RU2171809C2 - L-nucleosides eliciting anti-hbv or anti-ebv activity, method of inhibition of hbv or ebv infection - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, virology. SUBSTANCE: invention describes novel L-nucleosides of the general formula (I)

Description

 The invention relates to the field of methods for treating diseases caused by hepatitis B virus (also called HBV and Epstein-Barr virus (also called EBV, which include administering an effective amount of one or more of the active compounds disclosed herein, or their formally acceptable derivatives or prodrugs of one of these compounds.

BACKGROUND OF THE INVENTION
Hepatitis B virus diseases have reached epidemic levels worldwide. After a two to six-month incubation period during which the carrier is unaware of infection, HBV infection can lead to acute hepatitis and liver damage, stomach pain, jaundice, and elevated levels of certain enzymes in the blood. HBV can cause transient hepatitis, a rapidly developing, often fatal form of the disease in which large areas of the liver are destroyed. Patients usually recover from acute viral hepatitis. However, in some patients, high levels of viral antigens exist in the blood for a long or indefinite period of time, causing a chronic infection. Chronic infections can lead to chronic hepatitis. Chronic persistent HBV infected patients are most common in developing countries. By mid-1991, there were approximately 225 million chronic HBV carriers in Asia alone, and nearly 300 million carriers worldwide. Chronic persistent hepatitis can cause impaired function, liver cirrhosis and hepatocellular carcinoma, primary liver cancer.

 In western industrialized countries, those in contact with HBV carriers or their blood samples are at high risk of HBV infection. The epidemiology of HBV is actually very similar to the epidemiology of Acquired Immunodeficiency Syndrome, which explains why HBV infection is common among patients with AIDS (AIDS) or HIV-related infections. However, HBV is far more contagious than HIV.

 HBV is the second cause of human cancer after tobacco. The mechanism by which HBV causes cancer is unknown, although it is believed that it can directly involve the development of a tumor or cause the development of a tumor indirectly due to chronic inflammation, cirrhosis and degeneration of cells associated with the infection.

 Epstein-Barr virus (EBV) is a member of the genus Lymphocryptovirus, which belongs to the subfamily gammaherpesvirinae. It is noticeably lymphotrophic. EBV has the classical structure of herpes viruses, namely, its double-stranded DNA genome is enclosed in an aicosapentahedral nucleocapsid, which, in turn, is surrounded by a lipid membrane with viral glycoproteins. An amorphous shell protein occupies the space between the shell and the nucleocapsid.

 All human herpes viruses infect lymphocytes and replicate in them to some extent, but EBV does this more efficiently. Most importantly, the host pathogenesis and response to EBV infection is much more dependent on lymphocyte infection than it is with other human herpes viruses.

 EBV is currently considered to be the cause of lymphoproliferative diseases of B cells and is associated with various other serious and chronic diseases, including a rare syndrome similar to progressive mononucleosis and oral scalp leukoplakia in patients with AIDS (AIDS). The assumption that EBV is the main cause of chronic fatigue does not stand the test.

 EBV is transmitted mainly through saliva, although infection is sometimes transmitted through blood transfusion. More than 85% of patients with the acute phase of infectious mononucleosis secrete EBV.

 EBV is associated with cancer. At least two groups of patients are at risk of developing EBV-related lymphomas: those who have had a kidney, heart, bone marrow, liver or thymus transplant combined with immunosuppressive therapy, and AIDS patients. Cancers associated with EBV include Burkitt's lymphoma and nasopharyngial carcinoma.

 In light of the fact that hepatitis B virus and Epstein-Barr virus have a strong and often tragic effect on an infected patient, there is an urgent need to create effective pharmacological agents for the treatment of patients infected with these viruses, which would have low toxicity to the carrier.

 Therefore, the aim of the present invention is to provide a compound, composition and method of treating a disease caused by hepatitis B.

 Another object of the invention is to provide a compound, composition and method for treating a disease caused by the Epstein-Barr virus.

где R представляет пуриновое или пиримидиновое основание.Summary of invention
A method of treating a carrier and, in particular, a person infected with HBV or EBV, which includes the introduction of HBV or EBV, which includes the introduction of HBV or EBV-therapeutic amount of L-nucleoside of the formula (1)

where R represents a purine or pyrimidine base.

 In a preferred embodiment, a nucleoside is provided in the form of said enantiomer and with practically no corresponding enantiomer (i.e., as an enantiomerically enriched substance, including an enantiomerically pure form).

In one preferred embodiment, the active compound is 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine (also referred to as L-FMAU). This compound is an effective antiviral agent against HBV and EBV and is characterized by low cytotoxicity. Other specific examples of active compounds include N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-ethyluracil, N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl ) -5-iodocytosine and N ₁ - (2'-deoxy-2 '-fluoro-β-L-arabinofuranosyl) -5-iodouracil.

 Alternatively, an L-nucleoside is provided for the treatment of HBV or EBV, which contains a 2'-arabinohydroxyl group, for example, L-aratimidine, L-fludarabine, L-araganosine and L-arainosine, as shown in FIG. 1.

 The L-nucleosides disclosed herein and their pharmaceutically acceptable derivatives or pharmaceutically acceptable compositions containing these compounds are useful for the prevention and treatment of HBV infections and related conditions, such as conditions associated with anti-HBV antibody positive and HBV positive, chronic liver inflammation, caused by HBV, cirrhosis, acute hepatitis, transient hepatitis, chronic persistent hepatitis and fatigue. Similarly, these compounds can be used to treat diseases associated with EBV. These compounds or compositions can also be used to prevent and prevent or slow the development of clinical diseases in patients who are positive for anti-HBV or anti-EBV antibodies or HBV or EBV antigens, or those who have been in contact with HBV and EBV .

 In another embodiment, the active compound or its derivative or its salt may be administered in combination or alternating with another anti-HBV agent or anti-EBV agent, including those listed above, or an anti-HIV agent. Typically, with alternative therapy, an effective dose of each agent is administered serially, while in combination therapy, effective doses of two or more agents are administered together. Doses depend on the rates of absorption, inactivation and excretion (excretion) of the drug, as well as other factors known to those skilled in the art. It should be noted that dose rates will also depend on the severity of the condition requiring relief. It should also be noted that for each particular patient, specific dosage regimens and regimens should be reviewed over time in accordance with the need for the patient and the professional point of view of the doctor conducting the treatment.

 Non-limiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include the (-) - enantiomer of 2-hydroxymethyl-5- (5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC); (-) - enantiomer of 2-hydroxymethyl-5- (cytosin-1-yl) - 1,3-oxathiolane (3TC); carbovir, acyclovir, interferon, AZT, DDI (2 ', 3'-dideoxyinosine), DDC (2', 3'-dideoxycytidine), L-DDC, L-5-F-DDC and D4T.

Brief Description of Drawings
FIG. 1 is an illustration of selected L-nucleosides that are included in the scope of the present invention:
L-FMAU (2'-fluoro-5-methyl-β-L-arabinofuranosyluridine), L-FIAU (2'-fluoro-5-iodo-β-L-arabinofuranosyluridine), L-FC (2'-fluoro-β -L-arabinofuranosylcytosine), L-FIAC (2'-fluoro-5-iodo-β-L-arabinofuranosylcytosine), L-2-C1-2'-F-2'-deoxyadenine, L-FEAU (2'-fluorine -5-ethyl-β-L-arabinofuranosyluridine), L-aratimidine, L-fludarabine, L-araganosine and L-arainosine.

 FIG. 2 is a graph of percent viable cells versus drug concentration for L-FMAU in H1 cells.

 FIG. 3 is a schematic illustration of the preparation of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (compound 10).

 FIG. 4 is a diagram of an alternative preparation of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (compound 10).

 FIG. 5 is a schematic diagram of a process for preparing 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-β-L-arabinofuranose (compound 13).

FIG. 6 schematically represents a process for preparing N ₉ - (3 ', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -2,6-di-chloropurine (compound 15) and N ₉ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) - 2,6-di-chloropurine (compound 16).

 FIG. 7 represents a method for preparing a series of 2'-deoxy-2'-fluoro-β-L-arabinofuranosyl-pyrimidines (compounds 17-24).

FIG. 8 represents a process for the preparation of N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodocytosine) (compound 22).

 FIG. 9 represents a process for preparing 9-β-L-arabinofuranosyladenine.

 FIG. 10 represents an alternative method for preparing 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (compound 10) from 1,2-di-O-isopropylidene-α-L-xylofuranose (compound 3).

 FIG. 11 is a plot of plasma L- (-) - FMAU concentration in mice after oral administration versus time (cross-over, 10 mg / kg administered twice daily (bid) for 29 days before pharmacokinetic studies, and then studies are carried out on the thirtieth day with the introduction of the same concentration; the shaded circles - the introduction of 50 mg / kg twice a day for 29 days before the study, and then on the thirtieth day the study is carried out with the introduction of the same concentration; unshaded circles - the introduction of the first time 50 mg / kg on the first day of the study).

 FIG. 12 is a graph of the concentration of L- (-) - FMAU in the liver of mice after oral administration over time (cross-over, 10 mg / kg administered twice a day for 30 days before pharmacokinetic studies, and then studies are carried out on the thirtieth day with the same concentration; shaded circles - administration of 50 mg / kg twice a day for 30 days before the study, and then on the thirtieth day conduct research after administration of the same concentration; open circles - introduction of 50 mg / kg for the first time on the first day research).

 FIG. 13a represents the change in animal weight after 30 days in control female BDF1 mice.

 FIG. 13b and 13c represent the weight change after 30 days of administration to female mice of BDF1 doses of 10 mg / kg (13b) and 50 mg / kg (13c) twice daily L - (-) - FMAU. The animal weights shown represent the mean and standard deviation for 5-7 mice.

 FIG. 14-20 present a clinical analysis of the plasma of mice after administration of L - (-) - FMAU at a concentration of 10 mg / kg (three mice) or 50 mg / kg (three mice) twice a day for 30 days. FIG. 14 is a graph of the total plasma concentration of bilirubin in mice in mg / dl. FIG. 15 is a graph of mouse alkaline phosphatase concentration in U / L. FIG. 16 is a graph of plasma creatinine concentration in mice in mg / dl (deciliter). FIG. 17 is a graph of AST concentration (SCOT, serum glutamine oxalin transaminase) in mouse plasma in U / L. FIG. 18 is a graph of the concentration of ALT (SGPT, serum glutamine pyruvate transaminase) in mouse plasma in U / L. FIG. 19 is a graph of the concentration of lactic acid in the plasma of mice in mmol / L. FIG. 20 is a graph of the concentration of milk dehydrogenase in the plasma of mice in U / L.

DETAILED DESCRIPTION OF THE INVENTION
The term "enantiomerically enriched", as used herein, refers to a nucleoside composition that comprises at least 95%, and preferably about 97, 98, 99% or 100% of one enantiomer of that nucleoside.

The term alkyl, as used here, includes, but is not limited to, C ₁ -C ₁₀ alkyl groups including methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl , isopentyl, amyl, tert-pentyl, cyclopentyl and cyclohexyl.

 The term acyl, as used here, includes, but is not limited to, acetyl, propionyl, butyryl, pentanoyl, 3-methylbutyryl, acid succinate, 3-chlorobenzoate, benzoyl, acetyl, pivaloyl, mesylate, propionyl, valeryl, caproyl , capryloyl, capryl, lauryl, myristyl, palmityl, stearyl and oleyl.

 In the sense as used here and, if there are no other definitions, the term aryl refers to phenyl.

 The term “protected,” as used herein, refers to a group, unless otherwise defined, that is attached to an oxygen or nitrogen atom to prevent them from reacting in the process of derivatizing other fragments of the molecule in which these oxygen or nitrogen. A wide range of oxygen and nitrogen protecting groups is known to those skilled in the art of organic synthesis.

