MX2008004079A - Modified 4'-nucleosides as antiviral agents - Google Patents

Abstract

Compounds, methods and compositions for treating a host infected with human immunodeficiency virus and hepatitis B virus comprising administering an effective amount of a described 4'-C-substituted /3-D- and /3-L-nucleoside or a pharmaceutically acceptable salt or prodrug thereof, are provided.

Description

4'-NUCLEOSIDES MODIFIED AS ANTIVIRAL AGENTS Field of the Invention This invention relates to the area of pharmaceutical chemistry, and is in particular, a compound, method and composition for treating a host infected with the human immunodeficiency virus (subsequently referred to as " HIV " (for its acronym in English)), hepatitis B virus (referred to later as "HBV" by its acronym in English), or both HIV and HBV which comprises administering an effective amount of a β-D and β-L-4 '-C-substituted-3' -fluoro- and 3'-azido-3'-deoxynucleoside or a pharmaceutically acceptable salt or prodrug of the same. Background of the Invention In 1981, the acquired immunodeficiency syndrome (AIDS) is identified as a disease that severely compromises the human immune system which almost without exception leads to death. In 1983, the etiological cause of AIDS was determined to be HIV. In 1985, it was reported that the synthetic nucleoside 3'-azido-3 '-deoxitimidine (AZT) inhibits HIV replication. Since then, a variety of other synthetic nucleosides have been tested, including 2 ', 3' -dideoxinosine (DDI), 2 ', 3'-dideoxycytidine (DDC), and 2 ', 3'-dideoxy-2', 3 '-didehydrotimidine (D4T for its acronym in Ref.: 191424 English), to be effective against HIV. After cellular phosphorylation at 5'-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a viral DNA growth strain, which causes chain termination due to the absence of the 3'-hydroxyl group. These can also inhibit the viral enzyme reverse transcriptase. The success of the various synthetic nucleosides to inhibit HIV replication in vivo or in vitro has led a number of researchers to design and test the nucleosides that substitute a heteroatom for the carbon atom at the 3 'position of the nucleoside (Norbec et al. al., 1989, Tetrahedron Letters, 30 (46) 6246, European Patent Application Publication No. 0 337 713 and United States of America Patent No. 5,041,449). U.S. Patent No. 5, 047, 407 and European Patent Application Publication No. 0 382 526, describe a number of 2'-substituted-5 '-substituted-1,3-oxathiolane nucleosides with viral activity and reports specifically that the racemic mixture (approximately the C4 'position) of the Cl'-β isomer of 2-hydroxymethyl-5- (cytosin-1-yl) -1, 3-oxathiolane (+) - BCH-189) has approximately the same activity against HIV as AZT , and has no cellular toxicity at the tested levels. (+) -BCH-189 has also been found to inhibit the replication of AZT resistant HIV isolated in vitro from patients who have been treated with AZT for more than 36 weeks. The (-) -enantiomer of the isomer of BCH-189, known as 3TC, is highly potent against HIV and exhibits little toxicity. (-) -cis-2-hydroxymethyl-5- (5-fluorocytosin-1-yl) -1, 3-oxathiolane ("FTC") also has potent HIV activity (Sc inazi et al., 1992 Antimicrob Agent and Chemotherap 2423-2431). Recently, it has been reported that the substituted 4'-C nucleosides show potent anti-HIV activity (Siddiqui, MA et al., J. Med. Chem. 2004, 47, 5041-5048; Nomura, M. et al., J. Med. Chem. 1999, 42, 2901-2908). Another virus that causes a serious human health problem is HBV. 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 HBV can directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis and cell regeneration associated with the infection. After an incubation period of two to six months in which the host is not aware 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. 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 immunodeficiency syndrome, which is taken into account why HBV infection is common among patients with AIDS or the complex related to AIDS. However, HBV is more contagious than HIV. Both FTC and 3TC exhibit activity against HBV (Furman et al., 1992 Antimicrobial Agents and Chemotherapy, 2686-2692). A vaccine derived from human serum has been developed to immunize patients against HBV. While effective, the production of the vaccine is problematic since the supply of human serum from chronic carriers is limited, and the purification process is long and expensive. In addition, each batch of vaccine prepared from different sera should be tested on chimpanzees to ensure their safety. The vaccines have also been produced through genetic modification. Daily treatments with a-interferon, a genetically modified protein, have also shown promise.

In light of the fact that the acquired immunodeficiency syndrome, the complex related to AIDS, and the hepatitis B virus have achieved worldwide epidemic levels, and have tragic effects on the infected patient, it remains a need to provide new pharmaceutical agents. effective to treat these diseases and which have low toxicity in the host. Summary of the Invention The present invention describes compounds, their syntheses, methods and compositions for treating a host infected with HIV, HBV, or both HIV and HBV which comprises administering an effective amount of a β-D- and β-L-4. '-C-substituted-3' -fluoro- and 3'-azido-3 '-deoxynucleoside or a pharmaceutically acceptable salt or prodrug thereof. Brief Description of the Figures Figure 1 depicts the chemical structures of 4'-nucleosides modified as antiviral agents. Figure 2 is an illustrative non-limiting example of the synthesis of 4'-C-ethynyl-3 '-fluorothymidine (la, R1 = F, R2 = OH, R3 = ethynyl) or 4'-C-ethynyl-3' - azidothymidine (la, R1 = N3, R2 = OH, R3 = ethynyl). Figure 3 is an illustrative non-limiting example of the synthesis of 4'-C-ethynyl-3 '-fluoro-2', 3'-dideoxynucleosides (29, R1 = F) and 3 '-azido-2', 3 ' -dideoxynucleosides (29, R1 = N3). Detailed Description of the Invention The present invention relates to a method and composition for treating HIV, HBV or both HIV and HBV infections in a host which comprises administering an effective amount of a 3 '-fluoro- and 3'- substituted β-D- and β-L-4'-C-substituted azido-3'-dideoxynucleosides or their pharmaceutically acceptable salts and prodrugs thereof. More specifically, a first aspect of the present invention is directed to compounds, methods and compositions for treating a host infected with HIV, HBV, Both HIV and HBV which comprises administering an effective amount of a described β-D- and β-L-nucleoside of the formulas 1 and II or a pharmaceutically acceptable salt or prodrug thereof.

