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Liver targeted antivirus precursor medicament annular phosphoester and use thereof

A technology of phosphate esters and medicinal salts, applied in antiviral agents, drug combinations, pharmaceutical formulations, etc., can solve the problems of reducing curative effect and difficult to reach liver cells

Inactive Publication Date: 2009-07-08
廖国超
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ester hydrolases are widely distributed in the body, and most of ester prodrugs containing phosphoric acid, such as tenofovir disoproxil, have been metabolized into parent drugs with negatively charged membrane permeability before the drugs reach the liver cells. The parent drug that does not easily reach the hepatocytes is actively transported to the proximal tubule of the kidney, and the parent drug that contains phosphoric acid in high concentrations has some nephrotoxicity
[0005] Another type of nucleoside drugs without a phosphate group at the end of the sugar group, such as emtricitabine, entecavir, etc., can improve the cell membrane permeability, bioavailability, toxic and side effects of the drug, but the sugar group of the drug cannot be absorbed in the cell. Completely metabolized to active triphosphates, reducing efficacy

Method used

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  • Liver targeted antivirus precursor medicament annular phosphoester and use thereof
  • Liver targeted antivirus precursor medicament annular phosphoester and use thereof
  • Liver targeted antivirus precursor medicament annular phosphoester and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1 5-fluoro-1-(2R, 5S)-{2′,4′-cis-(4′S)-4′-[(3′-chlorophenyl)-2′-oxo- Preparation of 1', 3', 2'-dioxaphosphorin-2'-yl]oxymethyl-1,3-oxathione-5-yl}cytosine

[0099] In N,N-dimethylformamide (30ml) solution, add FTC (741.6mg, 3.0mmol), 4S-4-(3-chlorophenyl)-N,N-diisopropyl-1,3 , 2-dioxaphosphorinane-2-amine (1.45g, 4.5mmol) and 5-methylthiotetrazolium (527mg, 4.5mmol), cooled to minus 45°C, slowly added dropwise tert-peroxide Butanol, after reacting for 1 hour, warming up to room temperature for another 24 hours, distilling off the solvent under reduced pressure, silica gel column chromatography, eluting with methanol: dichloromethane = 1:18 to obtain 0.30 g of white powdery solid, yield 21.0% , melting point 98-100°C, R f =0.38 (methanol:dichloromethane=1:9). 1 HNMR (400MHz, DMSO), δ (ppm): 1.98-2.45 (m, 2H), 2.91-3.22 (m, 1H), 3.20-3.47 (m, 1H), 4.19-4.62 (m, 4H), 5.21- 5.60 (m, 2H), 6.16-6.32 (m, 1H), 7.20-7.51 (m, 4H), 8.22 (S, 1H); ESI-MS: 478.0 (M+1).

Embodiment 2

[0100] Example 2 5-fluoro-1-(2R, 5S)-{2', 4'-trans-(4'S)-4'-[(3'-chlorophenyl)-2'-oxo- Preparation of 1', 3', 2'-dioxaphosphorin-2'-yl]oxymethyl-1,3-oxathione-5-yl}cytosine

[0101] Prepared by the same method as in Example 1, 0.25 g of white powdery solid was obtained, yield 17.5%, melting point 92-94 ° C, R f =0.42 (methanol:dichloromethane=1:9). 1 HNMR (400MHz, DMSO), δ (ppm): 2.01-2.48 (m, 2H), 2.89-3.25 (m, 1H), 3.20-3.49 (m, 1H), 4.09-4.68 (m, 4H), 5.22- 5.59 (m, 2H), 6.18-6.30 (m, 1H), 7.20-7.51 (m, 4H), 8.22 (S, 1H); ESI-MS: 478.0 (M+1).

Embodiment 3

[0102] Example 3 5-fluoro-1-(2R, 5S)-{2′,4′-cis-(4′S)-[4′-(4′-pyridyl)-2′-oxo-1 Preparation of ', 3', 2'-dioxaphosphorin-2'-yl}oxymethyl-1,3-oxathione-5-yl]cytosine

[0103] Prepared by a method similar to Example 1, FTC (741.6mg, 3.0mmol), 4S-4-(4-pyridyl)-N,N-diisopropyl-1,3,2-dioxaphosphorus Heterocyclohexane-2-amine (1.27g, 4.5mmol) reacted with 5-methylthiotetrazolium (527mg, 4.5mmol) to obtain 0.28g brown powdery solid, yield 21.0%, R f =0.40 (methanol:dichloromethane=1:6). 1 HNMR (400MHz, DMSO), δ (ppm): 1 HNMR (400MHz, DMSO), δ (ppm): 2.01-2.38 (m, 2H), 2.91-3.26 (m, 1H), 3.22-3.50 (m, 1H), 4.10-4.67 (m, 4H), 5.20- 5.63(m, 2H), 6.19-6.35(m, 1H), 7.34(d, J=9.6Hz, 2H), 8.24(s, 1H), 8.56(d, J=9.6Hz, 2H); ESI-MS : 445.1 (M+1).

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Abstract

The invention provides a prodrug of an antiviral drug for use in liver of cyclic phosphate of a general formula (I) and isomers, pharmaceutical salts, hydrates, solvates and pharmaceutical compositions of the same. The invention provides uses of the compounds singly or together with other antiviral drugs in the treatment of viruses, in particular of hepatitis B viruses (HBV), hepatitis C virus (HCV), HIV viruses and / or human cytomegaloviruses (HCMV).

Description

technical field [0001] The present invention relates to an antiviral compound, in particular to a cyclic phosphate prodrug with liver-targeting antiviral effect, or all possible isomers, hydrates, solvates, pharmaceutically acceptable salts and drugs thereof combination. Background technique [0002] Many antiviral drugs are known: for example emtricitabine (FTC), tenofovir (Tenofovir), LB80331, LB80317, {2-[2-amino-6-(4-methoxyphenylmercapto) Purin-9-yl)-ethoxy]}methylphosphonic acid, Entecavir, Torcitabine, NM-107, Viramidine, Ribavirin, Racivir, Amdoxovir, MIV-210, PSI-6130, PSI-6206, etc. (Current Drug Targets-Infectious Disorders 2005, 5, 307-400; Drugs of the Future 2004, 29(2): 163-177). [0003] The above antiviral drugs belong to nucleosides. According to their chemical structure, they can be simply divided into two types: those with phosphate groups at the end of the sugar group and those without phosphate groups. Active triphosphate metabolites, thereby inhibit...

Claims

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Application Information

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IPC IPC(8): C07F9/6574A61K31/675A61K47/48A61P31/20A61P31/18A61P1/16A61P31/12A61K47/54
Inventor 廖国超
Owner 廖国超
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