The terms purine or pyrimidine base include, but are not limited to, adenine, N ⁶ -alkylpurines, N ⁶ -acylpurines (where acyl is C (O) alkyl, aryl, alkaryl or aralkyl), N ^6- benzylpurine, N ⁶ -halogenpurine, -vinilpurin N ^6, N ⁶ -atsetilenpurin, -atsilpurin N ^6, N ⁶ -gidroksialkilpurin, N ⁶ -tioalkilpurin, thymine, cytosine, 6-azapyrimidines, 2-mercaptopyrimidine, uracil, N ⁵ -alkilpirimidin, ⁵ -benzilpirimidiny N, N -galoidpirimidiny ^5, N ⁵ -vinilpirimidin, N -atsetilenpirimidin ^5, N ⁵ -atsilpirimidin, N -gidroksialkilpurin ^5, N ⁵ -tioalkilpurin, 5- azacytidine, 5-azauracil lil, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl.

 The functional groups of oxygen and nitrogen of the base can be protected if necessary or if desired. Suitable protecting groups are well known in the art and include trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, tritylmethyl, alkyl groups, acyl groups such as acetyl, propionyl, butyl, methylsulfonyl and paratoluylsulfonyl. They specifically include 5-methyluracil (thymine), 5-iodouracil, cytosine and 5-ethyluracil.

 The present invention also discloses a method and composition for treating HBV infections, EBV infections and other viral infections in which viruses replicate in humans or other animal carriers in the same manner as HIV, which comprises administering an effective amount of one or more of the above L-nucleosides or physiologically acceptable derivatives, or physiologically acceptable salts thereof, if desired, in a pharmaceutically acceptable carrier. The compounds of the present invention either have anti-HBV activity, anti-EBV activity, or are converted in the body to a compound or compounds that exhibit anti-HBV or anti-EBV activity. The compounds disclosed in the present invention can also be used to treat diseases associated with HBV and EBV.

The active compounds can be administered in the form of any derivative which, after administration to the recipient, is able to provide, directly or indirectly, a related compound or to exhibit activity itself. Non-limiting examples include pharmaceutically acceptable salts (otherwise referred to as “physiologically acceptable salts”), and 5 ′ and purine or pyrimidine-acylated or alkylated derivatives of the active compound (otherwise referred to as “physiologically active derivatives”). In one embodiment, the acyl group is a carboxylic acid ester (i.e., —C (O) R ′) in which the non-carbonyl moiety (R ′) of the ester group is selected from branched, unbranched or cyclic C ₁ -C ₁₀ alkyl, alkoxyalkyl including methoxymethyl, aralkyl, including benzyl, an alkoxyalkyl such as phenoxymethyl, aryl, including phenyl optionally substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, sulfonate esters such as alkyl or aralkyl sulfonyl, including methanesulfonyl, mono-, di- or tri-phosphate layers esters, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (for example, dimethyl-tert-butylsilyl) or diphenylmethylsilyl. Optimally, aryl groups in esters contain phenyl or benzyl groups. The alkyl group may be unbranched, branched or cyclic, and optimally represents a C ₁ -C ₁₀ group.

I. Synthesis of L-nucleosides
The L-nucleosides disclosed herein can be prepared, as described in detail below, or by other methods known to those skilled in the art.

Other standard reagents can be used in the synthesis scheme below, including equivalent acids, bases and solvents, instead of those listed, among those well known to those skilled in the art. A wide range of protecting groups can be used to protect oxygen and nitrogen, such as those described in the book: Greene et al., "Protective Groups in Organic Synthesis", John Wiley and Sons, 2nd. Ed., 1991. Suitable oxygen and nitrogen protecting groups include, for example, trisubstituted silyl groups such as trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyl diphenylsilyl, trityl, alkyl group, acyl groups such as acetyl, propionyl, benzoyl, p-NO ₂ -benzoyl, benzyl or toluyl, methylsulfonyl or p-toluylsulfonyl. The functional groups of oxygen and nitrogen at the heterocyclic base must be protected before condensation with sugar.

Suitable reducing agents include NaBH ₄ , diisobutylaluminium hydride (DIBAL-H), lithium borohydride (LiBH ₄ ) and sodium bis (2-methoxyethoxy) -aluminium hydride (Red-Al). Suitable oxidizing agents include aqueous acidic chromic acid (CrO ₃ ), sodium dichromate (Na ₂ CrO ₇ ), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), potassium permanganate (KMnO ₄ ,), lead tetraacetate / pyridine, oxygen over platinum catalyst / carbon, RuO ₄ , RuO ₄ / NaIO ₄ , dimethyl sulfoxide / dicyclohexylcarbodiimide (DMSO / DCC) and proton donors such as silver carbonate and triphenylbismuth carbonate, Oppenauer oxidation (aluminum alkoxides in acetone) and manganese dioxides (for selective oxidation of allyl or benzene alcohols in the presence of other sp mouths).

Friedel-Crafts catalysts (Lewis acids) that can be used in the condensation reaction include SnCl ₄ , ZnCl ₄ , TiCl ₄ , AlCl ₃ , FeCl ₃ , BF ₃ diethyl ether and BCl ₃ . These catalysts require anhydrous conditions, since the presence of water reduces their activity. These catalysts can also be inactivated in the presence of organic solvents with active hydrogens such as alcohols and organic acids. These catalysts are commonly used in solvents such as carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene, tetrachloroethane, chlorobenzene, benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or acetonitrile. Anhydrous aluminum chloride is insoluble in carbon disulfide (Niedballa, et al., J. Org. Chem. 39, 25 (1974)). A preferred catalyst is SnCl ₄ . The preferred solvent is 1,2-dichloroethane. Trimethylsilyl triflate can be used under the same conditions as previously indicated for Friedel-Crafts catalysts. The reaction proceeds at a temperature in the range of -10 to 200 ^° C. Desilylation can be carried out using various reagents, including acetic acid, trifluoroacetic acid, hydrogen fluoride, n-tetrabutylammonium fluoride, potassium fluoride and pyridinium HCl.

As shown in FIG. 3, starting from L-xylose (1a), the key intermediate 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (10) is obtained in 20% yield (L. Vargha Chem. Ber., 1954, 87, 1351; Holy A., et al., Synthetic Procedure in Nucleic Acid Chemistry, VI, 163-67). As shown in FIG. 4, Compound 10 can also be prepared from the more expensive L-ribose starting material (Holy A., et al., Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). FIG. 3 represents an alternative synthesis of compound 10 (yield 53%), which is fluorinated sequentially at C ₂ (J. Org. Chem., 1985, 50, 3644-47) to give 1,3,5-tri-O-benzoyl-2- deoxy-2-fluoro-L-arabinofuranose (13), which is condensed with various bases via brominated sugar to obtain 2'-deoxy-2'-fluoroarabinofuranosyl nucleosides in different yields.

1,2-Di-O-isopropylidene-α-L-xylofuranose (3)
To 650 ml of anhydrous acetone, 4 ml of concentrated sulfuric acid, 5 g of molecular sieves (4A), 80 g of anhydrous copper sulfate and 50 g of L-xylose were added, the resulting mixture was stirred at room temperature for 36 hours. The reaction mixture is filtered and washed thoroughly with acetone, the combined filtrates are neutralized with ammonium hydroxide, and then evaporated to dryness. 200 ml of ethyl acetate are added, then filtered and evaporated to give an oil which is dissolved in 250 ml of a 0.2% HCl solution and stirred at room temperature for 2.5 hours, the pH is adjusted to 8 with saturated NaHCO ₃ solution, then evaporated to dryness. the residue was extracted with ethyl acetate. Removal of the solvent gave a yellow oil, compound 3 (41.7 g, 82.3%).

¹ H-NMR (CDCl ₃ ): δ 5.979 (d, J = 3.78 Hz, 1H, H-1); 4.519 (d, J = 3.6 Hz, 1H, H-2); 4.308 (broad d, 1H, H-3); 4.080 (m, 3H, H-4 and H-5); 1.321 (s, 3H, CH ₃ ); 1.253 (s, 3H, CH ₃ ).

1,2-di-O-isopropylidene-3,5-di-Oo-tolylsulfonyl-α-L-xylofuranose (4)
Compound 3 (40 g, 210 mmol) was stirred in 500 ml of anhydrous pyridine at 0 ^° C., while TsCl (75 g, 393 mmol) was dissolved in 100 ml of CHCl ₃ by dropwise addition. After 3 hours, a second portion of TsCl (50 g, 262 mmol) in 50 ml of CHCl _{3 was} added in the same manner. The resulting mixture was stirred at room temperature for 24 hours, then cooled at 0 ^° C., 10 ml of water was added, then stirred at room temperature for 30 minutes. The reaction mixture was poured into 500 ml of ice-water, extracted with CHCl ₃ (150 ml x 4), washed with 1.5 M H ₂ SO ₄ , (150 ml x 4), saturated NaHCO ₃ solution (200 ml x 2), dried over magnesium sulfate. Removal of the solvent gave a brown syrup, which upon crystallization from EtOH gave compound 4 as a white solid (103.8 g, 99%).

¹ H-NMR (CDCl ₃ ): δ 7.282, 7.836 (m, 8H, OT); 5.849 (d, J = 3.51 Hz, 1H, H-1); 4.661, 4.779 (m, 2H, H-3 and H-4); 4.193 (dd, 1H, H-2); 4.011 (d, 2H, H-5); 2.448, 2.488 (2s, 6H, -OTs); 1.261, 1.320 (2s, 6H, CH ₃ ).

1,2-di-O-acetyl-3,5-di-Op-tolylsulfonyl-α, β - xylofuranose (5)
Compound 4 (70 g, 140.5 mmol) was dissolved in 700 ml of glacial AcOH and 100 ml of Ac ₂ O, dropwise at 0 ^° C., 50 ml of concentrated sulfuric acid. The resulting solution was stirred at room temperature overnight, and then poured into 1 L of ice-water, extracted with CHCl ₃ (200 ml x 4), washed with saturated sodium bicarbonate solution, dried over magnesium sulfate. After removal of the solvent in vacuo, compound 5 was obtained in the form of a syrup (84.2 g, 110% yield of crude product).

Methyl-3,5-di-Op-tolylsulfonyl-α, β - xylofuranose (6)
The crude product 5 (80 g) was stirred in 500 ml of a 1% mixture of HCl / CH ₃ OH at room temperature for 30 hours. The solvent was removed under reduced pressure, the residue was dissolved in 300 ml of CHCl ₃ , washed with saturated NaHCO ₃ , dried over magnesium sulfate. After removal of the solvent, compound 6 was obtained in the form of a syrup (60 g, 90% of 4).

Methyl-2-O-benzoyl-3,5-di-Op-tolylsulfonyl-α, β - xylofuranoside (7)
The syrup of compound 6 (60 g, 127 mmol) was dissolved in 200 ml of pyridine and stirred at 0 ^° C, dropwise benzoyl chloride (40 ml, 345 mmol), and the resulting solution was stirred at room temperature for 17 hours. It is concentrated to about 50 ml, then poured into 300 ml of an ice-water mixture, extracted with CHCl ₃ , washed with 3 N. H ₂ SO ₄ and saturated NaHCO ₃ , dried over magnesium sulfate. After evaporation of the solvent, compound 7 was obtained in the form of a syrup (71 g, 97%).

Methyl-2,3,5-tri-O-benzoyl-α, β-L-ribofuranoside (9)
The syrup of compound 7 (70 g) and sodium benzoate (100 g, 694 mmol) are suspended in 1200 ml of DMF and stirred with a mechanical stirrer while boiling under reflux for 16 hours. The mixture was cooled to room temperature and poured into 1 L of ice-water, extracted with ether, dried over magnesium sulfate. After evaporation of the solvent, syrup (50 g, 8a and 8b) is obtained, which is dissolved in 180 ml of pyridine and benzoylated (BzCl, 20 ml, 172 mmol) for 17 hours at room temperature. After treatment, compound 9 is obtained in the form of a brown syrup (48 g, 83% of 7).

