Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections

a technology of hepatitis virus infection and substituted compounds, which is applied in the field of methods, can solve the problems of unpredictability, inability to treat these often lethal diseases, and inability to achieve treatment. treatment, prevent the development of drug resistance, and reduce the toxicity of patients

Inactive Publication Date: 2006-11-23
UNITED THERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] As noted above, the use of the substituted-imino-D-glucitol compounds and derivatives thereof disclosed herein alone, or in combination with other anti-hepatitis virus compounds has, to the present inventor's knowledge, neither been suggested nor disclosed. The use of two or more anti-viral agents to provide improved therapy for the treatment of hepatitis B virus and hepatitis C virus infections is desirable due to the morbidity and mortality of the disease. Combination therapy is also desirable since it can reduce toxicity in patients as it enables the physician to administer lower doses of one or more of the drugs being given to a patient. Combination therapy can also help to prevent the development of drug resistance in patients (Wiltink, E. H. H., Pharmaceutish Weekblads Scientific Edition (1992) 14(4A):268-274). The result of an improved efficacy configuration combined with a relative lack of toxicity and development of resistance would provide a much improved drug treatment profile.

Problems solved by technology

However, combinations of N-substituted-imino-D-glucitol derivatives and other antiviral agents for the treatment of hepatitis virus infections have not been previously disclosed or suggested.
In any event, treatments for these diseases are badly needed since “With rare exceptions a treatment of these often lethal diseases is not possible to date.” (Kolter, T and Sandhoff, K, Inhibitors of Glycosphingolipid Biosynthesis, Chemical Society Reviews, 371-381 (1996), WO 98 / 02161.
For example, clinical tests on the use of the nucleoside analog fialuridine (FIAU) for treatment of chronic hepatitis B were suspended recently due to drug-related liver failure leading to death in some patients.
Unfortunately, the response rates are lower than desired.

Method used

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  • Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections
  • Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections
  • Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol

[0310] A solution of 1,5-dideoxy-1,5-imino-D-glucitol (5.14 g, 0.0315 mole), butyraldehyde (3.35 ml, 0.0380 mole) and Pd black (1 g) in 200 ml methanol was hydrogenated (60 psi / 29C / 21 hrs.). After filtering the resulting mixture, the filtrate was concentrated in vacuo to an oil. The title compound was crystallized from acetone, and recrystallized from methanol / acetone, m.p. ca. 132C. The structure assignment was supported by NMR, infrared spectra and elemental analysis.

[0311] Analysis calcd. for C10H21NO4: C, 54.78; H, 9.65; N, 6.39. Found: C, 54.46; H, 9.33; N, 6.46.

example 2

Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol, tetraacetate

[0312] Acetic anhydride (1.08 g, 0.0106 mole) was added to the title compound of Example 1 (0.50 g, 0.0023 mole) in 5 ml pyridine and stirred for 17 days at room temperature. The product was evaporated under nitrogen gas. The resulting title compound was purified by silica gel chromatography. Structure assignment was supported by NMR, infrared spectra and elemental analysis.

[0313] Analysis calcd. for C18H29NO8: C, 55.80; H, 7.54; N, 3.62. Found: C, 55.42; H, 7.50; N, 3.72.

example 3

Anti-Hepatitis B Virus Activity of Various N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds In Vitro

[0314] The anti-hepatitis B virus activity and effect on cell viability of a number of different N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds were assessed using an in vitro assay employing chronically hepatitis B virus secreting HepG2.2.15 cells. The method employed was essentially that described in Block et al. (1994) Proc. Natl. Acad. Sci. USA 91:2235-2239. The results are shown in Tables 2 and 3.

TABLE 2Effect of N-Substituted-1,5-Dideoxy-1,5-Imino-D-GlucitolCompounds on Hepatitis B Virus Secretion and Viability ofHepG2.2.15 CellsRelative amountofHBV secretedCompound and% ViableAs A %[Concentration]1+ / −1 S.D.2,5of Control3Control90 + / − 7 (n = 4)100NBDNJ[200]94 + / − 6 (n = 10) 37.0 + / − 13 (n = 15)NBDNJ[1000]88 + / − 8 (n = 10) 3.2 + / − 5 (n = 15)1 [200]90 + / − 2 (n = 4)85.0 + / − 5 (n = 8) 1 [1000]87 + / − 3 (n = 4)35.0 + / − 6 (n = 8) 2 [200]90 + / − 6 (n = 4) 107.0 + / − 1...

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Abstract

N-Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agents selected from among nucleosides, nucleotides, immunomodulators, immunostimulants or various combinations of such other agents.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to methods and compositions for treating hepatitis virus infections, especially hepatitis virus infections, particularly hepatitis B and hepatitis C, in mammals, especially humans. The methods comprise administering substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or, alternatively, in combination with immunomodulating / -immunostimulating agents. Administration of substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with both a nucleoside and / or nucleotide type antiviral agent and an immunomodulating / immunostimulating agent or agents is also contemplated. Combinations of anti-hepatitis viral agents show unexpected efficacy in inhibiting replication and secretion of hepatitis viruses in cells of mammals infected with these viruses. [0003] 2. Background of Inventi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/445A61K31/454C07D211/46A61K45/00A61K45/06A61P1/16A61P31/14A61P31/20
CPCA61K31/436A61K31/444A61K31/445A61K31/4535Y10S514/885A61K31/4545A61K31/5377A61K45/06A61K31/454A61P1/16A61P31/14A61P31/20
Inventor MUELLER, RICHARD A.BRYANT, MARTIN L.PARTIS, RICHARD A.
Owner UNITED THERAPEUTICS CORP
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