MXPA99009253A - Synthesis, anti-human immunodeficiency virus and anti-hepatitis b virus activities of 1,3-oxaselenolane nucleosides - Google Patents

Abstract

A method and composition for the treatment of HIV infection, HBV infection, or abnormal cellular proliferation in humans and other host animals is disclosed that includes the administration of an effective amount of a 1,3-oxaselenolane nucleoside or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

Description

ANTI-VIRUS ACTIVITIES OF HUMAN IMMUNODEFICIENCY AND ANTI-VIRUS OF HEPATITIS B OF THE SYNTHESIS OF 1,3-OXASELENOLAN NUCLEOSID BACKGROUND OF THE INVENTION The American government has rights in this invention as a result of the Investigation of the US Public Health Service. granted by the National Institute of Allergy and Infectious Diseases and the Department of Veterans Affairs, which partially founded the research leading to this invention. This invention is in the area of synthetic nucleosides and is directed specifically to nucleosides of 1,3-oxaselenolane and its pharmaceutical uses, compositions and method of preparation.In 1981, the acquired immunodeficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system and that almost without exception leads to death.In 1983, it was determined that the etiological cause of AIDS is human immunodeficiency virus (HIV) .In 1985, it was reported that 3'-azido- Synthetic nucleoside 3'-deoxythymidine (AZT) inhibits the reproduction of the immunodeficiency virus. human. Since then, several other synthetic nucleosides, including 2 ', 3' -dideoxyinosine (DDI), 2 ', 3' -dideoxycytidine (DDC), 2 ', 3'-dideoxy-2', 3 '-didehydrotimidine (D4T) and (S, 4R) -4- [2-amino-6-cyclopropyl-amino) -9H-purin-9-yl] -2-cyclopentene-1-methanol ("159U89") succinate have proven to be effective against HIV In general, after cellular phosphorylation at 5'-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a strand of viral DNA culture, causing chain termination due to the absence of the 3'-hydroxyl group. They can also alternatively inhibit viral enzyme reverse transcriptase or DNA polymerase. The success of several synthetic nucleosides in the inhibition of HIV replication in vi tro or in vi tro has led several researchers to design and examine nucleosides that substitute a heteroatom for the carbon atom at the 3 'position of the nucleoside. Norbeck, et al. , showed that the (±) -l - [(2ß, 4ß) -2- (hydroxymethyl) -4-dioxolanyl] t imine (referred to as (±) -dioxolane-T) exhibits a modest activity against HIV (EC50 of 20μM in ATH8 cells) and is non-toxic to uninfected control cells at a concentration of 200 μM. Tetrahedron Letters 30 (46), 6246, (1989). European Patent Application Publication No. 0337713 and the US Patent. No. 5,041,449, assigned to BioChem Pharma, Inc. disclose racemic, 2-substituted, 4-substituted 1,3-dioxolanes exhibiting antiviral activity. PCT applications published PCT / US91 / 09124 and PCT / US93 / 08044 disclose purified β-D-1,3-dioxolanyl nucleosides for the treatment of HIV infection. PCT discloses the use of purified β-D-1,3-dioxolanyl nucleosides for the treatment of HBV infection. PCT / US95 / 11464 discloses that (-) - (2S, 4S) -1- (2-hydroxymethyl-1,3-dioxolan-4-yl) cytosine is useful in the treatment of tumors and other abnormal cell proliferation. The U.S. Patent No. 5,047,407 and European Patent Application Publication No. 0382526, both from BioChem Pharma, Inc., disclose that some racemic, 3-substituted, 3-substituted-3-oxo-iola nucleosides have antiviral activity and specifically report that the racemic mixture of 2 - . 2-Hydroxymethyl-5- (cytosin-1-yl) -1,3-oxathiolane (referred to below as BCH-189) has approximately the same activity against HIV as AZT, with less toxicity The U.S. Patent No. 5,539,116 to Liotta, et al. , is directed to the (-) - enantiomer of BCH-189, known as 3TC, which is now marketed for the treatment of HIV in humans in the United States. It has also been reported that cis-2-hydroxymethyl -5- (5-fluorocytosin-1-yl) -1,3-oxat iolane (?, FTC ") has a potent HIV activity Schinazi, et al., "Selective Inhibition of Human Immunodeficiency Virus by Racemates and Enantiomers of cis-5-Fluoro-1 - [2 - (Hydroxymethyl) -1, 3 -Oxathiolane-5-yl] Cytosine" Agents Antimicrobials and Chemotherapy, November 1992, page 2423-2431. See also the U.S. Patent. No. 5,210,085; the Patent of E.U. No. 5,204,466, WO 91/11186 and WO 92/14743. Another virus that causes a serious human health problem is the Hepatitis B virus (referred to below as "HBV"). HBV is the second cause of human cancer, after tobacco. The mechanism by which HBV induces cancer is unknown. It is believed that it can directly drive tumor development or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration, associated with 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, which causes abdominal pain, jaundice and elevated levels of certain enzymes in the blood. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute hepatitis. However, in some patients, high levels of viral antigens persist in the blood for a prolonged or indefinite period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with persistent chronic HBV are more common in developing countries. By mid-1991, there were approximately 225 million chronic HBV carriers in Asia alone and almost 300 million carriers worldwide. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary cancer of the liver.

