Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-06-30
1997-09-02
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 46, 536 2714, A61K 3170, C07H 19173
Patent
active
056631545
DESCRIPTION:
BRIEF SUMMARY
This case is a 371 of PCT/GB 93/00004 filed Jan. 5, 1993.
The present invention relates to novel 2',3'-dideoxy-3'-fluoro-purine nucleoside compounds, physiologically functional derivatives thereof, processes for their preparation, pharmaceutical formulations containing them and the use of such analogues and derivative compounds in therapy, particularly the treatment or prophylaxis of viral infections.
One group of viruses which has assumed a particular importance is the retroviruses. Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first `reverse transcribe` the RNA of their genome into DNA (`transcription` conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome may be incorporated into the host cell genome, allowing it to take advantage of the host cell's transcription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell.
A species of retrovirus, Human Immunodeficiency Virus (HIV), has been reproducibly isolated from humans with Acquired Immune Deficiency Syndrome (AIDS) or with the symptoms that frequently precede AIDS. AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. Characteristically, AIDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT.sup.4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the OKT.sup.4 marker and it is now generally recognised that HIV is the etiological agent of AIDS.
Since the discovery that HIV is the etiological agent of AIDS, numerous proposals have been made for anti-HIV chemotherapeutic agents that may be effective in treating AIDS. Thus, for example, European Patent Specification No. 196185 describes 3'-azido-3'-deoxythymidine (which has the approved name zidovudine), its pharmaceutically acceptable derivatives and their use in the treatment of human retrovirus infections including AIDS and associated clinical conditions. Other nucleoside derivatives which have been suggested for the treatment of HIV infections include the 3'-fluoronucleosides described in European Patent No. 0 254 268. European Patent Specification No. 0 317 128 discloses certain 3'-fluoro-purine and pyrimidine nucleoside analogues having anti-HIV activity.
Another group of viral pathogens of major consequence worldwide are the hepatitis viruses, in particular hepatitis B virus (HBV). HBV is most common in Asian countries and prevalent in sub-Saharan Africa. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. In the United States more than ten thousand people are hospitalised for HBV-related illness each year and an average of 250 die with fulminant disease. The United States currently contains an estimated pool of 500,000-1 million infectious carriers. Chronic active hepatitis will develop in over 25% of carriers and often progresses to cirrhosis. It is estimated that 5000 people die from HBV related cirrhosis each year in the USA and that perhaps 1000 die from HBV-related liver cancer. Thus, there is a great need for effective antiviral agents, both to control the chronic infection and to reduce progression to hepatocellular carcinoma.
Clinical effects of infection with HBV range from headache to fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease as outlined above. In "Fields Virology" (Volume 2 Ed., Fields et al (1990) Raven, New York), Chapters 76 and 77 describe the etiology of viral hepatitis infections.
The anti-HIV and -HBV activity of the compound 2',3'-dideoxy-3'-fluoroadenine and 2',3'-dideoxy-3'-flu
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Burns Charlene Louise
Koszalka George Walter
Krenitsky Thomas Anthony
Glaxo Wellcome Inc.
Kunz Gary L.
Prus Karen L.
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