).1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (10)
Compound 9 (26 g, 54.6 mmol) was treated with 275 ml of glacial acetic acid, 55 ml of acetic anhydride and 16 ml of concentrated sulfuric acid at a temperature of from 0 ^° C. to room temperature for 17 hours. Then it is poured into 1 liter of ice-water, extracted with chloroform (200 ml x 4). The combined extract was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Removal of the solvent gave a brown syrup, which was treated with ethanol to give compound 10 as a white solid (8.8 g, 32%). Melting point 124.7 ^° C., literature. 129-130 ^o C; D form: 130-131 ^° C [α] _D = -45.613 (s 1.0, CHCl ₃ ); D form: [α] _D = +44.2.
¹ H-NMR (CDCl ₃ ): δ 7.317, 8.134 (m, 15H, OBz), 6.437 (s, 1H, H-1), 5.835 (m, H-2 and H-3), 4.649 (m, 3H , H-4 and H-5), 2.003 (s, 3H,

)

1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (from L-ribose)
L-ribose (5 g, 33.3 mmol) was suspended in 120 ml of 1% HCl / MeOH and stirred at room temperature for 3 hours, resulting in a clear solution. The reaction was quenched by adding 30 ml of anhydrous pyridine, and then evaporated under reduced pressure. The remaining syrup is evaporated together with pyridine (30 ml x 2), then dissolved in 80 ml of anhydrous pyridine and stirred at 0 ^° C, dropwise with benzoyl chloride (20 ml, 172 mmol). After stirring at room temperature for 17 hours, the reaction was completed. Add 10 ml of water, the resulting mixture was stirred at room temperature for 0.5 hours, then concentrated to about 50 ml, poured into 150 ml of ice-water, extracted with chloroform (50 ml x 4), washed successively with 3 N. H ₂ SO ₄ , (30 ml x 2), saturated sodium bicarbonate (30 ml x 3) and dried over magnesium sulfate. After removal of the solvent, compound 9 was obtained as 13 g of syrup.

The crude compound 9 was dissolved in 80 ml of HBr / AcOH (45%, w / v) and stirred at room temperature for 1.5 hours. Glacial acetic acid (50 ml) was added to this mixture, the resulting solution was stirred at 0 ^° C, slowly adding 34 ml of water to maintain the temperature below 7 ^° C. Then it was stirred at room temperature for 1 hour, poured into 200 ml of ice-cold mixture. water, extracted with chloroform (50 ml x 5). The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate. After removing the solvent, 13 g of syrup is obtained, which is dissolved in 40 ml of anhydrous pyridine, stirred at 0 ^° C. Then, acetic anhydride (14 ml, 148.4 mmol) is added dropwise. After completion of the reaction, the reaction mixture was poured into 150 ml of ice-water, extracted with chloroform (50 ml x 4), washed successively with 3 N. H ₂ SO ₄ , (30 ml x 2), saturated sodium bicarbonate solution (50 ml x 2) and dried over magnesium sulfate. After removal of the solvent and treatment with methanol, compound 10 was obtained as a white solid (9.2 g, 53.7% from L-ribose).

1,3,5-tri-O-benzoyl-α-L-ribofuranose (11)
Compound 10 (9 g, 17.84 mmol) was stirred in 100 ml of CH ₂ Cl ₂ at 0 ^° C., while 70 ml of CH ₂ Cl ₂ containing HBr (3.2 g, 30.5 mmol) was added immediately. The resulting mixture was stirred at 0 ^° C. for 3.5 hours, 55 ml of water was added, the resulting mixture was stirred at room temperature for 18 hours. The organic layer was isolated, washed with saturated sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvent, a foam is obtained, from which, after recrystallization from CH ₂ Cl ₂ and n-hexane, compound 11 is obtained in the form of a white solid (6.2 g, 75.5%). T. melting point 137-138 ^o C, from the literature: 140-141 ^o C, [α] _D = -81.960 (c 0.55, CHCl ₃ ; D form: [α] _D = +83.71.
¹ H-NMR (CDCl ₃ ): δ 7.312, 8.187 (m, 15H, OBz), 6.691 (d, J = 4.59 Hz, H-1); 5.593 (dd, J _4-3 = 6.66 Hz, J _2-3 = 1.8 Hz, 1H, H-30); 4.637, 4.796 (m, 4H, 4-2, H-4 and H-5); 2.3 (broad OH).

1,3,5-tri-O-benzoyl-2-O-imidazosulfuryl-α-L-ribofuranose (12)
Compound 11 (5.94 g, 12.84 mmol) was stirred in 50 ml of anhydrous CH ₂ Cl ₂ at -15 ^° C (dry ice-CCl ₄ mixture). Anhydrous DMF (15 ml) and sulfuryl chloride (3.2 ml, 3.98 mmol) are successively added. The resulting solution was stirred at -15 ^o C for 30 minutes, and then left at room temperature for 4 hours. Imidazole (9.7 g, 12.78 mmol) was added in three portions while cooling in an ice bath. Then it is stirred at room temperature for 17 hours. The resulting mixture was poured into 150 ml of ice-water, the aqueous phase was extracted with CH ₂ Cl ₂ (50 ml x 3). The combined organic layers were washed with water and dried over magnesium sulfate. Purify on a chromatographic column (hexane: EtOAc / 5: 1 to 1: 1), whereby compound 12 is obtained as a white solid (3.7, 49%). M.p. 124.5-125.5 ^° C; literature. 129 ^o C; [α] _D = -68.976; D form: +66.154.

¹ H-NMR (CDCl ₃ ): δ 6.9, 8.2 (m, 18H, Ar-H); 6.67 (d, J = 4.4 Hz, 1H, H-1); 5.59 (dd, 1H, H-3); 5.21 (dd, 1H, H-2); 4.5, 4.8 (m, 3H, H-4 and H-5).

1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-L-arabinofuranose (13)
A suspension of compound 12 (3.33 g, 5.62 mmol), KHF ₂ (1.76 g, 22.56 mmol) in 30 ml of 2,3-butanediol was stirred under argon. The mixture was heated to 150 ^° C. by adding 1 ml of HF / H ₂ O (48%, 27.6 mmol), and the resulting mixture was stirred at 160 ^° C. for 1.5 hours. To quench the reaction, add a brine-water mixture, and then the resulting solution was extracted with methylene chloride (50 ml x 4). The combined extracts were washed with brine, water, saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and activated carbon (Darco-60). All this was poured onto a layer of silica gel (5 cm x 5 cm), washed with methylene chloride and then EtOAc to give a syrup, which crystallized from 95% EtOH to give compound 13 (1.3 g, 49.8%). Melting point 77-78 ^o C (literature 82 ^o C).

¹ H-NMR (CDCl ₃ ): δ 7.314, 8.146 (m, 15H, OBz); 6.757 (d, J = 9.1 Hz, 1H, H-1); 5.38 (d, J = 48.5 Hz, 1H, H-2); 5.630 (dd, J = 22.5 Hz, 1H, H-3); 4.768 (m, 3H, H-4 and H-5).

-L-арабинофуранозил)-2,6-ди-хлорпурин (15)
Соединение 13 (464 мг, 1 ммоль) растворяют в 10 мл метиленхлорида, добавляя при этом 1,4 мл HBr/AcOH (45% вес/объем). Полученный раствор перемешивают при комнатной температуре в течение 24 часов, а затем выпаривают досуха. Остаток растворяют в 20 мл метиленхлорида и промывают водой, насыщенным раствором бикарбоната натрия, сушат над сульфатом магния. После фильтрования и выпаривания получают бромосахар - соединение 14 (100%, на основании данных ТСХ).N ₉ - (3 ', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-

-L-arabinofuranosyl) -2,6-di-chloropurine (15)
Compound 13 (464 mg, 1 mmol) was dissolved in 10 ml of methylene chloride, while 1.4 ml of HBr / AcOH (45% w / v) was added. The resulting solution was stirred at room temperature for 24 hours, and then evaporated to dryness. The residue is dissolved in 20 ml of methylene chloride and washed with water, saturated sodium bicarbonate solution, dried over magnesium sulfate. After filtration and evaporation, bromosugar - compound 14 (100%, based on TLC) was obtained.

 At the same time, 2,6-di-chloropurine (378 mg, 2 mmol) was suspended in 15 ml of HMDS (hexamethyldisilosane) and 2 mg of ammonium sulfate, and then refluxed for 2 hours. HMDS was evaporated under high vacuum in a nitrogen atmosphere to give a white silylated base.

Bromosugar 14 is dissolved in 25 ml of anhydrous 1,2-dichloroethane. The resulting solution was added to a silylated base in a nitrogen atmosphere. The resulting mixture was stirred at the boil under reflux for 2 days. Chloroform (30 ml) was added and washed successively with water (20 ml x 2), saturated sodium bicarbonate solution (20 ml x 2), saturated NaCl solution (20 ml x 2) and dried over magnesium sulfate. Compound 15 (105 mg, 19.7%) was crystallized from CHCl ₃ . T. melting point 158 ^° C; D form: 158 ^o C.

UV (methanol) λ _max = 238.5 nm, 273.0 nm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.82 (d, J = 1.5 Hz, 1H, H-8); 7.49, 8.33 (m, 10H, OBz); 6.767 (dd, J _HH = 4 Hz, K _FH = 13.8 Hz, 1H, 1-H '); 5.854 (dkv, J = 67.4 Hz, 1H, H-2 '), 5.910 (m, 1H, H-3'); 4.751 (m, 3H, H-4 'and H-5').

M ₉ (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) - 2,6-di-chloropurine (16)
Compound 15 (70 mg, 0.13 mmol) was dissolved in 25 ml of saturated NH ₃ / CH ₃ OH in a sealed steel bomb and heated at 90 ^° C. for 6 hours. After removal of the solvent under reduced pressure, a yellow semi-liquid substance is obtained, which is purified using preparative TLC (9: 1 / CHCl ₃ : CH ₃ OH). After lyophilization from water and 1,4-dioxane, a white powder is obtained - compound 16 (30 mg, 75%). UV (H ₂ O) pH2, λ _max = 212.00 nm, 263.5 nm (ε 6711); pH7, λ _max = 213.5 nm, 263.00 nm (ε 7590); pH11, λ _max = 213.5 nm, 263.00 nm (ε 5468).

¹ H-NMR (300 MHz, BMSO-d ₆ ): δ 8.279 (d, J = 1.5 Hz, 1H, H-8); 7.908 (br s, 2H, NH ₂ ); 6.321 (dd, J _HH = 4.4 Hz, J _FH = 13.8 Hz, 1H, H-1 '), 5.986 (t, 1H, 5'-OH), 5.230 (dt, J _FH = 52.6 Hz, 1H, H-2 '); 5.115 (d, 1H, 3'-OH); 4.425 (dkv, J _FH = 19 Hz, 1H, H-3 '); 3.841 (m, 1H, H-4 '); 3.636 (d, 2H, H-5 ').

N ₁ - (2'-deoxy-2'-fluoro-3 ', 5'-di-O-benzyl-β-L-arabinofuranosyl) -thymine (17)
To a solution of compound 13 (400 mg, 0.86 mmol) in anhydrous CH ₂ Cl ₂ (10 ml) was added hydrogen bromide in acetic acid (45% w / v, 1.5 ml), the resulting solution was stirred at room temperature for 17 hours. After removal of the solvent and co-evaporation with toluene, compound 14 is obtained.

 At the same time, thymine (215 mg, 1.72 mmol) was refluxed in NM (25 ml) under nitrogen for 17 hours until a homogeneous solution was obtained. After evaporation of the solvent, silylated thymine is obtained.

A solution of compound 14 in 50 ml of dichloroethane was added to silylated thymine and the resulting solution was boiled under nitrogen for 3 days. Water was added and then extracted with CHCl ₃ . The organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solvent, a crude product is obtained, which is purified using preparative TLC using 2% MeOH / CHCl ₃ to give compound 17 (235 mg, 58%). Melting point 99-101 ^o C. UV (methanol): 230, 264 nm [α] _D = +22.397 ..