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 the acquired immunodeficiency syndrome, which explains why infection with HBV is common among patients with AIDS or AIDS-related complexes. However, HBV is more contagious than HIV. Both FTC and 3TC exhibit activity against HBV. See Furman, et al. , "Activities of the Anti-Hepatitis B Virus, Ci totoxicities and Anabolic Profiling of the (-) and (+) Enantiomers of cis-5-Fluoro-l- [2- (Hydroxymethyl) -1,3-oxat iolan- 5 -yl] Cytosine "Antimicrobial Agents y_ Chemotherapy, December 1992, page 2686-2692; and Cheng, et al. , Journal of Biological Chemistry, Volume 267 (20), 13938-13942 (1992). A vaccine derived from human serum has been developed to immunize patients against HBV. However, vaccines have also been produced more recently through genetic engineering and are widely used today. Unfortunately, vaccines can not help those already infected with HBV. Also promising is the daily treatment with a-interferon, a protein created by genetic engineering, but this therapy is only successful in approximately one third of the treated patients. In addition, interferon can not be administered orally. Since the nucleosides of 1,3-dioxolane and 1,3-oxat iolane have exhibited promising antiviral and anticancer activities, it was important to synthesize an isothermal class of 1,3-oxaselenolane nucleoside compounds in search of biologically interesting nucleosides. Despite its structural similarity to nucleosides substituted by 3'-heteroatoms, the synthesis of 1,3-oxaselenolane nucleosides has been evaded since the construction of the oxaselenolane ring is difficult. For this reason, it seems that the nucleosides of 1,3-oxaselenolane have never been reported. In view of the fact that the acquired immunodeficiency syndrome, the complexes related to AIDS and the hepatitis B virus have reached epidemic levels worldwide and have tragic effects in the infected patient, there remains a strong need to provide new pharmaceutical agents effective to treat these illnesses . Accordingly, an object of the present invention is to provide a method and composition for the treatment of human patients infected with HIV. Another object of the present invention is to provide a method and composition for the treatment of human patients or other host animals infected with HBV. A further object of the invention is to provide a method for the synthesis of 1,3-oxaselenolanyl nucleosides. Still a further object of the invention is to provide 1,3-oxaselenolanyl nucleosides and pharmaceutical compositions including 1,3-oxaselenolanyl nucleosides. SUMMARY OF THE INVENTION A method and composition for the treatment of HIV or HBV infection in humans and other host animals is described, which includes the administration of an effective amount of a 1,3-oxaselenolane nucleoside or a pharmaceutically acceptable salt thereof. , optionally in a pharmaceutically acceptable vehicle. In one embodiment, the nucleoside of 1,3- Oxaselenolane has the formula: wherein B is a purine or pyrimidine base and R is hydrogen, acyl or a phosphate ester, including monophosphate, diphosphate or triphosphate. In another embodiment, the 1,3-oxaselenolanyl nucleoside is provided as a lipophilic or hydrophilic prodrug as discussed in more detail below. In another alternative embodiment, the selenium atom is oxidized in the molecule. Preferred 1,3-oxaselenolanyl nucleosides are those that exhibit anti-HIV or HBV activity at a concentration not greater than about 5 micromolar and more preferably about 1 micromolar or less in an in vitro assay such as that described in detail in this application . For the treatment of HIV and HBV, it is also preferred that the 1,3-oxaselenolanyl nucleoside exhibits an ICS0 toxicity in an in vitro assay such as that described herein of more than 50 micromolar and more preferably, approximately 100 micromolar or more . The nucleoside of 1,3-oxaselenolane is preferably either a β-L-nucleoside or a β-D- nucleoside, as an isolated enantiomer. In one embodiment, the nucleoside is a β-L- or β-D- nucleoside in substantially pure form, ie, substantially in the absence of the corresponding β-D- or β-L- nucleoside. Preferred compounds are 2-hydroxymethyl-4- (N-5'-cyclin-1'-yl) -1,3-oxaselenolane and 2-hydroxymethyl-4 - (N-5'-fluorocytosine-1'-yl) - 1, 3 -oxaselenolane. It has been found that the (-) - β-L-enantiomer isolated from these nucleosides is more potent than its β-D counterparts. However, the (+) - enantiomers of these compounds are not toxic to CEM cells. In another embodiment, the active compound or its derivative or salt may be administered in combination or in alternation with another antiviral agent, such as another anti-HIV agent or anti-HBV agent, as described in more detail in Section IV. In general, during alternation therapy, an effective dose of each agent is administered serially, whereas in combination therapy, an effective dose of two or more agents is administered together. Doses 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 should also be noted that the dose values will also vary with the severity of the condition being alleviated. It should be further understood that for any particular subject, the specific dosage schedules and schedules should be adjusted over time, according to the individual needs and professional judgment of the person administering or supervising the administration of the compositions. The compounds can also be used to treat equine infectious anemia virus (EIAV), feline immunodeficiency virus and simian immunodeficiency virus. (Wang, S., Montelaro, R., Schinazi, RR, Jagerski, B. and Mellors, JW,: Activity of nucleoside and non-nucleoside reverse transcriptase inhibitors (NNRTI) against equine infectious anemia virus (EIAV). First National Conference of Human Retroviruses and Related Infections, Washington, DC, Dec. 12-16, 1993, Sellon, DC, Equine Infectious Anemia, Vet. Clin, North Am. Equine Pract. United States, 9: 321-336, 1993; Philpott, MS, Ebner, JP, Hoover, EA, Evaluation of 9- (2- Therapy phosphonylmethoxyethyl) adenine for the feline immunodeficiency virus by the use of a quantitative polymerase chain rean, Vet. Immunol. Immunopathol. 35: 155166, 1992. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an illustration of a process for the preparation of a 1,3-oxaselenolanyl nucleoside according to the present invention, as described in Example 1. Figure 2 is an illustration of a process for the preparation of 1,3-oxaselenolanyl ß-D and ß-L nucleosides, according to the present invention, as described in Example 3. Figure 3 is the crystal structure of lightning X of [2- (1 R, 2'S, 5 'R) -ment il- (5-one-1,3-oxaselenolane)] -L-carboxylate. Figure 4 is an illustration of the structures of the enantiomers of (+) - ß- Se -ddC, (-) - β-Se-ddC, (+) - β-Se-FddC and (-) - ß- Se - FddC. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "isolated enantiomer" refers to a nucleoside composition that includes at least about 95% to 100%, or more preferably about 97% of a single enantiomer of that nucleoside. The term "substantially pure form" refers to a nucleoside composition of one enantiomer that includes no more than about 5% w / w of the other enantiomer, more preferably no more than about 2% and more preferably less than about 1% w / w. The term "purine" or "pyrimidine base" includes, without limitation, N-allylpurines, Ne acylpurines, N6-benzylpurine, N6-halopurine, Nfc vinylpurine, N6-acetylenic purine, N6-acylpurine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylphenines, N4-alkylpyrimidines, N4-acylpyrimidines, N4-benzylpurine, N4-halopyrimidines, N4-vinylpyrimidines, N4-pyrimidines acetylene, N4-acyl pyrimidines, N4-hydroxyalkyl pyrimidines, N6-thioalkyl pyrimidines, thymine, cytosine, -azapyrimidine, including 6 -azacytosine, 2- and / or 4-mercaptopyrimidine, uracil, C5-alkylpyrimidines, C5-benzylpyrimidines, halopyrimidines, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5- amidopyrimidine, C5-cyanopyrimidine, Cs-ni ropyrimidine, C5-amino-iridine, alkylpurines, N2-alkyl-6-thiopurines, azacytidinyl, 5-azauracilyl, trazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. The oxygen and nitrogen funnal groups in the base can be protected as needed or desired. Suitable proteg groups are well known to those skilled in the art and include trimethylsilyl, -dimethyl-hexylsilyl, t-butyldildyl-ylsilyl, and t-butyldiphenylsilyl, trifly, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl and phenyl. -toluenosul fonilo. Preferred bases include cytosine, 5-fluorocytosine, uracil, thymine, adenine, guanine, xanthine, 2,6-diaminopurine, 6-aminopurine and 6-chloropurine. The term alkyl, as used herein, unless otherwise specified, refers to a saturated, straight, branched or cyclic hydrocarbon, primary, secondary or tertiary, typically from C1 to C18 and specifically includes methyl, ethyl , propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl . The alkyl group can be optionally substituted with one or more units selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulphonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected, as necessary, as is known from those skilled in the art, for example, as contemplated in Greene, et al. , "Protee Groups in Organic Synthesis", John Wiley and Sons, Second Edition, 1991, incorporated herein by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a saturated, straight or branched alkyl group, from Cx to C4. 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 avoid further reaction or for other purposes. Those skilled in the art of organic synthesis know a wide variety of oxygen and nitrogen protecting groups. The term "aryl", as used herein and unless otherwise specified, refers to phenyl, biphenyl or naphthyl and preferably phenyl. The aryl group may be optionally substituted with one or more units selected from the group consisting of hydroxyl, halo, alkyl, alkenyl, alkynyl, alkaryl, aralkyl, amino, alkylamino, alkoxy, aryloxy, nitro, cyano, sulphonic acid, sulfate, phosphonic acid , phosphate or phosphonate, either unprotected or protected, as necessary, as is known to those skilled in the art, for example, as contemplated in Greene, et al. , "Protective Groups in Organic Synthesis", John Wiley and Sons, Second Edition, 1991. The term "alkaryl" or "alkylaryl" refers to an alkyl group with an aryl substituent atom. The term "aralkyl" or "arylalkyl" refers to an aryl group with an alkyl substituent atom. The term "halo", as used herein, includes chlorine, bromine, iodine and fluoro. The term "acyl" refers to the unit of the formula -C (0) R ', wherein R' is alkyl, aryl, alkaryl, aralkyl, heteroaromatic, alkoxyalkyl including methoxymethyl; arylalkyl including benzyl; aryloxyalkyl such as phenoxymethyl; aril which includes phenyl optionally substituted with halogen, C to C4 alkyl or C ± a C4 alkoxy, or the residue of an amino acid. As used herein, an "exit group" means a functional group that is separated from the molecule to which it is subjected under appropriate conditions. The term "amino acid" includes naturally occurring and synthetic amino acids, and includes without limitation, alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl , argininyl and histidinyl. The term "heteroaryl" or "heteroaromatic", as used herein, refers to an aromatic unit that includes at least one sulfur, oxygen or nitrogen in the aromatic ring. Non-limiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, and soquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxantyl and pteridinyl. The oxygen and nitrogen functional groups in the heterocyclic base can be protected as desired or necessary. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylsilylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trifly or substituted triflyl, alkyl groups, acyl groups such as acetyl and propionyl, methylsulphyl and p-toluene sulphonyl. The term "lipophilic prodrug" refers to a 1,3-oxaselenolanyl nucleoside which contains a covalent substituent atom that can be separated at the 5'-hydroxyl position which makes the nucleoside more lipophilic than the main nucleoside with a 5'-hydroxy lo group. The term "hydrophilic prodrug" refers to a 1,3-oxaselenolanyl nucleoside containing a covalent substituent atom at the 5'-hydroxyl position that renders the nucleoside more hydrophilic than the main nucleoside with a 5'- group. hydroxyl. The invention, as set forth herein, is a method and composition for the treatment of HIV or HBV infection and infections of other viruses with similar reproduction, in humans or other host animals, which includes the administration of an effective amount of nucleoside. of 1,3-oxaselenolanyl, a pharmaceutically acceptable derivative thereof, including a 1,3-oxaselenolanyl nucleoside with a 5 'leaving group, including an acylated or phosphorylated derivative or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically vehicle acceptable. The compounds of this invention either possess antiviral activity, such as anti-HIV-1, anti-HIV-2, anti-HBV or anti-simian immunodeficiency virus (anti-SIV) activity by themselves or are metabolized into a compound that exhibits antiviral activity. The exposed compounds or their pharmaceutically acceptable salts or derivatives, or pharmaceutically acceptable formulations containing these compounds, are useful in the prevention and treatment of HIV infections and other related conditions such as complexes.

