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Beta-L-2'-deoxy-nucleosides for the treatment of hepatitis B

a technology of hepatitis b and beta-l-2'-deoxy-nucleosides, which is applied in the field of treatment methods of hepatitis b virus, can solve the problems of fulminant hepatitis, rapid progression, and abdominal pain, and achieves the effects of reducing the risk of hepatitis b infection

Inactive Publication Date: 2006-02-02
INDENIX PHARM LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes.
HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection.
However, HBV is more contagious than HIV.
Unfortunately, vaccines cannot help those already infected with HBV.
Daily treatments with α-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients.
Further, interferon cannot be given orally.

Method used

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  • Beta-L-2'-deoxy-nucleosides for the treatment of hepatitis B
  • Beta-L-2'-deoxy-nucleosides for the treatment of hepatitis B
  • Beta-L-2'-deoxy-nucleosides for the treatment of hepatitis B

Examples

Experimental program
Comparison scheme
Effect test

example 1

Stereospecific Synthesis of 2′-Deoxy-β-L-Adenosine

9-(3,5-Di-O-benzoyl-β-L-xylofuranosyl)adenine (3)

[0062] A solution of 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine 2 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L. “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occuring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (October-November), 1229-1233] (8.30 g, 16.05 mmol) and hydrazine hydrate 98% (234 mL, 48.5 mmol) in a mixture of pyridine / glacial acetic acid (4 / 1, v / v, 170 mL) was stirred at room temperature for 22 h. The reaction was quenched by adding acetone (40 mL) and stirring was continued for one additional hour. The reaction mixture was reduced to one half of its volume, diluted with water (250 mL) and extracted with chloroform (2×150 mL). The organic layer was washed successively with an aqueous saturated solution of NaHCO3 (3×100 mL) and water (3×100 mL), dried, filtered, concentrated and co-evap...

example 2

Stereoselective Synthesis of 2′-Deoxy-β-L-Adenosine (β-L-dA)

[0070][0071] Precursor: L-ribose (Cultor Science Food, CAS [24259-59-4], batch RIB9711013) [0072] Reactants: Sulphuric acid 95-97% (Merck; ref 1.00731.1000); Benzoyl chloride (Fluka; ref 12930); Sodium sulfate (Prolabo; ref 28111.365) [0073] Solvents: Methanol P.A. (Prolabo; ref 20847.295); Pyridine 99% (Acros; ref 131780025); Dichloromethane P.A. (Merck; ref 1.06050.6025); Acetic acid P.A. (carlo erba; ref 20104298); Acetic anhydride (Fluka; ref 45830); Ethanol 95 (Prolabo; ref 20823.293) [0074] References: Recondo, E. F., and Rinderknecht, H., Eine neue, Einfache Synthese des 1-O-Acetyl-2,3,5-Tri-O-β-D-Ribofuranosides. Helv. Chim. Acta, 1171-1173 (1959).

[0075] A solution of L-ribose 140 (150 g, 1 mol) in methanol (2 liters) was treated with sulphuric acid (12 ml) and left at +4° C. for 12 hrs, and then neutralised with pyridine (180 ml). Evaporation gave an α,β mixture of methyl ribofuranosides 141 as a syrup. A solutio...

example 3

Stereospecific Synthesis of 2′-Deoxy-β-L-Cytidine

1-(3,5-Di-O-benzoyl-β-L-xylofuranosyl)uracil (11)

[0111] Hydrazine hydrate (1.4 mL, 28.7 mmol) was added to a solution of 1-(2-O-acetyl-3,5-di O-benzoyl-β-L-xylofuranosyl)uracil 10 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occuring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (October-November), 1229-1233] (4.79 g, 9.68 mmol) in pyridine (60 mL) and acetic acid (15 mL). The solution was stirred overnight at room temperature. Acetone was added (35 mL) and the mixture was stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-4%) in dichloromethane to give 11 (3.0 g, 68%) which was crystallized from cyclohexane / dichloromethane: mp=111-114° C.; 1H-NMR (DMSO-d6): δ 11.35 (br s, 1H, ...

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Abstract

This invention is directed to a method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside has the formula: wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. The 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2′-deoxy-β-L-erythro-pentofuranonucleoside or in combination with another anti-hepatitis B agent.

Description

[0001] This application is a continuation in part of U.S. Ser. No. 09 / 371,747 filed on Aug. 10, 1999, which claims priority to U.S. provisional applications U.S. Ser. No. 60 / 096,110, filed on Aug. 10, 1998 and U.S. Ser. No. 60 / 131,352, filed on Apr. 28, 1999.BACKGROUND OF THE INVENTION [0002] This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as “HBV”) that includes administering to a host in need thereof, either alone or in combination, an effective amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable prodrug or salt of one of these compounds. [0003] HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection. [0004] Hepatitis B virus has...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7072A61K31/7076A61K31/7068A61K31/708C07H19/06C07H19/16
CPCA61K31/70A61K31/7068A61K31/7072A61K31/7076A61K31/708C07H19/06C07H19/16A61K2300/00A61P31/12A61P31/20
Inventor GOSSELIN, GILLESIMBACH, JEAN-LOUISBRYANT, MARTIN L.
Owner INDENIX PHARM LLC
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