【专利】LDT

zasxz

      
     
   
  

  ( 3 of 6 )

--------------------------------------------------------------------------------
United States Patent  6,569,837  
Gosselin ,   et al.  May 27, 2003  

--------------------------------------------------------------------------------
.beta.-L-2'-deoxy pyrimidine nucleosides for the treatment of hepatitis B


Abstract
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-.beta.-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside has the formula: ##STR1## wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, 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-.beta.-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside or in combination with another anti-hepatitis B agent.


--------------------------------------------------------------------------------
Inventors:  Gosselin; Gilles (Montpellier, FR); Imbach; Jean-Louis (Montpellier, FR); Bryant; Martin L. (Carlisle, MA)  
Assignee:  Idenix Pharmaceuticals Inc. (Cambridge, MA)  
Appl. No.:  022276
Filed:  December 14, 2001

Current U.S. Class: 514/45; 514/46; 514/47; 514/48; 514/49; 514/50; 514/51; 536/28.5; 536/28.55  
Intern'l Class:  A61K 031/70; C07H 019/073
Field of Search:  514/45-51 536/28.5,28.55  



--------------------------------------------------------------------------------

References Cited [Referenced By]

--------------------------------------------------------------------------------

U.S. Patent Documents
4916122 Apr., 1990 Chu et al.   
4957924 Sep., 1990 Beauchamp.   
5190926 Mar., 1993 Chu et al.   
5194654 Mar., 1993 Hostetler et al.   
5223263 Jun., 1993 Hostetler et al.   
5256641 Oct., 1993 Yatvin et al.   
5411947 May., 1995 Hostetler et al.   
5463092 Oct., 1995 Hostetler et al.   
5539116 Jul., 1996 Liotta et al.   
5543389 Aug., 1996 Yatvin et al.   
5543390 Aug., 1996 Yatvin et al.   
5543391 Aug., 1996 Yatvin et al.   
5554728 Sep., 1996 Basava et al.   
5559101 Sep., 1996 Weis et al. 514/45.  
5565438 Oct., 1996 Chu et al.   
5567688 Oct., 1996 Chu et al.   
5587362 Dec., 1996 Chu et al.   
5939402 Aug., 1999 Weis et al. 514/44.  
5990093 Nov., 1999 Schinazi et al. 514/47.  
6025335 Feb., 2000 Weis et al. 514/44.  
6194391 Feb., 2001 Schinazi et al.   
6245749 Jun., 2001 Schinazi et al. 514/47.  
6297222 Oct., 2001 von Borstel et al.   
6395716 May., 2002 Gosselin et al. 514/45.  
Foreign Patent Documents
0 352 248 Jan., 1990 EP.   
0 350 257 Feb., 1990 EP.   
0 494 119 Jul., 1992 EP.   
0 355 131 Sep., 1996 EP.   
06-293645 Oct., 1994 JP.   
WO 89/02733 Apr., 1989 WO.   
WO 89/03838 May., 1989 WO.   
WO 90/00555 Nov., 1991 WO.   
WO 91/16920 Nov., 1991 WO.   
WO 91/18914 Dec., 1991 WO.   
WO 91/19721 Dec., 1991 WO.   
WO 92/08727 May., 1992 WO.   
WO 92/15308 Sep., 1992 WO.   
WO 92/18517 Oct., 1992 WO.   
WO 93/00910 Jan., 1993 WO.   
9420523 Sep., 1994 WO.   
WO 94/26273 Nov., 1994 WO.   
WO 95/07086 Mar., 1995 WO.   
WO 96/11204 Apr., 1996 WO.   
WO 96/13512 May., 1996 WO.   
WO 96/15132 May., 1996 WO.   
WO 96/40164 Dec., 1996 WO.   