Related to AIDS (ARC), 1 persistent generalized infadenopathy (PGL), neurological conditions related to AIDS, anti-HIV positive antibody and HIV positive 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 who have anti-HIV antibodies or HIV-positive antigens or who have been exposed to HIV. The compound or its pharmaceutically acceptable salts or derivatives, or pharmaceutically acceptable formulations containing the compound or its derivatives or salts, is also useful in the prevention and treatment of HBV infections and other related conditions such as anti-HBV antibody conditions. positive and positive HBV, chronic inflammation of the liver caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue. These compounds or formulations can also be used prophylactically to prevent or delay the progression of clinical disease in individuals with anti-HBV antibodies or antigens. of HBV positive or who have been exposed to HBV. The compound can be converted to a pharmaceutically acceptable ester by reaction with appropriate esterification agents, for example, an acid halide or anhydride. The compound or its 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 main compound, for example, by hydrolysis. In summary, the present invention includes the following features: (a) nucleosides of 1,3-oxaselenolane as outlined above, and derivatives and pharmaceutically acceptable salts thereof; (b) 1,3-oxaselenolane nucleosides, and the pharmaceutically acceptable derivatives and salts thereof for use in medical therapy, for example, for the treatment or prophylaxis of an HIV or HBV infection; (c) the use of nucleosides of 1,3-oxaselenolane and the derivatives and pharmaceutically acceptable salts thereof in the preparation of a medication for the treatment of an HIV or HBV infection; (d) pharmaceutical formulations comprising 1,3-oxaselenolane nucleosides or a pharmaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable carrier or diluent; (e) processes for preparation. of 1,3-oxaselenolane nucleosides; and (f) the use of 1/3-oxaselenolanyl nucleosides in the treatment of viral infections by administration in combination or alternation with another antiviral agent. I. Active Compound and Derivatives and Physiologically Acceptable Salts thereof The active compounds set forth herein are 1,3-oxaselenolane nucleosides, in the racemic form or as isolated enantiomers. The active compound can be administered as any derivative which after its administration to the container is capable of providing, directly or indirectly, the parent compound or which exhibits activity by itself. Non-limiting examples are pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts") and the acylated or alkylated derivatives of 5 'and N4pyrimidine or Nd-purine of the active compound (alternatively referred to as "physiologically active derivatives"). In one embodiment, the acyl group is a carboxylic acid ester in which the carbonyl-free unit of the ester group is selected from alkyl or lower alkyl, straight, branched or cyclic, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl ilo, aryl including optionally substituted phenyl. with halogen, C to C4 alkyl or C alkoxy? to C4, sulfonate esters such as alkyl or aralkyl, sulfonyl including methanesulfonyl, phosphate, including but not limited to, mono, di or triphosphate, trityl or monomethoxytitroyl ester, substituted benzyl, tialkyl silyl (eg, dimethyl-5-butylsilyl) ) or difenilmet ilsi 1 ilo. The aryl groups in the esters optionally comprise a phenyl group. Modifications of the active compound, and especially in N4pyrimidinyl or N6purine and the 5'-O positions, can affect the bioavailability and speed of metabolism of the active species, thus providing control in the supply of the active species. In addition, the modifications can affect the antiviral activity of the compound, increasing in some cases the activity on the main compound. This can be easily determined by preparing the derivative and examining its antiviral activity according to the methods described herein or other methods known to those skilled in the art. Nucleotide Prodroqas Any of the nucleotides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or to otherwise alter the properties of the nucleoside. Several nucleotide prodrug ligands are known. 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 groups of substituent atoms that can replace one or more hydrogens in the phosphate unit are alkyl, aryl, spheroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, An ti vi ral Research, 27 (1995) 1-17. Any of these can be used in combination with the exposed nucleosides to achieve a desired effect. In one embodiment, the 1,3-oxaselenolanyl nucleoside is provided as a lipophilic 5 '-hydroxyl prodrug. The non-limiting examples of the US patents which exhibit suitable lipophilic substituent atoms that can be covalently incorporated into the nucleoside, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include the US Patents. Nos. 5,149,794 (Sept. 22, 1992, Yatvin, et al.); 5,194,654 (March 16, 1993, Hostetler, et al.); 5,223,263 (June 29, 1993, Hostetler, et al.); 5,256,641 (Oct. 26, 1993, Yatvin, et al.); 5,411,947 (May 2, 1995, Hostetler, et al.); 5,463,092 (Oct. 31, 1995, Hostetler, et al.); 5,543,389 (August 6, 1996, Yatvin, et al.); 5,543,390 (August 6, 1996, Yatvin, et al.); 5,543,391 (August 6, 1996, Yatvin, et al.); and 5,554,728 (Sept. 10, 1996, Basava, et al.), all of which are incorporated herein by reference. Foreign patent applications that expose lipophilic substituent atoms that can annexed to the 1,3-oxaselenolanyl nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO / 15132, EP 0350287, EP 93917054.4, and WO 91/19721. Additional non-limiting examples of 1,3-oxaselenolanyl nucleoside derivatives are those containing substituent atoms as described in the following publications. 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Zabol 13, 47-48 (chem Abstr 72, 212); Robins, R.K. (1984) The potential of nucleotide analogs as inhibitors of retroviruses and tumors. Pharm. Res 11-18; Rosowsky, A., Kim, S.H., Ross and J. Wick, M.M. (1982) Lipophilic 5 '- (alkyl phosphate) esters of 1-β-D-arabinofuranosylcytosine and its derivatives of N4-ac i l and and 2, 2' -anhydro-3 ', 0-acyl as potential prodrugs. J. Med. Chem. 25, 171-178; Ross, W. (1961) Increased sensitivity of walker results to aromatic nitrogen mustards containing basic side chains that follow glucose pretreatment. Biochem. Pharm. 8, 235-240; Ryu, E.K., Ross, R.J., Matsushita, T., MacCoss, M., Hong, C.I. and West, C.R. (1982). Phospholipid-nucleoside conjugates 3. Synthesis and preliminary biological evaluation of 5'-diphosphate [-], 2-diacylglycolenes of 1-β-D-arabinofuranosylcytosine. J. Med. Chem. 25, 1322-1329; Saffhill, R. and Hume, W.J. (1986) The degradation of 5-iododeoxyurindine and 5-bromoeoxiuridine by serum from different sources and its consequences for the use of these compounds for incorporation into DNA. Chem. Biol. Interact. 57, 347-355; Saneyoshi, M., Morozumi, M., Kodama, K., Machida, J., Kuninaka, A. and Yoshino, H. (1980) Nucleosides and synthetic nucleotides XVI. Synthesis and biological evaluations of a series of 5 '-alkyl or arylphosphates of 1-β-D-arabinofuranosilcitosina. Chem. Pharm. Bull. 28, 2915-2923; Sastry, J.K., Nehete, P.N., Khan, S., Nowak, B.J., Plunkett, W., Arlinghaus, R.B. and Farquhar, D. (1992) 5'-membrane-permeable membrane-bound dideoxyuridine analogue that inhibits infection by human immunodeficiency virus. Mol. Pharmacol. 41, 441-445; Shaw, J.P., Jones, R.J., Arimilli, M.N., Louie, M.S., Lee, W.A. and Cundy, K.C. (1994) Oral bioavailability of PMEA from PMEA prodrugs in male Sprague-Dawley rats. 9th Annual AAPS Meeting. San Diego, CA (Abstract). Shuto, S., Ueda, S., Imamura, S., Fukukuawa, K., Matsuda, A. and Ueda, T. (1987) An easy synthesis of a 5'-phosphatidylnucleoside stage by a two-phase enzymatic reaction . Tetrahedron Lett. 28, 199-202; Shuti, S., Itoh, H., Ueda, S., Imamura, S., Kukukawa, K., Tsujino, M., Matsuda, A. and Ueda, T. (1988) An easy 5 'enzyme synthesis - (3-sn-phosphatidyl) nucleosides and their antileukemic activities. Chem. Pharm. Bull. 36, 209-217. A group of preferred phosphate prodrug is the group S-acyl -2-t ioet ilo, also referred to as "SATE". II. Preparation of Active Compounds To date, the production of 1,3-oxaselanolanyls nucleosides has been avoided due to the difficulties encountered in the construction of the 1,3-oxaselenolane ring. A process for the production of this ring is now provided. In Figure 1, one modality of the process is illustrated. Processes are also provided for the preparation of isolated 1,3-oxaselenolanyl (ie, 2R, 5S) nucleosides of β-D (ie, 2S, 5R) and β-L. Figure 2 illustrates an example of this process. In Figure 1 the numbering scheme for the compounds used in the following Examples is provided.