W Cp) wherein: X is hydrogen, halogen (F, Cl, Br, I), NH2, NHR4, NRR5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR, S (0) R4, S (0 ) 2R4, OH, OR4, N3, CN or CF3. Y is hydrogen, halogen (F, Cl, Br, I), NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4 , N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R1 is F O N3; R2 is OH, OR4, OC (0) R4, OPv03vMxR4yR5z, Pv03vMxRyR5Z / OCH2OPv03vMxR4yR5z, OP (0) (OQ) to (NHR4) b, SH, SR4, S (0) R4, S (0) 2R4, SC (0) R4, NH2, NHC (0) R4, NHR4, NR R 5 , NHOH, NHOR4, NHNH2, NRNH2 O NHNHR4, R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (C? -6), alkyl (Ci-β) substituted with one or three halogens, alkenyl (C? -6) or alkynyl (C? _6) with the proviso that when R1 is N3, R3 is not hydroxymethyl; Z is O, S, CH2 or C = CH2; A is N, CH, O CF; and R 4 and R 5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl, such as unsubstituted or substituted phenyl or benzyl M is at least one member selected from the group which consists of of H +, Na + and K +; v has a value of 1, 2 or 3; x, y and z are independent of each other and have a value of 0, 1, 2, 3 or 4; and a has a value of 0 or 1, b has a value of 1 or 2, and Q is M or R. A second aspect of the present invention is directed to the intermediary of the formula: wherein: X is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4 , N3, CN or CF3. Y is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NRNH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4, N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (Ci-e), alkyl (C6-6) substituted with one or three halogens, alkenyl (C6-6) or alkynyl (Ci-β) with the proviso that when R1 is N3, R3 is not hydroxymethyl; Pg is a hydroxyl protecting group that includes, but is not limited to trityl, dimethoxytrityl and t-butylsilyl; L is a leaving group including, but not limited to a sulfonyl, a trifluorosulfonyl, an unsubstituted sulfonate, a substituted sulfonate, an unsubstituted carbonate and a substituted carbonate; and R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl. A third aspect of the present invention is directed to a process for the preparation of an intermediate described in the second aspect of the present invention which comprises: (a) selectively protecting a 5'-OH with a protecting group, Pg, to form a group 5'-OPg; (b) activating a 3 '-OH with a leaving group, L, to form a 3'-0L group; (c) reacting a 3'-C with a hydroxide base in order to convert the 3'-C position from a ribo- to xylo- configuration; (d) activating a 3 '-OH which has a xyl configuration with a leaving group, L, to form a 3'-OL group; (c) P wherein the hydroxide base includes, but is not limited to NaOH, KOH, and R4NOH, and mixtures thereof. A fourth aspect of the present invention is directed to an intermediate of the formula: wherein: X is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NRNH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4, N3, CN or CF3. Y is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR, S (0) R4, S (0) 2R4, OH, OR4, N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (Ci-β), alkyl (Ci-β) substituted with one or three halogens, alkenyl (C6-6) or alkynyl (Ci-e) with the proviso that when R1 is N3, R3 is not hydroxymethyl; Pg is a hydroxyl protecting group that includes, but is not limited to trityl, dimethoxytrityl and t-butylsilyl; and R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl. A fifth aspect of the present invention is directed to a process for the preparation of an intermediate described in the fourth aspect of the present. invention which comprises: (a) activating a 3'-OH of a 5'-O-protected nucleoside with a leaving group L; to form a nucleoside group 3 '-0L-5' -O-protected; followed by (b) treating nucleoside 3 '-OL-5' -O-protected with DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) or DBN (1,5-diazabicyclo [4.3.0] non-5-ene); in order to obtain the intermediary; wherein L includes, but is not limited to a sulfonyl, a trifluorosulfonyl, a substituted sulfonate, an unsubstituted sulfonate, an unsubstituted carbonate, and a substituted carbonate. Various embodiments of the invention are now described in detail. As used in the description herein and in all the claims that follow, the meaning of "one, one, one, some, some" and "the, the, the," include both singular and plural references unless the context clearly dictates something else. Also, as used in the description of the present and in all the claims that follow, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, anywhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the invention and how to prepare and use them. For convenience, certain terms may be highlighted, for example using bold and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term: the scope and meaning of a term is the same, in the same context, whether it is highlighted or not. It will be appreciated that the same can be said in more than one way. Accordingly, the alternative language and synonyms for any one or more of the terms discussed herein may be used, it has no special meaning that it is placed whether or not a term is elaborated or discussed herein. The synonyms are provided for certain terms. A consideration of one or more synonyms does not exclude the use of other synonyms. The use of examples elsewhere in this specification, including examples of any terms discussed herein, is illustrative only, and does not limit in any way the scope and meaning of the invention or any exemplified terms. Similarly, the invention is not limited to several embodiments given in this specification. As used in this, "about" or "about" should generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. The numerical quantities given herein are approximate, which means that the term "about" or "about" may be inferred if not expressly stated. The disclosed compounds or their derivatives or pharmaceutically acceptable salts or their pharmaceutically acceptable formulations which contain these compounds are useful in the prevention and treatment of HIV infections and other related conditions such as the complex related to AIDS (ARC). , persistent generalized lymphadenopathy (PGL), neurological conditions related to AIDS, anti-HlV positive and HlV-positive antibody conditions, Kaposi's sarcoma, purpurea thrombocytopenia and opportunistic infections. In addition, these compounds or formulations can be used prophylactically to prevent or delay the progression of clinical disease in individuals which are anti-HIV antibody or HIV-positive antigen or who have been exposed to HIV. The compounds and their pharmaceutically acceptable derivatives or pharmaceutically acceptable formulations which contain the compound or its derivatives are also useful in the prevention and treatment of HBV infections and other related conditions such as anti-HBV positive and HBV positive antibody conditions, chronic liver inflammation. caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, persistent chronic hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or slow the progression of clinical disease in individuals who are anti-HBV antibody or HBV-positive antigen or who have been exposed to HBV. The compounds can be converted to a pharmaceutically acceptable ester by reaction with an appropriate esterifying agent, for example, a halide or acid anhydride. The compounds or their pharmaceutically acceptable derivatives can be converted to a pharmaceutically acceptable salt thereof in a conventional manner, for example, by treatment with an appropriate base. The ester or salt of the compound can be converted to the parent compound, for example, by hydrolysis. The term "independently" is used in the present to indicate that the variable, which is applied independently, varies independently from application to application. In this way, in a compound such as RaXYRa, where Ra is "independently carbon or nitrogen" both Ra can be carbon, both Ra can be nitrogen, or one Ra can be carbon and the other Ra nitrogen. As used herein, the term "enantiomerically pure" refers to a nucleoside composition comprising at least about 95% and preferably about 97%, 98%, 99% or 100% of a single enantiomer of that nucleoside. As used herein, the term "substantially free of" or "substantially in the absence of" refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98% by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of the non-designated enantiomer of that nucleoside. Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98% by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the rest comprising other chemical species or enantiomers. The term "alkyl" as used herein, unless otherwise specified, refers to a saturated, branched, or cyclic, primary, secondary or tertiary linear hydrocarbon of typically Ci to C? 0, and specifically includes methyl , trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl . The term includes both substituted and unsubstituted alkyl groups. The alkyl groups may be optionally substituted with one or more portions selected from the group which consists of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, or any another different viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected or protected as necessary, as is known to those skilled in the art, for example, as taught in Greene et al. 1991, Protective Groups in Organic Synthesis, John Wiley & Sons, 2nd edition, incorporated herein by reference. The term "lower alkyl", as used herein and unless otherwise specified, refers to a straight, branched, or, if appropriate, cyclic (for example, cyclopropyl) linear Ci to C4 alkyl group, which includes both substituted and non-substituted forms. Unless otherwise specifically stated in this application, when the alkyl is a suitable portion, lower alkyl is preferred.

