Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-12-17
2004-06-08
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S334000, C549S013000, C564S305000, C564S428000, C564S440000, C564S442000, C564S443000, C564S454000, C564S462000, C564S501000, C564S502000, C564S503000, C564S504000, C564S505000
Reexamination Certificate
active
06747149
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
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 administering glucamine compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/-immunostimulating agents. Such 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 of 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).
Iminosugars are anti-viral drugs that can induce the inhibition of viral interactions with and within mammalian cells such as attachment to cells, penetration of cells, maturation within cells and release from cells. The mechanism involved may be glucosidase inhibition, glycosyl transferase inhibition or others as discussed above.
Hepatitis B Virus (HBV, HepB) is a causative agent of acute and chronic liver disease including liver fibrosis, cirrhosis, inflammatory liver disease, and hepatic cancer that can lead to death in some patients (Joklik, Wolfgang K.,
Virology
, Third Edition, Appleton & Lange, Norwalk, Conn., 1988 (ISBN 0-8385-9462-X)). Although effective vaccines are available, there are still more than 300 million people worldwide, i.e., 5% of the world's population, chronically infected with the virus (Locarnini, S. A., et. al.,
Antiviral Chemistry
&
Chemotherapy
(1996) 7(2) :53-64). Such vaccines have no therapeutic value for those already infected with the virus. In Europe and North America, between 0.1% to 1% of the population is infected. Estimates are that 15% to 20% of individuals who acquire the infection develop cirrhosis or another chronic disability from HBV infection. Once liver cirrhosis is established, morbidity and mortality are substantial, with about a 5-year patient survival period (Blume, H., E., et.al.,
Advanced Drug Delivery Reviews
(1995) 17:321-331). It is therefore necessary and of high priority to find improved and effective anti-hepatitis therapies (Locarnini, S. A., et. al.,
Antiviral Chemistry
&
Chemotherapy
(1996) 7(2): 53-64)
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. These include, for example, those infecting ducks, woodchucks, cattle and mice.
Glucamine Compounds
Glucamine (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-glucamine 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). Inhibition of glycosyl transferase or glycosidase enzymes that affect the catabolism and metabolism of phopholipids, sphingolipids, cerebrosides, gangliosides by or and within mammalian cells or interference 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 immunodeficincy virus (HIV), cytomeglovirus CMV), hepatitis virus, respiratory syncytial virus (RSV) and herpes virus (HSV) infection has been reported. Again, treatment of these infections is desirable and an important public goal.
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 poly
Bryant Martin L.
Mueller Richard A.
Partis Richard A.
G. D. Searle & Co.
Keane J. Timothy
Meyer Scott J.
Owens Amelia
Senniger Powers Leavitt & Roedel
LandOfFree
Glucamine salts for treating hepatitis virus infections does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Glucamine salts for treating hepatitis virus infections, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Glucamine salts for treating hepatitis virus infections will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3317101