Example 1 Preparation of the 1,3-oxaselenolane ring Selenocyanate was prepared by the Kirby method of excellent production. In the first step, the ethylbromoacetate (BrCH2C02Et) reacts with selenyl acetate of potassium in alcohol to form selenocyanate 2. In order to build lactone 5, it was initially attempted to reduce selenocyanate 2 with NaBH4 and hydrolyze the resulting ester with NaOh aqueous to the acetic acid of selenol, which could be used for the construction of the ring system of oxaselenolano 5. However, selenol acetic acid decomposes during acidification with Hcl at pH 2. It has been reported that selenoles can easily be oxidized by oxygen in the air to stabilize the dimers that can be reduced back to selenoles by H3P02. It was discovered that the reduction of the bis (selenoacetic acid) to selenol as well as the iteration can take place in a reaction of a crucible without the isolation of the intermediates. In this manner, dimer 3 was prepared at 81% produced by reflux 1 with KSeCN in ethanol for 1 hour, followed by reduction with NaBH4 at 0 ° C for 20-30 minutes. Compared to the recently reported procedure for the preparation of diselenides, this method has the advantages of milder reaction conditions, high production and easier preparation. The lactone 5 was then prepared at 33% produced by hydrolysis of 3 with reflux of aqueous acetic acid (50%) for 24 hours, followed by reduction to acetic acid of selenol with H3P02, which was condensed in itself with 2-benzoyloxy-acetaldehyde in the presence of H3P02 under nitrogen. For the reduction of lactone 5, it was found that DIBAL-H can selectively reduce the lactone on the ester in THF, while no selectivity was observed in toluene. In this way, sugar acetate 7 was prepared by reduction of DIBAL-H of 5 in THF, followed by acetylation in itself with acetic anhydride. The condensation of acetate 7, without purification, with silylated bases in the presence of SnCl 4 or TMSOTf, gave inseparable mixtures of a- and β-8a and 8b isomers. Removal of the benzoyl protecting group of 8a and 8b by methylamine or ammonia in methanol gave the final nucleosides as a mixture of / β The nucleoside of acytosin was obtained by repeated recrystallization of the a / β mixture from MeOH / Et20 and then methanol, while the β-cytosine nucleoside (9a) was obtained by HPLC separation of the main liquor (C18-Column, 20% MeOH in H20). The ß and α-5-fluoro-cytosine nucleosides were obtained by chromatographically separating the silicon dioxide from the a / β mixture. The structures of the synthesized selenolane nucleosides are confirmed by elemental analysis, NMR of 1H and 13C. Stereochemical titrations were determined based on the 2D-NOESY experiments in which a correlation was observed between 2'-H and 5'-H of the β-isomer 9b while an absence of this correlation was observed in an a-isomer 10b . Stereochemistry was also supported by upward shifts of 2'H at 9a and 9b compared to 10a and 10b due to deprotection of the heterocyclic bases. Stereochemistry Since the 1 'and 4' carbons of the 1, 3-oxaselenolanil unit of the nucleoside are chiral, their substituent atoms other than hydrogen (the pyrimidine or purine base and the CHOR groups, respectively) can be either cis (on the same side) or trans (on opposite sides) with respect to the ring sugar system. Accordingly, the four optical isomers are represented by the following configurations (when the sugar unit is oriented in a horizontal plane such that the oxygen atom is in the back): cis (with both groups "up", which corresponds to the configuration of the naturally occurring nucleosides), cis (with both groups "down", which is a configuration not naturally occurring), trans (with the substituent atom C2 '"up" and the substituent atom C4' "down"), and trans (with the substituent atom C2 '"below" and the substituent atom C4' "above"). The "D-nucleosides" are cis nucleosides in a natural configuration and the "L-nucleosides" are cis nucleosides in the non-naturally occurring configuration. The nucleoside enantiomers of 1,3-oxaselenolanyl were obtained in two ways; by chiral chromatography of the nucleoside as described in Example 2 and by fractional crystallization of L-menthol 1,3-oxaselenolane disastereomers, followed by condensation of the resolved 1,3-oxaselenolanyl nucleoside, with the desired base in the presence of a Lewis acid that does not racemize the oxaselenolane ring. Example 2 Resolution of β-D and β-L enantiomers of 2-hydroxymethyl-4- (n-5 '-cynin-1' -yl) -1,3-oxaselenolane and 2-hydroxymethyl-4 - (n-5 '- fluoroci osin-1 '-il) -1,3-oxaselenolane by chiral chromatography 2-Hydroxymethyl -4 - (n-5'-cyclin-1'-yl) -1, 3 -oxaselenolane and 2-hydroxymethyl-4 - (N- 5 '-fluorocytosin-1'-yl) -1,3 -oxaselenolane were resolved by chiral chromatography. The compound (racemic, ca. 2 mg) was dissolved in a minimum amount (ca. 400 μL) of methanol (HPLC grade). The following conditions were used for resolution: Waters HPLC system; Column: Chiralpak AS 4.6 x 250 mm; Mobile phase: 2-propanol. Flow rate: 0.80 mL / min; Detector: UV-260 nm; Dew gas: Helium; Spray rate: 25 mL / min / solvent container; Injection quantity: 20 μL of the solution each time; Retention moments; (-) - (2S, 5R) -β-L-2 ', 3'-dideoxy-3'-seleno-cytidine, 5.50 min; (+) - (2R, 5S) -β-D-2 ', 3'-dideoxy-3'-seleno-cytidine, 6.92 min; (-) - (2S, 5R) -β-L-2 ', 3'-dideoxy-5-fluoro-3'-seleno-cytidine, 5.97 min; (+) - (2R, 5S) -β-D-2 ', 3'-dideoxy-5-fluoro-3'-seleno-cytidine, 9.62 min. The optical purities of the resolved compounds were > 95% us Example 3 Resolution of β-D and β-L enantiomers of 1,3-oxaselenolanyl intermediates by conversion to diastereomers, followed by separation of diastereomers by fractional crystallization (-) -L-mentholcarboxial was added to a mixture of (-) -L-menthol (30 g, 0.2 mol) and gluoxilic acid (36.8 g, 0.4 mol) in toluene (1000 ml) p-TsOH (5 g) and the reaction mixture was stirred at 100 C for 3 hours. When the reaction was over, the p-TsOH was neutralized with Et3N and evaporated to dryness. The residue was dissolved in CHC13 (500 mL), rinsed with water (3x500 mL), the organic layer was collected, dried (Na2SO4) and evaporated. The oil was crystallized from oil to give either (-) -L-mentholcarboxial as white crystals 20 g (50%): mp 82 ° C; XH NMR (CHC13) d 9.40 (s, 1H, CHO), 4. 78 (dt, J = 4.45, 11 Hz, 1H, 1-H), 0.75-2.03 (m, 19H); 13C NMR (CHC13) d 184.41, 170.22, 87.13, 46. 79, 40.40, 34.00, 31.42, 26.11, 23.28, 21.94, . 68, 16.15. Anal. Caled for C12H20O3: C, 67.89; H, 9.50; Found: C, 67.65; H, 9.67. M / S m / e 212.3 (M +). [2- (1 R, 2'S, 5'R) -mentyl- (5-one-l, 3-oxaselenolane)] - L-carboxylate (11) and [2 - (1 'R, 2' S, 5 'R) -mentyl - (5-one-1, 3 -oxaselenolan-)] -D-carboxylate. To a solution of (-) -L-mentholcarboxial (6.4 g, 30 mmol) in toluene (100 ml) was added (SeCH2COOH) 2 (4.15 g, 15 mmol) and the reaction mixture was heated slowly to 100 ° C under an argon atmosphere with stirring. Hypophosphorous acid (50% water solution, 2.7 ml) was added dropwise for one hour. The reaction mixture was then re-flowed for one hour with vigorous stirring under an argon atmosphere. The reaction mixture was evaporated to 20 mL, diluted with EtOAc (250 mL), and rinsed with water (3 x 500 mL). The organic layer was collected, dried (Na2SQ4) and evaporated. The residue was purified by column chromatography on Si02 using the mixture EtOAc-Hex (1:10, V / V) as eluent, to give 11 as a solid of 3.9. g (77.6%). Crystallization of the mixture compounds from hexanes at room temperature gave 11 as fine colorless needles: mp 106.5 ° C; [a] 25D = 59.86 ° (c 0.5, CHCL3); XH NMR (CHC13) d 5.83 (s, 1H, 2'-H), 4.77 (dt, J = 4.45, 12 Hz, 1H, 1-H), 3.97 (d, J = 15.34 Hz, 1H, 4'- Hb), 3.67 (dt, J = 15.35 Hz, 4J = 21.17 Hz, 1H, 4'-H3), 0.75-2.03 (m, 19H); 13C NMR (CHC13) d 173.97, 168.67, 76.88, 63.84, 47.07, 40.46, 34.02, 31.38, 26.07, 23.23, 22.65, 21.93, 20.71, 16.11. Anal. Caled for C14H2204Se: C, 50.45; H, 6.65; Found: C, 50.65; H, 6.62. M / S m / e 333 (M +). Main crystallization liquid at -5 ° C; [α] 25D = 111.71 ° (c 0.5, CHCL3); XH NMR (CHC13) d 5.83 (s, 1H, 2'-H), 4.78 (dt, .7 = 4.45, 12 Hz, 1H, 1-H), 3.95 (d, .7 = 15.41 Hz, 1H, 4 '-Ha), 3.68 (dt, "= 15.45 Hz, J" = 19.35 Hz, 1H, 4'-Ha), 0.75-2.03 (m, 19H); 13C NMR (CHC13) d 173.98, 168.63, 76.15, 63.76, 46.95, 39.88, 34.01, 31.32, 26.22, 23.24, 22.98, 21.94, 20.74, 16.14. Anal. Caled for C14H2204Se: C, 50.45; H, 6.65; Found: C, 50.47; H, 6.63. M / S m / e 333 (M +). 1-ß-L- (2 '-hydroxymethyl-1,3' -oxaselenolan-5 'yl) -5-fluorocytosine (15) and 1-α- (2' -hydroxymethyl-1 ', 3'-oxaselenolane- 5 '-il) -5-fluorocytosine (16). To a solution of lithium tri-ert-butoxyaluminohydride (6 mmol, 6 ml of 1M solution in THF) of the lactone in solution 11 (1 g, 3.33 mmol) in the 5 ml, THF was added dropwise to 10 ° C for one hour with stirring under an argon atmosphere. Then acetic anhydride (2 g, 20 mmol) was added slowly with stirring at -5-0 ° C. The reaction mixture was stirred additionally for one hour, diluted with EtOAc (100 ml), rinsed with water (3x100 ml), dried (Na 2 SO 4) and concentrated to dryness to give a crude 5'-acetate 13. The acetate of sugar 13 was dissolved in CH2C12 (5 ml) and added slowly to silylated 5-flurocytosine, prepared by stirring the mixture of 5-fluorocytosine (0.34 g, 2.63 mmol), 2, 4, 6-col idine (0.8 mi, 6.61 mmol) and t rifuloromethansulfonate of tert-butyldimethylsilyl (1.32 g, 5.08 mmol) for one hour under an argon atmosphere. To the resulting mixture was added iodotrimet ilsilane (0.35 g, 1.75 mmol), stirred at room temperature for 18 hours, diluted with CHC13 (100 mL), Na2S203 aqueous (100 ml), rinsed with water, dried (Na2S04) and concentrated until drought. The residue was purified by flash chromatography on silicon dioxide, using CHC13 as eluent to give crude 13 as a solid (0.15 g, 11.2%).