Similarly, when the alkyl or lower alkyl is a suitable portion, unsubstituted alkyl or lower alkyl is preferred. The term "lower alkenyl", as used herein, and unless otherwise specified, refers to an unsaturated linear or branched alkenyl group of C2 to C4, which includes both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when the alkenyl is a suitable portion, a lower alkenyl is preferred. Similarly, when the alkenyl or lower alkenyl is a suitable portion, an unsubstituted alkenyl or lower alkenyl is preferred. The terms "alkylamino" or "arylamino" refer to an amino group having one or two alkyl or aryl substituents, respectively. The term "protected" as used herein and unless otherwise defined, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. The term "aryl", as used herein, and unless otherwise stated, refers to phenyl, biphenyl or naphthyl, and preferably phenyl. The term includes both substituted and non-substituted portions. The aryl group can be substituted with one or more portions selected from the group which consists of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, whether or not protected, or protected as necessary, as is known to those skilled in the art, for example, as taught in Greene et al. 1991, Protective Groups in Organic Synthesis, John Wiley & amp;; Sons, 2nd edition. The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent. The term "halo", as used herein, includes chlorine, bromine, iodine and fluoro. The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl portion of the ester group is selected from alkyl or straight, branched or cyclic lower alkyl, alkoxyalkyl which includes methoxymethyl, aralkyl which includes benzyl, aryloxyalkyl such as phenoxymethyl, aryl which includes phenyl optionally substituted with halogen (F, Cl, Br, I), Ci to C4 alkyl or Ci to C4 alkoxy, sulfonate esters such as alkyl or aralkylsulfonyl which includes methanesulfonyl, the mono ester , di or triphosphate, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (for example dimethyl-t-butylsilyl) or diphenylmethylsilyl. The aryl groups in the esters optimally comprise a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl portion is lower alkyl. The term "host", as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including cell and animal lines, and preferably a human. Alternatively, the host may be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention. The term "host" refers specifically to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention. The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a compound which, upon administration to a patient , provides the active compound. The pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. 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. Typical examples of prodrugs include compounds having biologically labile protecting groups in a functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. 1. Non-limiting example of the synthesis of 4 '-c-ethynyl-3'-fluoro and 3'-azidothi idines (see Figure 2) The treatment of thymidine with 2.2-2.5 moles of t-butyldimethylsilyl chloride in sodium chloride methylene in the presence of imidazole followed by selective deprotection of the 5'-0-silyl group in 80% acetic acid in the presence of trifluoroacetic acid gives compound 2. Oxidation of 2 with DCC in DMSO in the presence of trifluoroacetate of pyridinium gives an aldehyde 3 after purification by silica gel column chromatography in excellent yield. Treatment of compound 3 with aqueous formaldehyde in a mixture of 1,4-dioxane and water in the presence of 2N NaOH followed by reduction of the resulting intermediate by NaBH, provides the diol 4. Selective protection of diol 4 with dimethoxytrityl chloride in pyridine yields compound 5. Treatment of compound 5 with t-butyldiphenylsilyl chloride in methylene chloride in the presence of imidazole followed by detritylation in acetic acid 80% gives compound 6. Oxidation of alcohol 6 with DCC in DMSO in the presence of pyridinium trifluoroacetate gives compound 7. Reaction of compound 7 with Wittig reagent chloromethylene followed by elimination by treatment with butyllithium produces 4'-C-ethynyl nucleoside 8. Treatment of 8 with tetrabutylammonium fluoride in THF gives 4'-C-ethynyl-thymidine 9. Treatment of 9 with DMTrCl in pyridine gives compound 10. Compound 10 is converted to 11 by treatment with MsCl followed by NaOH in EtOH. Treatment of compound 11 with DAST in methylene chloride at reflux temperature in the presence of pyridine affords 3'-fluoronucleoside (12, X = F): the 3 '-Azidonucleoside (12, X = N) is obtained by treatment of 11 with mesyl chloride in methylene chloride in the presence of triethylamine followed by NaN3 in DMF. The end products, 4 '-C-ethynyl-FLT (la, R1 = F, R2 = OH, R3 = ethynyl) and 4' -C-ethynyl-AZT (la, R1 = N3, R2 = OH, R3 = ethynyl ) are obtained by treatment of 12 with 80% acetic acid. Alternatively, reaction of 10 with MsCl in the presence of base, such as triethylamine and the like, followed by treatment of the resulting mesylate with base, such as DBU or DBN or the like, gives the intermediate 11 '. Treatment of 11 'with NaN3 or tetrabutylammonium fluoride (TBAF) also provides the same intermediate 12 with X = N3 or X = F, respectively, as described in Maillard, M. et al. Tetrahedron Lett, 1989, 30, 1955-1958. the present invention, by way of example, does not propose to be limited to thymidine mentioned above, and therefore the descriptions of US Pat. Nos. 6,949,522 are incorporated herein by reference.; U.S. Patent 6,403,568 and U.S. Application 2005/0009737, each of which discloses examples of purine and pyran dinas that are contemplated. 2. Non-limiting example of the synthesis of 4 '-C-ethynyl-3'-fluoro- and 3'-azido-2', 3'-dideoxynucleosides (see Figure 3) The treatment of compound 13 with the t-chloride -butyldimethylsilyl in methylene chloride in the presence of imidazole followed by removal of the chlorobenzyl protecting group with metal ammonia gives compound 15. Oxidation of compound 15 with DCC in DMSO in the presence of pyridinium trifluoroacetate gives an aldehyde 16 after chromatographic purification with silica gel column. Treatment of compound 16 with aqueous formaldehyde in a mixture of 1,4-dioxane and water in the presence of 2N NaOH followed by reduction of the resulting intermediate with NaBH 4 yields the diol 17. Selective protection with DMTCI followed by oxidation with DCC in DMSO in the presence of pyridinium trifluoroacetate gives an aldehyde 19. The reaction of 19 with Wittig's reagent chloromethylene followed by elimination in the presence of butyllithium provides 4'-C-ethynyl-xylofuranoside 20. The acetolysis of 20 with Acetic anhydride in acetic acid in the presence of concentrated sulfuric acid yields tetraacetate 21. Coupling of 21 with silylated bases in the presence of Lewis acid, such as TMSOTf or SnCl 4, followed by deprotection with methanolic ammonia provides 4'- C-ethynyl-xylofuranosyl-nucleosides 23. Treatment of compound 23 with acetone in the presence of a catalytic amount of HCl gives compound 24. Compound 2 4 is subjected to Barton deoxygenation to produce 2'-deoxynucleosides 25.

