Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1994-04-04
2001-06-26
Kunz, Gary L. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S026700, C536S026800, C536S026900, C536S026230, C536S026710, C536S027140, C514S045000, C514S049000, C514S050000, C514S051000
Reexamination Certificate
active
06252060
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the treatment of infections of hepatitis virus using lipid derivatives of antiviral nucleoside analogues. More particularly, the present invention relates to lipid, especially phospholipid, derivatives of antiviral nucleoside analogues which can be integrated into the structure of liposomes, thereby forming a more stable liposomal complex that can deliver greater amounts of antihepatitis drugs to target cells with less toxicity.
The publications and other reference materials referred to herein are hereby incorporated by reference, and are listed for convenience in the bibliography appended at the end of this specification.
Many nucleoside analogues are known to have activity against the hepatitis B virus (HBV). Recently, Lee et al.(1) as well as Kassanides et al.(2) have shown that dideoxynucleosides such as dideoxycytidine (ddC), dideoxyinosine (ddI), dideoxyadenosine (ddA), dideoxythymidine (ddT), dideoxyguanosine (ddG) and dideoxydiaminopurine are active against duck hepatitis B in vitro and in vivo (1,2). These drugs are thought to be effective because they inhibit a reverse transcriptase the hepatitis B virus utilizes at some stage of its life cycle. The triphosphates of other nucleosides such as acyclovir (ACV), bromovinyldeoxyuridine (BVdU), and deoxyfluoro-arabinosyliodocytosine (FIAC) have also been reported to inhibit the DNA polymerase of hepatitis B virus from humans and woodchucks (3). The arabinofuranosyladenines (ara-A) and arabinofuranosyl-cytidines (ara-C) inhibit the human hepatitis B DNA polymerase, and ara-A has activity when administered to individuals suffering from chronic type B hepatitis (4). Further, Matthes et al. report that 2′,3′-dideoxy-3′-fluorothymidine (FddThd), 2′,3′-didehydro-2′,3′-dideoxythymidine (ddeThd), 3′-fluoro-5-methyl-deoxycytidine (FddMeCyt), 3′-chloro-5-methyl-deoxycytidine ((ClddMeCyt), and 3′-amino-5-methyl-deoxycytidine (AddMeCyt) almost completely block production of hepatitis B virus particles in an HBV DNA-transfected cell line in vitro (5).
The antihepatitis B nucleoside analogues described above have very short half lives when administered to humans or animals as the free compound. After 4 to 6 hours, their levels in tissue and plasma are very low or negligible. These nucleoside analogues are also toxic, and their toxicity can be a limiting factor in therapeutic regimens. Clearly, it would be useful to administer the antihepatitis B nucleosides (dideoxynucleosides, acyclic nucleosides, and deoxynucleosides) in a form which could be targeted to the liver parenchymal cells, and which could maintain higher tissue levels over longer time periods.
SUMMARY OF THE INVENTION
The invention provides, in one embodiment, a compound having antiviral properties, comprising an antihepatitis B nucleoside analogue having a base portion comprising a purine or pyrimidine or analogue thereof, and a sugar portion comprising a pentose residue, wherein at least one portion is a non-naturally occurring nucleoside component; and a lipid moiety linked to the pentose residue; with the proviso that the compound is in the form of a liposome when the pentose residue is arabinofuranose and the base portion is cytosine or adenine. The non-naturally occurring nucleoside component can be an analogue of a naturally occurring base or pentose by virtue of substitution, deletion, or replacement. In preferred embodiments, the pentose residue is a 2′,3′-dideoxy, 2′,3′-didehydro, or halo derivative of ribose, or an acyclic hydroxylated fragment of ribose. In particularly preferred embodiments, the pentose residue is a 2′,3′-dideoxyribose, and the nucleoside analogue is 2′,3′-dideoxycytidine; 2′,3′-dideoxythymidine; 2′,3′-dideoxyguanosine; 2′,3′-dideoxyadenosine; 2′,3′-dideoxyinosine; or 2,6-diaminopurine, 2′,3′-dideoxyriboside. In other preferred embodiments, the pentose group is a halo- or an amino derivative of ribose and the nucleoside is 3′-fluoro-5-methyl-deoxycytidine(FddMeCyt),3′-chloro-5-methyl-deoxycytidine(ClddMeCyt), 3′-amino-5-methyl-deoxycytidine(AddMeCyt), or 2′,3′-dideoxy-3′-fluorothymidine. The nucleoside analogue can alternatively be acyclovir, 1-(2′-deoxy-2′-fluoro-1-&bgr;-D-arabinofuranosyl) -5-iodocytosine (FIAC) or 1(2′-deoxy-2′-fluoro-1-&bgr;-D-arabinofuranosyl)-5-iodouracil (FIAU). In particularly preferred embodiments, the nucleoside analogue is 2′,3′-didehydro-2′,3′-dideoxythymidine.