XH NMR (CHC13) d 8.35 (d, J "= 6.3 Hz, 1H, 6-H), 7.55, 7. 53 (2xbr s, 2H, NH2), 6.45 (M, 1-H, 5'H), 6.14 (m, 1H, 2'-H), 4.79 (m, 1H, 1-H), 3.66 (m, 2H, 6'-H). A solution of compound 14 (0.15 g, 0.33 mmol) in THF (lOml) at room temperature under argon for one hour. The reaction mixture was further stirred 1 hour, quenched with MeOH (5 mL) and the resulting mixture applied to a short column with silicon dioxide. The column was eluted with the mixture EtOAc -Hex-MeOH (1: 1: 1, V / V, 100 mi). The eluent was concentrated to dryness and resulted in a purified solid on SiO2, using CHCl3-EtOH (20: 1, V / V) as eluent to give the mixture of nucleosides ß-L- (15) and a-L- (16) as a white solid of 0.033 g (34%). The mixture was re-separated in the column on Si02 using as eluent the mixture of four solvents EtOAc -Hex-CHC13 -EtOH (5: 5: 2: 1, V / V). L-ß-L- (2 '-hydroxymethyl-1', 3'-oxaselenolan-5 '-yl) -5-f luoro cytosine (15). White solid (0.01 g, 10.2%); mp 186-189 ° C (MeOH); [α] 25 D = -55.69 ° (c 0.35, MEOH); UV (H2))? Max 280.0 nm (e 10646, pH2), 280.0 nm (e 7764, pH 11); 1R NMR (DMSO-d6) d 8.07 (d, .7 = 7.1 Hz, 1H, 6-H), 7.92, 7.67 (2xbr s, 2H, NH2, exchangeable D20), 6.06 (t, J "= 2.96 Hz, 1-H, 5'H), 5.42 (t, J = 4.82 Hz, 1H, 2'H), 5.34 (t, J "= 5.68 Hz, 1H, OH, exchangeable D20), 3.81 (m, 1H , 6 '-Ha); 3.68 (m, 1H, 6 '-Hb), 3.39 (dd, J "= 4.84 Hz, 1H, 4' -Hb), 3.08 (dd, .7 = 8.11 Hz, 1H, 4 '-Ha); 13C NMR (DMSO-d6) d 157.7 (C = 0), 153.3 (4-C), 137.6 (6-C), 135.2 (5-C), 88.3 (5'-C), 78.2 (2'-C), 64.0 (6 '-C), 28.9 (4' - C); Anal. Caled for C8H10O3N3FSe: C, 32.67; H, 3.43, N 14.29; Found: C, 32.62; H, 3.51, N, 14.41; M / S m / e 295 (M +). 1-a-L- (2 '-hydroxymethyl-1', 3 '-oxaselenolan-5' -yl) -5-fluorocytosine (16). White solid (0.013 g, 13.2%); mp 193-195 ° C (MeOH); [a] 2SD = + 84.20 ° (c 0.26, MEOH); UV (H20)? Max 279.5 nm (e 7638, pH 7), 287.5 nm (e 9015, pH 2); 281.0 nm (e6929, pH 11); H NMR (DMSO-d6) d 7. 91 (d, J = 7.1 Hz, 1H, 6-H), 7.88, 7.63 (2xbr s, 2H, NH2, exchangeable D20), 6.35 (t, J = 4.95 Hz, 1-H, 5'-H), 5.63 (dd, J = 4.83 Hz, 1H, 2'-H), 5.28 (t, J "= 5.67 Hz, 1H, OH, exchangeable D20), 3.70 (m, 1H, 6'-Ha); 3.53 (m, 1H, 6'-Hb), 3.47 (dd, J = 4.82 Hz, 1H, -Ha) 3.24 (dd, J = 7 Hz 1H, • H h 'i' C NMR (DMSO-d6) d 157.8 (C = 0), 153.2 (4-C), 137.3 (6-C), 134.9 (5-C), 88.6 (5'-C), 80.9 (2'-c), 65.5 (6'-C), 29.4 (4'-C); Anal. Caled for C8H10O3N3FSe: C, 32.67, H, 3.43, N, 14.29; Found: C, 32.59; H, 3.49, N, 14.20; M / S m / e 295 (M +). The synthesis of nucleosides 8 and 9 has been carried out in the same way from a lactone 3 (1 g, 3.33 mmol) to give 1-β-D- (2 '-hydroxymethyl-1', 3 '- oxaselenolan-5'-yl) -5-fluorocytosine 8. White solid (0.007 g, 8.5%); mp 186-189 ° C (meOH); [a] 5D = + 56.21 ° (c 0.33, MeOH); UV (H20)? Max 280.0 nm (e 8576, pH 7), 289.0 nm (e 10456, pH 2); 280.0 nm (e7795, pH 11): 1H NMR (DMS0-d6) d 8.07 (d, J = 7.1 Hz, 1H, 6-H), 7.92, 7.67 (2x br s, 2H, NH2, exchangeable D20), 6.06 (5, J "= 2.96 Hz, 1-H, 5 '-H), 5.42 (5, J" = 4.82 Hz, 1-H, 2' -H), 5.34 (5, J "= 5.68 Hz, 1H , OH, exchangeable D20), 3.81 (m, 1H, 6 '-Ha), 3.68 (m, 1H, 6' -Hb), 3.39 (dd, J "= 4.84 Hz, 1H, 4 '-Hb), 3.08 (dd, .7 = 8.11 Hz, 1H, 4 '-Ha); 13C NMR (DMSO-d6) d 157.7 (C = 0), 153.3 (4-C), 137.6 (6-C), 135.2 (5-C), 88.3 (5'-C), 78.2 (2'-C) ), 64.0 (6 '- C), 28.9 (4' - C); Anal. Caled for C8H10O3N3FSe: C, 32.67; H, 3.43, N 14.29; Found: C, 32.57; H, 3.39, N, 14.35; M / S m / e 295 (M +). 1-a-D- (2 '-hydroxymethyl-1', 3'-oxaselenolan-5'-yl) -5-f luoro cyclosine 9. White solid (0.01 g, 10%); mp 193 - 195 ° C (MeOH); [a] 5D = -85.49 ° (c 0.31, MeOH); UV (H20)? Max 279.5 nm (e 7644, pH 7), 287.5 nm (e 9067, pH 2), 281.0 nm (e 6983, Ph 11); * H NMR (DMSO-d6) d 7.91 (d, .7 = 7.1 Hz, 1H, 6-H), 7.88, 7.63 (2xbr s, SH, NH2, interchangeable D20), 6.35 (5, J "= 4.95 Hz , 1-H, 5 '-H), 5.63 (DD, "= 4.83 Hz, 1H, 2'H), 5.28 (5, J" = 5.67 Hz, 1H, OH, exchangeable D20), 3.70 (m, 1H, 6 '-Ha); 13C NMR (DMSO-d6) d 157.8 (C = 0), 153.2 (4-C), 137.3 (6-C), 134.9 (5-C), 88.6 (5'C) ), 80.9 (2 '-C), 65.5 (6' - C), 29.4 (4'-C); Anal. Caled for C8H10O3N3FSe: C, 32. 67; H, 3.43, N 14.29; Found: C, 32.67; H, 3.48, N, 14.47; M / S / e 295 (M +). Table 1 gives the separation results for (+) - β - Se - FddC, (-) - ß - Se - FddC, (+) - a - Se - FddC, (-) -a - Se - FddC y ( -) - ß-Se-ddC and compare the retention times and absorption wavelengths of these compounds with (-) - ß-FTC and (+) - ß- FTC. Table 1. Results of the Separation Table 2 provides the resolution and separation factors of the separated compounds in the ChiralPak AS. The separation factor is defined as the retention time of the second isomer eluted minus the time of resolution by the difference between the retention time of the first eluted isomer and the time of resolution. The resolution factor is defined as twice the difference in the retention time of isomers (+) and (-) by the bandwidth of the two peaks. Table 2. Comparison of the separations in the ChiralPak AS. Chromatographic conditions: mobile phase; 2-propanol; 100 μg in 10 μl of methanol was injected; UV detection at 254 n; Flow rate to ml / min. a Separation factor = (retention time of the second isomer eluted - time of resolution) / retention time of the first eluted isomer - time of resolution). b Resolution factor = 2 x [difference of the isomer retention time (+) and (-)] / (the bandwidth of the two peaks).