     

zasxz

Other References
Robins, "Selective Deoxygenation and Modification at C2' of Nucleosides," pp. 1-4 in Nucleic Acids Research Symposium Series, vol. No. 11, Kyoto, Japan, Nov. 24-26, 1982, A. E. Pritchard (ed.), IRL Press, Ltd., Oxford, England, 1982; see also Chemical Abstracts, 98, Abstract No. 107670u (1982).*
Verri et al., "Relaxed Enantioselectively of Human Mitochondrial Thymidine Kinase and Chemotherapeutic Uses of L-Nucleoside Analogues," Biochemical Journal, 328(1), 317-320 (Nov. 15, 1997).*
Lin et al., "Design and Synthesis of 2', 3'-Deoxy-2', 3'-didehydro-.beta.-L-cytidine (.beta.-L-d4C) and 2', 3'-Dideoxy-2', 3'-didehydro-.beta.-L-5-fluorocytidine (.beta.-L-Fd4C), Two Exceptionally Potent Inhibitors of Human Hepatitis B Virus (HBV) and Potent Inhibitors of Human Immunodeficiency Virus (HIV) In Vitro," Journal of Medicinal Chemistry, 39(9), 1757-1759 (Apr. 26, 1996).*
von Janta-Lipinski et al., "Newly Synthesized L-Enantiomers of 3'-Fluoro-Modified .beta.-2'-Deoxyribonucleoside 5'-Triphosphates Inhibit Hepatitis B DNA Polymerase But Not the Five Cellular DNA Polymerase .alpha., .beta., .gamma., .delta., and .epsilon. Nor HIV-1 Reverse Transcriptase," Journal of Medicinal Chemistry, 41(12), 2040-2046 (Jun. 4, 1996).*
Mansour et al., "Stereochemical Aspects of the Anti-HCMV Activity of Cytidine Nucleoside Analogues," Antiviral Chemistry & Chemotherapy, 6(3), 138-142 (1995).*
Spadari et al., "L-Thymidine Is Phosphorylated by Herpes Simplex Type 1 Thymidine Kinase and Inhibits Viral Growth," Journal of Medicinal Chemistry, 35(22), 4214-4220 (1992).*
Bryant et al., "Antiviral L-Nucleosides Specific for Hepatitis B Virus Infection," Antimicrobial Agents and Chemotherapy, 45(1), 229-235 (Jan., 2001).*
Wang et al., "Recovery of Liver Sinusoidal Endothelial Cell Function over Time After Hypothermic Preservation in Rat Orthotopic Liver Transplantation," AASLD Abstracts published in Hepatology, 24(No. 4, Pt. 2), p. 431A, Abstract No. 1219 (1996).*
Arner and Erikksson, "Mammalian Deoxyribonicleoside Kinases," Pharm. Ther., 1995, 67(2), 155-186.
Berk et al., "A Genetically Distinct Tymidine Kinase in Mammalian Mitochondria," J Biol Chem, 1973, 248, 2722-2729. (Issue No. 8, Apr. 25, 1973).
Bestwick et al., "Selective Expansion of Mitochondrial Nucleoside Triphosphate Pools in Antimetabolite-treated HeLa Cells," J Biol Chem, 1982, 257, 9300-9304.(No. 6; Aug. 25, 1982).
Bridges et al., "Characterization of a dCTP Transport Activity Reconstituted from Human Mitochondria," J. Biol. Chem, Feb. 19, 1999, 274(8), 4620-4625.
Bridges et al., "Identification of a novel mitochondrial dNTP carrier and its interaction with anti-HIV nucleoside analogs," Proc. Am. Assoc. Cancer Res., Mar. 1997, 38, Abstr. No. 414, p. 62.
Bridges et al., "Inhibition of Mammalian DNA Polymerase-Associated 3' to 5' Exonuclease Activity by 5'-Monophosphates of 3'-Azido-3'-Deoxythymine and 3'-Amino-3'-Deoxythymidine," Biochemical Pharmacology, 1993, 45(8), 1571-1576.
Chariot et al., "Zidovudine-induced mitochondrial disorder with massive liver steatosis myopathy, lactic acidosis, and mitochondrial DNA depletion," J. Hepatology, 1999, 30, 156-160
Chang et al., "Biochemical Pharmacology of (+)- and (-)-2',3'-Dideoxy-3'-thiacytidine as Anti-hepatitis B Virus Agents," J Biol Chem, Nov. 5, 1992, 267(31), 22414-22420.
Chen et al., "Characterization of Pyrimidine Deoxyribonucleoside Kinase (Thymidine Kinase) and Thymidylate Kinase as a Multifunctional Enzyme in Cells Transformed by Herpes Simplex Virus Type 1 and in Cells Infected with Mutant Strains of Herpes Simplex Virus," J Virol, Jun. 1979, 30, 942-945.
Chen et al., "Delayed Cytotoxicity and Selective Loss of Mitochondrial DNA in Cells Treated with the Anti-human Immunodeficiency Virus Compound 2',3'-Dideoxycytidine," J Biol Chem, 1989, 264, 11934-11937. (Issue No. 20; Jul. 15, 1989).