¹ H-NMR (CDCl ₃ ): δ 7.343-8.389 (m, 12H, Ar-H, NH); 6.34 (dd, J _HH = 2.97 Hz, J _FH = 28.32 Hz, 1H, H-1 '); 5.383 (dd, J _HH = 2.7 Hz, J _FH = 63.27 Hz, 1H, H-2 '); 5.565 (dd, 1H, H-3 '); 4.812 (d, 2H, H-5 '); 4.466 (m, 1H, H-4 '); 1.775 (s, 3H, CH ₃ ).

Elemental analysis (CH ₂₄ H ₂ 1N ₂ O ₇ F), C: 61.01; H: 4.57; N: 5.73; F: 3.92.

N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) - thymine (18)
Compound 17 (145 mg, 0.309 mmol) was treated with NH ₃ / CH ₃ OH at room temperature for 18 hours. After evaporation of the solvent and purification using preparative TLC (15% MeOH / CHCl ₃ ), compound 18 (70 mg, 87.5%) was obtained. Melting point 174-175 ^° C. UV: 264 nm, [α] _D = -104.36.
¹ H-NMR (DMSO-d ₆ ): δ 11.401 (s, 1H, NH); 7.575 (s, 1H, H-6); 6.093 (dd, J _HH = 4.41 Hz, J _FH = 15.6 Hz, H-1 '); 5.844 (d, 1H, 3'-OH); 5.019 (dt, J _FH = 53.3 Hz, 1H, H-2 '); 5.087 (t, 1H, 5'-OH); 4.194 (dq, 1H, H-3 '); 3.647 (m, 3H, H-4 'and H-5'); 1.781 (s, 3H, CH ₃ ).

Elemental analysis: (C ₁₀ H ₁₃ N ₂ FO ₅ ), C: 44.80; H: 4.97; N: 10.04; F: 7.03.

N ₁ - (2'-deoxy-2'-fluoro-3 ', 5'-di-O-benzoyl-β-L-arabinofuranosyl) -5-ethyluracil (19)
To a solution of compound 13 in anhydrous dichloromethane (10 ml) was added hydrogen bromide in acetic acid (45% w / v, 0.97 ml, 5.385 mmol). This solution was stirred at room temperature for 13 hours, after evaporation of the solvent and co-evaporation with toluene, compound 14 was obtained.

 At the same time, 5-ethyluracil (0.75 g, 5.39 mmol) was suspended in HMDS (10 ml) with ammonium sulfate (5 mg) and refluxed for 5 hours under nitrogen until a homogeneous solution was obtained.

The silylated base solution is evaporated to dryness, avoiding contact with moisture. To the resulting syrup was added a solution of compound 14 in anhydrous 1,2-dichloroethane (10 ml). The reaction mixture was stirred at 95 ^° C. under nitrogen for 20 hours, then evaporated to dryness in vacuo to give a yellow solid, which was mixed with CH ₃ OH / CHCl ₃ (1: 1) and filtered. The obtained filtrate was evaporated to a residue, which was processed on a chromatographic column (CH ₃ OH / CHCl ₃ , 0-1%) to obtain a white solid, compound 19 (0.557 g, 100%).

); 0,85 (т, 3H, CH₃). ¹ H-NMR (DMSO-d ₆ ): δ 11.55 (s, 1H, NH); 7.51, 8.08 (m, 10H, Ar-H); 7.32 (s, 1H, H-6); 6.29, 6.37 (dd, J _HH = 3.7 Hz, J _FH = 20 Hz, 1H, H-3 '); 5.47-5.65 (dd, J _FH = 54 Hz, 1H, H-2 '); 4.62-4.82 (m, 3H, H-4 'and H-5'); 2.01, 2.09 (q, 2H,

); 0.85 (t, 3H, CH ₃ ).

N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5- ethyluracil (20)
Compound 19 (500 mg) was dissolved in methanol ammonia (50 ml) and stirred at room temperature for 44 hours. The resulting solution was evaporated to dryness to obtain a white solid (0.4 g), which was processed on a chromatographic column with silica gel (CH ₃ OH / CHCl ₃ , 0-5%) to obtain a white solid, compound 20 (240 mg, 84%). T. melting point 158-161 ^o C.

UV (MeOH): λ _max = 260 nm.

¹ H-NMR (DMSO-d ₆ ): δ 11.42 (s, 1H, NH); 7.57 (s, 1H, H-6 '); 6.10, 6.17 (dd, J _HH = 5.0 Hz, J _FH = 14 Hz, 1H, H-1 '), 5.88 (br s, 1H, 3'-OH); 5.14, 5.19 (m, 2H, H-2 'and 5'-OH); 4.98 (t, 1H, H-3 '); 4.22, 4.28 (m, 1H, H-4 '); 3.55, 3.78 (m, 2H, H-5 ').

Elemental analysis (C ₁₁ H ₁₅ N ₂ O ₅ F): C: 7.93; H: 5.56; N: 10.06; F: 6.68.

N ₁ - (2-deoxy-2'-fluoro-3 ', 5'-di-O-benzoyl-β-L-arabinofuranosyl-N ^4- benzoyl-5-iodocytosine (21)
To a solution of compound 13 (150 mg, 0.323 mmol) in anhydrous methylene chloride (5 ml) was added hydrogen bromide in acetic acid (45% w / v, 0.29 ml, 1.615 mmol). The reaction mixture was stirred at room temperature for 9.5 hours. After evaporation of the solvent and co-evaporation with toluene, compound 15 is obtained in the form of a yellow syrup.

At the same time, N ^4- benzoyl-5-iodocytosine (550 mg, 1.615 mmol) was suspended in HMDS (8 ml) with ammonium sulfate (3 mg) and refluxed for 5 hours under nitrogen until a homogeneous solution was obtained .

The silylated base solution is evaporated to dryness, avoiding contact with moisture. To the resulting syrup was added a solution of compound 14 in anhydrous 1,2-dichloroethane (10 ml). The reaction mixture was refluxed under nitrogen for 23 hours, then evaporated to dryness to give a brown syrup, which was triturated with chloroform (30 ml). The precipitate obtained is filtered off and washed with chloroform. The resulting filtrate and washes were combined and evaporated to a brown syrup. The resulting mixture was separated using a silica gel column chromatography (CH ₃ OH) CHCl ₃ , 0-1%) to obtain a white solid, compound 21 (100 mg, 45%).

¹ H-NMR (CDCl ₃ ); δ 11.40 (br s, 1H, NH); 7.26, 8.20 (m, 17H, Ar-H, H-6 and NH); 6.36, 6.44 (dd, J _HH = 2.8 Hz, J _FH = 21 Hz, 1H, H-1 '); 5.62, 5.68 (dd, 1H, H-3 '); 5.39, 5.56 (dd, 1H, H-2 '); 4.58, 4.85 (m, 3H, H-4 'and H-5').

N ₁ - (2'-deoxy-fluoro-β-L-arabinofuranosyl) -5-iodocytosine (22)
Compound 21 (100 mg, 0.27 mmol) was treated with saturated NH ₃ / MeOH (60 ml) at room temperature for 24 hours. Chromatography on silica gel (0-10% CH ₃ OH / CHCl ₃ ) gave compound 22 (35 mg, 71%) as a white solid. [α] _D = -65.4 (c 0.34, CH ₃ OH). UV (MeOH) λ _max = 293 nm.
¹ H-NMR (DMSO-d ₆ ): δ 8.04 (s, 1H, H-6); 6.74, 7.94 (s, 1H, NH); 6.01, 6.08 (dd, J _HH = 3.9 Hz, J _FH = 16.6 Hz, 1H, H-1 '), 5.85 (d, 1H, 3-OH), 5.17 (t, 1-H, 5'-OH); 5.08 (t, 1H, H-2 '); 4.89 (t, 1H, H-3 '); 4.15-4.23 (m, 1H, H-4 '); 3.63-3.79 (m, 2H, H-5').

N ₁ - (2'-deoxy-2'-fluoro-3 ', 5'-di-benzoyl-β-L-arabinofuranosyl) -5-iodouracil (23)
To a solution of compound 13 (260 mg, 0.56 mmol) in 10 ml of anhydrous CH ₂ Cl ₂ add HBr / AcOH (45%, weight / volume, 0.5 ml, 2.8 mmol). The reaction mixture was stirred at room temperature for 36 hours, and then evaporated to dryness. The residue was dissolved in 20 ml of CH ₂ Cl ₂ , washed with water (10 ml), saturated sodium bicarbonate solution (10 ml) and dried over magnesium sulfate. After filtration and evaporation, bromosugar - compound 14 is obtained in the form of a syrup.

At the same time, 5-iodouracil (270 mg, 1.12 mmol) was suspended in 10 ml of HMDS and refluxed for 36 hours until a homogeneous solution was obtained. It is evaporated
in a vacuum to dryness. To this was added a solution of compound 14 in anhydrous 1,2-dichloroethane, and the resulting solution was refluxed under nitrogen for 1.5 days. CHCl ₃ (20 ml) was added and the resulting solution was washed successively with water (10 ml), brine (10 ml) and saturated sodium bicarbonate solution (10 ml), and then dried over magnesium sulfate. After removal of the solvent, a syrup was obtained, which was crystallized from CH ₂ Cl ₂ to give compound 23 as a yellow solid (237 mg, 73%). Part of it (70 mg) was recrystallized from 2-isopropanol to obtain a white solid (67 mg). UV (methanol): λ _max = 230.0 nm, 276 nm.

¹ H-NMR (CDCl ₃ ): δ 8.4, 7.3 (m, 12H, Ar-H); 6.29 (dd, J _HH = 2.43 Hz, J _FH = 21.6 Hz, 1H, H-1 '); 5.377 (dd, J _HH = 2.8 Hz, J _FH = 61.3 Hz, 1H, H-2 '); 5.55 (dd, 1H, H-3 '); 4.865, 4.793 (d, 2H, H-5 '); 4.588, 4.502 (m, 1H, H-4 ').

N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodouracil (24)
Compound 23 (40 mg, 0.069 mmol) was dissolved in 25 ml of saturated NH ₃ / MeOH and stirred at room temperature for 24 hours, and then evaporated to dryness. The resulting syrup was purified using preparative TLC (5: 1 / CHCl ₃ : MeOH) to give compound 24 as a solid (19 mg, 74%). UV (MeOH): λ _max = 280.5 nm.
¹ H-NMR (DMSO-d ₆ ): δ 11.82 (br s, CONH); 8.24 (s, 1H, H-6); 6.082 (dd, J _HH = 4.45 Hz, J _FH = 13.7 Hz, 1H, H-1 '); 5.947 (d, 1H, 3'-OH); 5.296 (t, 1H, 5'-OH); 5.07 (dt, J _FH = 53 Hz, 1H, H-2); 4.24 (brd, J _FH = 21 Hz, 1H, H-3 '); 3.81, 3.55 (m, 3H, H-4 ', H-5').