Table 3 gives the effects of various proportions of solvent and the chiral paratión of flow velocity of racemic ß-Se-ddC. Table 3. The effects of various proportions of solvent and the chiral paratión of flow velocity of racemic ß-Se-ddC The mono, di and triphosphate derivatives of the active nucleosides can be prepared as described according to published methods. The monophosphate can be prepared according to the procedure of Imai, et al. , J. Org. Chem. , 34 (6), 1547-1550 (June 1969). The diphosphate can be prepared according to the procedure of Davisson, et al. , J. Gold. Chem., 52 (9), 1794-1801 (1987). He triphosphate can be prepared according to the procedure of Hoard, et al. , J. Am. Chem. Soc., 87 (8), 1785-1788 (1965). III. Combination and Alternation Therapies It has been recognized that drug-resistant HIV and HBV variants may arise after prolonged treatment with an antiviral agent. For the most part, resistance to the drug typically occurs by mutation of a gene encoding an enzyme used in the viral life cycle and more typically in the case of HIV, reverse transcriptase, protease or DNA polymerase and in the case of HBV, the DNA polymerase. Recently, it has been shown that the efficacy of a drug against HIV infection can be prolonged, increased or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation to that caused by the starting drug. Alternatively, the pharmacokinetics, biodistribution or other parameters of the drug can be altered by such combination or alternation therapy. In general, combination therapy over the therapy of alternation because it induces multiple simultaneous tensions on the virus. In one embodiment, the second antiviral agent for the treatment of HIV may be a reverse transcriptase inhibitor (an "RTI"), which may be either a synthetic nucleoside (an "NRTI") or a non-nucleoside compound (an " NNRTI "). In an alternative embodiment, in the case of HIV, the second (or third) antiviral agent may be a protease inhibitor. In other embodiments, the second (or third) compound may be a pyrophosphate analog or a fusion binding inhibitor. In "Mutations in retroviral genes associated with drug resistance". In terna ti onal An ti vi ral News, Volume 1 (4), International Medical Press 1996, by Schinazi, et al. , is a list that compiles resistance data from in vi tro and in vi vo for several antiviral compounds. Preferred compounds for combination or alternation therapy for the treatment of HBV include FTC (the (-) -enantiomer or racemate), L-FMAU, interferon, β-D-dioxolanyl-guanine (DXG), β-D -dioxolanyl-2,6-diaminopurine (DAPD), and ß-d-dioxolanyl-6-chloropurine (ACP), famcicloviro, pencicloviro, BMS-200475, bis bom PMEA (adefoviro, dipivoxil); lobucaviro, gancicloviro and ribavarin. Preferred examples of antiviral agents that can be used in combination or alternation with the compounds disclosed herein for HIV therapy include 2-hydroxymethyl-5- (5-fluorocytosin-1-yl) -1,3-oxat ion (FTC); the (-) enantiomer of 2-hydroxymethyl-5 - (cyostin-1-yl) -1,3-oxathiolane (3TC); carboviro, acicloviro, inferred, AZT, DDI, DDC, D4T, CS-92 (3 '-azido -2', 3-dideoxy-5-methyl-cytidine) and ß-D-dioxolane nucleosides such as β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-6-chloropurine ( ACP) and MKC-442 (6-benzyl-l- (ethoxymethyl) -5-isopropyl uracil.) Preferred protease inhibitors include crixovan (Merck), nelfinavir (Agouron), ritonaviro (Abbot), saquinaviro (Roche) and DMP -450 (DuPont Merck) Non-limiting examples of compounds that can be administered in combination or alternation with any of the 1,3-oxaselenolenyl nucleosides include (lS, 4R) -4- [2-amino- 6 - succinate cyclopropyl-amino) -9H-purin-9-yl] -2-cyclopentene-1-methanol ("1592", an analogue of carboviro; Glaxo Wellcome); 3TC: (-) - ß -L- 2 ', 3' -dideoxy-3 '-thiacitidine (Glaxo Wellcome); α-APA R18893: a-nitro-indigo-phenylacetamide; A-77003; protease inhibitor based on C2 symmetry (Abbot); A-75925: protease inhibitor based on C2 symmetry (Abbott); AAP-BHAP: bisheteroarylpiperazine analogue (Upjohn); ABT-538: protease inhibitor based on C2 symmetry (Abbott); AzddU: 3 '-azido-2', 3'-dideoxyuridine; AZT: 3 '-azido-3' -deoxit imidine (Glaxo Wellcome); AZT-p-ddl: 3'-azido-3 '-deoxit imidilyl- (5', 5 ') - 2', 3'-dideoxyinosinic acid (Ivax): BHAP: bisheteroarylpiperazine; BILA 1906: N-. { ÍS -. { . { . { 3 - [2S -. { (1,1-dimet i let i 1) amino] carbonyl} -4R-] 3 -pyridinium-1met-yl) thio] -l-piperidinyl] -2-R-hydroxy-1S- (phenylmethyl) -propyl] amino] carbonyl] -2-met i lpropi 1.}. -2-quinolinecarboxamide (Bio Mega / Boehringer-Ingelheim); BILA 2185: N- (1, 1 -dimet ilet il) -1- [2S - [[2 -2, 6-dimethylphenoxy) -1-oxoet yl] amino] 2-R-hydroxy-4-phenylbutyl] 4R -pyridini lthio- 2 -piperidinecarboxamide (Bio Mega / Boehringer-Ingelheim); BM + 51.0836: thiazolo-isoindol inone derivative; BMS 186,318: HIV-1 protease inhibitor derived from aminodiol (Bristol-Meyers-Squibb); d4API: 9 - [2, 5 -dihydro- 5 - (phosphonomethoxy) -2-furanojadenine (Gilead); d4C: 2 ', 3' -didehydro-2 ', 3' -dideoxici t idina; d4T: 2 ', 3'-didehydro-3'-deoxy thymidine (Bristol -Myers -Squibb); ddC: 2 ', 3' -dideoxycytidine (Roche); ddl: 2 ', 3'-dideoxyinosine (Bristol -Myers-Squibb); DMP-266: 1 1, 4-dihydro-2H-3, 1-benzoxazin-2-one; DMP-450:. { [4 - (4-a, 5-a, 6-b, 7-b)] -hexahydro-5,6-bis (hydroxy) -1,3-bis (3-amino) phenyl] methyl) -4, 7-bis (phenylmethyl) -2H-1,3-diazepin-2-one} bismesylate (Avid); DXG: (-) - ß-D-dioxolane-guanosine (Triangle); EBU-dM: 5-ethyl-l-ethoxymethyl-6 - (3, 5 -dimethyl-il-benzyl) -uracil; E-EBU: 5-et il-1-ethoxymethyl-6-benziluracil; DS: dextran sulfate; E-EPSeU: 1- (ethoxymethyl) - (6-pheni lseleni 1) -5-ethyluracil; E-EPU: 1- (ethoxymethyl) - (6-phenyl-tio) -5-ethyluracil; FTC: ß - 2 ', 3' - dideoxy - 5 - f luoro - 3 '- thiazidine (Triangle); HBY097: S-4-isopropoxycarbonyl-6-methoxy-3 - (met ilt io-met il) -3,4-dihydroquinoxalin-2 (1 H) -thione; HEPT: l- [2-hydroxyethoxy) met il] 6 - (phenylthio) t imine; HIV-1: human immunodeficiency virus type 1; JM2763: 1,1 '- (1,3-propanediyl) -bis-1, 4,8,11-tetraazacyclotetradecane (Johnson Matthey); JM3100: 1, 1 '- [1,4-phenylenebis- (methylene)] -bis-1, 4,8,11-tetraazacycloth etradecane (Johnson Matthey); KNI-272: (2S, 3S) -3-amino-2-hydroxy-phenylbutyric acid-containing tripeptide; L-697,593; 5-ethyl-6-methyl-3 - (2-phthalimido-ethyl) pyridin-2 (1H) -one; L-735, 524: hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck); L-697, 661: 3 -. { [(-4,7-Dichloro-1,3-benzoxazol-2-yl) met il] amino} -5-ethyl-6-methylpyridin-2 (1H) -one; L-FDDC: (0) -β-L-5-fluoro-2 ', 3'-dideoxycytidine; L-FDOC: cytosine of (-) - ß-L-5-fluoro-dioxolane; MKC-442: 6-benzyl-1-ethoxymethyl-5-isopropyluracil (I-EBU: Triangle / Mi tsubishi); Nevirapine: 11-cyclopropyl-5,1-dihydro-4-methyl-6H-dipyridol [3,2-b: 2 ', 3'-ejdiazepin-6-one (Boehringer-Ingelheim); NSC648400: 1-benzyloxymethyl 1 - 5 - et il - 6 - (alpha-pyridylthio) uracil (E-BPTU); P9941: [2-pyridylacetyl-IlePheAla-i (CHOH)] 2 (Dupont Merck); PFA: phosphonoformate (foscarnet: Astra); PMEA: 9- (2-phosphonylmethoxyethyl) adenine (Gilead); PMPA: (R) -9- (2-phosphonylmethoxypropyl) adenine (Gilead); Ro 31-8959: HIV-1 protease inhibitor derived from hydroxyethylamine (Roche); RPI-312: peptidyl protease inhibitor, amide of 1 - [(3 s) -3- (n-alpha-benzyloxycarbonyl) -1-acetyl) -amino-2-hydroxy-4-phenylbutyl] -n-tert -but il-1 -prol ina; 2720: 6-chloro-3, 3-dimethyl-4 - (i sopropenyloxycarboni 1) - 3, 4 -dihydro- quinoxaline-2 (1H) thione; SC-52151: protease inhibitor of ilustrus isosterehydroxiet (Searle); SC-55389A: isosterehydroxyethyl urease protease inhibitor (Searle); TIBO R82150: (+) - (5S) -4,5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo [4, 5, lj] [1, 4] - benzodiazepin-2 (1 H) -thione (Janssen); TIBO 82913: (+) - (5S) -4, 5, 6, 7 -tetrahydro-9-chloro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4,5, ljk] [1,4] benzo-diazepin-2 (1 H) -thione (Janssen); TSAO-m3 T: [2 ', 5' -bi s -O- (tert -butyldimethyl-ilsilyl) -3 '-spiro-5' - (4'-amino-1 ', 2'-oxat iol -2' , 2'-dioxide)] -bD-pentofuranosyl-N3-methylthimine; U90152: 1 - [3 - [1 -met ilet-yl] -amino] -2-pyridinyl] -4 - [[5- [(meth i 1 sulphyl) -amino] - lH-indol-2-yl] carbonyl] piperazine; UC: thiocarboxanilide derivatives (Uniroyal); UC-781 = N- [4-chloro-3 - (3-methyl-2-buteni loxi) phenyl] -2-methyl-3-furancarbothioamide; UC-82 = N- [4-chloro-3- (3-methyl-2-butenyloxy) phenyl] -2met-il-3-t-iofenocarbothioamide; VB 11, 328: hydroxyethyl sulfonamide protease inhibitor (Vertex); VS-478: hydroxiet ilsul fonamide protease inhibitor (Vertex); XM 323: cyclic urea protease inhibitor (Dupont Merck).

IV. Ability of the nucleosides of 1,3-oxaselenolanil to inhibit the reproduction of HIV and HBV The ability of nucleosides to inhibit HIV can be measured by various experimental techniques. The technique used herein, and described below in detail, measures the inhibition of viral reproduction in peripheral blood mononuclear cells (PBM), human, stimulated by inhetohemaglutine (PHA), infected with HIV-1 (class LAV). The amount of virus produced is determined by measuring the reverse transcriptase enzyme encoded with virus. The amount of the enzyme produced is proportional to the amount of virus produced. Example 4 Anti-HIV activity of the 1,3-oxaselenolanyl nucleosides The anti-HIV activity of 2-hydroxymethyl-4- (N-5 '-cytosin-1' -yl) -1,3- was examined oxaselenolane and 2-hydroxymethyl-4 - (N-5 '-fluorocytosin-1'-yl) -1,3-oxaselenolane. PBM cells stimulated with three-day-old innate phytohemaglut (10 cells / ml) of hepatitis B and healthy HIV-1 seronegative donors were infected with HIV-1 (LAV class) at a concentration of approximately 100 times 50% of the tissue culture infection dose (TICD 50) per mi and were cultured in the presence and absence of various concentrations of antiviral compounds. Approximately one hour after infection, the medium, with (2 times the final concentration in the medium) or without the compound to be examined, was added to the flasks (5 ml, final volume 10 ml). AZT was used as a positive control. The cells were exposed to the virus (approximately 2 x 105 dpm / ml, as determined by the reverse transcriptase assay) and then placed in a C02 incubator. HIV-1 (LAV class) was obtained from the Disaster Control Center, Atlanta, Georgia. The methods used for the culture of the PBM cells, the virus collection and the determination of the reverse transcriptase activity were those described by McDougal, et al. , (J. Immun, Meth 76, 171-183, 1985) and Spira, et al. (J. Clin. Meth 25, 97-99, 1987), except that fungizone was not included in the medium (see Schinazi, et al., Antimicrob Agents Chemother, 32, 1784-1787 (1988); ., 34 .1061-1067 (1990)).

