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Methods for treating hepatitis delta virus infection with beta-L-2' deoxy-uncleosides

A-L-2, virus infection technology, applied in the direction of drug combination, antiviral agent, sugar derivatives, etc., can solve the problems of impact, lack of treatment, etc.

Inactive Publication Date: 2009-05-27
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] Due to the large population infected with hepatitis D virus, the devastating impact of hepatitis D virus on individuals, and the lack of effective treatments, there is a great need for new and effective treatments for hepatitis D virus infection

Method used

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  • Methods for treating hepatitis delta virus infection with beta-L-2' deoxy-uncleosides
  • Methods for treating hepatitis delta virus infection with beta-L-2' deoxy-uncleosides
  • Methods for treating hepatitis delta virus infection with beta-L-2' deoxy-uncleosides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1 9-(3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine (3)

[0169] 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine 2 [See: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L. "Synthesis and antiviral evaluation of β-L-xylofuranosyl nucleosides of five natural nucleobases", vol. Journal ofHeterocyclic Chemistry .1993,30,1229-1233] (8.30g, 16.05mmol) and hydrazine hydrate 98% (234mL, 48.5mmol) solution in pyridine / glacial acetic acid mixture (4 / 1, v / v, 170mL) at room temperature Stir for 22 hours. The reaction was quenched by adding acetone (40 mL) and stirring was continued for 1 hour. The volume of the reaction mixture was reduced to half, diluted with water (250 mL), and extracted with chloroform (2 x 150 mL). The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), dried, filtered, concentrated, and co-evaporated with toluene and methanol. Purification of the residue by silica gel column chroma...

Embodiment 2

[0171] Example 2 9-(3,5-di-O-benzoyl-2-deoxy-β-L-threo-pentofuranosyl)adenine (4)

[0172] To a solution of compound 3 (1.00 g, 2.11 mmol) in anhydrous acetonitrile (65 mL) was added 4-(dimethylamino)pyridine (0.77 g, 6.32 mmol) and phenoxythioformyl chloride (0.44 mL, 3.16 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (2 x 30 mL), aqueous hydrochloric acid 0.5N (30 mL) and water (3 x 30 mL). The organic layer was dried, filtered and concentrated to dryness. This thiocarbonylated intermediate was directly mixed with tris-(trimethylsilyl)silane hydride (0.78 mL, 5.23 mmol) and α,α'-azobyronitrile (AIBN, 0.112 g, 0.69 mmol) Reflux in dry dioxane (17 mL) for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to afford pure 4 (0.93 g, 96%) as a foam:

[0173] 1 H N...

Embodiment 3

[0174] Example 3 6-N-(4-Methoxytrityl)-9-(3,5-di-O-benzoyl-2-deoxy-β-L-threo-pentofuranosyl) Adenine (5)

[0175] To a solution of compound 4 (0.88 g, 1.92 mmol) in anhydrous pyridine (40 mL) was added 4-monomethoxytrityl chloride (1.18 g, 3.84 mmol). The mixture was stirred at 60°C for 24 hours. After adding methanol (5 mL), the solution was concentrated to dryness, the residue was dissolved in dichloromethane (50 mL), and washed successively with water (30 mL), saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene to give pure 5 (1.01 g, 72%) as a foam:

[0176] 1 H NMR (CDCl 3 ): δ 2.9-3.0 (m, 2H, H-2' and H-2"), 3.62 (s, 3H, OCH 3 ), 4.6-4.8 (m, 3H, H-4', H-5' and H-5"), 5.85 (pt, 1H, H-3'), 6.44 (dd, 1H, H-1', J 1’，2’ = 3.1Hz,J 1’，2” =7.3Hz), 6.9 (br s, 1H, NH-6), 6.7-6.8 and 7.2-7.4 (2m, 24H, 2 benzoyl and MMTr), 7.97 and 8.13 (2s, 2H, H-2 and H -8); ms: matrix G / T, (FAB ...

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Abstract

A method and composition for treating a host infected with hepatitis D comprising administering an effective hepatitis D treatment amount of a described 2'-deoxy-beta-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof.

Description

[0001] This application claims priority to US Provisional Application No. 60 / 207,538, filed May 26,2000. field of invention [0002] The present invention relates to methods and compositions for treating a host infected by hepatitis delta virus (also known as "HDV") comprising administering an effective amount of a β-L-2'-deoxynucleoside as defined herein or a pharmaceutically acceptable salt or prodrug thereof. Background of the invention [0003] Hepatitis D—the most severe form of viral hepatitis is due to infection with hepatitis D (delta) virus (HDV), a satellite subvirus of hepatitis B virus (HBV) (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75). Compared with other viral hepatitis, acute HDV infection is often associated with fulminant hepatitis—a rapidly progressive and often fatal type of disease in which large numbers of liver cells are destroyed. Chronic hepatitis D Typically characterized by necrotizing inflammatory lesions that resemble chronic HBV infecti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/706A61K31/7064A61K31/7068A61K31/7072A61K31/7076A61K31/708A61P31/12A61K31/70C07H19/073A61K45/00A61K45/06A61P31/20C07H19/173
CPCY10S514/894A61K45/06A61K31/7072A61K31/7076A61K31/7068A61K31/708A61P31/12A61P31/20A61K2300/00
Inventor J·-P·索马多斯M·L·布赖安特
Owner NOVARTIS AG
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