Synthesis Of Anti-HBV Purin Derivatives Of Acyclic Nucleoside Phosphonates

Hepatitis B harms human enormously for its infectivity, great damage and high incidence. At present, a few drugs are currently available for the clinical treatment of hepatitis B. However, most of them usually have various problems, such as low cure rates, inducing drug resistance and side effects etc. In our country, the incidence of hepatitis B is higher than the average level of the world. Research and development of new anti-HBV agents are necessary and significant.Nucleoside analogues are in the lead in research and application of the anti-HBV drugs. Lamivudine (LAM) is the first nucleoside oral drug approved by the FDA for the treatment of hepatitis B, but it has the problem of inducing drug resistance. Adefovir and tenofovir, both belonging to acyclic nucleoside phosphonates (ANPs), are known to have broad spectrum of activity against viruses, even including the HBV species that have drug resistance to lamivudine. MCC-478, a new ANP derivative, has showed excellent anti-HBV activity in clinical trials.The main feature of ANP molecule is to combine a phosphonate group with purine or pyrimidine via an aliphatic ether chain. Bearing the phosphonate group, the ANP drug molecule can avoid the rate-limiting step of phosphorylation in vivo. At present, the ANP analogues have became a focus in research and development of new anti-HBV agents.Taking MCC-478 and tenofovir as lead compounds and keeping the ANP's main pharmacophores, we designed and prepared series of derivatives by introducing different groups at purine ring's 6-position. First, taking MCC-478 as the lead compound, we prepared 23 ANP trifluloroethyl ester compounds (including MCC-478) as the type I target compounds, 20 of them were novel ones. Secondly, taking MCC-478 and tenofovir as the lead compounds, we prepared 25 ANP compounds (including tenofovir) as the type II target compounds, 23 of them were novel ones. Furthermore, during the process of trying to synthesize the target compounds, we explored novel route to tenofovir and the key intermediates of the type II target compounds.The structures of the key intermediates and the target compounds were determined by 1H-NMR and MS.Three of the target compounds were evaluated for their anti-HBV activitity and cytotoxicity in HepG2 2.2.15 cells. One of them, Z-101 showed similar activitity to LAM.