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

A technology for hepatitis D, virus, applied in the field of β-L-2'-deoxynucleoside or its pharmaceutically acceptable salt or prodrug, which can solve the problems of impact, lack of treatment, etc.

Inactive Publication Date: 2003-09-24
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] 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

[0106] 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl) adenine 2 [See: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L. "The synthesis and antiviral evaluation of β-L-xylofuranosyl nucleosides of five natural nucleic acid bases", Journal of Heterocyclic Chemistry .1993, 30, 1229-1233] (8.30g, 16.05mmol) and 98% hydrazine hydrate (234mL, 48.5mmol) in a pyridine / glacial acetic acid mixture (4 / 1, v / v, 170mL) at room temperature Stir for 22 hours. The reaction was stopped by adding acetone (40 mL) and continuing to stir for 1 hour. The volume of the reaction mixture was reduced to half, diluted with water (250 mL), and extracted with chloroform (2×150 mL). The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (3×100 mL) and water (3×100 mL), dried, filtered, concentrated, and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-3% MeOH in dichloromethane mixture) to obtain 3 (5.2 g, 68%), which was precip...

Embodiment 2

[0107] 1 H NMR(DMSO-d 6 ): δ4.5-4.9 (m, 4H, H-2’, H-4’, H-5’ and H-5"), 5.64 (t, 1H, H-3’, J 2’3’ =J 3’，4’ =3.5Hz), 6.3(br s, 1H, OH-2’), 6.45(d, 1H, H-1’, J 1’，2’ =4.6Hz), 7.3(br s, 2H, NH 2 -6), 7.4-7.9 (m, 10H, 2 benzoyl), 8.07 and 8.34 (2s, 2H, H-2 and H-8); ms: matrix G / T, (FAB + )m / z 476[M+H] + , 136[BH 2 ] + , (FAB - )m / z 474[M-H] - , 134[B] - ; UV (95% ethanol): λ max 257nm(∈16400), 230nm(∈29300), λmin 246nm(∈14800); [α] D 20 =-64(c 1.07, CHCl 3 ). Elemental Analysis C 24 H 21 N 5 O 4 (M=475.45) Calculated value: C, 60.43; H, 4.45; N, 14.73. Measured value: C, 60.41; H, 4.68; N, 14.27. Example 2 9-(3,5-Di-O-benzene Formyl-2-deoxy-β-L-threo-pentofuranosyl) adenine (4)

[0108] To a solution of compound 3 (1.00g, 2.11mmol) in anhydrous acetonitrile (65mL) was added 4-(dimethylamino)pyridine (0.77g, 6.32mmol) and phenoxythioformyl chloride (0.44mL, 3.16mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was dissolved in dichlorome...

Embodiment 3

[0109] 1 H NMR(DMSO-d 6): δ2.9-3.1 (m, 2H, H-2' and H-2"), 4.6-4.7 (m, 3H, H-4', H-5' and H-5"), 5.8 (br s, 1H, H-3'), 6.43(dd, 1H, H-1', J 1’，2’ =3.1Hz, J 1’，2” =7.6Hz), 7.3(br s, 2H, NH 2 -6), 7.4-7.9 (m, 10H, 2 benzoyl), 8.05 and 8.33 (2s, 2H, H-2 and H-8); ms: matrix G / T, (FAB + )m / z 460[M+H] + , 325[S] + , 136[BH 2 ] + , (FAB - )m / z 458[M-H] - , 134[B] - ; UV (95% ethanol): λ max 261nm (∈14400), 231nm (∈26300), λ min 249nm(∈12000); [α] D 20 = -38 (c1.04, DMSO). Example 3 6-N-(4-methoxytrityl)-9-(3,5-di-O-benzoyl-2-deoxy- β-L-threo-pentofuranosyl) adenine (5)

[0110] 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 with water (30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and water (30 mL) su...

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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 from U.S. Provisional Application No. 60 / 207,538 filed on May 26, 2000. Invention field [0002] The present invention relates to methods and compositions for treating hosts infected by hepatitis delta virus (also known as "HDV"), including administering an effective amount of β-L-2'-deoxynucleoside as defined herein Or its pharmaceutically acceptable salts or prodrugs. Background of the invention [0003] Hepatitis D-the most serious 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 progressing and often fatal type of disease in which a large number of liver cells are destroyed. Chronic hepatitis D is generally characterized by necrotizing inflammatory damage,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073A61K31/7068A61K31/7072A61K31/7076A61K31/708A61K45/00A61K45/06A61P31/12A61P31/20C07H19/173
CPCA61K31/7068A61K31/7072A61K31/7076A61K31/708A61K45/06A61P31/12A61P31/20A61K2300/00
Inventor J·-P·索马多斯M·L·布赖安特
Owner NOVARTIS AG
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