MX2008007379A - Antiviral nucleosides - Google Patents

Abstract

Compounds having the formula I wherein R1is as herein defined are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for inhibiting hepatitis replication, and processes for making the compounds of formula I.

Description

ANTIVIRAL UCLEOSIDES FIELD OF THE INVENTION The present invention provides acylated nucleosides which are prodrugs of an inhibitor of the Hepatitis C Virus (HCV) of RNA RNA-dependent viral polymerase. These compounds, when administered orally, are easily absorbed from the GI tract and effectively reverse the generator nucleoside in the blood. These prodrugs are inhibitors of viral RNA RNA-dependent replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication, and for the treatment of Hepatitis C infection in mammals. The invention relates to nucleoside prodrugs which are inhibitors of HCV replication. In particular, the invention relates to the use of acylated pyrimidine nucleoside compounds which provide for improved drug absorption when the nucleoside is administered orally.

BACKGROUND OF THE INVENTION The Hepatitis C virus is a major health problem and the cause that leads to chronic liver disease throughout the world. (Boyer, N. et al., J. Hepatol. 2000 32: 98-112). Patients infected with HCV are at risk of developing liver cirrhosis and subsequent hepatocellular carcinoma and, therefore, HCV is the most important indication for liver transplantation. According to the World Organization of Health, there are more than 200 million people infected worldwide with at least three or four million people who are being infected every year. Once infected, approximately 20% erase the virus; however, the rest can deal with HCV all their lives. Ten or twenty percent of chronically infected individuals eventually develop cirrhosis that destroys the liver or cancer. Viral disease is transmitted parentally through contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their children. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-a alone or in combination with nucleoside analogue ribavirin, are of limited clinical benefit while resistance develops rapidly. There is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. HCV has been classified as an element of the Flaviviridae virus family that includes the genera flaviviruses, pestiviruses and hepaciviruses which include hepatitis C viruses (Rice, CM, Flaviviridae: The virases and their replication, in: Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM, Lippincott-Raven Publishers, Philadelphia, Pa., Chapters 30, 931-959, 1996). HCV is a enveloped virus that contains a single-stranded, positive-sense RNA genome of approximately 9.4 k. The viral genome consists of an unconverted 5 'region (UTR), a long open reading frame (ORF) that encodes a polyprotein precursor of approximately 3011 amino acids, and a short UTR of 3 '. The 5 'UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein conversion. The genetic analysis of HCV has identified six main genotypes that show an > 30% divergence in its DNA sequence. Each genotype contains a series of closely related subtypes which show 20-25% divergence in nucleotide sequences (Simmonds, P. 2004 J. Gen. Virol. 85: 3173-88). More than 30 subtypes have been distinguished. In the United States, approximately 70% of the infected individuals have the Type Ia and Ib infection. Type Ib is the most subtype prevalent in Asia. (X. Forns and J.Bukh, Clinics in Liver Disease 1999 3: 693-716; J. Bukh et al., Semin. Liv Dis. 1995 15: 41-63). Unfortunately, Type 1 infections are more resistant to therapy than either 2 or 3 genotypes (N.N.Zein, Clin.Microbiol.Rev., 2000 13: 223-235). The genetic organization and polyprotein processing of the non-structural protein portion of the ORF of pestivirus and hepaci-virus is very similar. These positive single-stranded RNA viruses possess a single large ORF that encodes all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is processed co and post-conversion by virus and cell-encoded proteinase to produce the mature viral proteins. The viral proteins responsible for the replication of the viral RNA genome are located approximately within the carboxy-terminal. Two thirds of the ORF are considered non-structural proteins (NS). For pestiviruses and hepaci-viruses, mature non-structural proteins (NS), sequentially from the amino termini of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B. The NS proteins of pestivirus and hepaci-virus share the sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of viruses in both groups have characteristics of amino acid sequence motifs of serine proteinases and helicases (Gorbalenya et al., Nature 1988 333: 22, Bazan and Fletterick Virology 1989 171: 637-639, Gorbalenya et al. Nucleic Acid Res. 1989 17.3889-3897). Similarly, the NS5B proteins of pestiviruses and hepaci-viruses have the characteristics of RNA-directed RNA polymerase motifs (Koonin, E.V. and Dolja, V.V. Crit., Rev. Biochem. Molec., Biol. 1993 28: 375-430). The actual roles and functions of the NS proteins of pestivirus and hepaci-virus in the life cycle of the viruses are directly analogous. In both cases, the serine protein NS3 is responsible for all the proteolytic processing of the starting line of the polyprotein precursors from its position in the ORF (Wiskerchen and Collett Virology 1991 184: 341-350; Bartenschlager et al. Virol 1993, 67: 3835-3844, Eckart et al Biochem Biophys, Resm Comm 1993 192: 399-406, Grakoui et al., J. Virol 1993, 67: 2832-2843, Grakoui et al., Proc. Nati, Acad. Sci. USA 1993 90: 10583-10587; Ilijikata et al., J. Virol., 1993 67: 4665-4675; Tome et al., J. Virol. 1993 67: 4017-4026). The NS4A protein, in both cases, acts as a co-factor with the serine protease NS3 (Bartenschlager et al., J. Virol., 1994 68: 5045-5055, Failla et al., J. Virol., 1994 68: 3753-3760, Xu et al., J. Virol. 1997, 71:53, 12-5322). The NS3 protein of both viruses also functions as a helicase (Kim et al., Biochem Biophys, Res. Comm. 1995, 215: 160-166, Jin and Peterson Arch. Biochem. Biophys., 1995, 323: 47-53; Warren and Collett J. Virol. 1995 69: 1720-1726). Finally, the NS5B proteins of pestivirus and hepaci-virus have the activity of RNA-directed RNA polymerases predicted (Behrens et al., E, BO 1996 15: 12-22, Lechmann et al., J. Virol. 1997 71: 8416-8428; Yuan et al., Biochem Biophys, Res. Comm. 1997 232: 231-235; Hagedorn, PCT O 97/12033; Zhong et al., J. Virol. 1998 72: 9365-9369). Currently, there is a limited number of approved therapies available today for the treatment of HCV infection. New and existing therapeutic approaches to treat HCV and inhibition of HC5 NS5B polymerase have been reviewed: R.G. Gish, Sem. Liver. Dis. , 1999 19: 5; Di Besceglie, A.M. and Bacon, B.R., Scientific American, October: 1999 80-85; G. Lake-Bakaar, Current and Future Therapy for Liver Disease due to Chronic Hepatitis C Virus, Curr. Drug Targ. Infect Dis. 2003 3 (3): 247-253; P. Hoffmann et al., Recent Patents on Experimental Therapy for Hepatitis C Virus Infection (1999-2002), Exp. Opin. Ther. Patents 2003 13 (11): 1707-1723; F.F.Poordad et al. Developments in Hepatitis C therapy during 2000-2002, Exp. Opin. Emerging Drugs 2003 8 (l): 9-25; M.P. Walker et al., Promising Candidates for the Treatment of Chronic Hepatitis C, Exp. Opin. Investig. Drugs 2003 12 (8): 1269-1280; S.-L.Tan et al., Hepatitis C Therapeutics: Current Condition and Emerging Strategies, Nature Rev. Drug Discov. 2002 1: 867-881; R. De Francesco et al. Approach to a new era for hepatitis C virus therapy; serine protease inhibitors NS3-4A and RNA-dependent RNA polymerase NS5B, Antiviral Res. 2003 58: 1-16; Q.M.Wang et al. Hepatitis C virus encoded proteins: targets for antiviral therapy, Drugs of the Future 2000 25 (9): 933-8-94; J.A.Wu and Z.Hong, RNA Polymerase Dependent of NS5B Target for Chemotherapy Anti HCV Cur. Drug Targ. -Inf. Dis. 2003 3: 207-219. Reviews refer to compounds currently in various stages of the development process. Therapy in combination with two or three agents directed to the same or different targets has become a standard therapy to prevent or delay the development of resistant strains of a virus, and the compounds described in the previous reviews could be used in combination therapy. with compounds of the present invention and these revisions are, by incorporation as reference in their entirety. the: = C (= 0) N1I2 Ribavirin (la; 1- ((2R, 3R, 4S, 5R) -3, 4-Dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl) -1H- [1, 2, 4] triazole-3 carboxylic acid amide; VIRAZOLE®) is an antiviral synthetic nucleoside analog of broad induction spectrum of non-interferon, synthetic. Ribavirin has in vitro activity against various DNA and RNA viruses including Fiaviviridae (Gary L. Davis, Gastroenterology 2000 118: S104-S114). In monotherapy, ribavirin reduces serum aminotransferase levels to normal in 40% of patients; however, it does not decrease the serum levels of HCV-RNA. Ribavirin also exhibits significant toxicity and is known to induce anemia. Ribavirin is an inhibitor of inosine monophosphate hydrogenase. Ribavirin is not approved in monotherapy against HCV; however, the compound is approved in therapy in combination with interferon a-2a and interferon a -2b. Viramidine is a prodrug converted to hepatocytes. Interferons (IFNs) have been available for the treatment of chronic hepatitis for approximately a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. Two different types of interferons are recognized: Type 1 includes various alpha interferons and an interferon beta, type 2 includes interferon? . Interferon type 1 is produced mainly by infected cells and protects neighboring cells from de novo infection. IFNs inhibit viral replication of many viruses, including HCV, and when used as the sole treatment for hepatitis C infection, IFN suppresses HCV-RNA in serum for undetectable levels. Additionally, IFN normalizes aminotransferase levels in serum. Unfortunately, the effects of IFN are temporary. Cessation of therapy results in a 70% recidivism rate and only 10-15% exhibits a sustained virological response with serum alanine transferase levels. (L.B. Davis, supra). One limitation of early IFN therapy was the rapid evacuation of the blood protein. The chemical derivatization of IFN with polyethylene glycol (PEG) has resulted in proteins with pharmacokinetic properties substantially improved. PEGASYS® is an interferon conjugated to -2a and a branched mono-methoxy PEG 40 kD and PEG-INTRON® is a conjugate of interferon a -2b and a mono-methoxy PEG 12 kD. (B.A.Luxon et al., Clin Therap.2000 24 (9): 13631383; A. Kozlowski and J.. Harrisis, J. Control, Reléase, 2001 72: 217-224). Interferon-2a and interferon-2b are currently approved as monotherapy for the treatment of HCV. ROFERON-A® (Roche) is the recombinant form of interferon a-2a. PEGASYS® (Roche) is the pegylated form (ie, modified polyethylene glycol) of interferon a-2a. INTRON-A® (Schering Corporation) is the recombinant form of Interferona a-2b, and PEG-INTRON® (Schering Corporation) is the pegylated form of interferon a-2b. Other forms of interferon a, as well as of interferon ß,?, T, and? they are currently in clinical development for the treatment of HCV. For example, INFERGEN® (interferon alfacona-1) is being developed by Inter une, OMNIFERON® (natural interferon) by Viragen, ALBUFERON® by Human Genome Sciences, REBIF® (interferon β-la) by Ares -Serone, Omega Inferred by Biomedicine, Oral Inferred Alpha by Amarillo Biosciences, and Interferon, and Interferon Interferon-1b by InterMune.

