啶。2，4-二氨基-5-甲基-6-[2-（膦酰甲氧基）乙氧基]嘧啶也通过5-溴化合物与AlMe 3的交叉偶联，然后脱保护来合成。这些化合物对DNA病毒如单纯疱疹病毒1型和2型、巨细胞病毒、水痘-带状疱疹病毒和牛痘病毒的抑制活性很差（如果有的话）。与此相反，几个5-取代的2，4-二氨基嘧啶衍生物显着抑制逆转录病毒在细胞培养中的复制。该5-甲基衍生物对细胞培养物中的人类免疫缺陷病毒和莫洛尼鼠肉瘤病毒诱导的细胞病变具有精细的抑制作用（EC 50类似于0.00018 mumol/mL），但对CEM细胞培养物也具有细胞抑制作用。相反，5-卤素取代的衍生物显示出显著的抗逆转录病毒活性（EC 50 = 0.0023-0.0110 μ mol/mL），与参比药物阿德福韦和替诺福韦相当，但在0.3 μ mol/mL时没有可测量的毒性。
2,4-Diamino-6-hydroxypyrimidines substituted in position 5 by an allyl, benzyl, cyanomethyl, ethoxycarbonylmethyl, phenyl, cyclopropyl, or methyl group were prepared either by C5-alkylation or by formation of the pyrimidine ring by cyclization. Their alkylation with 2-[(diisopropoxyphosphoryl)methoxy] ethyl tosylate afforded N1- and O6-regioisomers that were separated and converted to the free phosphonic acids by treatment with bromotrimethylsilane followed by hydrolysis. Reaction of 2,4-diamino-6-{[(diisopropoxyphosphoryl)methoxy]ethoxy}pyrimidine with elemental bromine, N-chloro-, or N-iodosuccinimide gave the corresponding phosphorus-protected 5-bromo-, 5-chloro-, and 5-iodo derivatives, respectively. Their deprotection afforded 2,4-diamino-5-bromo- and -5-chloro-6-[2-(phosphonomethoxy)ethoxy]pyrimidines. 2,4-Diamino-5-methyl-6-[2-(phosphonomethoxy)ethoxy]pyrimidine was synthesized also by cross-coupling of the 5-bromo compound with AlMe3, followed by deprotection. The compounds showed poor, if any, inhibitory activity against DNA viruses such as herpes simplex virus type 1 and type 2, cytomegalovirus, varicella-zoster virus, and vaccinia virus. In contrast, several 5-substituted 2,4-diaminopyrimidine derivatives markedly inhibited retrovirus replication in cell culture. The 5-methyl derivative was exquisitely inhibitory to human immunodeficiency virus and Moloney murine sarcoma virus-induced cytopathicity in cell culture (EC50 similar to 0.00018 mumol/mL) but also cytostatic to CEM cell cultures. In contrast, the 5-halogen-substituted derivatives showed pronounced antiretroviral activity (EC50 = 0.0023-0.0110 mumol/mL), comparable to that of the reference drugs adefovir and tenofovir, but were devoid of measurable toxicity at 0.3,mumol/mL.