Chen et al., "The Role of Cytoplasmic Deoxycytidine Kinase in the Mitochondrial Effects of the Anti-human Immunodeficiency Virus Compound 2',3'-Dideoxycytine," J Biol Chem, Feb. 15, 1992, 267(5), 2856-2859.
Cui et al., "Effect of Nucleoside Analogs on Neurite Regeneration and Mitochondrial DNA Synthesis in PC-12 Cells," J. of Pharmacology and Experimental Therapeutics, 1997, 280(3), 1228-1234.
Davis et al., "In Situ Localization of Mitochondrial DNA Replication in Intact Mammalian Cells," J Cell Biol, 1996, 135, 883-893. (Issue No. 4; Nov., 1996).
Doong et al., "Inhibition of the replication of hepatitis B virus in vitro by 2',3'-dideoxy-3'-thiacytidine and related analogues," Proc. Natl. Acad. Sci., Oct. 1991, 88, 8495-8499.
Dutschman et al., "Metabolism of 2',3'-dideoxy-2',3'-didehydro-.beta.-L-(-)-5-Fluorocytidine and Its Activity in Combination with Climically Approved Anti-Humna Immunodeficiency Virus .beta.-D-(+) Nucleoside Analogs In Vitro," Antimicrobial Agents and Chemotherapy, Jul. 1998, 42(7), 1799-1804.
Hernandez-Santiago et al., "harmacology of .beta.-L-Thymidine and .beta.-L-2'-Deoxycytidine in HepG2 Cell and Primary Human Hepatocytes: Relevance to Chemotherapeutic Efficacy against Hepatitis B Virus," Antimicrobial Agents and Chemotherapy, Jun. 2002, 46(6), 1728-1733.
Jurovcik and Holy "Metabolism of pyrimdine L-nucleosides," Nucleic Acids Research, Aug. 1976, 3(8), 2143-2153.
Krayevsky and Chernov, "Can a Substrate Enantiomer Be a Substrate for the Same Enzyme?," Molecular Biology, 1996, 30(5), 585-591.
Krayevsky and Chernov, "Should the Asymmetric of Enzymatic Active Centers Always Correlate with the Asymmetry of their Substrates?," J. of Bionolecular Structure & Dynamics, 1996, 14(2), 225-230.
Labenz et al., "Analysis of the TK Enzyme Complex Induced by HSV Types 1 and 2 by Means of Isoelectric Focusing and Polyacyrlamide Gel Electrophoresis," Arch Virol, 1982, 71, 235-249.
Lin et al., "Synthesis and Biological Evaluation of 2',3'-Dideoxy-L-pyrimidine Nucleosides as Potential Antiviral Agents agains HIV and HBV," J. Med. Chem, 1994, 97, 798-803. (Issue No. 6).
Pan-Zhou et al., "Differential Effects of Antiretroviral Nucleoside Analogs on Mitochondrial Function in HepG2 Cells," Antimicrobial Agents and Chemotherapy, Mar. 2000, 44(3), 496-503.
Placidi et al., "Cellular pharmacology of .beta.-L-thymidine and .beta.-L-2'-deoxycytidine in HepG2 cells and primary rat, monkey and human hepatocytes," 3.sup.rd Int. Conf. Ther. Vir. Hepatitis, abstr. A122, 1999 [Antivir. Ther. 4, Suppl. 4]. (Dec. 12-16, 1999).
Soderlund and Arner, "Mitochondrial versus Cytosololic Activities of Deoxyribonucleoside Salvage Enzymes," Purine and Pyrimidine Metabolism in Man VIII, A.Shota & M. Taylor (ed.), Plenum Press, New York, 1995, 201-204.
Zhu et al., "Anti-Hepatitis B Virus Activity and Metabolism of 2',3'-dideoxy-2',3'-didehydro-.beta.-L-(-)-5-Fluorocytidine," Antimicrobial Agents and Chemotherapy, Jul. 1998, 42(7), 1805-1810.
Zhu et al., "Incorporation of Nucleoside Analogs into Nuclear or Mitochondrial DNA Is Determined by the Intracellular Phosphorylation Site," J Biol Chem, 2000, 275(35), 26727-26731 (Sep. 1, 2000).
Zhu et al., "Inhibition of Replication of Hepatitis B Virus by Cytallene In Vitro," Antimicrobial Agents and Chemotherapy, Aug. 1997, 41(8), 1755-1760.
Bloch, et al. "The Role Of The 5'-Hydroxyl Group Of Adenosine In Determining Substrate Specificity For Adenosine Deaminase." J. Med. Chem. 10(5), 908-12 (Sep. 1967).
Chang, et al., "Deoxycytidine Deaminase-resistant Stereoisomer is the Active Form of (-)-2',3'-thiacytidine in the Inhibition of Hepatitis B Virus Replication," Journal of Biological Chemistry, vol. 267(20), 13938-13942 (Jul. 15, 1992).
Davisson, et al., "Synthesis of Nucleotide 5'-Diphosphates from 5'-O-Tosyl Nucleosides," J. Org. Chem., 52(9), 1794-1801 (1987).