Desisopropylation of 25 with 80% acetic acid followed by selective protection with BzCl in pyridine provides the nucleosides 27. Treatment of compound 27 with DAST in methylene chloride at reflux followed by deprotection with methanolic ammonia provides the 4 ' -C-ethynyl-nucleosides end (29, RX = F). Treatment of 27 with methanesulfonyl chloride in methylene chloride in the presence of triethylamine followed by the reaction of the resulting mesylate with NaN3 in DMF gives 4 '-C-ethynyl-nucleosides (29, RX = N3). The synthetic schemes described above provided for the following contemplated compounds including, but not limited to: 4 '-C-substituted-3' -fluoro-2 ', 3'-dideoxynucleoside, a 4'-C substituted-3' - azido-2 ', 3' -dideoxynucleoside, a 4 '-C-ethynyl-3' -fluoro-2 ', 3'-dideoxynucleoside, a 4' -C-ethynyl-3 '-azido-2', 3 '- dideoonucleoside, a 4'-C-ethynyl-3'-fluoro-3'-deoxythymidine, and a 4'-C-ethynyl-3'-azido-3'-deoxythymidine. The antivirally active nucleosides can be administered as any derivative which upon administration to the host receptor is capable of providing, directly or indirectly, the parent compound, or which exhibits activity on its own. Non-limiting examples include pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts") and prodrugs. Modifications of the active compound, specifically at positions N4 and 5'-0, can affect the bioavailability and speed of metabolism of the active species, thereby providing control over the supply of the active species. In addition, the modifications may affect the antiviral activity of the compound, in some cases increasing the activity on the parent compound. This can be easily evaluated by preparing the derivative and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art. The use of an antivirally effective amount of any of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof is also contemplated in the present invention. Pharmaceutically Acceptable Salts and Prodrugs The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a compound which, upon administration to a patient, it provides the active compound. The pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic bases and acids. In cases where the compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. The pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. In particular, examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiologically acceptable anion, for example, but not limited to, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate , ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts. The pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting with a sufficiently basic compound such as an amine with a suitable acid which produces a physiologically acceptable anion. Alkali metal salts can also be prepared (for example, sodium, potassium or lithium) or alkaline earth metal (eg calcium) of carboxylic acids. The pharmaceutically acceptable prodrugs refer to a compound that is metabolized in the host to form the compound of the present invention. Typical examples of the prodrugs include compounds having biologically labile protecting groups in a functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated and / or dephosphorylated to produce the active compound. Any of the nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability, or otherwise alter the properties of the nucleoside. In general, the alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens in the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. bischofberger, Antiviral Research, 27 (1995) 1-17.

Any of these can be used in combination with the described nucleosides to achieve a desired effect. In various embodiments, the prodrugs of the nucleoside derivatives, in which R1 is F or N3, described herein involve substitution at the 5 'carbon (R2) with: OH, OR4, OC (0) R4, 0Pv03vMxRyR5z, Pv03vMxR4yR5z , OCH2Pv03vMxRyR52, 0P (O) (OQ) to (NHR4) b, SH, SR4, SC (0) R4, NH2, NHC (0) R4, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2 or NHNHR4. R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl, or aralkyl, such as phenyl or unsubstituted or substituted benzyl; M is at least one member selected from the group which consists of H +, Na + and K +; v has a value of 1, 2 or 3, - xy and z are independent of each other and have a value of 0, 1, 2, 3 or 4, - already has a value of 0 or 1, b has a value of 1 or 2, and Q is M or R4. The inventors appreciate that a person with ordinary experience should be able to recognize that for the phosphates and phosphonates represented above, that when v is 1 the sum of x, y and z is 2; when v is 2, the sum of x, y and z is 3; and when v is 3, the sum of x, y and z is 4. The phosphates (OPv03vMxRyR5z) comprise mono- (v = l), di- (v = 2) and triphosphates (v = 3) in the form of acid, salts or ester, including combinations thereof. In the case where v = 2, the nucleoside is substituted at the 5'-C position by an R2 which has the following structure: OP206MxRyR5z, where x, y and z have the meanings as defined above. A person with ordinary experience will recognize that the pure acid form is represented by (OP2OdH3), - the pure salt form is represented by (OP2? 6M3, M = Na +, K + or both Na + and K +); and the pure ester form is represented by (OP206R4 and R5z in which, as indicated above, R4 and R5 may be the same or different and if they are different the sum of y and z does not exceed 3). Of course, it is also contemplated that the phosphates may be in the mixed form. By the mixed form it is meant that the phosphate portion can be an acid (when M = H +), a salt (when M = Na + or K +, or even Ca2 +), or an ester (in which either or both of y and z of R4 and R5 do not have zero values). Without being limited by the form of the example, the following structures represent preferred examples of phosphates contemplated: OP03H2, OP206H3, OP309H4, OP03Na2, OP03R4R5, OP206Na3, OP206R2R5, OP309Na4, OP309R3R5, P03H2, P206H3, P309H4, P03Na2. It is contemplated that R4, R5 or both R4 and R5 may have the following formula: R6C (0) OR7, wherein R6 is an alkyl, such as a lower alkyl, and R7 is a lower alkylene (such as methylene, ethylene, propylene, and butylene, which may be unsubstituted or substituted (with a hydroxyalkyl, alkoxyalkyl, or haloalkyl), with the proviso that R7 is bonded to the phosphoester oxygen. , but it is contemplated that the nucleoside is substituted at the 5'-C position by a portion which has the following structure: OP (0) [OCH2OC (0) C (CH3) 3] 2. The binding of the 5'-position -C with the P of a portion (Pv03vMxR4yR5z) gives rise to the mono- (v = l), di- (v = 2), or triphosphonates (v = 3), which have acid, salt or ester forms, including combinations thereof In the case where v = l, the nucleoside is substituted at the 5'-C position by an R2 represented by (P03MxRyR5z) An ordinary expert will recognize that the pure acid form is represented by (P03H2); the pure salt form is represented by (OP03M2, M = Na +, K +, or both Na + and K +); and the pure ester form is represented by (OP03R4 and R5z, in which, as