The combination therapy of HCV with ribavirin and interferon a actually represent the optimal therapy. The combination of ribavirin and PEG-IFN (infra) results in a sustained viral response in 54-56% of patients. The SVR approaches 80% for the type of HCV 2 and 3. (Walter, supra). Unfortunately, the combination also produces side effects which have clinical challenges. Depression, flu symptoms and skin reactions are related to subcutaneous IFN-a, and hemolytic anemia is related to ribavirin-supported treatment. Other macromolecular compounds currently in pre-clinical or clinical development for the treatment of hepatitis C virus infection include: Interleukin-10 by Schering-Plow, IP-SOl by Intemeuron, Merimebodib (VX-497) by Vertex, HEPTAZYME® by RPI, IDN-6556 by Idun Pharma., XTL-002 by XTL. , HCV / MFS9 by Chiron, CIVACIR® (Hepatitis C Immune Globulin) by NABI, ZADAXIN® (thymosin a-1) by SciClone, thymosin plus pegylated interferon by SciClone, CEPLENE®; a therapeutic vaccine directed to E2 by Innogenetics, therapeutic vaccine by Intercell, therapeutic vaccine by Epimmune / Genencor, a therapeutic vaccine by Merix, a therapeutic vaccine, Chron-VacC, by Tripep. Other macromolecular approaches include ribozymes directed to HCV RNA. Ribozymes are short molecules that occur naturally with endonuclease activity that catalyzes the specific cleavage of the RNA sequence. An alternative approach is the use of oligonucleotide binding antisensitive to RNA and stimulate the mediated unfolding of RNaseH. Currently, a number of potential molecular targets have been identified for the development of drugs as anti-HCV therapeutics including, but not limited to, NS2-NS3 autoprotease, N3 protease, N3 helicase and NS5B polymerase. RNA-dependent RNA polymerase is absolutely essential for the replication of the single-stranded, positive-sense RNA genome, and this enzyme has aroused significant interest among medicinal chemists. The NS5B polymerase nucleoside inhibitors can act, either as a non-natural substrate resulting in chain termination or as a comparative inhibitor which competes with the binding of nucleotides to the polymerase. To function as a chain terminator, the nucleoside analog must begin to be the cell and be converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to triphosphate is mediated, usually, by cellular kinases which impart structural requirements in a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direction of the evaluation of nucleosides as inhibitors of HCV replication to cell-based tests capable of in situ phosphorylation.

B = adenine, thymidine, uracil, cytidine, guanine and hypoxanthine In WO 01 90121 published on November 29, 2001, J.-P. Sommadossi and P.Lacolla describe and exemplify the activity of anti-HCV polymerase 1'-alkyl - and 2'-alkyl nucleosides of formulas 2 and 3. In WO 01/92282, published on December 6, 2001, J.-P. Sommadossi and P.Lacolla describe and exemplify the treatment of Flaviviruses and Pestiviruses with 1 ' -alkyl- and 2'-nucleoside alkyl of the formulas 2 and 3. In WO 03/026675 published on April 3, 2003, G. Gosselin describes 4'-alkyl-4-nucleosides to treat Flaviviruses and Pestiviruses. In WO 2004003000 published on January 8, 2004, J.-P. Sommadossi et al. describes prodrugs 2'- and 3 'of 1 '-, 2' -, 3'- and 4'- which replace the ß-D and ß-L nucleosides. In WO 2004/002422 published on January 8, 2004, 2'-C-methyl-3'-O-cytidine ribofuransyl valine ester for the treatment of Flaviviridae infections. Idenix has reported clinical trials for a related NM283 compound, which is believed to be valine 5 ester of cytidine analog 2 (B = cytosine). In WO 2004/002999 published on January 8, 2004, J.-P. Sommadossi et al. describes a series of prodrugs 2? 3 'of 1', 2 ', 3', or 4 'branched nucleosides for the treatment of flavivirus infections including HCV infections. In WO2004 / 046331 published June 3, 2004, J. -P. Sommadossi et al. describes branched 2 'nucleosides and the Flaviviridae mutation. In WO03 / 026589 published on April 3, 2003 G. Gosselin et al. describes methods for the treatment of hepatitis C virus using 4 'modified nucleosides. In WO2005009418 published February 3, 2005, R.Storer et al. describes the purine nucleoside analogs for the treatment of diseases caused by Flaviviridae including HCV. Other patent applications describe the use of certain nucleoside analogs to treat hepatitis C virus infection. In WO 01/32153 published May 10, 2001, R.Storer describes the nucleoside derivatives for treating viral diseases. In published WO 01/60315 on August 23, 2001, H. Ismaili et al., describes the methods of treatment or prevention of Flavivirus infections with nucleoside compounds. In WO 02/18404 published on March 7, 2002, R. Devos et al. describes 4'-substituted nucleotides to treat the HCV virus. In WO 01/79246 published October 25, 2001, K.A.Watanabe discloses 2'- or 3'- hydroxymethyl nucleoside compounds for the treatment of viral diseases. In WO 02/32920 published on April 25, 2002 and in WO 02/48 165 published on June 20, 2002 L.Stuyver et al. describes the nucleoside compounds for the treatment of viral diseases. 6a Wn WO 03/105770 published December 24, 2003, B. Bhat et al. describes a series of carbocyclic nucleoside derivatives that are useful for the treatment of HCV infections. In WO 2004/007512 published on January 22, 2003 B. Bhat et al. describes nucleoside compounds that inhibit viral RNA polymerase dependent on RNA. The nucleosides described in this publication is mainly substituted 2'-methyl-2'-hydroxy nucleosides. In WO 2002/057425 published July 25, 2002 S.S.Carroll et al. describes the nucleoside derivatives which are RNA-dependent viral polymerase inhibitors and methods for treating HCV infection. In WO02 / 057287 published July 25, 2002, S.S.Carroll et al. describes the related 2a-methyl and 2β-methyltybibos derivatives wherein the base is a 6-radical of 7H-pyrrolo [2,3-d] pyrimidine optionally substituted. The same application describes an example of a nucleoside 2 > ß-methyl. S.S.Carroll et al. (J. Biol. Chem. 2003 278 (14): 11979-11984) describes the inhibition of HCV polymerase by 2 '-O-methylcytidine (6a). In WO2004 / 009020 published on January 29, 2004, D.B.Olsen et al. describes a series of thionucleoside derivatives as viral RNA polymerase inhibitors of RNA. PCT Publication Number W099 / 43691 for Emory University, entitled "2'-Fluoronucleosides" describes the use of certain 2'-fluoronucleosides to treat HCV. U.S. Patent Number 6,348,587 to Emory University entitled "2'-fluoronucleosides" describes a family of 2'-Fluoronucleosides useful for the treatment of hepatitis B, HCV, HIV and abnormal cell proliferation. Both configurations of the 2'-fluoro substituent are described.

Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, Sixteenth International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.)) Described the relationship of the structural activity of modified 2'-nucleosides for HCV inhibition . Bath et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, Sixteenth International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.); P A75) describes the synthesis and pharmacokinetic properties of nucleoside analogues as possible inhibitors of HCV RNA replication. The authors report that the 2'-modified nucleosides demonstrate potent inhibitory activity in cell-based replication assays. Olsen et al. (Oral Session V, Hepatitis Virus C, Flaviviridae; Sixteenth International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) P A76) also described the effects of modified 2'-nucleosides on the replication of HCV RNA. Non-nucleoside reverse transcriptase inhibitors of HIV reverse transcriptase have proven effective therapeutics alone and in combination with inhibitors of nucleosides and with protease inhibitors. Various classes of NS5B HCV inhibitors without nucleosides have been described and are currently in various stages of development including: benzimidazoles, (H. Hashimoto et al., WO 01/47833, H. Hashimoto et al., WO 03/000254, PL Baulieu et al., WO 03/020240 A2; PL Baulieu et al., US 6,448,281 Bl; PLBeaulieu et al. WO 03/007945 Al); idols, (P.L. Beaulieu et al., WO 03/0010141 A2); benzothiadiazines, for example, 7, (D.Dhanak et al., WO 01/85172 Al; D.Dhanak et al., WO 03/037262 A2; KJDuffy et al., WO03 / 099801 Al, D. Chai et al., WO 2004052312 , D.Chai et al., WO2004052313, D.Chai et al., WO02 / 098424, JKPratt et al., WO 2004/041818 Al; JKPratt et al., WO 2004/087577 Al), thiophenes, for example, 8, ( CKChan et al. WO 02/100851); X benzothiophenes (D.C.Young and T.R.Bailey WO 00/18231); ß-ketopiruvates (S.Attamura et al., US 6,492,423 Bl, A.Attamura et al., WO 00/06529); pyrimidines (C. Gardelli et al WO 02/06246 Al); pyrimidinediones (T.R.Bailey and D.C.Young WO 00/13708); triazines (K.-H. Chung et al. WO 02/079187 Al); Rhodanin derivatives (T.R.Bailey and D.C.Young WO 00/10573, J.C.Jean et al., WO 01/77091 A2); 2, 4-dioxypyrans (R.A.Love et al., EP 256628 A2); Phenylalanine derivatives (M. Wang et al. al.J.Biol.Chem. 2003 278: 2489-2495). The NS3 protease has emerged as a primary target for the discovery of a new anti-HCV therapy. In WO 98/22496 published May 28, 1998. M.R.Attwood et al. has described inhibitors in active site based on protease mechanisms (MRAttwood et al., Antiviral Chemistry and Chemotherapy 1999 10: 259-273; MRAttwood et al., Preparation and use of amino acid derivatives as anti-viral agents. , German Patent Publication DE 19914474). In W098 / 17679 published April 30, 1998, R.D.Tung et al. described the inhibitors of peptides based on mechanisms on the NS3 protease. In WO99 / 07734 published February 18, 1999 and in WO00 / 09543 published August 9, 1999, M Llinas-Brunet et al. describes the inhibitors of protease peptides. In WO00 / 59929 published October 12, 2000, Y. S. Tsantrizos et al. describes the macrocyclic tripeptides which are potent inhibitors of the HCV NS3 protease. A series of patents related to Boehringer-Ingleheim describe the related protease inhibitors and have led to the identification of the BILN 2061 tripeptide derivatives (M. Llinas-Brunet et al., Biorg.Med.Chem.Lett.2000 10 (20) : 2267-70; J.Med Chem.2004 47 (26): 6584-94; J.Med Chem.2004 47 (7): 1605-1608; Angew.Chem. Int. Ed. Eng.2003 42 (12 ): 1356-60).

Other inhibitors of tripeptides identified by Bristol-Myers Squibb have been described, inter alia, in WO03 / 099274 published on December 4, 2003, in WO2004 / 032827 published on April 22, 2004, in WO03 / 053349 published July 3. , 2003, in WO2005 / 046712 published on May 26, 2005 and in WO2005 / 051410 published on June 9, 2005. In O2004 / 072234 published on August 26, 2004 and in WO2004 / 093798 published on November 4, 2004 the additional tripeptide protease inhibitors were described by Enanta Pharmaceuticals. In WO2005 / 037214 published on April 28, 2005 L.M.Blatt et al. describes still other peptide derivatives that inhibit the NS3 protease of HCV. In WO2005 / 030796 published on April 7, 2005, S. Venkatraman et al. describes the macrocyclic inhibitors of the serine protease NS3 of HCV. In O 2005/058821 published on June 30, 2005, F.Velazquez et al. describes inhibitors of serine protease NS3 / NS4a of HCV. In WO02 / 48172 published June 20, 2002, Z. Zhu describes the diaryl peptides as NS3 protease inhibitors. In WO02 / 08187 and in WO02 / 08256 both published on January 31, 2002, A.Saksena et al. describes peptide inhibitors of HCV NS3 protease. In WO02 / 08251 published January 31, 2002 M.Lim-Wilby et al. describes the inhibitors of NS3 protease peptides. In US 6,004,933 published on December 21, 1999, L.W.Spruce et al. describes the derivatives of heterocyclic peptides which inhibit cysteine proteases including the HCV endopeptidase. NS3 protease inhibitors based on non-substrates such as 2, 4, 6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., BBRC 1997 238: 643-647; Sudo K. et al.) Antiviral Chemistry and Chemotherapy 1998 9: 186), which include RD3-4082 and RD3-4078, the former substituted on the amide with a carbon 14 chain and the latter processing a para-phenoxyphenyl group is also being investigated. SCH 68631, a phenanthrenequinone, is a protease inhibitor of HCV (Chu M. et al, Tetrahedron Lett, 1996 37: 7229-7232). In another example by the same authors, SCH 351633, isolated from the fungi Penicillium gríseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorg, Med Chem. Lett, 1999 9: 1949-1952). The nanomolar potency against the NS3 HCV protease enzyme has been achieved through the design of selective inhibitors based on the macromolecule eglin c. Eglin c, isolated from leeches, is a potent inhibitor of various serine proteases such as the proteases S.griseus A and B, α-chymotrypsin, chymase, subtisilin (Qasim, A. et al., Biochemestry 1997 36: 1598-1607 ).

The thiazolidine derivatives, which show relevant inhibition in a reverse-phase HPLC test with an NS3 / 4A fusion protein and NS5A / 5B substrate (Sudo K. et al., Antiviral Research 1996 32: 9-18), compounds in particular of RD-1-6250, which possess a portion of fused cinnamoyl substituted with a long chain of alkyl, RD4 6205 and RD4 6193. The thiazolidines and benzanilides were identified by N.Kakiuchi et al. in FEBS Let. 1998 421: 217-220 and N. Takeshita et al. Anal Biochem. 1997 247: 242-246. Imidazolidinones as inhibitors of HCV serine NS3 protease are described in WO 02/08198 for Schering Corporation published January 31, 2002 and in WO 02/48157 for Bristol ayers Squibb published on June 20, 2002. In WO02 / 48116 published on June 20, 2002 P. Glunz et al. describes the pyrimidinone inhibitors of NS3 protease. Other enzymatic targets for anti-HCV include the IRES site of HCV (Internal Ribosome Entry Site) and the HCV helicase. The IRES inhibitors have been registered by Immusol, Rigel Pharmaceuticals (R803) and by Anadys (ANA245 and ANA246). Vértex has described a helicase inhibitor of HCV. Combination therapy, which can suppress resistant mutant deformations, has become a well-established approach to antiviral chemotherapy. The nucleoside inhibitors described herein can be combined with other nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, and HCV protease inhibitors. Like other classes of HCV drugs, for example, inhibitors of viral entry, helicase inhibitors, IRES inhibitors, ribozymes and antisensing oligonucleotides that arise and are developed will also be excellent candidates for combination therapy. The interferon derivatives have already been successfully combined with ribavirin and interferons, and the chemically modified interferons will be useful in combination with the nucleosides described herein. Nucleoside derivatives are frequently potent anti-virals (e.g., HIV, HCV, Herpes simplex, CMV) and anti-cancer chemotherapeutic agents. Unfortunately, its practical usefulness is usually limited by two factors. First, deficient pharmacokinetic properties limit the absorption of the nucleoside from the digestive tract and the intracellular concentration of the nucleoside derivatives and, secondly, the sub-optimal physical properties restrict the formulation options which can be used to facilitate the release of the active ingredient.

