3′,5-difluoro-2′,3′-didehydropyrimidine...

Details 3′,5-difluoro-2′,3′-didehydropyrimidine... 3′,5-difluoro-2′,3′-didehydropyrimidine...

2002-05-15

2004-01-20

Wilson, James D. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C536S026230, C536S026260, C536S026700, C536S026800, C536S028200

Reexamination Certificate

active

06680303

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is in the area of biologically active nucleosides, and specifically includes antiviral compositions that include a [5-carboxamido or 5-fluoro]-2′,3′-dideoxy-2′,3′-didehydro-pyrimidine nucleoside or [5-carboxamido or 5-fluoro]-3′-modified-pyrimidine nucleoside, or its physiologically acceptable derivative, or physiologically acceptable salt.
In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that almost without exception leads to death. In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). The World Health Organization estimates that currently 13 million people worldwide are infected with HIV and that forty million people will be infected by the year 2000. Each day approximately 5,000 people are newly infected.
In 1985, it was reported that the synthetic nucleoside 3′-azido-3′-deoxythymidine (AZT) inhibit the replication of human immunodeficiency virus. Since then, a number of other synthetic nucleosides, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), and 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), have been proven to be effective against HIV. After cellular phosphorylation to the 5′-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3′-hydroxy group. They can also inhibit the viral enzyme reverse transcriptase.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3′-position of the nucleoside. Norbeck, et al., disclosed that (±)-1-[(2&bgr;,4&bgr;)-2-(hydroxymethyl)-4-dioxolanyl]thymine (referred to as (±)-dioxolane-T) exhibits a modest activity against HIV (EC
50
of 20 &mgr;M in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 &mgr;M.
Tetrahedron Letters
30 (46), 6246, (1989). European Patent Application Publication No. 0 337 713 and U.S. Pat. No. 5,041,449, assigned to IAF BioChem International, Inc., disclose that racemic 2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviral activity.
U.S. Pat. No. 5,047,407 and European Patent Application Publication No. O 382 526, also assigned to IAF Biochem International, Inc. disclose a number of racemic 2-substituted-5-substituted-1,3-oxathiolane nucleosides with antiviral activity, and specifically report that the racemic mixture (about the C4′-position) of the C1′-&bgr; isomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (referred to below as (±)-BCH-189) has approximately the same activity against HIV as AZT, and no cellular toxicity at the tested levels. (±)-BCH-189 has also been found to inhibit the replication of AZT-resistant HIV isolates in vitro from patients who have been treated with AZT for longer than 36 weeks. The (−)-enantiomer of the &bgr;-isomer of BCH-189, known as 3TC, which is highly potent against HIV and exhibits little toxicity, is in the final stages of clinical review for the treatment of HIV.
It has also been disclosed that (−)-cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (“FTC”) has potent HIV activity. Schinazi, et al., “Selective Inhibition of Human Immunodeficiency Viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]Cytosine”
Antimicrobial Agents and Chemotherapy,
November 1992, page 2423-2431;
Another virus that causes a serious human health problem is the hepatitis B virus (referred to below as “HBV”). HBV is second only to tobacco as a cause of human cancer. The mechanism by which HIV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
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 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 persistant 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 very similar to that of acquired immune deficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or AIDS-related complex. However, HBV is more contagious than HIV.
Both FTC and 3TC exhibit activity against HBV. Furman, et al., “The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (−) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]Cytosine”
Antimicrobial Agents and Chemotherapy,
December 1992, page 2686-2692; ***
A human serum-derived vaccine has been developed to immunize patients against HBV. While it 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 treated in chimpanzees to ensure safety. Vaccines have also been produced through genetic engineering. Daily treatments with &agr;-interferon, a genetically engineered protein, has also shown promise.
In light of the fact that acquired immune deficiency syndrome, AIDS-related complex, and hepatitis B virus have reached epidemic levels worldwide, and have tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat these diseases and that have low toxicity to the host.
Therefore, it is an object of the present invention to provide a method and composition for the treatment of human patients infected with HIV.
It is another object of the present invention to provide a method and composition for the treatment of human patients or other host animals infected with HBV.
SUMMARY OF THE INVENTION
A method and composition for the treatment of HIV and HBV infections in human and other host animals is disclosed that includes the administration of an effective amount of a [5-carboxamido or 5-fluoro]-2′,3′-dideoxy-2′,3′-didehydro-pyrimidine nucleoside or a [5-carboxamido or 5-fluoro]-3′-modified-pyrimidine nucleoside, or a mixture or a pharmaceutically acceptable derivative thereof, including a 5′ or N
4
alkylated or acylated derivative, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
Specifically, compounds of the structure:
wherein:
X is O, S, CH
2
, CHF, or CH
2
;
Y is O, S. CH
2
, CHF, CF
2
;
Z is independently O, S or Se;
R
1
is independently H or F;
R
2
is independently H, OH, C
1
to C
6
alkyl, or C(O)(C
1
to C
6
alkyl);
R
3
is H, C(O)(C
1
-C
6
alkyl); alkyl, or mono-, di- or triphosphate; and
R
4
is independently H, F, Cl, Br, I, OH, —O(C
1
-C
6
alkyl), —SH, —S

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