Phosphate prodrugs of nucleoside analogues and their applications

Abstract

The invention provides a phosphate prodrug of a nucleoside analog as shown in the general formula I as well as all possible isomers and medicinal salts of the phosphate prodrug. The invention also provides an application of the compound to preparation of drugs for preventing and treating tumor diseases or virus related diseases.

Description

technical field [0001] The present invention relates to the field of pharmacy, more specifically, relates to a kind of phosphate prodrug of nucleoside analogs and its synthesis, and its application in antiviral or antitumor and other related diseases. Background technique [0002] As the structural unit of nucleic acid, nucleosides participate in the molecular mechanism of gene information retention, replication and transcription in the process of biosynthesis. Nucleoside analog drugs mainly include anti-virus and anti-tumor drugs, and their mechanism of action is basically by interfering with the DNA synthesis of viruses or tumor cells and the synthesis of raw materials such as pyrimidine, purine and nucleotides required for DNA synthesis. , so as to inhibit the survival and replication metabolic pathways of viruses or tumor cells, as well as the enzymes or nucleic acids required for the synthesis of nucleic acids as targets to produce pharmacological effects. [0003] The...

AI Technical Summary

Problems solved by technology

Although it is theoretically possible to rationally design putative prodrugs based on the chemical functional groups in the molecule, chemical modification of the parent drug results in an entirely new molecular entity that may exhibit deleterious physicochemical or biologically active properties not present in the parent compound

Although it may seem simple to conceive of prodrug candidate compounds, due to the complexity of human-drug interactions, identification with appropriate physicochemical and pharmacokinetic properties, in vivo transformation, and safety is a complex multidisciplinary task that in practice is often Prodrugs obtained through "rational design" are often far from the expected results, and even "prodrugs" with worse physical and chemical properties or biological activities than the parent drug, such as nucleosides that also contain an aryloxyphosphate amide structure The analogue prodrugs IDX-184, GS-6620, Thymectacin and BMS-986094 have not been able to successfully market the prodrug Sofosbuvir with the same structure as this kind, and stopped in the first or second phase due to the problems of drug efficacy, toxicity or pharmacokinetic properties Clinical research (J.Med.Chem.2014,57:1836-1844.)

In addition, there are even aryloxyphosphate amide prodrugs of ribavirin obtained through this strategy, whose logP is significantly improved, but the biological activity results are not improved or worse than the parent drug, which may be due to the new compounds obtained The prodrug cannot be hydrolyzed by phosphoramidite to release ribavirin with monophosphate (Bioorg.Med.Chem., 2010,18:2748-2755). The same example also has no anticancer nucleoside drug AraU prodrug Biological activity (Bioorg.Med.Chem.,2010,18:2439–2446)

Sometimes even the simplest and most "universal" carbamate prodrug design principle is unpredictable for a specific nucleoside drug, such as the carbamate of the anti-hepatitis C drug PSI-6130 The pentyl ester prodrug PSI-6149 has the same prodrug modification part as capecitabine, but PSI-6149 is difficult to be hydrolyzed by hydrolase in vivo to release its parent drug PSI-6130, but is metabolized into other non- Active product, almost no curative effect (Antimicrob.Agents.Chemother.,2007,2877-2882)

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