2,3,5-tri-O-benzyl-L-arabinose
As illustrated in FIG. 9, 30 grams (0.2 mol) of L-arabinose powder (5) and then 0.4 ml of concentrated sulfuric acid are added to 600 ml (14.8 mol) of anhydrous methanol. This suspension is stirred and heated under mild reflux until a clear solution is obtained for 2 hours. Then the reaction mixture was neutralized with 1.5 g of sodium bicarbonate, dried over magnesium sulfate, and then evaporated in vacuo to obtain a thick syrup (compound 6), which was diluted with 50 ml of freshly purified tetrahydrofuran and concentrated again (35-40 ^° C bath) to remove residual methanol. Freshly purified tetrahydrofuran (400 ml) was added and the resulting mixture was treated with 30 g of Drierite, 156 g (2.78 mol) of potassium hydroxide and 200 ml (1.74 mol) of benzyl chloride. The resulting mixture was heated at low boiling under reflux overnight, cooled, filtered through a thin layer of celite and concentrated in vacuo, and then under high vacuum and 100 ^o C (bath). The crude syrupy methyl 2, 3,5-tri-O-benzyl-L-arabinoside (7) was dissolved in 400 ml of glacial acetic acid. The hydrolysis mixture is heated to 65-70 ^o C for 2 hours, concentrated in vacuo to one third of the volume and poured into 2.5 l of a mixture of ice and water. After the introduction of the seed (seed crystals were initially obtained chromatographically by elution with dichloromethane), the resulting mixture was kept at 5 ^° C. overnight. The aqueous layer is decanted from a partially crystalline mass, and the latter is dissolved in 200 ml of dichloromethane. The resulting solution was washed with cold aqueous sodium bicarbonate, dried over magnesium sulfate, filtered through a thin layer of decolorizing charcoal and concentrated in vacuo to obtain a syrup, which was dissolved in 200 ml of cyclohexane. After seeding, the solution was kept at room temperature for 1 hour and then at 5 ^° C. overnight to obtain 27.7 g (33.2%) of 2,3,5-tri-O-benzyl-L-arabinose ( 8). Melting point 68-73 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -1.69 (C 2.01, 9: 1 (v / v p-dioxane-water)),
UV (MeOH) λ _max = 220;
¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.48-3.62 (m, 2H, H-5); 3.94-4.18 (m, 3H, H-2, 3.4); 5.33 (d, 1H, J = 4.07, H-1); 5.29 (s, H-1); 7.25-7.33 (m, 15, H-aroma.).

2,3,5-tri-O-benzyl-1-O- (p-nitrobenzoyl) -L-arabinose (9)
Compound 8 (Fig. 9) (2 g, 4.76 mmol) was dissolved in 7.5 ml of dichloromethane, a solution of 0.95 g (5.1 mmol) of p-nitrobenzoyl chloride in a mixture of 5 ml of dichloromethane and 1 was added to this solution. 5 ml of pyridine. The reaction mixture was kept at room temperature overnight, and then washed sequentially with 1 N. hydrochloric acid (10 ml x 2), aqueous sodium bicarbonate (10 ml x 2) and water (30 ml x 3). The moisture is removed with Na ₂ SO ₄ , the resulting solution is concentrated in vacuo to obtain 2.67 g (98.4%) of the mixture of anomers of compound 9. T. melting point 68-82 ^o C. Additional purification on a chromatographic column with silica gel (hexane: acetone 8: 1) provides a melting point of 89-93 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 13.04 (C 6.8, CH ₂ Cl ₂ ),
UV (MeOH) λ _max = 215.5 and 258.5,
¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.54-3.69 (m, 2H, H-5); 4.06 (m, 1H, H-4 '); 4.22 (m, 1H, H-3 '); 4.33 (m, 1H, H-2 '); 4.38-4.78 (m, 6H, benzyl CH ₂ ); 6.50 (d, 1H, J = 2.35, H-1); 7.23-7.36 (m, 15H, H-aromat. Benzyl group); 8.01-8.25 (m, 4H, H-aromat. Nitrobenzyl group).

10 (2,3,5-tri-O-benzyl-β-L-arabinosyl) thymine (12)
0.444 g (3.52 mmol) of thymine and 2 mg of ammonium sulfate are suspended in hexamethyldisilazane (10 ml); the suspension is refluxed (140 ^° C.) overnight under nitrogen until a clear solution is obtained. Excess hexamethyldisilazane is removed in vacuo while avoiding contact with moisture, resulting in a syrup compound 11.

Compound 9 (1 g, 1.76 mmol) was added to 17 ml of dichloromethane, previously saturated with anhydrous hydrogen chloride at 0 ^° C. After 2 hours at 0 ^° C., the precipitated p-nitrobenzoic acid (0.25 g) was removed by filtration, and the obtained the filtrate was concentrated in vacuo to obtain a syrup, and then kept in high vacuum at room temperature for 2 hours, resulting in 2,3,5-tri-O-benzyl-α - L-arabinosyl chloride (compound 10).

молекулярных сит. Реакционную смесь перемешивают при комнатной температуре в атмосфере аргона в течение 18 часов. Реакционную смесь разбавляют 50 мл дихлорметана и выливают в 2 мл насыщенного водного NaHCO₃ при интенсивном перемешивании. Появляется белый осадок (гидроксид олова), который отфильтровывают на слое целита. Органический слой отделяют от водного и промывают водой (30 мл x 3). Водный слой экстрагируют дихлорметаном, объединенные дихлорметановые слои сушат над сульфатом натрия, а затем выпаривают в вакууме до получения сиропа, который очищают на хроматографической колонке с силикагелем (хлороформ:метанол (100:1)) до получения соединения 12 в виде сиропа (0,68 г, 73%). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -56,71 (C 0,6, CH₂Cl₂).Compound 10 thus obtained is dissolved in 15 ml of anhydrous dichloromethane, the resulting solution is added to a mixture of silylated thymine (11) and 3 g

molecular sieves. The reaction mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was diluted with 50 ml of dichloromethane and poured into 2 ml of saturated aqueous NaHCO ₃ with vigorous stirring. A white precipitate (tin hydroxide) appears, which is filtered off on a layer of celite. The organic layer was separated from the aqueous and washed with water (30 ml x 3). The aqueous layer was extracted with dichloromethane, the combined dichloromethane layers were dried over sodium sulfate and then evaporated in vacuo to obtain a syrup, which was purified on a silica gel column chromatography (chloroform: methanol (100: 1)) to obtain compound 12 as a syrup (0.68 g, 73%). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -56.71 (C 0.6, CH ₂ Cl ₂ ).

UV (MeOH) λ _max = 218 and 265;
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.67 (d, 3H, J = 1.11, CH ₃ ); 3.66-3.70 (m, 2H, H-5 '); 4.06 (m, 1H, H-4 '); 4.13 (t, 1H, J = 4.7, H-3 '); 4.41, 4.54, 4.56 (m, 6H, benzyl CH ₂ ); 6.28 (d, 1H, J = 5.24, H-1 '); 7.15-7.33 (m, 15H, H-aromat.); 7.43 (d, 1H, J = 1.31, H-6).

1- β-L-arabinofuranosylthymine (13)
Palladium chloride (680 mg, 3.835 mmol) is suspended in 100 ml of methanol and reduced by shaking at room temperature in a hydrogen atmosphere. A solution of 450 mg of compound 12 in 25 ml of methanol is then added to the acidified suspension of palladium black. The reaction mixture was shaken at room temperature in a hydrogen atmosphere for 38 hours. After removal of the catalyst, the solution was neutralized with Dowex (HCO ₃ ) to pH 7 and concentrated in vacuo to give a white solid, which after recrystallization from ethanol gave compound 13 (105 mg, 47.7%). T.plav. 244-249 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -91.48 (0.25, H ₂ O).

IR (KBr): 1750, 1600 cm ^-1 (CO); UV (MeOH): λ _max = 268 nm;
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 1.76 (s, 3H, CH ₃ ), 3.62 (t, 2H, J = 4.56, H-5); 3.69 (m, 1H, H-4); 3.90 (t, 1H, J = 3.88, H-3); 3.99 (t, 1H, J = 4.10, H-2 '); 5.08 (bs, 1H, C'5-OH, exchanged); 5.54 (d, 1H, J = 5.23, C'2-OH or C'3-OH, exchanged); 5.97 (d, 1H, J = 4.64, H-1 '); 7.51 (d, 1H, J = 0.97, H-6); 11.26 (s, 1H, NH, exchanged). Elemental analysis for C ₁₀ H ₁₄ N ₂ O ₆ ;
Calculated: C 46.51 H 5.46 N 10.85
Found: C 46.67 H 5.63 N 10.56
1- (2,3,5-tri-O-benzyl-β-L-arabinosyl) cytosine (15)
Cytosine (0.61 g, 6 mmol) and ammonium sulfate (2 mg) were suspended in hexamethyldisilazane (15 ml), and all this was refluxed (140 ^° C.) under nitrogen for 2 hours until a clear solution was obtained. The silylated cytosine mixture was evaporated to dryness in vacuo, avoiding contact with moisture, to give compound 14 as a syrup.

Compound 9 (2.82 g, 5 mmol) was added to 47 ml of dry dichloromethane, previously saturated with anhydrous hydrogen chloride at 0 ^° C. After 2 hours at 0 ^° C., the precipitated p-nitrobenzoic acid (0.807 g) was removed by filtration, which was obtained the filtrate was concentrated in vacuo to give compound 10, - 2,3,5-tri-O-benzyl-α-L-arabinosyl chloride in syrup form.

. Реакционную смесь перемешивают при комнатной температуре в атмосфере азота в течение 5 дней. Затем реакционную смесь разбавляют 50 мл дихлорметана и 20 мл воды и выливают в 2 мл насыщенного водного NaHCO₃ при интенсивном перемешивании. Появляется белый осадок (гидроксид олова), который отфильтровывают на слое целита. Органический слой отделяют от водного и промывают водой (30 мл x 3). Водный слой экстрагируют дихлорметаном, объединенные дихлорметановые слои сушат над сульфатом натрия, а затем выпаривают в вакууме до получения сиропа, который очищают на хроматографической колонке с силикагелем (хлороформ:метанол 96:4) до получения соединения 15 в виде твердого вещества белого цвета, которое после перекристаллизации из 2-пропанола составляет 1,53 г (60%). Т.плавления 146-148^oC, [α]²⁵= -105,2 (C1, CH₂Cl₂); УФ (MeOH): λ_макс= 211,5, λ_мин= 272,5, при pH 7; λ_макс= 211,5, λ_мин= 284 при pH 9.Compound 10 thus obtained is dissolved in 28.5 ml of anhydrous dichloromethane, the resulting solution is added to a mixture of silylated cytosine (14) and 8.3 g of molecular sieves

. The reaction mixture was stirred at room temperature under nitrogen for 5 days. Then the reaction mixture was diluted with 50 ml of dichloromethane and 20 ml of water and poured into 2 ml of saturated aqueous NaHCO ₃ with vigorous stirring. A white precipitate (tin hydroxide) appears, which is filtered off on a layer of celite. The organic layer was separated from the aqueous and washed with water (30 ml x 3). The aqueous layer was extracted with dichloromethane, the combined dichloromethane layers were dried over sodium sulfate and then evaporated in vacuo to obtain a syrup, which was purified on a silica gel column chromatography (chloroform: methanol 96: 4) to obtain compound 15 as a white solid, which after recrystallization from 2-propanol is 1.53 g (60%). M.p. 146-148 ^° C, [α] ²⁵ = -105.2 (C1, CH ₂ Cl ₂ ); UV (MeOH): λ _max = 211.5, λ _min = 272.5, at pH 7; λ _max = 211.5, λ _min = 284 at pH 9.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.65 (d, 2H, J = 4.85, H-5 '); 4.00 (t, 1H, J = 3.72, H-3 '); 4.11 (m, 1H, H-4 '); 4.28 (m, 1H, H-2 '); 4.38-4.55 (m, 6H, benzyl CH ₂ ); 5.56 (d, 1H, J = 7.5, H-5); 6.39 (d, 1H, J = 4.59, H-1 '); 7.12-7.31 (m, 15H, H-aromat.); 7.63 (d, 1H, J = 7.5, H-6).