indicated above, R4 and R5 may be the same or different and if they are different the sum of y and z does not exceed 2). Of course, it is also contemplated that the phosphonates may be in a mixed form. By a mixed form it is understood that the phosphonate portion can be an acid (when M = H +), a salt (when M = Na + or K +; or even Ca2 +), or an ester (in which either or both y and z of R4 and R5 have no zero value). Without being limited by the exemplary form, the following preferred examples of R2 substituents give rise to contemplated phosphonates: P03H2, P206H3, P309H4, P03Na2, P206Na3, P309Na4, P03R4R5, P206R42R5, P309R3R5. Additionally, pro-drugs of the nucleoside derivatives that involve substitution at the 5 'carbon with phosphoramidates (-OP (O) (OQ) to (NHR4) b), - in which a has a value, are contemplated in the present invention. of 0 or 1, b has a value of 1 or 2, and Q is M or R. The active nucleoside can also be provided as a 5'-phosphoether lipid or a 5'-ether lipid, as described in the following references, which are incorporated herein by reference: Kucera, L.S., et al. 1990, AIDS Rex Hum. Retro Viruses. 6: 491-501, Piantadosi, G., et al., 1991, J. Med. Chem. 34: 1408.1414; Hosteller, K.Y., et al. 1992, Antim. Agents Chemother. 36: 2025-2029; Hosetler, K.Y., et al. 1990, J. Biol. Chem. 265: 61127. Non-limiting examples of US patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include US Pat. from North America No. 5,149,794; 5,194,654; 5,223,263; 5,256,641; 5,411,947; 5,463,092; 5,543,389; 5,543,390; 5,543,391 and 5,554,728, all of which are incorporated herein by reference. Foreign patent applications that describe lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparations, include the applications WO 89/02733, WO 90100555, WO 91/16920, WO 91/18914, WO 93/00910 , WO 94/26273, WO 96/15132, European Patents EP 0 350 287, EP 93917054.4 and application WO 91/19721. Pharmaceutical Compositions Pharmaceutical compositions based on a nucleoside compound of the formula (I) or (II) or its pharmaceutically acceptable salt or prodrug thereof can be prepared in a therapeutically effective amount to treat a viral infection by HBV or HIV or cell proliferation. abnormal, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient. The therapeutically effective amount may vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient to be treated. In an aspect according to the present invention the compound is preferably formulated in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition in orally administrable form, but formulations can be administered by means of some parental, intravenous, intramuscular, transdermal, buccal, subcutaneous, suppository or other route. The intravenous and intramuscular formulations are preferably administered in sterile saline. One of ordinary skill in the art can modify the formulation within the teachings of the specification to provide numerous formulations for a particular route of administration without leading the compositions of the present invention to be unstable or compromise their therapeutic activity. In particular, a modification of a desired compound to render it more soluble in water or another vehicle, for example, can be easily accomplished by routine modification (salt formulation, esterification, etc.). In certain dosage dosage forms, the prodrug form of the compound, especially which includes acylated derivatives (acetylated or other) and ether, the phosphate esters and various forms of salts of the present compounds, are preferred. One of ordinary skill in the art will be recognized as readily modifying the present compound to a prodrug form to facilitate delivery of the active compound to a target site within the host organism or patient. The expert will also take advantage of the favorable pharmacokinetic parameters of the prodrug form, where applicable, to deliver the desired compound to a target site within the host organism or patient to maximize the proposed effect of the compound in the treatment of viral infections by HBV and HIV. The amount of the compound included within the therapeutically active formulations, according to the present invention, is an amount effective to treat the infection or condition, in preferred embodiments, a viral infection by HBV or HIV. In general, a therapeutically effective amount of the present compound in the form of a pharmaceutical dose is usually in the range of about 0.1 mg / kg to about 100 mg / kg or more and all values and sub-ranges therebetween, depending on the compound used, the condition or infection treated and the route of administration. For purposes of the present invention, a prophylactically or preventively effective amount of the compositions, according to the present invention, fails within the same concentration range as indicated above for a therapeutically effective amount and is usually the same as a therapeutically effective amount. Administration of the active compound may be in the range of continuous administrations (intravenous infusion) to several oral administrations per day (eg, QID, BID, etc.) and may include oral, topical, parental, intramuscular, intravenous, subcutaneous, transdermal administration (which may include a penetration enhancing agent), buccal administration and suppository, among other administration routes. The enteric coated oral tablets can also be used to increase the bioavailability and stability of the compounds from an oral route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent chosen, as well as the severity of the disease in the patient. Oral dosage forms are particularly preferred, due to the ease of administration and favorable adaptability of the patient in the package. To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is preferably mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical composition techniques to produce a dose. A carrier can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parental. To prepare the pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives can be used which include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives which include starches, carriers of sugars, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, Lubricants, binders, disintegrating agents and the like can be used. If desired, the tablets or capsules can be enterically coated for sustained release by standard techniques. The use of these dosage forms can significantly impact the bioavailability of the compounds in the patient. For parental formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, although other ingredients, which include those that aid dispersion, may also be included. Where sterile water will be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions can also be prepared, in which case the appropriate liquid carriers, suspending agents and the like can be employed. Liposomal suspensions (which include liposomes targeted to viral antigens) can also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate by the provision of the free nucleosides, acyl nucleosides or