Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-14
2003-04-08
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235500, C514S302000, C514S315000, C514S316000, C514S319000, C514S326000, C514S328000, C514S885000, C546S115000, C546S116000, C546S193000, C546S205000, C546S207000, C544S129000
Reexamination Certificate
active
06545021
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
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.
2. Background of Invention
Over half the biologically important proteins are glycosylated and that glycosylation may vary with disease. Based upon this information, the use of drugs to control glycosylation patterns, glycoforms, changes or rates of change will have a biochemical effect, and may provide a beneficial therapeutic result. Control of glycolipid and glycoprotein sugar patterns as well as their synthesis and degradation leads to basic physiological effects on mammals including humans, agricultural animals and pets. Possibly, this is through influences on, for example, N-linked glycans, O-linked glycans, glucosoaminoglycans, glycosphingolipids, glycophospholipids, lectins, immuneoglobulin molecules, antibodies, glycoproteins and their biochemical intermediates or conversion products. Modification of glycosalation site occupancy influences receptor and enzyme binding site specificity, selectivity, capacity, protein folding, enzyme activity, kinetics and energetics. Glycosidase and glycosyltransferase systems are two biochemical mechanisms that are suggested to affect such systems (Dwek, Raymond A., Glycobiology: Toward Understanding the Function of Sugars, Chemical Reviews, 96, 683-720 (1996).
Other hepatitis viruses significant as agents of human disease include Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis Delta, Hepatitis E, Hepatitis F, and Hepatitis G (Coates, J. A. V., et.al.,
Exp. Opin. Ther. Patents
(1995) 5(8):747-756). Hepatitis C infection is also on the increase and effective treatments are needed. In addition, there are animal hepatitis viruses that are species-specific, but serves as excellent models for the human disease. These include, for example, those infecting ducks, woodchucks, cattle and mice.
1,5-dideoxy-1,5-imino-D-glucitol Compounds
1,5-dideoxy-1,5-imino-D-glucitol (also known as 1-deoxynojirimycin, DNJ) and its N-alkyl derivatives (together, “imino sugars”) are known inhibitors of the N-linked oligosaccharide processing enzymes alpha glucosidase I and II (Saunier et al.,
J. Biol. Chem
. (1982) 257:14155-14161 (1982); Elbein,
Ann. Rev. Biochem
. (1987) 56:497-534). As glucose analogs, they also have potential to inhibit glucose transport, glucosyl-transferases, and/or glycolipid synthesis (Newbrun et al.,
Arch. Oral Biol
. (1983) 28: 516-536; Wang et al.,
Tetrahedron Lett
. (1993) 34:403-406). Their inhibitory activity against glucosidases has led to the development of these compounds as anti-hyperglycemic agents and antiviral agents. See, for example, PCT International Publication WO 87/03903 and U.S. Pat. Nos. 4,065,562; 4,182,767; 4,533,668; 4,639,436; 4,849,430; 4,957,926; 5,011,829; and 5,030,638.
Glucosidase inhibitors such as N-alkyl-1,5-dideoxy-1,5-imino-D-glucitol compounds wherein the alkyl group contains between three and six carbon atoms have been shown to be effective in the treatment of Hepatitis B infection (PCT International Publication WO 95/19172). For example, N-(n-butyl)-deoxynojirimycin (N-butyl-DNJ; N-(n-butyl)-1-5-dideoxy-1,5-imino-D-glucitol) is effective for this purpose (Block, T. M.,
Proc. Natl. Acad. Sci. USA
(1994) 91:2235-2239; Ganem, B.
Chemtracts: Organic Chemistry
(1994) 7(2), 106-107). N-butyl-DNJ has also been tested as an anti-HIV-1 agent in HIV infected patients, and is known to be well tolerated. Another alpha glucosidase inhibitor, deoxynojirimycin (DNJ), has been suggested as an antiviral agent for use in combination with N-(phosphonoacetyl)-L-aspartic acid (PALA) (WO 93/18763). 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. From results obtained in a woodchuck animal model of hepatitis virus infection, Block et al. ((1998)
Nature Medicine
4(5):610-614) suggested that glucosidase inhibitors such as N-nonyl DNJ, which interfere with specific steps in the N-linked glycosylation pathway of hepatitis virus glycoproteins, may be useful in targeting glycosylation processing as a therapeutic intervention for hepatitis B virus.
Compounds such as N-butyl-DNJ (N-butyl-deoxynojirimycin) and N-butyl-DGNJ (N-butyl-desoxynogalactonojirimycin) are reported as treatments of lysosomal storage diseases such as Tay-Sachs disease, Gauchers disease and related ailments. In addition, treatment of cholera has been reported (U.S. Pat. No. 5,399,567) via inhibition of the synthesis of glycolipids (U.S. Pat. No. 5,472,969). It has been reported that inhibition of glycosyl transferase or glycosidase enzymes affects the catabolism and metabolism of phopholipids, sphingolipids, cerebrosides, gangliosides by or and within mammalian cells or interferes with such biochemical processes as attachment to cells, penetration of cells and/or release from cells. 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.
The use of N-butyl-1,5-dideoxy-1,5-imino-D-glucose and certain other imino-glucose compounds for the treatment of diseases caused or induced by human immunodeficiency virus (HIV), cytomeglovirus CMV), hepatitis virus, respiratory syncytial virus (RSV) and herpes virus (HSV) infection has been reported.
Nucleoside and Nucleotide Antiviral Agents
Reverse transcriptase inhibitors, including the class of nucleoside and nucleotide analogs, were first developed as drugs for the treatment of retroviruses such as human immunodeficiency virus (HIV), the causative agent of AIDS. Increasingly, these compounds have found use against other viruses, including both RNA and DNA viruses, via viral screening and chemical modification strategies. Nucleoside and nucleotide analogs exert their antiviral activities by inhibiting the corresponding DNA and RNA polymerases responsible for synthesis of viral DNA and RNA, respectively. Because viruses contain different forms of polymerases, the same nucleoside
ucleotide compound can have a dramatically different effect against different viruses. For example, lamivudine (3TC) appears to be useful against HBV infection, whereas zidovudine (AZT) appears to have little use against the same virus (Gish, R. G., et al.,
Exp. Opin. Invest. Drugs
(1995) 4(2):95-115).
AZT is an example of a nucleoside
ucleotide analog that can effect glycosylation processes at clinically achievable concentrations rather than interfere with DNA replication or protein synthesis (Yan, J., et al., J. Biol. Chem., 270, 22836 (1995).
Toxicity has been significant with some nucleoside analog antivirals. 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. Consequently, there is still a need for safer drug regimens for the treatment of hepatitis B infections and hepatitis (Mutchnick, M. G., et. al.,
Antiviral Research
(1994) 24:245-257).
Immunomodulators and Im
Bryant Martin L.
Mueller Richard A.
Partis Richard A.
Chang Ceila
G.D. Searle & Co.
Senniger Powers Leavitt & Roedel
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