Hydrochloride salt of (16) 1-β-L-arabinofuranosylcytosine obtained by catalytic hydrogenation of compound 15
Palladium chloride (315 mg, 1.78 mmol) is suspended in 160 ml of methanol and reduced by shaking at room temperature in a hydrogen atmosphere. To this acid suspension of palladium black is added a solution of 300 mg of compound 15 in 15 ml of methanol. The reaction mixture was shaken with hydrogen at room temperature for 3 hours. After removal of the catalyst, the resulting solution was neutralized with Dowex (HCO ₃ ), concentrated in vacuo, and then purified using preparative TLC (MeOH: CHCl ₃ , 3: 5) to obtain a syrup, which was dissolved in 3 ml of methanol, to which was added 1% solution HCl in MeOH to pH 1, concentrated to dryness and triturated thoroughly with 2-propanol, whereby 36 mg (22.1%) of compound 16 were obtained. Melting point 190-194 ^° C [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -115.47 (C 0.07, H ₂ O); UV (H ₂ O) λ _max = 275 nm at pH 7; λ _max = 209.5 273 at pH 11; λ _max = 280 nm at pH 1.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 3.61 (d, 2H, H-5 '), 3.82 (m, 1H, H-4'); 3.93 (m, 1H, H-2 'or H-3'); 4.04 (br s, 1H, H-2 'or H-3'); 5.18 (br s, 1H, C5'-OH, exchanged); 5.61 (br s, 1H, C2'-OH or C3'-OH, exchanged); 5.67 (br s, 1H, C2'-OH or C3'-OH, exchanged); 6.00 (d, 1H, J = 4.02, H-1 '); 6.01 (d, 1H, J _5.6 = 7.8, H-5), 7.92 (d, 1H, J _5.6 = 7.8, H-6), 8.49 (br. s, 1H, NH, exchangeable), 9.38 (br s, 1H, NH, exchangeable).

Hydrochloride salt of 1-β-L-arabinofuranosylcytosine (16) obtained by treating compound 15 with boron trichloride
5 ml of 1M boron trichloride in dichloromethane is cooled to -72 ^o C (dry ice-acetone). To a solution of boron trichloride, a solution of compound 15 (180 mg, 0.351 mmol) in 3 ml of dichloromethane is slowly added. After 2.75 hours (total reaction time), the cooling bath was removed, the solvent and gas were removed in vacuo. The residue was dissolved in cold dichloromethane (10 ml) and the resulting solution was evaporated to dryness (three times until a white solid residue was obtained), a cold saturated sodium bicarbonate solution was added to establish a pH of 6-7. The resulting mixture was diluted with ethanol, heated to a boil, treated with charcoal and filtered. The filtrate was evaporated to dryness to give a syrup, which was dissolved in 3 ml of methanol, a 1% solution of HCl in methanol was added to pH 1, concentrated to dryness and triturated with 2-propanol to give compound 16 (66 mg, 78.4%).

. Реакционную смесь перемешивают при комнатной температуре в течение 1 недели, фильтруют через слой целита и концентрируют в вакууме до получения сиропа, который обрабатывают на хроматографической колонке с силикагелем, используя смесь гексаны-ацетон (3: 1, R_f = 0,22). Полученный продукт выделяют и концентрируют в вакууме до получения сиропа, который растворяют и перемешивают с метильным аммиаком (20 мл) в бомбе из нержавеющей стали, а затем нагревают в течение ночи при 50-55^oC. Полученный раствор затем концентрируют при пониженном давлении до получения полутвердого вещества, которое после перекристаллизации из теплого изопропилового спирта дает соединение 18 (2,4 г, 50,7%. Т.плавления 128-129^oC. [α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D/}}$ = -20,04 (1,04 CH₂Cl₂);
УФ (CH₂Cl₂): λ_макс= 213, 258,5.;
¹H-ЯМР (250 МГц, CDCl₃): δ 1,95 (шир.с, 14, NH, способен к обмену); 3,69 (д, 2H, J = 4,82, Н-5'); 4,18-4,30 (м, 6H, бензил CH₂); 4,51-4,64 (м, 3H, Н-2', 3', 4'); 5,73 (шир. с, 1H, H, способен к обмену); 6,52 (д, 1H, J = 4,00, Н-1'); 6,89-6,93, 7,17-7,37 (м, 15 H, H-аромат.бензильной группы); 8,17 (C, 1H, Н-2 или Н-8); 8,32 (с, 1H, Н-2 или Н-8).9- (2,3,5-tri-O-benzyl-β-L-arabinosyl / adenine (18)
The thoroughly dried Compound 9 (5 g, 8.8 mmol) was added to 82 ml of dichloromethane, previously saturated with anhydrous hydrogen chloride at 0 ^° C. After 2 hours of reaction at 0 ^° C., p-nitrobenzoic acid precipitated (1.53 g) removed by filtration, and the obtained filtrate was concentrated in vacuo to obtain a syrup, which was kept in complete vacuum at room temperature for 2 hours. The 2,3,5-tri-O-benzyl-δ-L-arabinosyl chloride (compound 10) thus obtained was dissolved in 50 ml of dichloromethane, and this solution was added to a mixture of 4.5 g (18.8 mmol) of dried N-benzoyladenine ⁵ (17) and 14.5 g molecular sieves

. The reaction mixture was stirred at room temperature for 1 week, filtered through a pad of celite and concentrated in vacuo to obtain a syrup, which was processed on a silica gel column chromatography using hexanes-acetone mixture (3: 1, R _f = 0.22). The resulting product was isolated and concentrated in vacuo to obtain a syrup, which was dissolved and stirred with methyl ammonia (20 ml) in a stainless steel bomb, and then heated overnight at 50-55 ^o C. The resulting solution was then concentrated under reduced pressure to obtain semi-solid substance, which after recrystallization from warm isopropyl alcohol gives compound 18 (2.4 g, 50.7%. Melting point 128-129 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D /}}$ = -20.04 (1.04 CH ₂ Cl ₂ );
UV (CH ₂ Cl ₂ ): λ _max = 213, 258.5 .;
¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.95 (br s, 14, NH, exchangeable); 3.69 (d, 2H, J = 4.82, H-5 '); 4.18-4.30 (m, 6H, benzyl CH ₂ ); 4.51-4.64 (m, 3H, H-2 ', 3', 4 '); 5.73 (br s, 1H, H, capable of exchange); 6.52 (d, 1H, J = 4.00, H-1 '); 6.89-6.93, 7.17-7.37 (m, 15H, H-arom. Benzyl group); 8.17 (C, 1H, H-2 or H-8); 8.32 (s, 1H, H-2 or H-8).

9- β-L-arabinofuranosiladine (19)
Boron trichloride (5 ml, 1M) in dichloromethane is cooled to -72 ^o C (dry ice-acetone). A solution of compound 18 (150 mg, 0.279 mmol) in 5 ml of dichloromethane was slowly added to a solution of boron trichloride. After 3.5 hours of reaction, the cooling bath was removed, and the solvent and gas were removed in vacuo. The residue was dissolved in cold dichloromethane (10 ml), the resulting solution was evaporated to dryness (6 times, until a yellow solid was obtained). A cold saturated sodium bicarbonate solution is added to establish a pH of 7-8. The resulting mixture was diluted with ethanol, heated to boiling, the suspension was filtered through celite, the resulting filtrate was concentrated in vacuo to a syrup, which was crystallized from water. The yield of the compound was 55 mg (74%). T. melting point 256-258 ^o C. UV (H ₂ O): λ _max = 259.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 3.62-3.66 (m, 2H, H-5 '); 3.77 (br s, 1H, H-4 '); 4.13 (br s, 2H, H-2 ', 3'); 5.12 (t, 1H, J = 5.4, C'5-OH, exchangeable), 5.54 (d, 1H, J = 3.78, C'2-OH or C'3-OH capable of exchange); 5.63 (d, 1H, J = 4.32, C'2-OH or C'3-OH, exchangeable); 6.25 (d, 1H, J = 4.02, H-1 '), 7.25 (br s, 2H, NH ₂ , exchangeable); 8.13 (s, 1H, H-2 or H-8); 8.18 (s, 1H, H-2 or H-8).

 FIG. 10 is an illustration of an alternative method for producing 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (compound 10) from 1,2-di-O-isopropylidene-α-L-xylofuranose ( compound 3).

80 г безводного сульфата меди (2) и 40 г L-ксилозы. Полученную смесь перемешивают при комнатной температуре в течение 36 часов. Реакционную смесь фильтруют и тщательно промывают ацетоном, объединенные фильтраты нейтрализуют гидроксидом аммония, а затем выпаривают досуха. Добавляют 200 мл этилацетата, а затем фильтруют и выпаривают, получая масло, которое растворяют в 250 мл 0,2% HCl, и полученный раствор перемешивают при комнатной температуре в течение 2,5 часов. За счет насыщенного NaHCO₃ устанавливают pH 8, а затем выпаривают досуха. Остаток экстрагируют этилацетатом. После удаления растворителя получают масло желтого цвета - соединение 3 (41,7 г, 82,3%).1,2-di-O-isopropylidene-α-L-xylofuranose (3)
To 650 ml of anhydrous acetone add 4 ml of concentrated sulfuric acid, 5 g of molecular sieves

80 g of anhydrous copper sulfate (2) and 40 g of L-xylose. The resulting mixture was stirred at room temperature for 36 hours. The reaction mixture is filtered and washed thoroughly with acetone, the combined filtrates are neutralized with ammonium hydroxide, and then evaporated to dryness. 200 ml of ethyl acetate are added and then filtered and evaporated to give an oil which is dissolved in 250 ml of 0.2% HCl, and the resulting solution is stirred at room temperature for 2.5 hours. Saturated NaHCO _{3 was} adjusted to pH 8 and then evaporated to dryness. The residue was extracted with ethyl acetate. Removal of the solvent gave a yellow oil — compound 3 (41.7 g, 82.3%).

¹ H-NMR (CDCl ₃ ): δ 5.979 (d, J = 3.73 Hz, 1H, H-1); 4.519 (d, J = 3.6 Hz, 1H, H-2); 4.308 (broad d, 1H, H-3); 4.08 (and, 3H, H-4 and H-5); 1.321 (s, 3H, CH ₃ ); 1.253 (s, 3H, CH ₃ ).

5-O-benzoyl-1,2-di-O-isopropylidene-α-L-xylofuranose (25)
Compound 3 (41 g, 215.6 mmol) was stirred in pyridine (150 ml) and CH ₂ Cl ₂ (150 ml) at 0 ^° C. BzCl (27.5 ml, 237 mmol) dissolved in 30 ml of pyridine was added to this mixture dropwise. After 30 minutes, 5 ml of water was added, the resulting mixture was evaporated to dryness, dissolved in EtOAc, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an orange syrup, which was crystallized from Et ₂ O to give compound 20 (36 g). The mother liquor was evaporated to dryness, and the residue was purified by silica gel column chromatography (1% CH ₃ OH / CHCl ₃ ) to obtain another portion of compound 25 (12 g, 76% total yield). Melting point 82-83 ^o C (literature. ¹ D _form 83.5-84.5 ^o C).

¹ H-NMR (CDCl ₃ ): δ 7.43, 8.07 (m, 5H, Ar-H); 5.97 (d, 1H, J = 3.6 Hz, H-1); 4.80 (q, 1H, H-4); 4.60 (d, 1H, J = 3.6 Hz, H-2); 4.40, 4.20 (m, 3H, H-5, H-5 ', H-3); 3.50 (br s, 1H, D ₂ O, exchangeable, 3OH); 1.51, 1.32 (2s, 6H, 2CH ₃ ).

5-O-benzoyl-1,2-di-O-isopropylidene-α-L-erythropentofuranose-3-ulose (26)
Compound 25 (40 g, 136 mmol) was stirred in 450 ml of CH ₂ Cl ₂ . Pyridinium dichromate (PDC, 30.7 g, 81.6 mmol) and Ac ₂ O (42.3 ml, 448.8 mmol) were added to this mixture. The resulting mixture was concentrated to 1/5 of its initial volume, and then EtOAc (50 ml) was added thereto. The resulting solution was filtered, the obtained filtrate was poured onto a silica gel layer (10 cm x 5 cm), EtOAc was eluted, the combined eluate was concentrated and evaporated together with toluene (50 ml x 2). After crystallization from hexane and EtOAc, compound 26 was obtained as a white solid (38 g, 96%). M.p. 91-93 ^° C, [α] _D : -132 ^° (s, 1.0, CHCl ₃ ); literature. ² D _form : mp 93-94 ^° C, [α] _D : +135 (s, 1.0, CHCl ₃ ); IR (KBr): 1773 (ArCO), 1730 cm ^-1 (CO).