Albert introduced the term prodrug to describe a compound that lacks intrinsic biological activity; however, it is capable of metabolic transformation to the substance of the active drug (A. Albert, Selective Toxicity, Chapman and Hall, London, 1951). Prodrugs have recently been reviewed (P.Ettmayer et al., J.Med.Chem.2004 47 (10): 2393-2 04; K.Beaumont et al., Curr. Drug Metab. 2003 4: 461-485; .Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and che entities in Design of Prodrugs, H.Bundgaard (ed) Elsevier Science Publishers, Amsterdam 1985, GMPauletti et al., Adv. DrugDeliv, Rev. 1997 27: 235 -256; RJ Jones and N. Bischofberger, Antiviral Res. 1995 27; 1-15 and CR agner et al., Med.Res. Rev. 2000 20: 417-45). While the metabolic transformation can be catalyzed by specific enzymes, usually hydrolases, the active compound can also be regenerated by non-specific chemical processes. The pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form the compound of the present invention. Bio-conversion should avoid fragments of formation with toxicological risks. Common examples of prodrugs include compounds that have been biologically labile that protect groups bound to a functional portion of the active compound. The alkylation, acylation or other lipophilic modification of the hydroxy group (s) in the sugar portion has been used in the design of pronucleotides. The pronucleotides can be hydrolyzed or dealkylated in vivo to generate the active compound. The factors that limit oral bioavailability are often absorbed from the gastrointestinal tract and first-pass excretion through the wall of the digestive tract and the liver. The optimization of transcellular absorption through the GI tract requires a D (7.4) greater than zero. The optimization of the distribution coefficient; however, it does not ensure success. The prodrug may have to avoid transporters of active discharge into the enterocyte. The intracellular metabolism in the enterocyte can result in passive transport or active transport of the metabolite by means of the discharge pumps in the passage of the digestive system. The prodrug must also be able to resist undesirable bio-transformations in the blood before reaching target cells or receptors. While putative prodrugs can sometimes, rationally, be designed based on the chemical functionality present in the molecule, the chemical modification of an active compound produces a a completely new molecular entity which can exhibit undesirable physical, chemical and biological properties absent in the generating compound. The regulatory requirements for the identification of metabolites may have challenges in case multiple pathways lead to a plurality of metabolites. In this way, the identification of prodrugs remains a challenging and uncertain exercise. In addition, the evaluation of the pharmacokinetic properties of potential prodrugs is an expensive and challenging effort. The pharmacokinetic results of animal models can be difficult to extrapolarize to humans.

SUMMARY OF THE INVENTION The object of the present invention is to provide new compounds, methods and compositions for the treatment of a host infected with the hepatitis C virus. The present invention is directed to the novel di-acyl derivatives of 4-amino-1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -lH-pyrimidine-2-one (also referred to as (2R 2'-deoxy-2-methyl-2-fluoro-cytidine). The compounds of the present invention possess a structure according to formula I. wherein: R1 is selected from the group consisting of branched or unbranched alkyl C2-5, branched or unbranched alkenyl C2-5, branched or unbranched alkynyl C2-5, lower haloalkyl C2-5, cycloalkyl C3- 6, and C2-4 alkoxy; e, hydrates, solvates and acid addition salts thereof. The compounds of the present invention are useful for the treatment of a disorder mediated by HCV. The invention further comprises methods for the treatment of HCV with compounds of the present invention and pharmaceutical compositions containing said compounds. In one embodiment of the present invention, there is provided a compound according to formula I wherein R 1 is as defined herein above. In another embodiment of the present invention, there is provided a compound according to formula I wherein R 1 is ethyl, r-propyl, iso-propyl, n-butyl or iso- Butyl In still another embodiment of the present invention, there is provided a compound according to formula I wherein R 1 is ethyl or iso-propyl. In still another embodiment of the present invention, there is provided a compound according to formula I wherein R 1 is iso-propyl and the compound is a hydrochloride or sulfate salt. In a further embodiment of the present invention, there is provided a compound according to formula I wherein R 1 is iso-propyl and the compound is a hydrochloride salt. In yet another embodiment of the present invention, a compound according to formula I is provided wherein R 1 is ethoxy, n-propoxy or iso-propoxy. In yet a further embodiment of the present invention, there is provided a compound according to formula I for use in therapy, in particular, for use in the therapy of a disease mediated by the HCV virus. In still another embodiment of the present invention, there is provided the use of a compound according to formula I for the preparation of a medicament for the treatment of a disease mediated by the HCV virus.

DETAILED DESCRIPTION OF THE INVENTION A compound according to formula I can, in particular, be used for the preparation of a medicament for administration to a patient in need thereof in an effective dose in a therapeutic manner, preferably in a dose of 0.1 to 10g per day, more preferably in a dose of 0.5 to 7g per day and, even more preferably, in a dose of 1.Og to 6.0g per day. A compound according to formula I can further be used for the preparation of a medicament which may further comprise an therapeutically effective amount or at least one modulator of the immune system such as an interferon, a chemically derivatized interferon, an interleukin , a tumor necrosis factor or a colony stimulation factor and / or at least one antiviral agent that inhibits the replication of HCV, such as a protease inhibitor of HCV, another inhibitor of nucleoside HCV polymerase, an inhibitor of HCV polymerase without nucleoside, a helicase inhibitor of HCV, a primase inhibitor of HCV or an inhibitor of fusion of HCV. In still another embodiment of the present invention, there is provided a method for treating a disease mediated by the HCV virus comprising the administration to a patient in need thereof, an effective dose, in a therapeutic manner, of a compound according to formula I as defined above. In still another embodiment of the present invention, there is provided a method for treating a disease mediated by the HCV virus comprising administering to a patient in need thereof a dose of 0.1 to 10Og per day of a compound according to formula I as It was defined earlier. In yet another modality, the dose between 0.5 and 7g per day and in an additional modality the dose is between 1.0 and 6.0g per day. In another embodiment of the present invention, there is provided a method for treating a disease mediated by the HCV virus comprising the co-administration to a patient in need thereof, an effective dose, therapeutically, of a compound according to the formula I as defined above and a therapeutically effective amount of at least one immune system modulator and / or at least one antiviral agent that inhibits HCV replication. In another embodiment of the present invention there is provided a method for treating an HCV-mediated disease comprising co-administration to a patient in need thereof, an effective dose, Therapeutically, a compound according to formula I as defined above and a therapeutically effective amount of at least one modulator of the immune system which is an interferon, interleukin, tumor necrosis factor or colony stimulation factor. . In another embodiment of the present invention, there is provided a method for treating an HCV mediated disease comprising the co-administration to a patient in need thereof, an effective dose, therapeutically, of a compound according to formula I as defined above and a therapeutically effective amount of at least one modulator of the immune system which is an interferon or a chemically derivatized interferon. In another embodiment of the present invention, there is provided a method for treating an HCV mediated disease comprising the co-administration to a patient in need thereof, an effective dose, therapeutically, of a compound according to formula I as defined above and an at least one therapeutic effective amount of another antiviral compound. In another embodiment of the present invention, there is provided a method for treating an HCV mediated disease comprising co-administration to a patient in need thereof, an effective dose, therapeutic, of a compound according to formula I as defined above and an effective amount, therapeutically, at least one other antiviral compound which is a protease inhibitor of HCV, another inhibitor of nucleoside HCV polymerase, a nucleoside inhibitor of HCV polymerase, a helicase inhibitor of HCV, an inhibitor of HCV primase or a fusion inhibitor of HCV. In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound according to formula I as defined above mixed with at least one pharmaceutically acceptable carrier, diluent or excipient. In another embodiment of the present invention, there is provided a process for the preparation of a compound according to formula I as defined above, the process comprises steps (i) - (v) listed in claim 15 and represented in examples The process comprises treatment I in a basic aqueous organic medium which may be homogeneous or biphasic with an acylated agent as defined herein in the presence of D-PA and sufficient base to preserve the solution at a pH at least approximately of 7.5. The present process allows acylation without the concomitant reaction of the heterocyclic base.

