Acyclic nucleoside phosphonate derivative and medicinal application thereof

Abstract

The invention relates to an acyclic nucleoside phosphonate derivative and medicinal application thereof, in particular to an acyclic nucleoside phosphonate derivative or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, which has high resistance to virus activity such as hepatitis B virus activity and low cytotoxicity and is shown as a formula I, wherein R1 is H or methyl; each R2 is independently -R3 or -OR3 respectively; and each R3 is independently C1-C8 alkyl or C3-C8 cycloalkyl respectively. The invention also relates to a preparation method of compounds of the formula I, and medicinal compositions and medicinal application of the compounds. The acyclic nucleoside phosphonate derivative can effectively resist virus activity such as the hepatitis B virus activity and has good in vivo behavior characteristics.

Description

technical field [0001] The present invention relates to an acyclic nucleoside phosphonate derivative with potent antiviral activity such as hepatitis B virus and low cytotoxicity, its preparation method and its use in the preparation of medicine for treating viral infection such as hepatitis B virus infection. Background technique [0002] Viral hepatitis, such as viral hepatitis B, is a major disease that threatens people's lives and health. The fundamental way to treat hepatitis B is antiviral therapy. Currently clinically effective anti-HBV drugs are mainly interferon and lamivudine. However, the effective rate of interferon therapy is only 30-50%, and it has dose-limiting toxic and side effects. Lamivudine has a definite anti-hepatitis B virus effect, but long-term use is prone to drug resistance. After 2 years of continuous drug use, the incidence of drug resistance is as high as 40-50%, which can lead to serious consequences such as acute attack of hepatitis . [00...

AI Technical Summary

Problems solved by technology

In terms of chemical structure, unlike the currently known nucleoside anti-hepatitis B drugs, in addition to modifying the sugar base structure, the MCC-478 molecule is substituted with a phenylthio group at the 6-position of the nucleoside base core; in pharmacology In nature, MCC-478 also exhibits different characteristics from other anti-HBV drugs, by inhibiting the initiation reaction and assembly reaction of protein synthesis, thereby inhibiting the replication of the virus (Clark Chan, et al. Clinical Pharmacokin etics of Alamifovir and Its Metabolites. Antivicrob Agents Chemother , 2005, 49(5): 1813-1822); it has a highly selective inhibitory effect on HBV, and its in vitro activity is as high as 20-80 times that of lamivudine, and 10-20 times that of adefovir (adefovir) However, it has no effect on other retroviruses such as HIV and HSV (Kamiya N, et al.Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B Virus.Antimicrob Agents Chemother 2002; 46 (9): 2872), Shows unique pharmacological properties; MCC-478 is also effective against lamivudine-resistant HBV strains (SuzaneKioko Ono-Nita, Ono-Nita SK, et al.Novel Nucleoside analogueMCC-478(LY582563) is effective against wild -type orlamivudine-resistant hepatitis B virus. Antimicrob Agents Chemother 2002;46:2602-2605)

[0010] As a prodrug of nucleotide analogs, after entering the body, MCC-478 is hydrolyzed to release free acid (602076) to play an antiviral role; however, pharmacokinetic studies show that the main metabolite of MCC-478 in the human body is nuclear Monoglycolic acid monoester (602074), the plasma concentration of free acid 602076 has only 1 / 10 of monoester 602074 (Clark Chan, etal.Clinical Pharmaco-kinetics of Alamifovir and Its Metabolites.Antivicrob Agents Chemother, 2005, 49(5): 1813-1822), while the cytotoxicity of monoester 602074 (CC 50 =548μM) significantly higher than MCC-478 and 602076 (CC 50 All>1000μM) (Kamiya N, et al. Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B Virus. Antimicrob Agents Chemother 2002; 46(9): 2872)

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