¹ H-NMR (CDCl ₃ ): δ 7.97, 7.42 (m, 5H, Ar-H); 6.14 (d, 1H, J = 4.4 Hz, H-1); 4.74, 4.68 (m, 24, H-4, H-2); 4.50, 4.44 (m, 2H, H-5, H-5 '); 1.52, 1.44 (2s, 6H, 2CH ₃ ). Elemental analysis for (C ₁₅ H ₁₆ O ₆ ): Calculated: C 61.64 H 5.52;
Found: C, 61.42; H, 5.53.

1,2-di-O-isopropylidene-α-L-ribofuranose (27)
Compound 26 (37 g, 127 mmol) was dissolved in EtOH / H ₂ O (400 ml / 100 ml) at 0 ^° C., NaBH ₄ (23.3 g, 612 mmol) added in portions. The resulting suspension was stirred at room temperature for 4 hours. It is filtered and the resulting filtrate is evaporated to dryness and evaporated together with methanol. After chromatographic treatment on silica gel (0-15%, CH ₃ OH / CH ₂ Cl ₂ ) and crystallization from EtOAc / hexane, compound 27 is obtained in the form of white needles (19 g, 79%). Melting point 86-87 ^° C., [α] _D = -31.5 (s, 0.62, CHCl ₃ ), literate. ³ D _form : mp 86-87 ^° C, [α] _D = +37 ^° (s, 0.59, CHCl ₃ ).

IR (KBr) 3356 cm ^-1 (OH).

¹ H-NMR (CDCl ₃ ): δ 5.83 (d, 1H, J = 3.98 Hz, H-1); 4.595 (t, 1H, H-2), 4.055, 3.72 (m, 4H, H-3, H-4, H-5, H-5 '); 2.38 (d, 1H, D ₂ O, exchangeable, 3-OH); 1.83 (t, 1H, D ₂ O, exchangeable, 5-OH); 1.58, 1.38 (2s, 6H, 2CH ₃ ); Elemental analysis (C ₈ H ₁₄ O ₅ ): Calculated: C, 50.50; H, 7.42;
Found: C, 50.62; H, 7.46.

3,5-di-O-benzoyl-1,2-di-O-isopropylidene-α-L-ribofuranose (28)
Compound 27 (19 g, 100 mmol) was stirred in 300 ml of pyridine at 0 ^° C., dropwise with BzCl (40 ml, 348 mmol), and then stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was extracted with EtOAc, washed with saturated NaHCO ₃ solution, dried over sodium sulfate, the solvent was evaporated and crystallized from ether to give compound 28 as a white solid (39 g, 98%). T. melting 83-85 ^o C.

¹ H-NMR (CDCl ₃ ): δ 8.07, 7.36 (m, 10H, Ar-H); 5.94 (d, 1H, J = 3.6 Hz, H-1); 5.05, 5.00 (m, 1H, H-2); 4.73, 4.63 (m, 3H, H-4, H-5, H-5 '); 1.58, 1.35 (2s, 6H, 2CH ₃ ). Elemental analysis (C ₂₂ H ₂₂ O ₇ ). Calculated: C, 66.50; H, 5.64;
Found: C, 66.32; H, 5.57.

1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (31)
Compound 23 (38 g, 95 mmol) was stirred in 300 ml of 1% HCl / CH ₃ OH at room temperature for 30 hours, 20 ml of pyridine was added, and then the solution was evaporated to dryness. The residue was evaporated together with pyridine (30 ml x 2) and then dissolved in 100 ml of anhydrous pyridine, dropwise dropping BzCl (17 ml, 146 mmol) at 0 ^° C, then stirring at room temperature for 3 hours. The solvent is evaporated, and the residue is dissolved in EtOAc, washed with 0.5 N. HCl, then saturated with NaHCO ₃ , dried over sodium sulfate. Evaporation of the solvent gave crude compound 30 as a syrup. This crude compound was stirred in glacial acetic acid (400 ml) and then Ac ₂ O (100 ml) at 0 ^° C., dropwise concentrated sulfuric acid (10 ml). This solution was stirred at room temperature overnight. The resulting mixture was poured into ice-water, extracted with CHCl ₃ , neutralized with saturated sodium bicarbonate solution, and then dried over magnesium sulfate. After evaporation of the solvent, a light yellow syrup is obtained, which is crystallized from methanol to give compound 31 as a white solid (23.89 g, 49.6%, from 28-31). Melting point 124.7 ^° C [α] _D = 45.613, CHCl ₃ (s, 1.0, CHCl ₃ ); literature. ⁴ , M.p. 129-130 ^° C., [α] _D = -43.6 (s, 1.0, CHCl ₃ ).

). ¹ H-NMR (CDCl ₃ ): δ 7.317, 8.134 (m, 15H, OBz); 6.437 (s, 1H, H-1); 5.835 (m, 2H, H-2 and H-3); 4.649 (m, 3H, H-4 and H-5); 2.003 (s, 3H,

)

II. Biological activity
The compounds disclosed herein can be evaluated in terms of their activity against HBV and EBV, as described in detail below, or by other methods known to those skilled in the art.

Example 1. Biological activity against HBV
Use human hepatoma cells with HBV (2.2.15 cells) in this assay. These cells are grown to fusion in a nutrient medium with the minimum required set of 10% calf fetal serum. The medium is replaced at three-day intervals. When merging, treatment with drugs is started, and then continue for 3 days. Once again, the same concentration of the drug is added after removing the medium from the cultures, and these cultures are kept for another 3 days. The medium after six days of treatment is collected and the viral particles are precipitated using polyethylene glycol. Then the particles are digested and Southern analysis is performed. The resulting blots hybridize with an HBV-specific probe and assess the amount of viral DNA compared to the levels of DNA from cultures that were not treated with drugs. Genomic DNA is digested with Hind 111 and Southern analysis is performed. Episomal DNA levels are determined in relation to the integrated HBV DNA. The concentrations of drugs that cause 50% inhibition of DNA (ID ₅₀ ) are calculated compared to control samples. The results obtained are summarized in table 1.

Example 2. Biological activity against EBV
H1 cells are maintained in the long phase of growth for two days before the start of the primary treatment. Cells are centrifuged at 600 g for 10 minutes at room temperature in order to separate them from the medium containing preexisting viral particles. H1 cells are seeded in plates with 24 cells at a density of 1 • 10 ⁵ cells per cell in 2 ml of fresh medium with or without medicine and incubated at 37 ^° C for 5 days. The virion-containing medium is stored and used to evaluate the inhibitory effect of drugs on the productivity and infectivity of the virus using bioassay. The virion is precipitated from cell-free medium by centrifugation at 45,000 rpm for 90 minutes in a SW-50 Ti rotor (Beckman). The virions are resuspended in 1 ml of growth medium and then used to infect 1 x 10 ⁶ Raji cells for 48 hours. Since the level of EBV DP activity in Raji cells after superinfection is proportional to the number of varions added, EBV-induced specific DP activity can be determined. The inhibitory effect of the drug is calculated by comparing EBV DP activity with multiple diluted controls. If the cells are treated with 1 mM L-FMAU for 6 days, then there is no inhibition of mitochondrial DNA content in H1 cells.

Slot blotting - The amount of mitochondrial DNA is determined using the slot blotting method (2). Treated and untreated H1 cells in an amount of 2 • 10 ⁵ are lysed in 200 μl of 10 mM Tris.HCl (pH 7.5) solution by freeze / thaw method. The cell lysate is treated with 10 μg / ml PHase A at 37 ^° C for 30 minutes, and then proteinase K (100 μg / ml) at 55 ^° C for 2 hours. Equal amounts of 20 x SSC buffer are added to each cell lysate. After boiling for 10 minutes, the samples are applied to nylon membranes (Hyhond-N, Amersham Corp.). A radiolabeled fragment of human mitochondrial DNA is used as a probe for DNA hybridization. The same membranes again probe human Alu DNA after removal of the mitochondrial DNA probe. The amount of mitochondrial DNA in the treated and untreated H1 cells is counted using a densitometer (LKB Ultroscan XL).

 The results are presented in table 2.

EBV Compound Inhibition Effect: A CD ₅₀ value is obtained by exposing H1 cells to various concentrations of the compounds in normal growth medium at 37 ^° C. for 72 hours, then the cells are counted and the values obtained are compared with the control. H1 cells are treated for 5 days and ID _{90 is} determined in bioassays.

Example 3. Removal of L - (-) - FMAU from plasma and liver
Evaluation of the purification of the plasma and liver of mice from L - (-) - FMAU after oral administration. Mice are administered L - (-) - FMAU labeled with tritium (radio specificity 9.3 μmol / μ Curie).

 FIG. 11 is a graph of the concentration of L- (-) - FMAU in the plasma of mice after oral administration over time, and FIG. 12 is a graph of the concentration of L - (-) - FMAU in the liver of mice after oral administration over time (cross-section, 10 mg / kg is administered twice daily for 30 days before pharmacokinetic studies, and then studies are carried out on the thirty-first day, after administration the same concentration; the shaded circles - the introduction of 50 mg / kg twice a day for 30 days before the studies, and then on the thirty-first day conduct studies after the introduction of the same concentration; unshaded circles - the introduction of the first time 50 mg / kg first day of the study).

 At the indicated time points (see FIGS. 10 and 11), mice were bled from the retro-orbital sinus using heparin-treated capillaries. The plasma is extracted with trichloroacetic acid and neutralized with freon / trioctylamine. The supernatants are measured directly and concentrations are calculated.

 As shown in FIG. 10 and 11, a peak concentration of L - (-) - FMAU in the liver and plasma is observed after about one hour. The compound is practically eliminated both from plasma and from the liver after four hours.

Example 4. Toxicity L - (-) - FMAU for female BDF1 mice
FIG. 13a illustrates a change in body weight after thirty days in control BDF1 female mice. FIG. 13b and 13c illustrate changes in body weight after 30 days in female BDF1 mice administered 10 mg / kg (13b) and 50 mg / kg (13c) twice daily L - (-) - FMAU. Body weight is presented representatively as mean and standard deviation for 5-7 mice. As can be seen from FIG. 13 and 13c, L - (-) - FMAU does not appear to have a significant effect on the weight of mice for thirty days, indicating good tolerance to the compound.

Example 5. Clinical analysis of the plasma of mice after treatment with L - (-) - FMAU
In FIG. Figures 14–20 present the results of clinical analyzes of the chemical composition of the plasma of mice after administration of L - (-) - FMAU at doses of 10 mg / kg (three mice) or 50 mg / kg (three mice) twice a day for thirty days.

 FIG. 14 is a graph of the total plasma bilirubin concentration in mice in mg / dl. FIG. 15 is a graph of mouse alkaline phosphatase concentration in U / L. Total bilirubin and alkaline phosphatase are indicators of liver function. The bilirubin values in mice fall within the normal range for humans (less than 1.2 mg / dl), but the values for alkaline phosphatase are slightly higher than the normal levels for humans (30-114 U / L).

 FIG. 16 is a graph of mouse plasma creatinine concentrations in mg / dl. Creatinine is an indicator of liver function. With the exception of the mouse, 50-2 creatinine levels in the treated mice did not differ from the levels in the control mice.

 FIG. 17 is a graph of AST concentration (SGOT, serum glutamine oxal transaminase) in mouse plasma in U / L. FIG. 18 is a graph of AST concentrations (SGPT, serum glutamine pyruvic grape transaminase) in murine plasma in U / L. SGOT and SGPT are indicators of liver function. With the exception of mouse 50-2 (for both SGOT and SGPT) and mouse 10-2 (only for SGOT), the enzyme levels of the treated mice did not differ from the levels observed in control animals.