The compounds described can further comprise a monophosphate, diphosphate, or triphosphate linking group between the 5′ position of the pentose residue and the lipid moiety.
The lipid moiety of the compound can be a fatty acid, a monoacylglycerol or a diacylglycerol, a phosphatidic acid, a diphosphatidyl glycerol, a bis(diacylglycero)-phosphate, a D,L-2,3-diacyloxypropyl-(dimethyl)-&bgr;-hydroxyethyl ammonium group, or 1-O-stearoyl-rac-3-glycerol.
According to another embodiment, the invention provides a method for treating hepatitis B infection in a mammal, comprising administering to the mammal an effective hepatitis B virus-inhibiting dose of any of the compounds disclosed. The invention also provides a method for inhibiting the replication of hepatitis B virus in a cell, comprising contacting the cell with an effective hepatitis B virus-inhibiting dose of any of the compounds disclosed. In particular embodiments of this aspect of the invention, the hepatitis B virus infection is in a human cell, and the compound is phosphatidyl-dideoxycytidine (p-ddC), phosphatidyl-FIAC, FIAC diphosphate diglyceride, phosphatidyl-FIAU, or FIAU diphosphate diglyceride. In a preferred embodiment, the infection is in a human cell and the compound comprises 1-O-stearoyl-rac-3-glycerol attached to an antihepatitis B nucleoside analogue through a phosphate group.
According to yet another aspect of the invention, the lipid derivatives of nucleoside analogues are incorporated into liposomes. In a preferred embodiment, substantially all of the liposomes have a diameter less than about 100 nanometers, with a mean diameter of from about 30 to 80 nanometers. The liposomes are accordingly sized appropriately to pass through the hepatic sinusoids and to be selectively taken up by hepatocytes and targeted to the reservoir of infection. In a particularly preferred embodiment, the compound is administered parenterally to a mammal, either intravenously, subcutaneously, intramuscularly, or intraperitoneally. In an alternative embodiment, the compound is administered orally to a mammal.
The invention also provides a method for delivering an active mono-, di-, or triphosphate of a nucleotide analogue selected from the group consisting of dideoxycytidine (ddC), FIAU, FIAC, or FMAU to a cell, comprising delivering to the cell the lipid prodrug of the nucleoside analogue, and permitting the enzymatic cleavage of the prodrug to deliver the active phosphate to the cell.
The invention further provides a pharmaceutical composition, comprising an antihepatitis B compound of the invention and a pharmaceutically acceptable carrier. In one embodiment of this aspect of the invention the pharmaceutical composition further comprises a different antiviral agent.
REFERENCES:
patent: 4283394 (1981-08-01), West
patent: 4291024 (1981-09-01), Turcotte
patent: 4429008 (1984-01-01), Martin et al.
patent: 4464359 (1984-08-01), Suhadolnik et al.
patent: 4471113 (1984-09-01), MacCoss
patent: 4533254 (1985-08-01), Cook et al.
patent: 4579849 (1986-04-01), MacCoss
patent: 4605645 (1986-08-01), Watanabe et al.
patent: 4622392 (1986-11-01), Hong et al.
patent: 4670424 (1987-06-01), MacCoss
patent: 4692433 (1987-09-01), Hostetler et al.
patent: 4737323 (1988-04-01), Martin et al.
patent: 4797479 (1989-01-01), Shuto
patent: 4810697 (1989-03-01), Speiser et al.
patent: 4867973 (1989-09-01), Goers et al.
paten
Kunz Gary L.
NeXstar Pharmaceuticals, Inc.
Swanson & Bratschun L.L.C.
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