The phrase "an" or "an" entity as used herein refers to one or more of said entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" may be used interchangeably in this document. The terms "optional" or "optionally" as used herein, mean that an event or circumstance described subsequently; however, it may need not to occur, and that the description includes, examples where the event or circumstance occurs and examples where it does not. For example, "optional link" means that the link may or may not be present, and that the description includes single, double or triple links. The term "independently" is used here to indicate that a variable is applied in any instance without counting the presence or absence of a variable that has the same or different definition within the same compound. In this way, in a compound in which R appears twice and is defined as "carbon or nitrogen independently", both R's can be carbon, both R's can be nitrogen, or one R 'can be carbon and the other R's can be 'nitrogen. The term "alkenyl", as used herein, denotes a chain radical of unsubstituted hydrocarbon having from 2 to 10 carbon atoms having one or two olefinic double bonds [preferably a double olefinic bond]. "C2-10 alkenyl", as used herein, refers to an alkenyl compound of 2 to 10 carbons. Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl). The term "alkyl" as used herein denotes a branched or unbranched chain, a saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" denotes a branched or straight chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-10 alkyl" as used herein refers to an alkyl compound of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, p-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl. The term (ar) alkyl or (heteroaryl) alkyl indicates that the alkyl group is optionally substituted by an aryl or a heteroaryl group, respectively. The term "alkynyl", as used herein, denotes a branched or unbranched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one bond triple. "C2-10 alkynyl", as used herein, refers to an alkynyl compound of 2 to 10 carbons. Examples are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 2-butynyl or 3-butynyl. The term "cycloalkyl", as used herein, denotes a saturated carbocyclic ring containing 3 to 8 carbon atoms, ie, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7 cycloalkyl," as used herein, refers to a cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring. The term "haloalkyl", as used herein, denotes a branched or unbranched chain alkyl group as defined above wherein 1,2,3 or more hydrogen atoms are replaced by a halogen. "C1-3 haloalkyl", as used herein, refers to a haloalkyl composed of 1 to 3 carbons and 1 to 8 halogen substituents. Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2- chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl. The term "alkoxy", as used herein, means an O-alkyl group, wherein the alkyl is as defined above. Examples are methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy. The "lower alkoxy," as used herein, denotes an alkoxy group with a "lower alkyl" group as previously defined. "Ci-io alkoxy" refers to a 0-alkyl wherein alkyl is Ci-io. The term "di-acyl" derivative, as used herein, refers to a derivatized nucleoside compound, as herein described, wherein the 3'- and 5'-hydroxy are of an OC-ester ( = 0) R1 and 0C (= 0) R2 wherein R1 and R2 are as defined in claim 1. The term "acylated agent", as used herein, refers to either an anhydride, halide, chlorocarbonylalcoxide ( for example, ethyl chloroformate) or an activated derivative of a protected alpha amino acid N. The term "anhydride", as used herein, refers to the compounds of the general structure R1C (0) -0-C ( 0) R1 wherein R1 is as defined in claim 1. The term "halide acid", as used herein, refers to compounds of the general structure R1C (0) X wherein X is a halogen. The term "imidazole acyl" refers to a compound of general structure R1C (0) X wherein X is N-imidazolyl. The term "activated derivative" of a compound, as used in the present document, refers to a transient reagent form of the parent compound, which presents the active compound in a desired chemical reaction, in which the parent compound is only, in a moderate way, a reactant or non-reactive. The activation is achieved by the formation of a derivative or a chemical that is grouped within the molecule with a higher free energy content than the original compound, which has the activated form more susceptible to react with another reagent. In the context of the present invention, it is described, in more detail below, the activation of the carboxy group is of particular importance and corresponds to the activation agents or groupings that activate the carboxy group. The carboxylic acid and the carboxylic acid chlorides are of particular interest for the present invention. The phrase "heterogeneous aqueous solvent mixture", as used herein, refers to a mixture of water and an organic co-solvent which produces a phase two or heterogeneous mixture. This heterogeneous aqueous solvent mixture can result from a co-solvent with limited aqueous solubility or the ionic strength of the aqueous component can be adjusted to limit the solubility of the co-solvent in the aqueous phase. The term "alkyl metal hydroxide" is refers to a compound of formula MOH wherein M is lithium, potassium or cesium sodium, "alkyl metal bicarbonate" refers to a group HC03 wherein M is sodium or potassium and "alkyl metal carbonate" refers to a group M2CO3 where M is sodium or potassium. One skilled in the art will appreciate that other bases can be used to preserve the pH with the desired range and other bases are within the scope of the invention. Abbreviations used in this application include: acetyl (Ac), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), atmospheres (Atm), high pressure liquid chromatography (HPLC), methyl (Me), tert- butoxycarbonyl (Boc), acetonitrile (MeCN), pyrocarbonate or boc di-tert-butyl anhydride (BOC2O), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), benzyl (Bn), butyl (Bu), methanol (MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), diimidazole carbonyl (CDI), MeS02- (mesyl or Ms), 1,4-diazabicyclo [2.2.2] octane (DABCO), spectrum mass (ms), methyl butyl ether (MTBE), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) ), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), 1/2-dichloroethane (DCE), N, N '-dicyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC), dichloromethane (DCM), propyl (Pr ), kg / cm2, diisopropylethylamine (DIPEA, Hunig's Base), pyridine (pyr), room temperature, rt or RT, N, N-dimethyl acetamide (DMA), tert-butyldimethylsilyl or t-BuMe2Si, (TBDMS), 4-N, N-dimethylaminopyridine (DMAP), triethylamine ( Et3N or TEA), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), trifluoroacetic acid (TFA), thin layer chromatography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF), diethyl ether (Et20) ), trimethylsilyl or Me3Si (TMS), ethyl (Et), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4S02- or tosyl (Ts), iso-propyl (i-Pr), N-urethane -N-carboxyanhydride (UNCA), ethanol (EtOH). The conventional nomenclature that includes the normal (n), iso (i-), secondary (sec-), tertiary (tert-), and neo prefixes have their usual meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.). Examples of representative compounds encompassed by the present invention and within the scope of the invention are provided in TABLE 1. These examples and following preparations are provided to enable those skilled in the art to have a clearer understanding and practice of the art. present invention. These should not be considered as limiting the scope of the invention; however, as merely illustrative and representative of these.

In general, the nomenclature used in this Application is based on AUTONO ™ v.40, a Beilstein Institute computer system for the generation of the IUPAC systematic nomenclature. In case there is a discrepancy between the structure represented and a name given to the structure, the structure represented must be in accordance with a greater weight. In addition, in case the stereochemistry of a structure or a portion of a structure is not indicated, for example, with bold or dotted lines, the structure or portion of the structure will be interpreted as encompassing all the stereoisomers thereof. The numbering system for these ring systems is as follows: COMPOUNDS AND PREPARATION The HCV polymerase inhibitory activity of (2R) -2 '-deoxi-2' -fluoro-2 '-C- has been described methylcytidine (J.L. Clark et al., J. Med. Chem. 2005 48 (17): 5504-8; J. Clark, U.S. Publication Number 2005/0009737 and both publications are hereby incorporated by reference in their entirety). In clinical practice, it would be convenient to administer, initially, high doses of 1-6 to rapidly inhibit the HCV polymerase and, therefore, decrease viral levels under conditions that minimize the opportunity for the virus to mutate and to select the resistant deformations. Sufficiently high levels can be difficult to achieve with the nucleoside generator. Prodrugs provide a strategy for improving the pharmacokinetic and physical properties of a compound and; therefore, they optimize bio-availability. US Publication 2005/0009737 suggests the general approaches for the prodrugs of 2'-deoxy-2'-fluoro-2'-methyl nucleoside nucleosides. While pro-drug candidates are simple, in a deceptive way, to predict, the identification of compounds with the appropriate physicochemical and pharmacodynamic properties, in vivo transformations and safety profile is a complex multidisciplinary commitment that requires significant experimentation. Overcoming the obstacles for the identification of prodrugs for oral delivery includes retaining sufficient aqueous solubility, stability chemistry and lipophilicity at the same time that allows the rapid and efficient release of the subsequent administration of the active portion. Additionally, the metabolism of non-esterase and the free passage mediated by the prodrug transporter should be minimized (K.Beaumont et al., Curr. Drug.Metab.2003 4 (6): 461-485). Also, inhibition or induction of cytochrome P450 enzymes can produce unfavorable drug-drug interactions that are inconvenient. The lower alkyl diesters of 1-6 represented in TABLE 1 have been found, surprisingly, to significantly improve the bioavailability of 1-6. The pharmacokinetic behavior of potential prodrugs was evaluated in both rats and monkeys to try to minimize the variability of intra-species and genetic polymorphisms which can result in intra-species artifacts. To the extent that the enzymatic transformations are responsible for the hydrolysis of the ester linkages, the specific affinity for the prodrugs may depend on the specific structure of the esterase and / or peptidase which could catalyze the transformation. It has been shown, frequently, that esterase activity in rats is significantly greater than that of man (J.A.Fix et al., Pharm.Res.1990 7 (4): 384-387; W.Li et al. al.Antimicrob.AgentsChemotherl998 42 (3): 647-653). Another potentially important parameter was the bioconversion of the cytidine base to uridine by a deaminase. Although the cytidine and uridine triphosphates are polymerase inhibitors, the in vivo phosphorylation of uridine is inefficient compared to cytidine. In this way, increased uridine levels are considered inconvenient. The lack of efficacy exhibited by the uridine derivative in the HCV replicon has been reported (J. Clark et al., J. Med. Chem., Supra). 1. -Cmax is the peak concentration of 1-7 in the blood. 2. -AUC (cyt) is the area under the curve for the cytidine nucleoside. AUC (urd) is the area under the curve for the uridine nucleoside. 3. -EC90 in the replicon is 5.40 + 2.6 μ (J. Clark et al., J. Med. Chem., Supra) Surprisingly, it has been found that C 2-5 alkyl diesters of 1-6 exhibit excellent prodrug properties. Substantially, the highest levels of the fluorinated nucleoside are observed in the blood in both the rat and the monkey. In addition, the ratio of cytidine to uridine in the fluorinated base is greater in both species when the nucleoside was administered as the diester. In addition, the diesters are capable of forming two different monosters and the non-esterified nucleoside. The pharmacokinetic analysis in this situation can be complex in case all the species are present in blood in significant concentrations. The presence of multiple metabolites in the blood adds additional burdens to establish that the prodrug is safe. Surprisingly, the hydrolysis of both esters is very easy and the only significant metabolite observed in the blood in addition to the nucleoside generator is the 3'-monoster which is rapidly converted to 1-6. To further evaluate the potential behavior in human subjects, transport through Caco-2 cells was evaluated for putative prodrugs. Caco-2 cells are usually used to evaluate the absorption / permeability of the molecules' potential (G. Gaviraghi et al., In Pharmacokinetic optimization in drug research, Bilogical, Pharmacokinetic and Computational Strategies, B. Testa et al. eds, Wiley Interscience VCH, Zurich 2001 pp 3-14). The permeability Caco-2 was found to be acceptable for C2-5 alkyl diesters of 1-6. In addition to efficient biotransformation in vivo a prodrug for oral administration must also exhibit adequate physicochemical properties to formulate the drug and ensure absorption of the digestive system in a compartment where the desired biotrans formation can occur. The solubility in water, the partition coefficient and the stability in gastric and intestinal fluids are particularly relevant. The values for these parameters are shown in TABLE 2. 1. - Octanol calculated / water partition coefficient 2. - Distribution coefficient determined experimentally in pH 7.4 3. - Solubility in aqueous medium, water or pH 6.5 of regulator (mg / mL). 4. - Stability in simulated gastric fluid (SGF, pH 1.2) . - Stability in simulated intestinal fluid (SIF, pH 7.4) 6.- Solubility in SGF is 13.3 mg / mL 7. - Not determined 8. - The medium is SIF, the solubility in SGF is 13.6 mg / mL 9. - The medium is SIF, the solubility in SGF is 0.16 mg / mL . - Measured in water and pH regulator 6 11.- Diminished degradation observed in a period of 12.- Determined in pH 5.5 The oil / water partition coefficient Po / w (clogP is Po / w calculated) is an important property for oral administration drugs. The substance of the drug must have sufficient aqueous solubility to dissolve in the formulation and in the gastrointestinal fluids (GI) to contact the endothelial cells in the stomach and intestine and the sufficient solubility of lipids to travel the path through the membrane of bi -layer of lipids of these cells and finally in the blood. The optimum range for the P-record of a compound for oral bioavailability is between 1 and 3 which is exhibited by compounds of the present invention. The term Po / w, as used herein, refers to the partition coefficient of octanol / water. The term clogP, as used herein, refers to calculated Po / w. Computer programs that calculate Po / w are readily available to the pharmaceutical and medicinal chemist. The term distribution coefficient refers to the partition coefficient determined experimentally between octanol and the regulated aqueous solution. The partition coefficient and the distribution coefficient are, in general, similar; however, the latter is a function of the pH of the aqueous solution where the Po / "is independent of the pH. The solubility in water of a prodrug administered orally should be greater than at least about 0.1 mg / mL for the optimal formulation and the half-lives in the simulated gastric fluid and the simulated intestinal fluid should be l-2h and 2- 4h, respectively, to allow enough time to travel the stomach and be absorbed in the intestine. The compounds of the present invention are conveniently prepared in one step by the acylation of 1-6 in an aqueous organic solvent. The solvent may be a homogeneous aqueous solution or a two-phase solution. The pH of the aqueous organic solvent is conserved above 7.5 when the base is added to neutralize the acid produced by the acylation. The base can be an alkali or alkali metal hydroxide or a tertiary amine. The reaction is carried out in the presence of D AP which is known in the art to be a catalyst for acylation. An advantage of the present process in the desired product can be obtained without the acylation of the heterocyclic base. The protection group that eliminates the need for a protection / deprotection step is not required. The process in the attached examples.