phosphate ester prodrug forms of the nucleoside compounds according to the present invention. In addition, the compounds according to the present invention can be administered in combination or alternation with one or more antiviral, anti-HBV, anti-HIV or interferon, anti-bacterial agents, including other compounds of the present invention. Certain compounds according to the present invention can be effective to increase the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds and as such, they are co-administered for this proposed effect. Combination or Alternating Therapy In another embodiment, for the treatment, inhibition, prevention and / or prophylaxis of viral infection, the active compound or its derivative or salt may be administered in combination or alternatively with another antiviral agent. In general, in combination therapy, effective doses of two or more agents are administered together, while during alternative therapy, an effective dose of each agent is administered in series. The dose will depend on the absorption, inactivation and excretion rates of the drug as well as other factors known to those skilled in the art. It is noted that the dose values will also vary with the severity of the condition to be alleviated. It will also be understood that for any particular subject, the specific dose regimens and schedules must be adjusted over time according to the individual need and professional judgment of the person who administers or supervises the administration of the compositions. Non-limiting examples of antiviral agents that can be used in combination with the compounds described herein include, but are not limited to, acyclovir (ACV), ganciclovir (GCV or DHPG) and their prodrugs (eg, valil-ganciclovir), E-5- (2-bromovinyl) -2'-deoxyuridine (BVDU), (E) -5-vinyl-l-β-D-arabonosyluracil (VaraU per its acronym in English), (E) -5- (2-bromovinyl) -1-ß-D-arabinosiluracil (BV-araU for its acronym in English), l- (2-deoxy-2-fluoro-β-D arabinosil) -5-iodocytosine (D-FIAC), 1- (2-deoxy-2-fluoro-β-L-arabinosyl) -5-methyluracil (L-FMAU), ( S) -9- (3-hydroxy-2-phosphonylmethoxypropyl) adenine ((S) -HPMPA for its acronym in English), (S) -9- (3-hydroxy-2-phosphonylmethoxypropyl) -2,5-diaminopurine ( (S) -HPMPDAP for its acronym in English), (S) -1- (3-hydroxy-2-phosphonyl-methoxypropyl) cytosine ((S) -HPMPC, or cidofivir), and (2S, 4S) -1- (2- (hydroxymethyl) -1, 3-dioxolan-4-yl) -5-iodouracil (L-5-IoddU), FTC, entecavir, interferon-a, lamivudine (3TC), LdT (or its prodrug), LdC (or its prodrug), and adefovir, protease inhibitors (Agenerase, Crixivan, Fortovase, Invirose, Kaletra, Lexiva, Norvir, Reyataz, Aptivus and viracept), and inhibitors of non-nucleoside reverse transcriptase (Rescriptor, Sustiva and viramune). Non-limiting examples of antiviral agents that can be used in combination with the compounds described herein include, but are not limited to, the (-) - enantiomer of 2-hydroxymethyl-5- (5-fluorocytosin-1-yl) - 1,3-oxathiolane ((-) - FTC); the (-) -enantiomer of 2-hydroxymethyl-5- (cytosin-1-yl) -1, 3-oxathiolane (3TC), carbovir, acyclovir, interferon, famciclovir, penciclovir, AZT, DDI, DDC, L - (- ) -FMAU and D4T. Without attempting to limit the scope of the invention, exemplary methods and their related results are given below according to the embodiments of the present invention. Note that the titles or subtitles may be used in the examples for the convenience of a reader, which in no way should limit the scope of the invention. On the other hand, certain theories are proposed and described in the present, however, they should not be in any way, independently, if they are correct or erroneous, limit the scope of the invention as long as the data are processed, sampled, converted or similar according to the invention without departing from any particular theory or scheme of action. EXAMPLES Example 1: Preparation of 4'-C-ethynyltimidine The 4'-C-ethynyltimidine is prepared according to the literature methods. (Nomura, M et al., J. Med. Chem. 1999, 42, 2901-2908; and Ohrui, H. et al., J. Med. Chem. 2000, 43, 4516-4525). Example 2. Preparation of 4 '-C-ethynyl-5' -0- (dimethoxytrityl) thymidine (10, Figure 2) To a solution of 4'-C-ethynyltimidine (1 mmol) in pyridine (10 ml) is added chloride of dimethoxytrityl (1.2 mmol) at 0 ° C and the resulting solution is stirred for 3 hours. EtOAc (100 ml) is added and the solution is washed with water and dried (Na 2 SO 4). The solvent is evaporated to dryness under reduced pressure. The residue is co-evaporated with toluene (2 x 20 mL) and purified by silica gel column chromatography (5% MeOH in methylene chloride) to give '-C-ethynyl-5' -O- (dimethoxytrityl) Thymidine (10). Example 3. Preparation of 4 '-C-ethynyl-5' -O- (dimethoxytrityl) -2,3 '-anhydrothymidine (11', Figure 2) Add to a solution of 10 (1 mmol) in methylene chloride ( 20 mL) triethylamine (1 mL) and methanesulfonyl chloride (1.2 mmol) and the solution is stirred at room temperature for 16 hours. EtOAc (50 mL) is added and the mixture is washed with water, dried (Na2SO4). The solvent is removed and the residue is dissolved in anhydrous tetrahydrofuran (THF, 20 ml). DBU (3 mmol) is added to the solution and the resulting solution is refluxed for 16 hours. The solution is diluted with EtOAc (50 mL) and washed with brine. Dry the organic solution (Na2SO4) and remove the solvent and purify the residue by silica gel column chromatography (2% MeOH in methylene chloride) to provide compound 11 '. Example 4. Preparation of 4 '-C-ethynyl-5' -O- (dimethoxytrityl) -3'-azido-3'-deoxythymidine (12, X = N3, Figure 2). To a solution of 11 '(1 mmol) in dry DMF (10 mL) is added NaN3 (3 mmol) and the mixture is stirred at 100 ° C for 16 hours. The solvent is evaporated to dryness under reduced pressure. The residue is co-evaporated with toluene (2 x 20 mL) and purified by silica gel column chromatography (20-50% EtOAc in hexanes) to yield 4 '-C-ethynyl-5' -0- ( dimethoxytrityl) -3'-azido-deoxythymidine (12, X = N3). Example 5. Preparation of 4 '-C-ethynyl-3' -azido-3 '-deoxitimidine (la, X = N3, Figure 2). A solution of 4 '-C-ethynyl-5' -0- (dimethoxytrityl) -3'-azido-3'-deoxythymidine (12, X = N3 (1 mmol) in a solution of trifluoroacetic acid in methylene chloride is stirred. (20 ml) at room temperature for 3 hours and neutralized with ammonium hydroxide.The solvent is evaporated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (2-5% MeOH in ethyl chloride). methylene) to give 4 '-C-ethynyl-AZT (la, X = N3) Example 6. Preparation of 4' -C-ethynyl-5 '-O- (dimethoxytrityl) -3'-fluoro-3'-deoxythymidine (12, X = F, Figure 2). To a solution of 11 '(1 mmol) in dry DMF (10 mL) tetrabutylammonium fluoride (TBAF, 3 mmol) is added and the mixture is stirred at 100 ° C for 16 minutes. The solvent is evaporated to dryness under reduced pressure, the residue is coevaporated with toluene (2 x 20 ml) and purified by silica gel column chromatography (20-50% EtOAc in hexanes) to yield 4'C. -etinyl-5 '-0- (dimethoxytrityl) -3' -fluo ro-3 '-deoxymethymidine (12, X = F). Example 