On day 6, the cells and the supernatant were transferred to a 15 ml tube and centrifuged at approximately 900 g for 10 minutes. 5 ml of supernatant was removed and the virus was concentrated by centrifugation at 40,000 rpm for 30 minutes (Ti Beckman rotor 70.1). The solubilized virus granule was processed for the determination of the reverse transcriptase levels. The results are expressed in dpm / ml supernatant sample. Viruses from smaller volumes of supernatant (1 ml) can also be concentrated by centrifugation before solubilization and determination of reverse transcriptase levels. The median effective concentration (EC50) was determined by the medium effect method (Antimicrob Agents Chemother, 30, 491-498 (1986)). In summary, the percent inhibition of the virus as determined from the reverse transcriptase measurements was plotted against the micromolar concentration of the compound. The EC50 is the concentration of the compound in which there is a 50% inhibition of the viral culture. Human PBM cells, uninfected, stimulated by mitogen (3.8 x 10 5 cells / ml) were they cultured in the presence and absence of drug under conditions similar to those used for the antiviral assay described above. The cells were counted after 6 days by the use of a hemacytometer and the trypan blue exclusion method, as described by Schinazi, et al. , (Antimicrobial Agent and Chemotherapy, 22 (3), 499 (1982)). IC50 is the concentration of the compound that inhibits 50% of normal cell growth. Table 4 provides the EC50 values (concentration of nucleosides that inhibits the reproduction of viruses at 50% in PBM cells, estimated error factor 10%) and IC50 values (concentration of nucleosides that inhibits 50% of the growth of human PBM cells, uninfected , stimulated with mitogen, CEM cells and in Vero cells) of 2-hydroxymethyl-4- (N-5'-cytosin-1'-yl) -1,3-oxaselenolane and 2-hydroxymethyl-4- (N-5 '-fluorocytosin-1' -yl) -1,3 -oxaselenolane. Table 4. Oxaselenolane nucleoside anti-HIV activities Table 5 provides percentage purity. The EC50 values (μM), EC90 values (μM) and IC50 values in the PBM cell of racemic ß-Se-ddC, its isomers (+) - and (-) - and for ß-Se-FddC and its isomers (+) - and (-) -. Table 5. Anti-HIV activity and cyto-toxicity of Racemates and Enantiomers of Nucleosides of Oxitosis Cycloles The anti-HIV activity of ß-Se-ddC, its (+) - and (-) - isomers and the racemic ß-Se-FddC, its (+) - and (-) - isomers, were also examined in the cells of PBM infected with HIV that exhibit a mutation in codon 184 in the reverse transcriptase gene. The results are given in Table 6. As indicated, the (-) - β-Se-ddC and racemic 55 -. 55 - exhibits significant activity against the mutated virus. Table 6. Effect of Oxitosplantocytosis Cytosine Nucleosides against HIV-1 M184, Cloned Enantiomer Compound% Virus EC50μM EC90μM Fl Fl Purity EC50 EC90 ß-Se-ddC 50 xxBRU 1.84 6.90 ß-Se-ddC = 100 xBRU 0.11 0.95 ß- Se-ddC: 96 xxBRÜ 8.62 35.1 ß-Se-FddC + _ 50 M184V 108 337 59 49 M184V > 50 > 50 > 455 > 53 ß-Se-FddC - = 100 M184V > 50 > 50 > 6 > 1 ß-Se-FddC + = 96 Note: Fl (fold increase) ECS0 = EC50 data from the cloned virus / EC50 duration from xxBRU EXAMPLE 5 Anti-HBV activity of the Oxaselenolanyl Nucleosides The ability of the active compounds to inhibit virus development in cell cultures of 2.2.15 (HepG2 cells transformed with hepatitis virion) can be evaluated as described in detail below. A summary and description of the trial for antiviral effects has been described in this system of culture and the analysis of HBV DNA has been described (Korba and Milman, 1991, Antiviral Res., 15: 217). The antiviral evaluations are carried out in two separate steps of cells. All perforations, in all the plates, they are sown at the same density and at the same time. Due to inherent variations in both intracellular and extracellular HBV DNA levels, only depressions greater than 3.5-fold (for HBV virion DNA) or 3.0 fold (for intermediate HBV DNA replication compounds) the average levels of these HBV DNA forms in untreated cells are considered statistically significant (P <; 0.05). The HBV DNA levels integrated into each cell DNA preparation (which remains constant on a per-cell basis in these experiments) are used to calculate the levels of intracellular forms of HBV DNA, thereby ensuring that equal amounts of HBV DNA are compared. Cellular DNA between the separated samples. Typical values for the extracellular DNA of HBV virion in untreated cells vary from 50 to 150 pg / ml culture medium (average of approximately 76 pg / ml).

The intermediate intracellular HBV DNA reproduction compounds in untreated cells vary from 50 to 100 μg / pg of cellular DNA (average of approximately 74 pg / μg of cellular DNA). In general, depressions in intracellular HBV DNA levels due to treatment with antiviral compounds are less pronounced and occur more slowly than depressions in virion DNA levels of HBV (Korba and milman, 1991, Antiviral Res. , 15: 217). The manner in which the hybridization analyzes are carried out for these experiments results in an equivalence of approximately 1.0 pg of intracellular HBV DNA for 2-3 genomic copies per cell and 1.0 pg / ml of extracellular HBV DNA for 3 x 105 viral particles / ml. Toxicity analyzes can be carried out to determine if any observed antiviral effect is due to a general effect on cell viability. One method that can be used is the measurement of neutral red dye-taking, a standard and widely used assay for cell viability in a variety of virus host systems, including VSH and HIV. The toxicity tests are carried out in plates of flat bottom tissue culture, 96 perforations. Cells for toxicity analyzes are cultured and treated with test compounds with the same schedule described for the following antiviral evaluations. Each compound is examined in 4 concentrations, each in triplicate cultures (perforations "A", "B" and "C" .9 The natural red dyeing is used to determine the relative level of toxicity. internal at 510 nm (As? n) was used for quantitative analysis.The values are presented as a percentage of the average As? n values in 9 separate cultures of untreated cells, maintained in the same 96-well plate. Test compounds Example 6 Use of 1/3-Oxaselenolanyl Nucleosides to Treat Abnormal Cell Proliferation Some of the 1,3-oxaselenolanyl nucleosides described herein can be used to treat abnormal cell proliferation, including tumors and cancer. degree of antiprol activity iferativa can be easily determined by assaying the compound according to the following procedure in a CEM cell or other a9 proliferative or tumor cell line assay. The CEM cells are human lymphoma cells (a T-lymphoblastoid cell line available from ATCC, Rockville, MD). The toxicity of a compound for CEM cells provides useful information regarding the activity of the compound against tumors. Toxicity is measured as Ic50 micromolar. The IC50 refers to the concentration of test compounds that inhibit the growth of 50% of the tumor cells in the culture. The lower the ICS0, the more active the compound is as an antitumor agent. In general, the 1,3-oxaselenolanyl nucleoside exhibits anti-tumor activity and can be used in the treatment of abnormal cell proliferation if it exhibits a toxicity in the CEM or other immortalized tumor cell line of less than 10 micromolar, more preferably less than about 5 micromolar, and more preferably less than 1 micromolar. Drug solutions, including cycloheximide as a positive control, are plated in triplicate plates in a 50 μl culture medium at 2 times the final concentration and allowed to equilibrate at 37 ° C in a 5% C02 incubator.

The logarithmic phase cells are added in a 50 μl culture medium to a final concentration of 2.5 x 103 (CEM and Sk-MEL-28), 5 x 103 (MNAN, MDA-MB-435S, SKMES-1, DU -145, Lncap), or 1 x 104 (PC-3, MCF-7) cells / perforation and incubated for 3 hours.

(DU-145-PC-3, MNAN), 4 (MCF-7, SK-MEL-28, CEM), or 5 (SK-MES-1, MDA-MB-435S, LNCap) days at 37 ° C under an air atmosphere with 5% C02. The control perforations include single media (blank) and cells plus the medium without drug. After the culture period, 15 μl of the test dye solution of the Cell Title 96 equipment was added (Promega, Madison, Wl) to each perforation and the plates are incubated for 8 hours at 37 ° C in a 5% C02 incubator. The assay top solution of the Promega 96 Cell Title device is added to each perforation and incubated for 4-8 hours in the incubator. Absorption is read at 570 nm, suppressing in the middle only the perforations using a plate reading of Biotek Biokinetics (Biotek, Winooski, VT). An average percentage inhibition of growth is calculated in comparison with the untreated control. IC50, IC90, the declination value and r are calculated using the Chou and Talaly method. Chou T-C, Talalay P.

Quantitative analysis of dose relationships-effect: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22: 27-55. IV. Preparation of Pharmaceutical Compositions Humans suffering from diseases caused by any of the diseases described herein, including HIV infection, HBV infection or abnormal cell proliferation, can be treated by administering to the patient an effective amount of a nucleoside of 1, 3-oxaselenolanil optionally in a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, in liquid or solid form. The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of compound to inhibit viral reproduction in vi, especially the reproduction of HIV and HBV, without causing serious toxic effects in the patient. the patient treated. By "inhibitory amount" is meant a amount of active ingredient sufficient to exert an inhibitory effect as measured by, for example, an assay such as those described herein. A preferred dose of the compound for all the above-mentioned conditions will be in the range from about 1 to 50 mg / kg, preferably from 1 to 20 mg / kg, of body weight per day, more generally from 0.1 to about 100 mg per kilogram of container body weight per day. The effective dose range of pharmaceutically acceptable derivatives can be calculated based on the weight of the major nucleoside to be delivered. If the derivative exhibits activity by itself, the effective dose can be estimated as above by using the weight of the derivative, or by other means known to those skilled in the art. The compound is conveniently administered in unit or any suitable dosage form, including but not limited to one containing from 7 to 3000 mg, preferably from 70 to 1400 mg of active ingredient per unit dosage form. An oral dose of 50-1000 mg is usually convenient.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.2 to 70 pM, preferably from about 1.0 to 10 pM. This can be achieved, for example, by the venous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline or administered as a bolus of the active ingredient.The concentration of the active compound in the composition of the drug will depend on the absorption, inactivation and excretion proportions of the drug as well as other factors known to those skilled in the art should be noted that the dose values will also vary with the severity of the condition being alleviated. In particular, the specific dosage regimens should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions and that the concentration ranges set forth herein are only exemplary and do not attempt to limit the scope or practice of the claimed composition. active it can be administered at one time or it can be divided into several smaller doses to be administered at varying time intervals. A preferred mode of administration of the active compound is oral. The oral compositions will generally include an inert diluent or an edible vehicle. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, pills or capsules. The pharmaceutically compatible binding agents, and / or the adjuvant materials can be included as part of the composition. Tablets, pills, capsules, pills and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as a microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as a starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as a magnesium stearate or esters; a slider such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier, such as fatty oil. In addition, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, water, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and dyes and flavors. The compound or a pharmaceutically acceptable derivative or salt thereof can also be mixed with other active materials that do not impair the desired action, such as antibiotics, antifungals, anti-inflammatories or other nucleoside or non-nucleoside antiviral agents, as discussed in more detail below. The solutions or suspensions used for parenteral, intradermal application, subcutaneous or topical, may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; extender agents such as etheranediaminetetraacetic acid; regulators such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose routes made of glass or plastic. If administered intravenously, the preferred vehicles are physiological saline or phosphate-buffered saline (PBS). In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biocompatible, biodegradable polymers can be used, such as ethylene vinyl acetate, polyanhydrides, acid polyglycolic, collagen, polyorthoesters and polylactic acid. The methods for the preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation. Liposomal suspensions (including liposomes targeted to cells infected with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art., for example, as described in the U.S. Patent. No. 4,522,811 (which is incorporated herein in its entirety for reference). For example, liposome formulations can be prepared by dissolving appropriate lipid (s) such as phosphat idylethanolamine stearoyl, phosphatidylcholine estearoyl, arachidyl phosphatidylcholine and cholesterol) in an organic solvent which is then evaporated, leaving behind a film thin dry lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate and / or derivatives is then introduced into the container. triphosphate. The container is then stirred manually to release the lipid material from the sides of the container and to disperse the lipid aggregates, thereby forming the liposomal suspension. The invention has been described with reference to its preferred embodiments. Variations and modifications of the invention will be obvious to those skilled in the art from the above detailed description of the invention. It is intended that all of these variations and modifications be included within the scope of this invention.

