Nucleosides with anti-hepatitis B virus activity

Details Nucleosides with anti-hepatitis B virus activity Nucleosides with anti-hepatitis B virus activity

1998-07-09

2001-06-12

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S026700, C536S027140

Reexamination Certificate

active

06245749

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as “HBV”) that includes administering an effective amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable derivative or prodrug of one of these compounds.
HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute viral hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer. In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is in fact very similar to that of acquired immunodeficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or HIV-associated infections. However, HBV is more contagious than HIV.
Daily treatments with &agr;-interferon, a genetically engineered protein, has shown promise. A human serum-derived vaccine has also been developed to immunize patients against HBV. Vaccines have been produced through genetic engineering. While the vaccine has been found effective, production of the vaccine is troublesome because the supply of human serum from chronic carriers is limited, and the purification procedure is long and expensive. Further, each batch of vaccine prepared from different serum must be tested in chimpanzees to ensure safety. In addition, the vaccine does not help the patients already infected with the virus.
European Patent Application No. 92304530.6 discloses that a group of 1,2-oxathiolane nucleosides are useful in the treatment of hepatitis B infections. It has been reported that the 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane has anti-hepatitis B activity. Doong, et al.,
Proc. of Natl. Acad. Sci USA,
88, 8495-8499 (1991); Chang, et al.,
J. of Biological Chem., Vol
267(20), 13938-13942. The anti-hepatitis B activity of the (−) and (+)-enantiomers of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane has been published by Furman, et al., in
Antimicrobial Agents and Chemotherapy,
Dec. 1992, pages 2686-2692.
PCTAUS92/03144 (International Publication No. WO 92/18517) filed by Yale University discloses a number of &bgr;-L-nucleosides for the treatment of both HBV and HIV. Other drugs explored for the treatment of HBV include adenosine arabinoside, thymosin, acyclovir, phosphonoformate, zidovudine, (+)-cyanidanol, quinacrine, and 2′-fluoroarabinosyl-5-iodouracil. An essential step in the mode of action of purine and pyrimidine nucleosides against viral diseases, and in particular, HBV and V, is their metabolic activation by cellular and viral kinases, to yield the mono-, di-, and triphosphate derivatives. The biologically active species of many nucleosides is the triphospahte form, which inhibits DNA polymerase or reverse transcriptase, or causes chain termination. The nucleoside derivatives that have been developed for the treatment of HBV and HIV to date have been presented for administration to the host in unphosphorylated form, notwithstanding the fact that the nucleoside must be phosphorylated in the cell prior to exhibiting its antiviral effect, because the triphosphate form has typically either been dephosphorylated prior to reaching the cell or is poorly absorbed by the cell. Nucleotides in general cross cell membranes very inefficiently and are generally not very not very potent in vitro. Attempts at modifying nucleotides to increase the absorption and potency of nucleotides have been described by R. Jones and N. Bischofberger,
Antiviral Research,
27 (1995) 1-17, the contents of which are incorporated herein by reference.
In light of the fact that hepatitis B virus has reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat humans infected with the virus that have low toxicity to the host.
Therefore, it is another object of the present invention to provide a method and composition for the treatment of human patients or other hosts infected with HBV.
SUMMARY OF THE INVENTION
A method for the treatment of a host, and in particular, a human, infected with HBV is provided that includes administering an HBV-treatment amount of a nucleoside of the formula:
wherein:
R
1
is hydrogen, fluoro, bromo, chloro, iodo, methyl or ethyl; and R
2
is OH, Cl, NH
2
, or H; or a pharmaceutically acceptable salt of the compound, optionally in a pharmaceutically acceptable carrier or diluent.
In an alternative embodiment, the &bgr;-L-enantiomer of a compound of the formula:
wherein R
5
is adenine, xanthine, hypoxanthine, or other purine, including an alkylated or halogenated purine is administered to a host in an HBV-treatment amount as described more fully herein.
In another alternative embodiment, the nucleoside is of the formula:
wherein B is a purine or pyrimidine base;
Y
1
, Y
2
, Y
3
, and Y
4
are independently H, OH, N
3
, NR
1
R
2
, NO
2
, NOR
3
, —O-alkyl, —O-aryl, halo (including F, Cl, Br, or I), —CN, —C(O)NH
2
, SH, —S-alkyl, or —S-aryl, and wherein typically three of Y
1
, Y
2
, Y
3
, and Y
4
are either H or OH. The —OH substituent, when present, is typically a Y
1
or Y
3
group. As illustrated in the structure, y
2
and Y
4
are in the arabino (exytliro) configuration, and Y
1
and Y
3
are in the threo (ribose) configuration. R is H, monophosphate, diphosphate, triphosphate, alkyl, acyl or a phosphate derivative, as described in more detail below. R
1
, R
2
, and R
3
are independently alkyl (and in particular lower alkyl), aryl, aralkyl, alkaryl, acyl, or hydrogen.
In a preferred embodiment, the nucleoside is provided as the indicated enantiomer and substantially in the absence of its corresponding enantiomer (i.e., in enantiomerically enriched form).
In another embodiment, the invention includes a method for the treatment of humans infected with HBV that includes administering an HBV treatment amount of a prodrug of the specifically disclosed nucleosides. A prodrug, as used herein, refers to a pharmaceutically acceptable derivative of the specifically disclosed nucleoside, that is converted into the nucleoside on administration in vivo, or that has activity in itself. Nonlimiting examples are the 5′ and N
4
-pyrimidine or N
6
-purine acylated or alkylated derivatives of the active compound.
In a preferred embodiment of the invention, the nucleoside is provided as the monophosphate, diphosphate or triphosphate in a formulation that protects the compound from dephosphorylation. Formulations include liposomes, lipospheres, microspheres or nanospheres (of which the latter three can be targeted to infected cells). In an alternative preferred embodiment, the nucleoside is provided as a monophosphate, diphosphate or triphosphate derivative (i.e., a nucleoti

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