 FIG. 19 is a graph of murine plasma lactic acid concentrations in mmol / L. FIG. 20 is a graph of mouse plasma dehydrogenase concentrations in U / L. Lactic acid is produced in the muscles during glycolysis. Lactic dehydrogenase (LDH) is present in the form of various isoenzymes in various tissues. Plasma LDH release can be an indicator of tissue damage. The levels of lactic acid and lactic dehydrogenase in the treated mice do not differ markedly from the levels for control animals.

III. Oligonucleotides
The oligonucleotides of the desired sequences can be modified by replacing one or more of the L-nucleosides disclosed herein with a nucleoside in an oligonucleotide. In a preferred embodiment, the L-nucleoside is placed on one end of the oligonucleotide. The modified oligonucleotide can be used, for example, in antisense technology.

 Antisense technology typically refers to modulating gene expression by a process in which a synthetic nucleotide is hybridized to a complementary nucleic acid sequence to inhibit transcription or replication (if the target sequence is DNA), to inhibit translation (if the target sequence is RNA), or to inhibit processing (if the target the sequence is pre-RNA). Using this technique, a wide range of cellular activities can be modulated. A simple example is the inhibition of protein biosynthesis due to the antisense oligonucleotide associated with mRNA. In another embodiment, the synthetic oligonucleotide is hybridized to a specific gene sequence in double-stranded DNA to form a tri-chain complex (triplex), which inhibits the expression of this gene sequence. Antisense oligonucleotides can also be used to activate gene expression indirectly, inhibiting the biosynthesis of a natural repressor. AOT can be used to suppress the expression of pathogenic genes, for example, those that facilitate the replication of viruses, including human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes virus, as well as cancers, especially solid tumors such as gliomas, cancer breast and melanoma.

 The stability of the selected oligonucleotide with respect to nucleases is an important factor for in vivo applications. It is known that 3'-exonuclease activity is responsible for the destruction of unmodified antisense oligonucleotides in serum (Vlassov V.V., Yakubov L.A., Prospects for Antisense Nucleic Acid Therapy of Cancer and AIDS, 1991, 243-266, Wiley-Liss, Inc., New York; Nucleic Acids Res., 1993, 21, 145). In one embodiment, the L nucleotides disclosed herein can be used to minimize antisense oligonucleotides by a 3'-exonuclease.

 The oligonucleotides of the present invention, which are capable of binding to polyribonucleic acid or polydeoxyribonucleic acid, can be used as antisense agents in such a way as conventional antisense agents. See mainly: Antisense Molecular Biology and S-oligos, Synthesis 1 (Oct. 1988) (published by Synthecell Corp., Rockville, Md.); 2 Discoveries in Antisense Nucleic Acids (C. Brakel and R. Fraley eds. 1989); Uhlmann, et. al. , "Antisense Oligonucleotides: A New Therapeutic Technique", Chem. Rev. 90 (4), 1990; and Milligan J.F., Matteucci M.D., Martin J. C., J. Med. Chem., 1993, 36, 1923-1937. The antisense agents of the present invention can be used to construct an antisense agent that is capable of selectively binding to a predetermined polydeoxyribonucleic acid sequence or a polyribonucleic acid sequence to a cell containing such a sequence (for example, adding an antisense agent to a culture medium containing such a cell) so that the antisense the agent was captured by the cell, bound to a predetermined sequence and blocked its transcript broadcast, broadcast, or replication. Requirements for the selective binding of an antisense agent are known (for example, a length of 17 bases for selective binding to the human genome).

IV. Obtaining pharmaceutical compositions
The compounds and their pharmaceutically acceptable salts, prodrugs and derivatives disclosed herein can be used to prevent and treat HBV and EBV infections, as well as other related conditions, such as anti-HBV or anti-EBV positive antibodies and HBV or EBV positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant (transient) hepatitis, chronic persistent hepatitis and fatigue. These compounds or compositions can also be used prophylactically to prevent or slow the progression of clinical diseases in individuals with anti-HBV and anti-EBV antibodies or HBV or EBV positive antigens, or those who have been in contact with HBV or EBV.

 Patients with any of these conditions can be treated by administering to them an effective HBV or EBV treatment amount of one of the active compounds described herein or a mixture thereof, or a pharmaceutically acceptable derivative or salt thereof, optionally in a pharmaceutically acceptable carrier or diluent. The active substances can be administered in any suitable way, for example, parenterally, orally, intravenously, subcutaneously, through the skin or externally, in liquid or solid form.

 The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient that does not cause serious toxic effects in the patient being treated.

 A preferred dose of the active compound for all of the above conditions will be in the range of from about 1 to 60 mg / kg, preferably from 1 to 20 mg / kg of body weight per day, usually from 0.1 to about 100 mg / kg of body weight per day. An effective dosage range can be calculated based on the weight of the starting nucleoside to be added. If the derivative itself is active, then the effective dose can be set, as described above, using the weight of the derivative, or other methods known to specialists. In one embodiment, the active compound is administered as directed on the drug product insert or in the Physician's Desk Reference for 3'-azido-3'-deoxythymidine (AZT), 2 ', 3'-dideoxyinosine (DDI), 2'3'-dideoxycytidine (DDC) or 2 ', 3'-dideoxy-2', 3'-didehydrothymidine (D4T) for HIV indication.

 The compound is usually administered in a separate suitable dosage form, including, but not limited to, a dose containing from 7 to 3000 mg, preferably from 70 to 1400 mg of the 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 a peak plasma concentration of the active compound from about 0.2 to 70 μM, preferably from about 1.0 to 10 μM. This can be achieved, for example, by intravenous administration of from 0.1 to 5% solution of the active ingredient, as an option, in saline or in the form of a pill with the active ingredient.

 The active compound can be prepared in the form of a pharmaceutically acceptable salt. As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or nucleoside complexes that retain the desired biological activity of the parent compound and exhibit minimal, if any, undesirable toxic effects. Non-limiting examples of such salts are (a) inorganic acid addition salts (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts of organic acids such as acetic acid, oxalic acid, tartaric acid acid, succinic acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid and polygalacturo oic acid; (b) base addition salts formed with cations such as sodium, potassium, zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with organic cations such as formed N, N-dibenzylethylenediamine, ammonia or ethylenediamine; or (c) a combination of (a) and (b), for example, a zinc tannate salt or the like.

Modifications of the active compound, specifically at the N ⁶ or N ⁴ and 5'-O positions, can affect the bioavailability and metabolic rate of the active compounds, providing control over the intake of the active compound.

 The concentration of the active compound in the drug composition depends on the rates of absorption, inactivation and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that the dose depends on the severity of the patient's condition, which should be alleviated. It should also be understood that for a particular subject, the specific dosage regimen should change over time in accordance with the individual needs and professional experience of the treating physician, and the concentration ranges given here are merely examples and should in no way limit the scope of the invention or the practical use of the claimed compositions. The active ingredient can be taken immediately or it can be divided into several smaller doses and taken at different intervals between doses.

 A preferred method of administering the active compound is oral. Oral compositions typically include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or may be compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated into excipients and used in the form of tablets, lozenges or capsules.

 Part of the composition may be pharmaceutically compatible binding agents and / or adjuvants.

 Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth resin or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel or corn starch, glidants such as magnesium stearate or Sterotes or colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or flavoring agents such as mint, methyl salicylate, or orange concentrate. If the unit dosage form is a capsule, it may contain, in addition to the types indicated above, a liquid carrier such as fatty oil. In addition, the unit dosage form may contain various other materials that modify the unit dose form, for example, sugar, shellac or other coatings for oral administration.

 The active compound or a pharmaceutically acceptable salt or derivative thereof can be administered as part of an elixir, suspension, syrup, wafer, chewing gum and the like. The syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and some preservatives, colorants and perfumes.

 The active compound or a pharmaceutically acceptable derivative or salt thereof can also be mixed with other active materials that do not have the desired effect, or materials that supplement the desired action, for example, with antibiotics, antifungal drugs, anti-inflammatory or other antiviral drugs, including anti-HBV , anti-EBV, anti-cytomegalovirus or anti-HIV or anti-EBV agents.

 Solutions or suspensions used for parenteral, intradermal, subcutaneous or external use may include the following components; sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol and other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tone control agents such as sodium chloride or dextrose. Preparations for parenteral administration can be enclosed in ampoules, disposable syringes or reusable dose vials made of glass or plastic.

 If the drug is administered intravenously, the preferred carriers are saline or buffered saline with phosphate buffer (PBS). In a preferred embodiment, the active compound is prepared with carriers that protect the compound from rapid excretion from the body, for example, in the form of controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for preparing such compositions are known to those skilled in the art. These materials are also available from Alza Corporation and Nova Pharmaceuticals, Inc.

 Liposomal suspensions (including liposomes that target infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. They can be obtained in accordance with methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (which is incorporated by reference). For example, liposome compositions can be prepared by dissolving the corresponding lipid (s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, which is then evaporated, leaving a thin film of dry lipid on the surface. Then, an aqueous solution of the active compound or its monophosphate, diphosphate and / or triphosphate derivatives is introduced into the vessel. Then this vessel is rotated manually to release the lipid material from the walls of the vessel and disperse the lipid fragments, resulting in a liposome suspension.

 The present invention has been disclosed with reference to its preferred options. Other variations and modifications of the invention should be apparent from the foregoing detailed description of the invention. All of these options and modifications are included in the scope of the attached claims.

Claims (13)

1. L-Nucleoside of General Formula (1)

where R represents a residue of uracil, thymine, cytosine or purine, which may be substituted by a halogen atom and alkyl;
R ″ represents a hydrogen atom, acyl, alkyl, monophosphate, diphosphate or triphosphate, or its pharmaceutically acceptable salts.  2. The L-Nucleoside of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof as an active component of a pharmaceutical composition having anti-HBV or anti-EBV activity.  3. The L-Nucleoside of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof having anti-HBV or anti-EBV activity.  4. The L-Nucleoside according to claim 1, which is 2'-fluoro-5-methyl-β-L-arabinofuranosyl uracil. 5. The L-Nucleoside according to claim 1 or 3, selected from the group consisting of N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-ethyluracil, N ₁ - (2'-deoxy -2'-fluoro-β-L-arabinofuranosyl) -5-iodocytosine; and N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodouracil.  6. The L-Nucleoside according to claim 1 or 3, wherein the base is selected from the group consisting of 5-methyluracil (thymine), 5-iodouracil, cytosine and 5-ethyluracil.  7. The L-Nucleoside according to claim 2, which is 2'-fluoro-5-methyl-β-L-arabinofuranosiluracil. 8. The L-Nucleoside according to claim 2, which is selected from the group consisting of N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-ethyluracil, N ₁ - (2'-deoxy- 2'-fluoro-β-L-arabinofuranosyl) -5-iodocytosine; and N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodouracil.  9. The L-Nucleoside of claim 2, wherein the base is selected from the group consisting of 5-methyluracil (thymine), 5-iodouracil, cytosine, and 5-ethyluracil.  10. A method of inhibiting HBV or EBV infection, characterized in that L-nucleosyl of the formula (1) according to claim 1 is administered in a dose of 0.1 to 100 mg / kg body weight per day.  11. The method according to claim 10, characterized in that the L-nucleoside is 2'-fluoro-5-methyl-β-L-arabinofuranosyluracil. 12. The method according to p. 10, characterized in that the L-nucleoside is selected from the group comprising N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-ethyluracil, N ₁ - (2 '-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodocytosine; and N ₁ - (2'-deoxy-2'-fluoro-β-L-arabinofuranosyl) -5-iodouracil.  13. The method according to claim 10, characterized in that the base is selected from the group comprising 5-methyluracil (thymine), 5-iodouracil, cytosine and 5-ethyluracil.

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