DOSAGE AND ADMINISTRATION The compounds of the present invention can be formulated in a wide variety of carriers and oral administration doses. Oral administration can be in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered in suppositories, among other routes of administration. The most convenient form of administration is usually oral using a convenient daily dose regimen which can be adjusted according to the severity of the disease and the patient's response to antiviral medication. A compound or compounds of the present invention, as well as their pharmaceutically usable salts, together with one or more conventional excipients, carriers or diluents, may be placed in the form of pharmaceutical compositions and unit doses. The pharmaceutical compositions and dosage unit forms may comprise conventional ingredients in conventional proportions, with or without additional active compounds, and the dosage unit forms may contain any suitable effective amount of the active ingredient. in proportion to the intended daily dose range to be used. The pharmaceutical compositions can be used as solids, such as filled tablets or capsules, semi-solids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration. A common preparation will contain about 5% to about 95% active compound (s) (w / w). The term "preparation" or "dosage forms" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters. The term "excipient", as used herein, refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and not biologically inconvenient, and includes excipients that are acceptable for veterinary use as well as use human pharmacist The compounds of this invention can be administered alone; however, they will usually be administered mixed with one or more suitable pharmaceutical excipients, diluents or carriers selected with respect to the route of administration that is intended and standard pharmaceutical practice. A "pharmaceutically acceptable salt" form of an active ingredient may also treat a desirable pharmacokinetic property in the active ingredient which was absent in the salt-free form, and may also positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound, as used herein, means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the generating compound. Said salts include: (1) acid addition salts formed with organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3- (-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, acid methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naptalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid lauryl, gluconic acid, glutamic acid, salicylic acid, muconic acid and Similar. It should be understood that all references for pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same acid addition salt. Solid form preparations include powders, tablets, pills, capsules, suppositories and dispersed granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is a mixture with the active component finely divided. In tablets, the active component is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax , cocoa butter, and the like. The solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubility agents and the like. Liquid formulations are also suitable for oral administration and include the liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. The emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or can contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous suspensions can be prepared by dispersing the active component finely divided in water with viscous material, such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other well-known suspending agents. The compounds of the present invention can be formulated for administration as suppositories. A low melting wax, such as a mixture or glycerides of fatty acids or cocoa butter first melts and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into the molds of suitable size, they cool and solidify. The compounds of the present invention can be formulated for vaginal administration. Pessaries, stoppers, creams, gels, ointments, foams or sprays which contain in addition to the active ingredient said carriers known in the art as suitable. Suitable formulations together with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Artin, Mack Publishing Company, nineteenth edition, Easton, Pennsylvania. An expert formulator scientist can modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without offering the compositions of the present invention as unstable or compromised with their therapeutic activity. The modification of the present compounds to present them more soluble in water or another vehicle, for example, can be easily carried out by minor modifications (eg, salt formulation), which are well known to one skilled in the art. . It is also well known to one skilled in the art to modify the administration route and dosage regimen of a particular compound for manage the pharmacokinetics of the compounds present for the maximum benefit effect in patients. The term "pharmaceutically effective amount", as used herein, means an amount required to reduce the symptoms of the disease in an individual. The dose will be adjusted to the requirements of the individual in each particular case. The dose can vary within wide limits depending on the numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medications with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dose between about 0.1 and about 10Og per day should be suitable in monotherapy and / or combination therapy. A preferred daily dose is between about 0.5 and about 7.5g per day, more preferably 1.5 and about 6.0g per day. In general, the treatment starts with a large initial "loading dose" to reduce or eliminate the virus quickly, following a dose reduction at a sufficient level to prevent the resurgence of the infection. An expert in the treatment of diseases described here will be capable, with due experimentation and with the confidence of his personal knowledge and experience, and the descriptions of this application, find out a therapeutically effective amount of the compounds of the present invention for a disease and patient. Therapeutic efficacy can be ascertained from liver function tests including, but not limited to, protein levels such as whey proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotrans ferases). example, alanine transaminase, aspartate transaminase), 5 '-nucleosidase, and -glutaminyltranspeptidase, etc.), bilirubin synthesis, cholesterol synthesis and synthesis of bile acids; a metabolic function of the liver that includes, but is not limited to, carbohydrate metabolism, amino acid and ammonium metabolism. Alternatively, therapeutic efficacy can be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized. In embodiments of the invention, the active compound or a salt can be administered in combination with another antiviral agent such as ribavirin, another nucleoside HCV polymerase inhibitor, a non-nucleoside polymerase inhibitor of HCV, an inhibitor of HCV protease, an HCV helicase inhibitor or an HCV fusion inhibitor. When the active compound or its derivative or salt are administered in combination with another antiviral agent, the activity can be increased over the generating compound. When the treatment is combined with therapy, said administration may be concurrent or sequential with respect to that of the nucleoside derivatives. "Concurrent Administration", as used here, includes, in this way, the administration of the agents at the same time or at different times. The administration of two or more agents at the same time can be achieved by a simple formulation containing two or more active ingredients or by the simultaneous administration, substantially, of two or more dosage forms with a single active agent. It will be understood that the references of the present document for the treatment extend to the prophylaxis as well as to the treatment of the existing conditions. In addition, the term "treatment" of an HCV infection, as used herein, also includes the treatment or prophylaxis of a disease or condition related to or mediated by HCV infection, or the clinical symptoms thereof. Example 1 Propionic acid (2R, 3R, 4R, 5R) -5- (4-amino-2-oxo-2H-pyrimidine-1-yl) -4-fluoro-4-methyl-3-propionyloxy-tetrahydrofuran -2-ylmethyl ester (1-3).