Du et al, Synthesis, "Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Activities of Novel Oxaselenolane Nucleosides," J. of Med. Chem., (40)19, 2991-2993 (Sep. 12, 1997).
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, 36(12) 2686-1692 (Dec. 1992).
Gosselin, G. et al. "Synthesis and Antiviral Evaluation of .beta.-L-Xylofuranosyl Nucleosides of the Five Naturally Occuring Nucleic Acid Bases", Journal of Heterocyclic Chemistry, 1993, 30 (Oct.-Nov.), 1229-1233.
Hoard, et al., "Conversion of Mono- and Oligodeoxyribonucleotides to 5'-Triphosphates," J. Am. Chem. Soc., 87(8), 1785-1788 (1965).
Holy. "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.
Hostetler, K.Y., et al. "Greatly Enhanced Inhibition Of Human Immunodeficiency Virus Type 1 Replication In CEM And HT4-6C Cells By 3'-Deoxythymidine Diphosphate Dimyristoylglycerol, A Lipid Prodrug Of 3'-Deoxythymidine." (Sep. 1992) Antimicrob Agents Chemother. 36:2025-2029.
Hostetler, K.Y., et al. "Synthesis And Antiretroviral Activity Of Phospholipid Analogs Of Azidothymidine And Other Antiviral Nucleosides." (Apr. 15, 1990) J. Biol Chem. 265(11):6112-7.
Imai et al., "Studies on Phosphorylation. IV. Selective Phosphorylation of the Primary Hydroxyl Group in Nucleosides." J. Org. Chem., 34(6), 1547-1550 (Jun. 1969).
Jones,R. et al., "Mini Review: Nucleotide prodrugs," Antiviral Research, 27, 1-17 (1995).
Korba et al., "A cell culture assay for compounds which inhibit hepatitis B virus replication," Antiviral Res., 15:217 (1991).
Kucera, L.S., et al., "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation." AIDS Res Hum Retroviruses. 6:491-501 (May 1990).
Lin et al., "Synthesis of Several Pyrimidine L-Nucleoside Analogues as Potential Antiviral Agents," Tetrahedron:, vol. 51(4), 1055,1068 (1995).
Maga et al., "Lack of stereospecifity of suid pseudorabies virus thymidine kinase," Biochem. J. , 294(2), 381-385 (Sep. 1, 1993).
Nakayama, C., et al., "Synthetic Nucleosides and Nucleotides. XX. Synthesis of Various 1-.beta.-Xylofuranosyl-5-Alkyluracils and Related Nucleosides." Nucleosides, Nucleotides, 1, 139-146 (1982).
Norbeck, Tetrahedron Letters, 30 (46), 6246 (1989).
Robins, M. J. et al. "urine nucleosides. XXIX. The synthesis of 2'-deoxy-L-adenosine and 2'-deoxy-L-guanosine and their alpha anomers." J. Org. Chem. Mar. 1970, 35, 636-639.
Robins, M.J., et al., "Nucleic Acid Related Compounds. 42. A General Procedure for the Efficient Deoxygenation of Secondary Alcohols. Regiospecific and Stereoselective Conversion of Ribonucleosides to 2'-Deoxynucleosides." J. Am. Chem. Soc. 105, 4059-4065 (1983). (Jun. 15, 1983).
Saneyoshi, M., et al., "Synthetic Nucleosides and Nucleotides. XIII. Stannic Chloride Catalyzed Ribosylation of Several 6-Substituted Purines." Chem. Pharm. Bull., 27, 2518-2521 (1979).
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, 36(11), 2423-2431 (1992). (Nov., 1992).
Schinazi, et al., "Effect of Combinations of Acylovir with Vidarabine or its `Monophosphate` on Herpes Simplex Viruses in Cell Culture and in Mice," Antimicrobial Agents and Chemotherapy, 22(3), 499, (1982). (Jul., 1982).
Shuto, S., et al. "A facile one-step synthesis of 5'-phosphatidylnucleosides by an enzymatic two-phase reaction." Tetrahedron Letters. 28. 199-202 (1987).
Tyrsted et al. "Inhibition of the synthesis of 5-phosphoribosyl-1-pyrophosphate by 3'-deoxy-adenosine and structurally related nucleoside analogs." Biochim. Biophys. Acta. (Feb. 26, 1968), 155(2), 619-22.
Verri et al. "Lack of enantiospecificity of human 2'-deoxycytidine kinase: relevance for the activation of beta-L-deoxycytidine analogs as antineoplastic and antiviral agents." Molecular Pharmacology. (Jan. 1997), 51(1), 132-138.
Zedeck et al. "seudomonas testosteroni," Mol. Phys. (1967), 3(4), 386-95.
Zhang, W., et al. "Removal of Silyl Protecting Groups from Hydroxyl Functions with Ammonium Fluoride in Methanol." Tetrahedron Letter., 33, 1177-1180 (192).  