Claims (57)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore what is described in the following claims is claimed as a property. 1. A 1,3-oxaselenolane nucleoside of the formula: wherein B is a purine or pyrimidine base and R is hydrogen, acyl, a mono-, di- or triphosphate ester, a stabilized phosphate, or an ester lipid, or a pharmaceutically acceptable salt thereof, and in where the nucleosides exhibit an ECS0 of less than 10 micromolar in PBM cells infected with HIV.
2. 2. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that B is a pyrimidine base.
3. 3. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that B is a purine base.
4. 4. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is hydrogen.
5. 5. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is acyl.
6. 6. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is monophosphate.
7. 7. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is diphosphate.
8. 8. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is triphosphate.
9. 9. The 1,3-oxaselenolane nucleoside according to claim 2 or 3, characterized in that R is a stabilized phosphate.
10. 10. The 1,3-oxaselenolane nucleoside according to claim 3, characterized in that R is a lipid ether.
11. 11. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that B is cytosine.
12. 12. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that B is 5-fluorocytosine.
13. 13. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that B is guanine.
14. 14. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that it is 2 - . 2 - . 2-hydroxymethyl-4- (N-5'-cyclin-1 '-yl) -1,3-oxaselenolane or a pharmaceutically acceptable salt thereof.
15. 15. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that it is 2-hydroxymethyl-4- (N-5 '-fluorocytosin-1' -yl) -1,3-oxaselenolane or a pharmaceutically acceptable salt thereof.
16. 16. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that it is (-) - β-L- 2 -hydroxymethyl-4- (N-5'-cytosin-1-yl) -1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof.
17. 17. The 1,3-oxaselenolane nucleoside according to claim 1, characterized in that it is (-) - β-L-2-hydroxymethyl-4- (N-5 '-fluorocytosin-1'-yl) -1,3-oxaselenolane as an isolated enantiomer or a pharmaceutically acceptable salt thereof.
18. 18. A pharmaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, characterized in that it comprises an effective amount of a 1,3-oxaselenolane nucleoside according to claim 1 together with a pharmaceutically acceptable carrier.
19. 19. A pharmaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, characterized in that it comprises an effective amount of a 1,3-oxaselenolane nucleoside according to claim 2 together with a pharmaceutically acceptable carrier.
20. 20. A pharmaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, characterized in that it comprises an effective amount of a 1,3-oxaselenolane nucleoside according to claim 3 together with a "pharmaceutically acceptable carrier.
21. A pharmaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, characterized in that it comprises an effective amount of a 1,3-oxaselenolane nucleoside according to one of claims 4 to 17 together with a pharmaceutically acceptable carrier.
22. 22. The method for the treatment of HIV in humans, characterized in that it comprises administration of an effective amount of a nucleoside of 1,3-oxaselenolane of the formula: wherein B is a purine or pyrimidine base and R is hydrogen, acyl, or a phosphate ester, or a pharmaceutically acceptable salt thereof, and wherein the nucleosides exhibit an ECS0 of less than 10 micromolar in PBM cells infected with HIV.
23. 23. The method for treating HIV according to claim 22, characterized in that B is a pyrimidine base.
24. 24. The method for treating HIV according to claim 22, characterized in that B is a purine base.
25. 25. The method for treating HIV according to claim 22, characterized in that R is hydrogen.
26. 26. The method for treating HIV according to claim 22, characterized in that R is acyl.
27. 27. The method for the treatment of HIV according to claim 22, characterized in that R is monophosphate.
28. 28. The method for the treatment of HIV according to claim 22, characterized in that R is diphosphate.
29. 29. The method for treating HIV according to claim 22, characterized in that R is triphosphate.
30. 30. A method for the treatment of HIV according to claim 22, characterized in that R is hydrogen.
31. 31. A method for the treatment of HIV according to claim 22, characterized in that R is acyl.
32. 32. A method for the treatment of HIV according to claim 22, characterized in that R is monophosphate.
33. 33. A method for the treatment of HIV according to claim 23, characterized in that R is di triphosphate.
34. 34. A method for the treatment of HIV according to claim 24, characterized in that R is triphosphate.
35. 35. A method for the treatment of HIV according to claim 25, characterized in that the 1,3-oxaselenolane nucleoside is 2-hydroxymethyl- (N-5'-cytosin-1'-yl) -1,3-oxaselenolane or a salt 55 -. 55 - pharmaceutically acceptable thereof.
36. 36. A method for the treatment of HIV according to claim 26, characterized in that the nucleoside of 1,3-oxaselenolane is 2-hydroxymethyl-4- (N-5'-fluorocytosin-1'-yl) -1,3-oxaselenolane or a pharmaceutically acceptable salt thereof.
37. 37. A method for the treatment of HIV according to claim 27, characterized in that the nucleoside of 1,3-oxaselenolane is (-) - β-L-2-hydroxymethyl-4- (N-5 '-cytosin-1' - il) -1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof.
38. 38. A method for the treatment of HIV according to claim 28, characterized in that the nucleoside of 1,3-oxaselenolane is (-) - β-L-2-hydroxymethyl-4- (N-5 '-fluorocytosine-1' - il) -1,3-oxaselenolane as an isolated enantiomer or a pharmaceutically acceptable salt thereof.
39. 39. A method for the treatment of HBV in humans and other host animals, characterized in that it comprises administering an effective amount for HIV of a nucleoside of 1,3-oxaselenolane of the formula: wherein B is a purine or pyrimidine base and R is hydrogen, acyl, or a phosphate ester, or a pharmaceutically acceptable salt thereof, in racemic form or as an isolated enantiomer.
40. 40. A method for the treatment of HBV according to claim 39, characterized in that B is a pyrimidine base.
41. 41. A method for the treatment of HBV according to claim 39, characterized in that B is a purine base.
42. 42. A method for the treatment of HBV according to claim 39, characterized in that R is hydrogen.
43. 43. A method for the treatment of HBV according to claim 39, characterized in that R is acyl.
44. 44. A method for the treatment of HBV according to claim 39, characterized in that R is monophosphate.
45. 45. A method for the treatment of HBV according to claim 39, characterized in that R is di triphosphate.
46. 46. A method for the treatment of HBV according to claim 39, characterized in that R is triphosphate.
47. 47. A method for the treatment of HBV according to claim 39, characterized in that R is hydrogen.
48. 48. A method for the treatment of HBV according to claim 39, characterized in that R is acyl.
49. 49. A method for the treatment of HBV according to claim 39, characterized in that R is monophosphate.
50. 50. A method for the treatment of HBV according to claim 39, characterized in that R is diphosphate.
51. 51. A method for the treatment of HBV according to claim 39, characterized in that R is triphosphate.
52. 52. A method for the treatment of HBV according to claim 39, characterized in that the nucleoside of 1,3-oxaselenolane is 2-hydroxymethyl-4- (N-5 '-cynin-1'-yl) -1,3-oxaselenolane or a pharmaceutically acceptable salt thereof.
53. 53. A method for the treatment of HBV according to claim 39, characterized in that the nucleoside of 1,3-oxaselenolane is 2-hydroxymethyl-4- (N-5'-fluorocytosin-1'-yl) -1,3-oxaselenolane or a pharmaceutically acceptable salt thereof.
54. 54. A method for the treatment of HBV according to claim 39, characterized in that the nucleoside of 1,3-oxaselenolane is (-) - β-L-2-hydroxymethyl-4- (N-5'-cyclin-1 '-yl) -1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt of the same.
55. 55. A method for the treatment of HBV according to claim 39, characterized in that the nucleoside of 1,3-oxaselenolane is (-) - β-L-2-hydroxymethyl-4- (N-5 '-fluorocytosin-1'-yl) -1,3-oxaselenolane as an isolated enantiomer or a pharmaceutically acceptable salt thereof .
56. 56. The use of 1,3-oxaselenolane nucleosides according to claim 1 and the derivatives and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of HIV or HBV infection.
57. 57. The use of 1,3-oxaselenolane nucleosides according to claim 1 and the derivatives and pharmaceutically acceptable salts thereof, in the treatment of viral infections by their administration in combination or alternation with other antiviral agents.