Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-10-05
1997-06-10
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 2714, 536 2761, C07H 19173, A61K 3170
Patent
active
056375743
DESCRIPTION:
BRIEF SUMMARY
This case is a 35 USC 371 stage of PCT/GB93/00005 filed Jan. 5, 1993.
The present invention relates to novel 2',3'-dideoxy-3'-fluoro-purine nucleoside compounds, salts, esters and physiologically functional derivatives thereof, processes for their preparation, pharmaceutical formulations containing them and to their use in therapy, particularly in the treatment or prophylaxis of viral infections.
In the field of antiviral chemotherapy, few drugs exist which effectively combat the virus per se, owing to the difficulty of attacking the virus while leaving uninfected host cells unimpaired. It has been established that certain stages in the virus life-cycle, which vary from species to species, are specified by the virus itself. These stages may prove susceptible to attack where they differ sufficiently from any corresponding host-cell function. However, owing to great similarity between viral and host functions, effective treatments have proved very difficult to identify.
One group of vital 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 illness each year, 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 U.S.A. and that perhaps 1000 die from HBV-related liver cancer. Even when a universal HBV vaccine is available, the need for effective anti-HBV compounds will continue. The large reservoir of persistently infected carriers, estimated at 220 million worldwide, will receive no benefit from vaccination and will continue to be at high risk for HBV induced liver disease. This carrier population serves as a source of infection for susceptible individuals perpetuating the incidence of disease, particularly in endemic areas or high risk groups, such as drug abusers and homosexuals. 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.
HBV is a small DNA-containing virus which infects humans. It is a member of the class of closely related viruses know as the hepadnaviruses, each member of which selectively infects either mammalian or avian hosts, such as the woodchuck and the duck.
In "Fields Virology" (Volume 2, Ed., Fields et al (1990) Raven Press, New York), Chapters 76 and 77 describe in detail the etiology of hepatitis infections, in particular HBV infections.
Compounds of formula (I) below fall within the scope of the compounds disclosed in European Patent Specification No. 0 317 128. However, there is no specific disclosure of the compounds of formula (I) or of their use in medical therapy.
We have now surprisingly and unexpectedly found that the compounds of formula (I) below are suitable for use in the treatment or prophylaxis of hepatitis viral infections, especially HBV.
According to a first aspect of the present invention there is provided a compound of formula (I): ##STR2## wherein R.sup.1 represents an n-propoxy, cyclobutoxy, cyclopropylamino, piperidino, or pyrrolidino group; or a salt, ester or physiologically functional derivative of a compound of formula (I) or a solvate of any thereof.
The compounds of formula (I) may be named as follows: 2-Amino-9-(2,3
REFERENCES:
patent: 4381344 (1983-04-01), Rideout et al.
Korba et al., "A Cell Culture Assay for Compounds Which Inhibit Hepatitis B Virus Replication," Antiviral Research, 15, 217-228 (1991).
Robinson, "Fields Virology," Edited by Fields et al., vol.2, (1990) Raven Press, New York, Chapters 76 and 77.
Herdewijn et al., "Synthesis and Anti-HIV Activity of Different Sugar-Modified Pyrimidine and Purine Nucleosides," J. Med. Chem., 31, 2040-2048 (1988).
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Etzold et al., "Nucleoside Von Fluorzuckern-V1.sup.1, " Tetrahedron, 27, 2463-2472 (1971).
Montgomery et al., "Synthesis of Potential Anticancer Agents. XXVI. The Alkylation of 6-Chloropurine.sup.2, " J. Amer. Chem. Soc., 83, 630-635 (1961).
Robins et al., "Potential Purine Antagonists. IV. Synthesis of Some 9-Methyl-6-substituted-purines.sup.1, " J. Amer. Chem. Soc., 79. 490-494 (1957).
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Burns Charlene L.
Daluge Susan M.
Koszalka George W.
Krenitsky Thomas A.
Brown Donald
Glaxo Wellcome Inc.
Kunz Gary L.
Prus Karen L.
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