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N4-Acylcytosine Nucleosides for Treatment of Viral Infections

a technology of acylcytosine and nucleosides, which is applied in the field of n4acylcytosine nucleosides for treatment of viral infections, can solve the problems of fulminant hepatitis, jaundice and elevated blood levels of certain enzymes, and inability to fully recover, so as to improve the inhibitory activity, the effect of treating or preventing hiv and/or hbv infection

Inactive Publication Date: 2007-04-05
GILEAD PHARMASSET LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] It has been found that certain N4-acyl-cytosine nucleosides, and in particular, N4-acyl-2′,3′-dideoxy-5-fluorocytidine and N4-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-cytidine, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of HIV and / or HBV infection in a host, and in particular, a human, is provided that includes administering an effective amount of a N4-acyl-cytosine nucleoside.

Problems solved by technology

After a 2- to 6-month incubation period, during which the host is typically unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, resulting in 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 large 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.

Method used

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  • N4-Acylcytosine Nucleosides for Treatment of Viral Infections
  • N4-Acylcytosine Nucleosides for Treatment of Viral Infections
  • N4-Acylcytosine Nucleosides for Treatment of Viral Infections

Examples

Experimental program
Comparison scheme
Effect test

example 1

(S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid (2)

[1752] To a mixture of L-glutamic acid (1, 25 g, 170 mmol) in water (67 mL) and conc. HCl (35 mL) at 0° C. with stirring was added a solution of NaNO2 (17.5 g, 253.6 mmol) in water (37.5 mL) over a period of 4 h, and then the resulting clear solution was stirred at room temperature overnight. After removal of the solvent by evaporation in vacuo, the residue was treated with EtOAC (80 mL) and filtered. The filtrate was dried over Na2SO4, and concentrated. The residue, after crystallization from EtOAc / benzene / hexane, afforded the title compound 2 as a white crystalline solid (13.12 g, 59%). M.P. 71-73° C.; 1H NMR (400 MHz, CD3OD) δ 4.20 (m, 1H, CHO), 1.8-2.3 (m, 4H, CH2CH2).

example 2

(S)-(+)-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (3)

[1753] To a solution of 2 (10 g, 76.85 mmol) in anhydrous THF (200 mL) at 0° C. was slowly added BH3-SMe2 (2 M solution in THF, 46.1 mL, 92.2 mmol) over a period of 10 min. The reaction solution was stirred at 0° C. for 3 h under nitrogen, followed by the slow addition of anhydrous MeOH (20 mL). After removal of the solvent, the residue was purified by flash chromatography on silica gel eluting with CH2Cl2 / MeOH (95:5) to give the title compound 3 as a colorless oil (8.41 g, 94%). 1H NMR (CDCl3) δ 4.66-4.65 (m, 1H, H-5), 3.95-3.91 (m, 1H, CH2OH), 3.72-3.65 (m, 1H, CH2OH), 2.65-2.57 (m, 2H, H-3), 2.30-2.17 (m, 3H, H-4, OH).

example 3

(S)-5-[(tert-Butyldiphenylsilyl)hydroxymethyl]-dihydro-2(3H)-furanone (4)

[1754] To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) in anhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and the solution was stirred at room temperature under a nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residue was dissolved in CHCl3, washed with water and brine, dried (Na2SO4), filtered, and concentrated. After crystallization from hexane, the oily residue gave the title compound 4 as a white crystalline solid (20.6 g, 97%). M.P. 76° C.; 1H NMR (CDCl3) δ 7.68-7.65 (m, 4H, arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5), 3.90-3.87 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.70-3.67 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H, H-3), 2.32-2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).

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PUM

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Abstract

The present invention is directed to a method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N.sup.4-acyl-2′,3′-dideoxy-5-fluorocytidine or N.sup.4-acyl-2′,3′-didehyd-ro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof

Description

[0001] The present application claims priority to U.S. patent application Ser. No. 10 / 318,511 filed on Dec. 13, 2002, which claimed priority to U.S. Patent Application Ser. No. 60 / 341,555 filed on Dec. 14, 2001.FIELD OF THE INVENTION [0002] The present invention is directed to compounds, methods and compositions for the treatment or prevention of viral infections using nucleoside analogues. More specifically, the invention describes N.sup.4-acyl-substituted cytosine nucleoside analogues, pharmaceutically acceptable salts, prodrugs, or other derivatives thereof, and the use thereof in the treatment of a viral infection, and in particular a human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection. BACKGROUND OF THE INVENTION [0003] In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that without exception leads to death. In 1983, the etiological cause of AIDS was determined to be what is ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/14A61K31/7076A61K31/7072A61K31/675A61K31/513C07F9/6512C07D409/04C07D405/04A61P1/16A61P31/12A61P31/18A61P31/20A61P31/22A61P43/00C07D405/14C07D409/14C07H19/06C07H19/16
CPCC07D405/04C07D409/14C07H19/06C07H19/16A61P1/16A61P31/12A61P31/14A61P31/18A61P31/20A61P31/22A61P43/00C07D473/18C07D473/32C07D473/34C07H19/02
Inventor OTTO, MICHAEL J.SHI, JUNXINGWATANABE, KYOICHI A.
Owner GILEAD PHARMASSET LLC
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