Primary Examiner: Richter; Johann
Assistant Examiner: Crane; L Eric
Attorney, Agent or Firm: King & Spalding L.L.P., Knowles; Sherry M.

zasxz

--------------------------------------------------------------------------------

Parent Case Text

--------------------------------------------------------------------------------


This application is a continuation application of U.S. patent application Ser. No. 09/371,747 filed on Aug. 8, 1999, now U.S. Pat. No. 6,395,716, which claims priority to U.S. provisional application No. 60/096,110, filed on Aug. 10, 1998 and U.S. provisional application No. 60/131,352, filed on Apr. 28, 1999.
--------------------------------------------------------------------------------

Claims

--------------------------------------------------------------------------------


We claim:

1. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR20##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), or pharmaceutically acceptable salt thereof.

2. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR21##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), or pharmaceutically acceptable salt thereof.

3. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR22##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyl-uridine (L-FMAU), or pharmaceutically acceptable salt thereof.

4. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR23##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD), or pharmaceutically acceptable salt thereof.

5. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR24##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of famciclovir, or pharmaceutically acceptable salt thereof.

6. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR25##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of penciclovir, or pharmaceutically acceptable salt thereof.

7. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR26##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475), or pharmaceutically acceptable salt thereof.

8. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR27##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil), or pharmaceutically acceptable salt thereof.

9. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR28##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of lobucavir, or pharmaceutically acceptable salt thereof.

10. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR29##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of ganciclovir, or pharmaceutically acceptable salt thereof.

11. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR30##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of ribavirin, or pharmaceutically acceptable salt thereof.

12. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR31##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), or pharmaceutically acceptable salt thereof.

13. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR32##

or pharmaceutically acceptable salt thereof.

14. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of .beta.-L-thymidine of the formula: ##STR33##

or pharmaceutically acceptable salt thereof.

15. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a combination of the following nucleosides: ##STR34##

or pharmaceutically acceptable salt thereof.

16. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR35##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinofuranosyl-uridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin.

17. A method the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR36##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinofuranosyl-uridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin.

18. The method of claim 13, wherein the .beta.-L-2'-deoxycytidine is at least 95% in its designated enantiomeric form.

19. The method of claim 13, wherein the .beta.-L-2'-deoxycytidine is administered in a pharmaceutically acceptable carrier.

20. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

21. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

22. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

23. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

24. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for subcutaneous deliery.

25. The method of claim 19, wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

26. The method of claim 19, wherein the compound is in the form of a dosage unit.

27. The method of claim 26, wherein the dosage unit contains 10 to 1500 mg of the compound.

28. The method of claim 26 or 27, wherein the dosage unit is a tablet or capsule.

29. The method of claim 14, wherein the .beta.-L-thymidine is at least 95% in its designated enantiomeric form.

30. The method of claim 14, wherein the .beta.-L-thymidine is administered in a pharmaceutically acceptable carrier.

31. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

32. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

33. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

34. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for intradermnal delivery.

35. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.

36. The method of claim 29, wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

37. The method of claim 29, wherein the compound is in the form of a dosage unit.

38. The method of claim 37, wherein the dosage unit contains 10 to 1500 mg of the compound.

39. The method of claim 37 or 38, wherein the dosage unit is a tablet or capsule.

40. A method for the treatment of a heptitis B virus infection in a human compriding administering an effective amount of a compound of the formula: ##STR37##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), or pharmaceutically acceptable salt thereof.

41. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR38##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyl-uridine (L-FMAU), or pharmaceutically acceptable salt thereof.

42. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR39##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD), or pharmaceutically acceptable salt thereof.

43. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR40##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of famciclovir, or pharmaceutically acceptable salt thereof.

44. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR41##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of penciclovir, or pharmaceutically acceptable salt thereof.

45. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR42##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475), or pharmaceutically acceptable salt thereof.

46. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR43##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil), or pharmaceutically acceptable salt thereof.

47. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR44##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of lobucavir, or pharmaceutically acceptable salt thereof.

48. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR45##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of ganciclovir, or pharmaceutically acceptable salt thereof.

49. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR46##

or pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of ribavirin, or pharmaceutically acceptable salt thereof.

zasxz

--------------------------------------------------------------------------------

Description

--------------------------------------------------------------------------------


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 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.

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 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 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.

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 .alpha.-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.

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 A1 filed by BioChem Pharma, Inc.

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).

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.

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.

U.S. Pat. No. Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of 2'-fluoro-5-methyl-.beta.-L-arabinofuranolyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus.

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.

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.

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).

Giovanni et al. tested 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides against partially pseudorabies virus (PRV), Biochem. J. (1993), 294(2), 381-5.

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).

.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.

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 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

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 .beta.-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.

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.

In one embodiment of the present invention, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is a compournd of the formula: ##STR2##

wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, 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 optionally be substituted.

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is .beta.-L-2'-deoxyadenosine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: ##STR3##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofiuranonucleoside derivative is .beta.-L-2'-deoxycytidine or pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR4##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilzied nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is .beta.-L-2'-deoxyuridine or pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR5##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilzied nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is .beta.-L-2'-deoxyguanosine or pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR6##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is .beta.-L-2'-deoxyinosine or pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR7##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivative is .beta.-L-thymidine or a pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR8##

wherein R is H, mono, di or tri phosphate, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).

In another embodiment, the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside is administered in alternation or combination with one or more other 2'-deoxy-.beta.-L-erythro-pentofuranonucleosides or one or more other compounds which exhibit activity against hepatitis B virus. In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents are administered together. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

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 disclosed 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside derivatives. A prodrug, as used herein, refers to a compound that is converted into the nucleoside on administration in vivo. Nonlimiting examples include pharmaceutically acceptable salt (alternatively referred to as "physiologically acceptable salts"), the 5'and N.sup.4 (cytidine) or N.sup.6 (adenosine) acylated or alkylated derivatives of the active compound, or the 5'-phospholipid or 5'-ether lipids of the active compound.

及时雨

谁大概给翻译一下,谢谢.