The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Hepatitis C virus inhibitors

For many decades, the design of new nucleoside analogs as potential therapeutic agents focused on both sugar and nucleobase modifications. These nucleoside analogs rely on cellular kinases to undergo stepwise addition of phosphate groups to form the corresponding active nucleoside triphosphate to express their therapeutic effect.1 However, nucleosides triphosphates cannot be considered as viable drug candidates as they usually have poor chemical stability along with high polarity that hinders them from transporting across cell membranes. Within the nucleoside analog phosphate activation process, the first phosphorylation has often been identified as the limiting step, which led medicinal chemists to prepare stable “protected” monophosphate nucleosides capable of delivering nucleoside monophosphates intracellularly. These nucleoside monophosphate prodrugs are designed to efficiently cross the biological barriers (as opposed to nucleoside monophosphates; Figure ​Figure1,1, eq 1) and reach the targeted cells or tissues. Once inside the cell, the biolabile protecting groups are then degraded enzymatically and/or chemically, releasing the free nucleoside analog in the monophosphate form, which can often efficiently express its therapeutical potency by intracellular conversion to the corresponding nucleoside triphosphate (Figure ​(Figure1,1, eq 2).




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Figure 1


Mechanism of action of nucleoside monophosphate prodrugs.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Prodrugs of phosphates and phosphonates.

Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

Strategies for development of Dengue virus inhibitors.

We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4‘-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4‘-Azidouridine did not inhibit HCV, although 4‘-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4‘-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4‘-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel a...

Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside.

The present invention relates to the use of nucleoside derivatives of formula I wherein B signifies a 9-purinyl residue B1 of formula or a 1-pyrimidyl residue B2 of formula wherein the symbols are as defined in the specification, and of pharmaceutically acceptable salts thereof;
 
for the treatment of diseases mediated by the Hepatitis C Virus (HCV), for the preparation of a medicament for such treatment and to pharmaceutical compositions containing such compounds.

4'-substituted nucleoside derivatives as inhibitors of hcv rna replication

We report on the synthesis of the anti hepatitis C virus (HCV) agent 4‘-azidoadenosine (1) and the application of the phosphoramidate ProTide technology to this nucleoside. The synthesis of 1 was achieved through an epoxide intermediate followed by regio- and stereoselective ring opening by azidotrimethylsilane in the presence of a Lewis acid. Compound 1 did not inhibit HCV replication in cell culture at concentrations up to 0.1 mM. However, a submicromolar active agent could be derived from 1 by the application of the ProTide technology. All the phosphoramidates prepared were l-alanine derivatives with variations in the aryl moiety and in the ester part of the amino acid. The benzyl ester and the 1-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18−21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity.

First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.

4-Amino-1-((2R,3S,4S,5R)-5-azido-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (I:R 1 =R 2 =R 3 =R 4 =H) and prodrugs thereof are hepatitis C(HCV) polymerase inhibitors. Also disclosed are compositions and methods for inhibiting HCV and treating HCV-mediated diseases, processes for making the compounds and synthetic intermediates employed in the process.

Anti-viral nucleosides

4-Amino-1-((2R,3S,4S,5R)-5-azido-3,4-diyhdroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (I:R1=R2=R3=R4=H) and prodrugs thereof are hepatitis C (HCV) polymerase inhibitors. Also disclosed are compositions and methods for inhibiting HCV and treating HCV-mediated diseases, processes for making the compounds and synthetic intermediates employed in the process. (I)

Joseph Armstrong Martin

Papers

Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside.

4'-substituted nucleoside derivatives as inhibitors of hcv rna replication

First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.

Anti-viral nucleosides

Antiviral 4'-azido-nucleosides