Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi, Gilead Sciences & IOCB Research Centre, Flemingovo nám 2, CZ-166 10, Prague 6, Czech Republic.
Bioorg Med Chem. 2010 Jan 1;18(1):387-95. doi: 10.1016/j.bmc.2009.10.044. Epub 2009 Oct 29.
Two methods for preparation of 6-substituted derivatives of anti DNA-viral agent 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC) were developed: (1) ammonia mediated ring-opening reaction of diisopropyl esters of HPMP-5-azaC (4) to carbamoylguanidine derivatives followed by ring-closure reaction with orthoesters and (2) condensation reaction of 6-substituted 5-azacytosines with diisopropyl (1S)-[2-hydroxy-1-tosyloxymethyl)ethoxy]methylphosphonate (15). Deprotection of diisopropyl esters to free phosphonic acids was performed with bromotrimethylsilane in acetonitrile followed by hydrolysis. In contrast to parent compound HPMP-5-azaC, a substantial decrease of antiviral activity in case of 6-substituted analogues occurred. Surprisingly, N-3 isomer of 6-methyl-HPMP-5-azaC in the form of isopropyl ester revealed activity against RNA viruses (Sindbis virus).
两种方法用于制备抗病毒药物 1-(S)-[3-羟基-2-(膦酸甲酯基)丙基]-5-氮杂胞嘧啶(HPMP-5-azaC)的 6-取代衍生物：(1)氨介导的 HPMP-5-azaC(4)二异丙酯的开环反应生成氨甲酰胍衍生物，然后与原酸酯环化反应，(2)6-取代 5-氮杂胞嘧啶与二异丙基(1S)-[2-羟基-1-对甲苯磺酰氧基甲基)乙氧基]甲基膦酸酯(15)的缩合反应。用溴代三甲基硅烷在乙腈中脱除二异丙酯保护基得到游离膦酸，然后水解。与母体化合物 HPMP-5-azaC 相比，6-取代类似物的抗病毒活性显著降低。令人惊讶的是，6-甲基-HPMP-5-azaC 的 N-3 异构体以异丙酯的形式对 RNA 病毒(Sindbis 病毒)表现出活性。