7. Preparation of 4 '-C-ethynyl-3'-fluoro-3'-deoxythymidine (la, X = F, Figure 2) A solution of 4' -C-ethynyl-5 '-0- (imethoxytrityl) is stirred ) -3 '-fluoro-3'-deoxythymidine (12, X = F) (1 mmol) in a solution of 1% trifluoroacetic acid in methylene chloride (20 ml) at room temperature for 3 hours and neutralized with hydroxide of ammonium. The solvent is evaporated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (2-5% MeOH in methylene chloride) to give 4'-C-ethynyl-FLCT (la, X = F ). Anti-HIV activity Example 8. MTT method using MT-4 cells A test agent (100 μl) is diluted in a 96-well microplate. The MT-4 cells infected with HIV-1 (strain IIIb, 100 TCID50) and uninfected MT-4 cells are added to the microplate in such a way that the number of cells in each well becomes 10,000. The cells are cultured at 37 ° C for five days. MTT (20 μl, 7.5 mg / ml) is added to each well, and the cells are further cultured for 2-3 hours. The culture medium (120 μl) is sampled, and the MTT termination solution (isopropanol which contains 4% Triton X-100 and 0.04 N HCl) is added to the sample. The mixture is stirred to form formazan, which is dissolved. The absorbance at 540 nm of the solution is measured. Since the absorbance is proportional to the number of viable cells, the concentration of the test agent in which an average value of the absorbance in a test is measured using infected MT-4 cells represents EC50, while the concentration of the test agent in which a mean value of the absorbance in a test is measured using uninfected MT-4 cells represents CC50. Example 9. MAGI assay using He cells at CD4 / LTR-beta-Gal HeLa CD4 / LTR-beta-Gal cells are added to 96 wells in such a way that the number of cells in each well is 10,000. After 12-24 hours, the culture medium is removed, and a diluted test agent (100 μl) is added. A variety of strains of HIV are added (wild strain: WT, drug resistant strain: MDR, M184V, NL4-3, 104pre, and C; each equivalent to 50 of TCID50), and the cells are further cultured for 48 hours. The cells are fixed for five minutes using PBS which contains 1% formaldehyde and 0.2% glutaraldehyde. After the fixed cells are washed with PBS three times, the cells are stained with 0.4 mg / ml X-Gal for one hour, and the number of cells stained with blue from each well is counted under a stereoscopic transmission microscope. The concentration of the test agent in which the cells stained with blue decrease to 50% and 90% in number is represented as EC5o and EC90, respectively. In a manner similar to that used in the MTT method, cytotoxicity is measured by the use of HeLa CD4 / LTR-beta-Gal cells. Anti-HBV activity Example 10. Anti-HBV AD38 assay A HepG2-AD38 cell line is established in a culture medium comprising DMEM-F / 12, 10% fetal bovine serum, 100 IU / ml / 100 μg / ml penicillin / streptomycin, 50 μg / ml kanamycin, 0.3 μg / ml tetracycline, and 200 μg / ml G418. The assay medium for the HepG2-AD38 cell line comprises RPMI-1640, 10% fetal bovine serum, 100 IU / ml / 100 μg / ml penicillin / streptomycin, 50 μg / ml kanamycin and 200 μg / ml G418 . Other materials used for this assay are as follows: phosphate buffered saline (PBS), 96-well bio-coated plates, DNeasy 96 tissue kit (Qiagen), QIAvac 96 vacuum manifold, 96-well reaction plates Micro amp wells (Applied Biosystems), Micro amp optical caps (Applied Biosystems), Tagman Universal PCR Mastex Mix (Applied Biosystems). Sequence detector 7700 (Applied Biosystems), a primer and probe for HBV DNA: forward 1125 nM primer (primer 1), GGA CCC CTG CTC GTG TTA CA; reverse primer 1125 nm (primer 2), GAG AGA AGT CCA CCA CGA GTC TAG A; and 250 nM probe, FAM-TGT TGA CAÁ GAA TCC TCA CAÁ TAC CAC. Method Cell Test: Wells of a biorecovered plate of 96 wells are seeded with the appropriate amount of cells, such as 5 x 10 4 cells / well, and incubated at 37 ° C with 5% C02. After 2 days, the supernatant is carefully removed, and the cell layer is washed with PBS, and subsequently renewed with assay medium with or without test compounds in an appropriate amount (such as 10 μM or in a dose response with a proportion of 1: 3 starting at 10 μM The samples are tested in duplicate The cells are allowed to grow for a further 5 days, in which on day 7, an amount of supernatant, such as 180 μl, is collected and stored in an appropriate container such as in a blue rack included in the DNeasy 96 tissue equipment at either -80 ° C or room temperature depending on whether or not the extraction step is to be performed immediately or at some time after of this.Removal of viral HBV DNA from the supernatant.The supernatant samples on day 7 are either frozen or used as they are.Transfer a proteinase K development solution / ATL buffer, which comprises e 2 ml of Proteinase K and 18 ml of ATL buffer is transferred to the top of the supernatant samples. The tubes are then sealed and mixed by repeated inversion. The tubes are then centrifuged, up to 3000 rpm, in order to collect any solution from the caps, which are subsequently used and referred to as the cap solution. The tubes are incubated at 55 ° C for 15 minutes, and then they are centrifuged up to 3000 rpm again. To each sample, 410 μl of AL / E buffer is added. The tubes are sealed again, placed in a rack, and shaken vigorously for an appropriate amount of time (such as 15 seconds), and the tubes are then centrifuged up to 3000 rpm. At this point the DNeasy 96 plate is placed on top of QIAvac 96 vacuum manifold. The cap solution is then transferred to the DNeasy 96 plate, and the vacuum is applied for an appropriate amount of time. An amount of AWl buffer (such as 500 μL) is added to each well, and then the vacuum is applied again for an appropriate amount of time (such as about 1 minute). A quantity of Shock Absorber AW2 (such as 500 μL) is added to the wells, and vacuum is applied again for a quantity of time (such as 1 minute). The contents of the solution in the wells are then agitated, and the vacuum is then applied for a quantity of time (such as 10 minutes). The DNA is eluted by adding pre-heated AE buffer to each well and subsequently vacuum is added. Real-time PCR Real-time PCR. It is necessary to prepare sufficient HBV primers and probe solution for 200 wells (1500 μl total) by employing the following solution comprising 100 μM primer 1, 100 μm primer 2, 50 μM probe in nuclease-free water. It is also necessary to prepare a sufficient amount of a reaction mixture comprising Universal PCR Master Mix, the HBV primers and the probe solution, and nuclease-free water. To each well of a 96-well optical reaction plate is added an appropriate amount of the reaction mixture and HBV DNA from each sample. The wells are covered with optical caps and then centrifuged for the appropriate amount of time. The plate is placed in a sequence detector (such as a sequence detector 7700), and the reporter is selected by FAM, and the volume parameter is selected for 25 μ. The machine is started and after a certain period of time (approximately 2 hours), the dCt and the reduction in viral load for each