For a suspension of 1-6 (30g, 0.116 mol), DMAP (1.4g, 11.57 mol) in THF (300mL) and water (150mL) was added TEA (35.lg, 0.347 mol) to obtain a clear solution (pH around 11). The reaction mixture was cooled to 5-10 ° C and propionic anhydride (30 μg, 0.231 mol) was added in drops to the stirred biphasic reaction. The pH was monitored and preserved at approximately 11-12 by the simultaneous addition of KOH solution. The progress of the reaction was monitored by HPLC analysis and after the propionyl chloride was added there were approximately 52% of the diester, 30% of monosters and 15% of the starting material. The additional propionic anhydride (45.2g, 0.347 mol) was added dropwise under the conditions described above. The reaction mixture remained overnight without agitation. HPLC of the organic phase indicated ca. 96% diester and ca. 2% monoster. The phases were separated and the aqueous phase was extracted twice with THF (100 mL). The combined organic phases were washed with brine. The organic phase is filtered, evaporated and the residue dissolved in water (ca. 500 mL) and then diluted with IPA (ca. 100 mL). The resulting mixture is cooled slowly to room temperature with stirring. The resulting precipitate was filtered, washed with water and heptane, dried at about 60 ° C in vacuum for ca. 60h to support 3.45g (80.3%) of 1-3 which was 98.75% pure by HPLC. Example 2 Isobutyric acid (2R, 3R, 4R, 5R) -5- (4-amino-2-oxo-2H-pyrimidine-1-yl) -4-fluoro-3-isobutyryloxy-4-methyl-tetrahydrofuran -2-ylmethyl ester (1-2). 1-6 1-2 For an ice-cooled suspension of 1-6 (970g, 3.74 mol) and DMAP (50g, 0.412 mol) in THF (10L) was added TEA (2.3kg, 16.5 mol) and water (7L) which produced a clear solution . Isobutyryl chloride (3 equivalents) was added slowly to the stirred mixture while keeping the temperature at ca. 0 ° C. 1.2 then 0.7 equivalents of additional isobutyl chloride were added until the HPLC indicated that the reaction had proceeded, essentially, to completion (a total of 1.95kg). The reaction mixture was acidified with HC1 to a pH of ca. 6.4 and the organic phase was washed with EtOAc (2xlOL). The combined extracts were washed with water (lxl5L). The organic phase is filtered and concentrated in vacuo. The residue was dissolved in IPA (ca. 20kg) and heptane (14.2 kg) was added. The solution was heated to ca. 74-75 ° C to produce a clear solution, then the ca. 5L was removed by distillation. The resulting solution was cooled slowly for RT. A precipitate was formed at ca. 42-43 ° C. The cooling was continued slowly at 5 ° C and stirred overnight. The resulting solid was filtered and the filtrate was washed with IPA / heptane (1: 8) mixture (13.4kg), vacuum drying at approximately 60-70 ° C to withstand 1.295kg (86.65%) of 1-2 which was 99.45% pure by HPLC. Example 3 Carbonic acid (2R, 3R, R, 5R) -5- (4-amino-2-oxo-2H-pyrimidine-1-yl) -4-fluoro-2-isobutoxycarbonylsimethyl-4-methyl-tetrahydrofuran -3-ester isobutyl ester ilo (1-4).

A suspension of 1-6 (700mg), DMAP (33mg) in THF (7mL), was diluted with brine (7mL). Dilute NaOH was added until the pH was ca. 11. The reaction mixture was cooled in an ice bath and isobutyl chloroformate (1.llg) was added dropwise to the stirred biphasic reaction mixture which retained the pH approximately 11 by adding NaOH as required. HPLC analysis indicated most of the dicarbonate contaminated with ca. 15% of monocarbonates. An additional aggregate of 1 eq. Isobutyl chloroformate was added dropwise to the solution cooled on ice. HPLC indicated almost complete conversion. The resulting mixture remained overnight in RT. EtOAc (ca.50mL) was added and the pH of the aqueous phase adjusted to ca. 7.5 with with HC1. The phases were separated and the organic phase was washed with water (3x) and evaporated to dryness to support a colorless solid (ca 1.22g). The solid is dissolved in hot acetone resulting in a clear solution that was cooled slowly to RT which produces a solid mass. The solid was diluted with IPA (ca. 20mL) that produced a slurry that was filtered and then washed, sequentially, with IPA and heptane, subsequently dried to support 0.85g (68.5%) of 1-4 which was 97.5% pure by HPLC. Example 4 Carbonic acid (2R, 3R, 4R, 5R) -5- (-amino-2-oxo-2H-pyrimidine-1-yl) -4-fluoro-4-methyl-2-propoxycarbonyloxymethyl-tetrahydrofuran- 3-ester propyl ester; hydrochloride salt (1-5). For a suspension of 1-6 (700mg, 2.70 mol), DMAP (33mg, 0.27 mol) in THF (7mL) and diluted in brine (7mL) was added diluted KOH to adjust the pH to ca. 11. The reaction was cooled to ca. 5 ° C and n-propyl chloroformate (1Og) was added dropwise to the stirred biphasic reaction mixture. HPLC analysis indicated the formation of the desired product together with ca. 20% of monocarbonates. Two additional amounts of propyl chloroformate (2x1 equivalent) were added to the cold solution until HPLC analysis indicated that the reaction had proceeded to completion. The reaction mixture was diluted with EtOAc (30 mL) and the pH of the aqueous phase adjusted to ca. 6.5 with with HC1. The phases were separated and the organic phase was washed with water (3x) and evaporated to dryness to obtain a colorless solid (ca.l.lg). A hot IPA solution was acidified with 4N HC1. { AC. lmL) and evaporated to dryness. The resulting solid was re-dissolved in hot EtOH (ca. 115mL) and stirred overnight at RT. A solid mass was formed which was filtered and the residue was washed with MeOH / heptane (1: 1). The remaining solid was dried in vacuo at about 60 ° C to support 0.325g (25.8%) of 1-5 which 97.5% is pure by the HPLC test. Example 5 Determination of pharmacokinetic parameters in rats The intact male Wistar Han Rats Crl: WI (GLx / BRL / Han) IGS BR. Rats (Hanover-Wistar) weighing 200-250 g were used. Groups of three rats were used for each dose level of an experimental compound. The animals were allowed normal access to food and water throughout the experiment. The test substance was formulated as an aqueous suspension containing Captex355EP, Capmul MC, EtOH, and propylene glycol (30: 20: 20: 30) in a dose equivalent to 10mg / kg of 1-6 and was orally administered by fattening . A blood sample (0.3mL) was taken from the rats treated in 0.25, 0.5, 1, 3, 5 and 8 h of a jugular cannula and in 24 h by cardiac puncture. Potassium oxalate / NaF was added to the samples that were stored on ice during the sampling procedure. The samples were rotated in a refrigerated centrifuge at -4 ° C as soon as the plasma samples were stored in a freezer of - 80 ° C until analysis. The aliquots of plasma (0.05mL) were mixed with 0. lmL of acetonitrile. The internal standard (0.05mL in water) and 0.02mL of blank solvent was added. A set of calibration standards was prepared by mixing 0.05-mL of plasma aliquots from untreated rats with 0. lmL of acetonitrile, 0.02-mL aliquots of standard solution in methanol: water (1: 1) and 0.05-mL aliquots of the internal standard in water. Each plasma sample and the calibration standard were made as a whirlwind and then centrifuged at 3000 rpm for 5 minutes to precipitate the protein. The supernatant (100 μL each) of the centrifugation was transferred into a well plate 96 containing 200 μL of aqueous mobile phase during LC / MS / MS analysis. The prodrugs were analyzed using high performance liquid chromatography with mass spectrometry one after another (HPLC / MS / MS). A Thermo Aquasil C18 4.6 x 50 mm column (5 μ?) Was used for the separation. Electrospray Ionization (ESI) was used for the ionization process. Mobile phase A contained 5mM of ammonium acetate in water with 0.1% formic acid and mobile phase B contained MeOH with 0.1% formic acid. The elution was carried out with the following gradient with a flow rate of lmL / min: Example 6 Determination of pharmacokinetic parameters in monkeys Three male Cynomolgus monkeys weighing 8-10kg were used. The animals were allowed normal access to food and water throughout the experiment. Animal weights were recorded at the time of drug administration and adverse drug reactions. The test substance was formulated as an aqueous suspension formulation containing hypromellose (2910, 50 cps), ÜSP, polysorbate 80, NF, benzyl alcohol NF (5.0, 4.0 and 9.0 mg / mL) and sterile water (sufficient amount for yield l.OmL) in a dose equivalent to 10mg / kg of 1-6 and 0.5mL / kg was administered orally by priming. A blood sample was taken (0.5- l.OmL) at O, 0.083, 0.25, 0.5, 1, 3, 5, 8 and 24 h. The analysis and handling of the sample were carried out as described in the rat experiment. A 5mL sample of urine was taken from each monkey before the dose and at 0-8h. The urine samples were stored at -80 ° C and analyzed by LC / MS / MS. Standard curves were prepared in mono-blank plasma containing NaF and potassium oxalate. Example 7 Caco Materials Protocol: Powders from the Krebs-Henseleit regulator, calcium chloride dihydrate and sodium bicarbonate were purchased from Sigma (St. Louis, MO). Caco-2 cells (Passage ~ 100) were obtained from Roche Basel. The DMEM / medium high, 4- (2-hydroxyethyl) -1-piperazineethane-sulfonic acid (HEPES), and the bovine serum were obtained in JRH Bioscience (Lenexa, KS). The non-essential amino acids E, L-glutamine, penicillin and streptomycin were obtained from GIBCO Labs, Life Tech. LLC (Grand Island, NY). Snapwell cell culture inserts (6.5mm in diameter, 1.12cm2, 0.4 μ? In poriferous size) were obtained from Costar (Cambridge, MA). Cell cultures: The cells grew in 75-cm2 flasks and preserved at 37 ° C in an atmosphere of 5% CO2 and 95% air. The culture medium consisted of DMEM / high medium supplemented with 5% bovine serum, 25 mM HEPES, 1% non-essential amino acids MEM, 1% L-glutamine, 100 U / mL penicillin and 100 μg / mL of streptomycin. The crops were passed each week for a fractional ratio of 1-3. For permeability studies, Caco-2 cells in passage number 110-120 were anodized at a density of 400,000 cells / cm2 in Transwell polycarbonate filters in Snapwell inserts and allowed to culture for 7 days before use. Krebs-Henseleit Regulator: The Krebs-Henseleit bicarbonate buffer containing 10 mM glucose and 2.5 mM CaCl2 adjusted to a pH of 6.5 and 7.4 were prepared by package instructions. The powder salts were dissolved, quantitatively, in approximately 90% of the required volume with Millipore water. Calcium chloride dihydrate and sodium bicarbonate were added before adjusting the pH with 1N HC1 or 1N NaOH. Additional Millipore water was added to bring the solution to the final volume. The solution was sterilized by filtration through the use of a membrane with a porosity of 0.22 microns and stored in the refrigerator (~ 20 ° C) until its use. Preparation of the cells: The differentiated cells were obtained from the Cell Culture Core Facility and allowed to equilibrate at 37 ° C in an atmosphere of 5% CO2 and 95% air. Snapwell inserts containing caco-2 monolayers were rinsed in a pH regulator of 7.4 Krebs-Henseleit at 37 ° C. Method: The cell insert was used as the diffusion chamber. The pH of the Krebs-Henseleit regulator in the apical and basolateral chambers was 6.5 and 7.4, respectively, and the initial concentration of the substrate on the apical side was 100 μ ?. The cells with the compound tested in the apical chamber were previously incubated for approximately 30 minutes at 37 ° C under an atmosphere of 5% CO2 and 95% air. Experiments were initiated when inserts of cells with 100 μ? in the pH Krebs-Henseleit regulator 6.5 were transferred into a new plate with regulator previously balanced in the basolateral chamber. Samples from the donor side at minute 0, and both donor and recipient sides in 30 minutes were collected for analysis. Post-Experiment Control: Lucifer Yellow was used to evaluate the performance of the diffusion system. By following the last Sampling for the test compounds, Lucifer Yellow was added to the apical chamber to give an initial concentration of 100 μ ?. After 60 minutes of incubation, 250 μL of the basal chamber was removed and tested. Calculation of the Permeability Coefficient (Papp): The Papp was calculated by using the following formula: V x dC = (cm / sec) A x C0 x dt Where V is the volume (cm3) of the receiving solution, A is the surface area (cm2) of the Snapwell insert, Co is the initial concentration (nM), and dC / dt is the change in concentration in the chamber receptor over time, that is, the decline (nM / min) of the concentration in the receiving chamber against time. The concentrations at each point of the sampling time were corrected to account for the aliquots removed or the transfer of donor inserts to new plates depending on the experiment. Example 8 Pharmaceutical compositions of the subject substances for administration by various routes were prepared as described in Example 8.

