| Beta-l-2'-deoxy-nucleosides for the treatment of hepatitis b -> Monitor Keywords |
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  Beta-l-2'-deoxy-nucleosides for the treatment of hepatitis bUSPTO Application #: 20080064655Title: Beta-l-2'-deoxy-nucleosides for the treatment of hepatitis b Abstract: wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-axyl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. The 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2′-deoxy-β-L-erythro pentofuranonucleoside or in combination with another anti-hepatitis B agent.
This invention is directed to a method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2′deoxy-β-L-erythro-pentofuranonucleoside has the formula: (end of abstract)
Agent: Jones Day - New York, NY, US Inventors: Gilles Gosselin, Jean-Louis Imbach, Martin L. Bryant USPTO Applicaton #: 20080064655 - Class: 514050000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, 2,4-diketone Pyrimidine Or Derivative (e.g., Uracil, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20080064655. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. provisional application Ser. No. 60/096,110, filed on Aug. 10, 1998 and U.S. Ser. No. 60/131,352, filed on Apr. 28, 1999. BACKGROUND OF THE INVENTION [0002] This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as "HBV") that includes administering to a host in need thereof, either alone or in combination, an effective amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable prodrug or salt of one of these compounds. [0003] 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. [0004] 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. [0005] 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 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. [0006] 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 (AIDS), which accounts for why HBV infection is common among patients with AIDS or AIDS related complex. However, HBV is more contagious than HIV. [0007] However, more recently, vaccines have also been produced through genetic engineering and are currently used widely. Unfortunately, vaccines cannot help those already infected with HBV. Daily treatments with a-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients. Further, interferon cannot be given orally. [0008] A number of synthetic nucleosides have been identified which exhibit activity against HBV. The (-)-enantiomer of BCH-189, known as 3TC, claimed in U.S. Pat. No. 5,539,116 to Liotta, et al., has been approved by the U.S. Food and Drug Administration for the treatment of hepatitis B. See also EPA 0 494 119 Al filed by BioChem Pharma, Inc. [0009] Cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane ("FTC") exhibits activity against HBV. See WO 92/15308; 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; and Cheng, et al., Journal of Biological Chemistry, Volume 267(20), 13938-13942 (1992). [0010] von Janta-Lipinski et al. disclose the use of the L-enantiomers of 3'-fluoro-modified .beta.-2'-deoxyribonucleoside 5'-triphosphates for the inhibition of hepatitis B polymerases (J. Med. Chem., 1998, 41,2040-2046). Specifically, the 5'-triphosphates of 3'-deoxy-3'-fluoro-.beta.-L-thymidine (.beta.-L-FTTP), 2',3'-dideoxy-3'-fluoro-.beta.-L-cytidine (.beta.-L-FdCTP), and 2',3'-dideoxy-3'-fluoro-.beta.-L-5-methylcytidine (.beta.-L-FMethCTP) were disclosed as effective inhibitors of HBV DNA polymerases. [0011] WO 96/13512 to Genencor International, Inc. and Lipitek, Inc. discloses that certain L-ribofuranosyl nucleosides can be useful for the treatment of cancer and viruses Specifically disclosed is the use of this class of compounds for the treatment of cancer and HIV. [0012] U.S. Pat. Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of2'-fluoro-5-methyl-.beta.-L-arabinofuranolyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus. [0013] Yale University and University of Georgia Research Foundation, Inc. disclose the use of L-FddC (.beta.-L-5-fluoro-2',3'-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517. [0014] The synthetic nucleosides .beta.-L-2'-deoxycytidine (.beta.-L-2'-dC), .beta.-L-2'-deoxythymidine (.beta.-L-dT) and .beta.-L-2'-deoxyadenosine (.beta.-L-2'-dA), are known in the art. Antonin Holy first disclosed .beta.-L-dC and (.beta.-L-dT in 1972, "Nucleic Acid Components and Their Analogs. CLIII. Preparation of 2'-deoxy-L-Ribonucleosides of the Pyrimidine Series," Collect. Czech. Chem. Commun. (1972), 37(12), 4072-87. Morris S. Zedeck et al. first disclosed .beta.-L-dA for the inhibition of the synthesis of induced enzymes in Pseudomonas testosteroni, Mol. Phys. (1967), 3(4), 386-95. [0015] Certain 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides are known to have antineoplastic and selected antiviral activities. Verri et al. disclose the use of 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides as antineoplastic agents and as anti-herpetic agents (Mol. Pharmacol. (1997), 51(1), 132-138 and Biochem. J. (1997), 328(1), 317-20). Saneyoshi et al. demonstrate the use of 2'-deoxy-L-ribonucleosides as reverse transcriptase (I) inhibitors for the control of retroviruses and for the treatment of AIDS, Jpn. Kokai Tokkyo Koho JP06293645 (1994). [0016] Giovanni et al. tested 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides against partially pseudorabies virus (PRV), Biochem. J. (1993), 294(2), 381-5. [0017] Chemotherapeutic uses of 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides were studied by Tyrsted et al. (Biochim. Biophys. Acta (1968), 155(2), 619-22) and Bloch, et al. (J. Med. Chem. (1967), 10(5), 908-12). [0018] .beta.-L-2'-deoxythymidine (.beta.-L-dT) is known in the art to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK). Iotti et al., WO 92/08727, teaches that (.beta.-L-dT selectively inhibits the phosphorylation of D-thymidine by HSV-1 TK, but not by human TK. Spaldari et al. reported that L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth, J. Med. Chem. (1992), 35(22), 4214-20. [0019] 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. [0020] Therefore, it is an object of the present invention to provide new methods and compositions for the treatment of human patients or other hosts infected with hepatitis B virus. SUMMARY OF THE INVENTION [0021] A method for the treatment of hepatitis B infection in humans and other host animals is disclosed that includes administering an effective amount of a biologically active 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside (referred to alternatively herein as a .beta.-L-d-nucleoside or a P-L-2'-d-nucleoside) or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. The term 2'-deoxy, as used in this specification, refers to a nucleoside that has no substituent in the 2'-position. [0022] The disclosed 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides, or pharmaceutically acceptable prodrugs or salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of hepatitis B infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV. Continue reading... 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