test compound are calculated. Example 11. day 8 cytotoxicity assay HepG2 cell lines are established (hepatic), BxPC3 (pancreatic) and CEM (lymphocytic) in an appropriate culture medium. For example, the culture medium for the HepG2 cell line comprises DMEM, 10% fetal bovine serum and 100 IU / ml / 100 μg / ml penicillin / streptomycin. The test medium for BxPC3 and CEM comprises RPMI-1640, 10% fetal bovine serum, and 100 IU / ml / 100 μg / ml penicillin / streptomycin. Methodology. A quantity of 2x dilutions of the drug is added to the wells of a 96-well plate. Add 50 μl of dilutions 2? of drug in a 96-well plate. In each assay, a "no drug" control (medium only) is used to determine the minimum absorbance values and a "cells + medium only" control is used for the maximum absorbance value. A solvent control is also used if the drug is dissolved in DMSO. The cells are counted and resuspended in the appropriate assay medium. It is noted that the cells must be added in 2000 cells per well. New cell suspensions are added to each well and the plate is incubated at 37 ° C with 5% C02 for 8 days. After 8 days of incubation, the MTS dye is added to each well and the plate is incubated for 2 hours at 37 ° C with 5% C02. The plates are then read using an ELISA plate reader at a wavelength of 490 nm. The absorbance of the control is calculated with medium only. The 50% inhibition value (CC5o) is determined by comparing the absorbance in the cell-free control wells with the absorbance in wells containing test drug cells. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (16)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound characterized in that it comprises a β-D- and β-L-nucleoside or a pharmaceutically acceptable salt or prodrug thereof, which has a structure defined by formula (I) or by formula (II) (I) (H) where: X is hydrogen, F, Cl, Br, I, NH2, NHR \ NR4R, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR, S (0) bR4, OH, OR, N3, CN or CF3. Y is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR4, S (0) bR4, OH, OR4, N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R1 is F or N3; Rz is OH, OR ", OC (0) R% OPvOsMxR'yR'z, Pv03vMxR ,, and R:, z, OCH2Pv03vMxR4yR5z, OP (O) (OQ) to (NHR) b, SH, SR4, S (0) bR4, SC (0) R4, NH2, NHC (0) R4, NHR4, NRR5, NHOH, NHOR4, NHNH2, NR4NH2 or NHNHR4; R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (Ci-β) alkyl (Ci-β) substituted with one or three halogens, alkenyl (Ci-e) or alkynyl (C? -) with the proviso that when R1 is N3, R3 is not hydroxymethyl, Z is O, S, CH2 or C = CH2; A is N, CH, O CF, and R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl, M is at least one member selected from group which consists of H +, Na + and K +, v has a value of 1, 2 or 3; x, y and z are independent of each other and have a value of 0, 1, 2, 3 or 4; 0 or 1, b has a value of 1 or 2, and Q is M or R 4.
2. 2. The compound according to the claim 1, characterized in that the nucleoside is a 4 '-C-substituted-3' -fluoro-2 ', 3'-dideoxynucleoside.
3. 3. The compound according to claim 1, characterized in that the nucleoside is a 4 '-C-substituted-3' -azido-2 ', 3'-dideoxynucleoside.
4. 4. The compound according to claim 1, characterized in that the nucleoside is a 4 '-C-ethynyl-3' -fluoro-2 ', 3'-dideoxynucleoside.
5. 5. The compound according to claim 1, characterized in that the nucleoside is a 4 '-C-ethynyl-3' -azido-2 ', 3'-dideoxynucleoside.
6. 6. The compound according to claim 1, characterized in that the nucleoside is a 4 '-C-ethynyl-3' -fluoro-3'-deoxythymidine.
7. 7. The compound in accordance with the claim 1, characterized in that the nucleoside is a 4 '-C-ethynyl-3' -azido-3'-deoxythymidine.
8. 8. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a compound of any of claims 1-7 and a carrier or diluent.
9. 9. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a compound according to any of claims 1-7 and at least one of other antiviral agents.
10. A method for the treatment or prophylaxis of a host infected with the human immunodeficiency virus characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-7, or a pharmaceutically acceptable salt or prodrug thereof. , alone or in combination with another agent.
11. 11. A method for the treatment or prophylaxis of a host infected with the hepatitis B virus characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-7, or a pharmaceutically acceptable salt or prodrug of the same, alone or in combination with another agent.
12. 12. The use of an antivirally effective amount of a compound according to any of claims 1-7 or a pharmaceutically acceptable salt or prodrug thereof.
13. 13. An intermediary of the formula: characterized in that: X is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4, N3, CNO CF3. Y is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4, N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (C6-6), alkyl (C6-6) substituted with one or three halogens, alkenyl (C6-6) or alkynyl (C6-6) with the condition that when R1 is N3, R3 is not hydroxymethyl; Pg is a hydroxyl protecting group; L is a leaving group; and R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl. A process for the preparation of an intermediate according to claim 13, characterized in that it comprises: (a) selectively protecting a 5'-OH with a protecting group, Pg, to form a 5'-0Pg group; (b) activating a 3 '-OH with a leaving group, L, to form a 3'-OL group; (c) reacting a 3'-C with a hydroxide base in order to convert the 3'-C position from a ribo- to xylo- configuration; (d) activating a 3 '-OH which has a xyl configuration with a leaving group, L, to form a group 3 '-OL; (c)

    15. An intermediary characterized because it has the formula: wherein: X is hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NR4NH2, NHNHR4, SH, SR, S (0) R4, S (0) 2R4, OH, OR4, N3, CN or CF3. And it's hydrogen, F, Cl, Br, I, NH2, NHR4, NR4R5, NHOH, NHOR4, NHNH2, NRNH2, NHNHR4, SH, SR4, S (0) R4, S (0) 2R4, OH, OR4, N3, CN, CF3, hydroxymethyl, methyl, optionally substituted or unsubstituted ethyl, optionally substituted or unsubstituted vinyl, optionally substituted or unsubstituted 2-bromovinyl, optionally substituted or unsubstituted ethynyl; R3 is F, cyano, azido, ethynyl, chlorovinyl, fluorovinyl, alkyl (Ci-e), alkyl (C6-6) substituted with one or three halogens, alkenyl (Ci-e) or alkynyl (Ci-e) with the condition that when R1 is N3, R3 is not hydroxymethyl; Pg is a hydroxyl protecting group; and R4 and R5 are the same or different and are lower alkyl, lower alkenyl, carbon acyl 1-17, aryl or aralkyl. 16 A process for the preparation of an intermediate according to claim 15, characterized in that it comprises: (a) activating a 3'-OH of a 5'-O-protected nucleoside with a leaving group L; to form a protected 3 '-OL-5' -0- nucleoside group; followed by (b) treating the 3'-0L-5'-O-protected nucleoside with DBU or DBN; in order to obtain the intermediary; wherein L is selected from the group which consists of a sulfonyl, a trifluorosulfonyl, a substituted sulfonate, and an unsubstituted sulfonate.