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Nucleosides with anti-hepatitis B virus activity

A compound, acyl technology, applied in the field of treatment of hepatitis B virus, can solve the problem of not being very effective, nucleotides can not effectively pass through the cell membrane, etc.

Inactive Publication Date: 2005-08-31
CENT NAT DE LA RECHERCHE SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Usually nucleotides do not cross cell membranes efficiently and are generally not very efficient in vitro

Method used

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  • Nucleosides with anti-hepatitis B virus activity
  • Nucleosides with anti-hepatitis B virus activity
  • Nucleosides with anti-hepatitis B virus activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Preparation of β-L-(3'-azido)-2',3'-dideoxy-5-fluorocytosine

[0069] Melting points were determined in open capillary tubes with a Gallenkamp MFB-595-010 M instrument and were uncorrected. UV absorption spectrum was measured in ethanol with Uvikon931 (KONTRON) spectrophotometer. 1 H-NMR at room temperature in DMSO-d 6 Measured with Bruker AC 250 or 400. Chemical shifts are expressed in ppm, DMSO-d 6 Set at 2.49ppm as a reference. Perform deuterium exchange, decoupling experiments or 2D-COSY to confirm the arrangement of hydrogen nuclei, and the multiplicity of signals is represented by s (singlet), d (doublet), dd (doublet doublet), t (triplet), q (quartet), br (broad), m (multiplet), and all J values ​​are expressed in Hz. FAB mass spectra were recorded with a JEOL DX300 mass spectrometer in positive (FAB>0) or negative (FAB-1 deg cm 2 g -1 express. Elemental analyzes were performed according to the "Service de Microanalyses du CNRS, Division de Vernaison" (...

Embodiment 2

[0100] Example 2 Preparation of β-L-(2'-azido)-2',3'-dideoxy-5-fluorocytosine

[0101] The general procedure and apparatus used have been described in Example 1 for the synthesis of the 3'-isomer (3'-N 3 - Experimental recording part of β-L-FddC).

[0102] 1-(2-O-acetyl-3-deoxy-5-O-benzoyl-β-L-erythro-pentofuranosyl)-5-fluorouracil 13

[0103]

[0104] A suspension of 5-fluorouracil (5.15 g, 39.6 mmol) was treated with hexamethyldisilazane (HMDS, 257 mL) and a catalytic amount of ammonium sulfate and refluxed for 18 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure to give a residue as a colorless oil which was diluted with anhydrous 1,2-dichloroethane (290ml). To the resulting solution was added 1,2-di-O-acetyl-3-deoxy-5-O-benzoyl-L-erythro-pentofuranose in dry 1,2-dichloroethane 12 (8.5g, 26.4mmo) [Reference: Mathe, C., Ph.D. Dissertation, Universite de Montpellier II-Sciences et Techniques du Languedoc, Montpellier (France), ...

Embodiment 3

[0146] Example 3 Toxicity of compounds

[0147] The ability of the active compounds to inhibit virus growth in 2.2.15 cell culture (HepG2 cells transformed with hepatitis virions) was evaluated. As can be seen from Table 1, no overt toxicity (greater than 50% inhibition of the level of dye uptake observed in untreated cells) was observed for any of the compounds tested at a concentration of 100 mM.

[0148] Toxicity assays were performed on 96-well flat-bottomed tissue culture plates. Cells for toxicity analysis were cultured and treated with test compounds in the same manner as for antiviral evaluation. Four concentrations of each compound were tested in triplicate cultures, and relative levels of toxicity were determined using neutral red dye uptake. The absorption of the dye that will enter the interior at 510nM (A 510 ) for quantitative analysis. Average A of 9 independent cultures of untreated cells kept in the same 96-well plate 510 Quantitative analysis results wer...

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Abstract

Compounds and pharmaceutical compositions active against hepatitis B virus are provided, as is a method for the treatment of hepatitis B virus infection in humans and other host animals is provided comprising administering an effective amount of a beta -L-(2' or 3'- azido)-2',3'-dideoxy-5-fluorocytosine of formula (I) wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and R' is H, acyl, or alkyl.

Description

technical field [0001] The present invention relates to a method for treating hepatitis B virus (also known as "HBV") comprising administering an effective amount of one or more β-L-(2' or 3'-azido)-2', 3' - Dideoxy-5-fluorocytosine is administered to a host in need of treatment. Background technique [0002] HBV is second only to tobacco as a cause of cancer in humans. Although it is assumed that it may directly cause tumor development or indirectly through chronic inflammation, liver cirrhosis, and infection-related cell regeneration, the mechanism by which HBV induces cancer is still unclear. clearly. [0003] The hepatitis B virus has reached epidemic proportions worldwide. After an incubation period of 2-6 months (at which time the host is unaware of infection), HBV infection can lead to acute hepatitis and liver damage, which causes abdominal pain, jaundice, and elevated levels of certain enzymes in the blood. HBV can cause fulminant hepatitis, a rapidly progressive...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/7042A61K31/7052A61K31/7064A61K31/7068A61K31/7072A61P31/20C07H19/06C07H19/10
CPCC07H19/10C07H19/06A61P1/16A61P31/12A61P31/20A61K31/7068
Inventor 吉勒·戈瑟兰让-路易斯·因巴赫让-皮埃尔·索马多西雷蒙德·F·斯基纳齐
Owner CENT NAT DE LA RECHERCHE SCI
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