Composition for the granular formulation for oral administration (A): The ingredients are mixed, granulated and distributed in hard gelatine capsules containing approximately 500 mg of active compound. Composition for Oral Administration (B): The ingredients are combined and granulated using a solvent such as water. The formulation is then dried and formed into tablets containing about 500 mg of active compound with a suitable tablet machine. Composition for Oral Administration (C) The ingredients are mixed to form a suspension for oral administration. Suppository formulation (D): The ingredients are melted together and mixed in a steam bath, then poured into molds containing 2.5g of total weight. The features described in the foregoing description, or the following claims, expressed in their specific forms or in terms of a means to carry out the function described, or a method or process to achieve the result described, as appropriate, may, separate form, or in any combination of said characteristics, be used to understand the invention in various forms. The above invention has been described in some detail as a means of illustration and example for purposes of clarity and understanding. It will be apparent to one skilled in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it should be understood that the foregoing description is intended to be illustrative and not restrictive. The scope of the invention must, therefore, be determined not with reference to the foregoing description but must be determined with reference to the following appended claims, together with the full scope of equivalents for which said claims are authorized. All patents, patent applications and The publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same degree as if each individual patent, patent application or publication were indicated individually.

Claims (17)

1. NOVELTY OF THE INVENTION
2. Having described the present invention, it considers as a novelty and, therefore, property is claimed as contained in the following:
3. CLAIMS 1.- A compound of formula I characterized in that: R1 is selected from the group consisting of branched or unbranched alkyl C2-5, branched or unbranched alkenyl C2-5, branched or unbranched alkynyl C2-5, lower haloalkyl C2-5, cycloalkyl C3-6, and C2-4 alkoxy; e, hydrates, solvates and acid addition salts thereof. 2. A compound according to claim 1, characterized in that R1 is ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl. 3. A compound according to claim 1 or 2, characterized in that R1 is ethyl or iso-propyl.
4. 4. A compound according to claims 1 to 3, characterized in that R1 is iso-propyl and the compound is the hydrochloride or sulfate salt.
5. 5. A compound according to claims 1 to 4, characterized in that R1 is iso-propyl and the compound is the hydrochloride salt.
6. 6. - A compound according to claim 1 characterized in that R1 is ethoxy, n-propyloxy or iso-propyloxy.
7. 7. - A compound according to claims 1 to 6 for use in therapy.
8. 8. - A compound according to claims 1 to 6 for use in the therapy of a disease mediated by the virus (HCV) Hepatitis C virus.
9. 9. - A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 to 6 mixed with at least one pharmaceutically acceptable carrier, diluent or excipient.
10. 10. The use of a compound according to claims 1 to 6 for the preparation of a medicament for the treatment of a disease mediated by the virus (HCV) Hepatitis C Virus.
11. 11. The use according to claim 10, characterized in that the medicament is administered to a patient in need thereof, a therapeutically effective dose.
12. 12.- Use in accordance with the claim 10, characterized in that the medicament is administered to a patient in need thereof, a dose between 0.1 and 10Og per day.
13. 13. The use according to claims 10 to 12, characterized in that the medicament is further administered with at least one modulator of the immune system and / or at least one antiviral agent that inhibits the replication of HCV.
14. 14. - A method for treating a disease mediated by the virus (HCV) Hepatitis C virus which comprises administering to a patient in need thereof, a therapeutically effective dose of a compound according to claims 1 to 6.
15. 15. - The method according to claim 14, characterized in that a dose between 0.1 and 10Og per day is administered to the patient.
16. 16. - The method according to claim 14 or 15, further comprising at least one modulator of the immune system and or at least one antiviral agent that inhibits the replication of HCV.
17. 17. - A process for the selective O-acylation of a nucleoside I to support an O-acyl II nucleoside under basic reaction conditions (II) characterized in that R1 is selected from the group consisting of branched or unbranched alkyl C2-5, branched or unbranched alkenyl C2-5, branched or unbranched alkynyl C2-5, lower haloalkyl C2-5, C3-6 cycloalkyl and alkoxy C2-4, whose process comprises the steps of: (i) dissolving II and DMAP in a heterogeneous aqueous solvent mixture and adding the aqueous base to adjust the pH from about 7.5 to about 12; (ii) optionally adding enough saturated aqueous NaCl to produce a biphasic reaction mixture; (iii) adding an additional acylating agent and base sufficient to maintain the pH from about 7.5 to about 12; (iv) monitor the reaction and discontinue the addition of said acylation agent and said base when the conversion reaches a satisfactory level; (v) contacting, optionally, the f-O-acyl nucleoside with a pharmaceutically acceptable acid to form an additional acid salt of the O-acyl nucleoside.