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

a technology of n-substituted imino-d-glucitol and hepatitis virus infection, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of death in some patients, the combination of n-substituted-imino-d-glucitol derivatives and other antiviral agents for the treatment of hepatitis virus infections has not been disclosed or suggested

Inactive Publication Date: 2005-12-01
MUELLER RICHARD A +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] As noted above, the use of the N-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 infections is desirable due to the morbidity and mortality of the disease. Combination therapy is also desirable since it should 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

Such vaccines have no therapeutic value for those already infected with the virus.
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.
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 N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
  • Use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
  • Use of N-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

[0219] 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 / 29° C. / 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. 132° C. The structure assignment was supported by NMR, infrared spectra and elemental analysis.

[0220] 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

[0221] 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.

[0222] 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

[0223] 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 2

Effect of N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds on Hepatitis B Virus Secretion and Viability of HepG2.2.15 Cells

[0224]

TABLE 2Effect of N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compoundson Hepatities B Virus Secreation and Viability of HepG2.2.15 CellsRelative amount ofCompound andHBV secreted, as[Concentration]1% Viable + / − 1 S.D.2a % of control3Control90 + / − 7 (n = 4)100NBDNJ4[200]94 + / − 6 (n = 10) 37.0 + / − 13 (n = 15)NBDNJ4[1000]88 ...

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Abstract

Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immuno-stimulating agents.

Description

RELATED APPLICATION DATA [0001] This application claims the benefit of priority of U.S. provisional application Ser. No. 60 / 074,508, filed Feb. 12, 1998. This application is also a continuation in part of U.S. application Ser. No. 09 / 023,401, filed Feb. 12, 1998. The contents of each of these applications is incorporated by reference herein in their entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to methods and compositions for treating hepatitis virus infections, especially hepatitis B virus infections, in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating / immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide ant...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/445A61K31/7042A61K31/7052A61K31/7064A61K31/7068A61K45/06A61P1/16A61P31/20C07D211/46C07H19/10
CPCA61K31/445C07D211/46A61K45/06A61P1/16A61P31/14A61P31/20
Inventor MUELLER, RICHARD A.BRYANT, MARTIN L.PARTIS, RICHARD A.JACOB, GARY S.BLOCK, TIMOTHY M.DWEK, RAYMOND A.
Owner MUELLER RICHARD A
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