MXPA06010863A

MXPA06010863A - 4'-c-substituted 2-haloadenosine derivative

Info

Publication number: MXPA06010863A
Application number: MXPA/A/2006/010863A
Authority: MX
Inventors: Hiroshi Ohrui; Eiichi Kodama; Satoru Kohgo; Hiroaki Mitsuya; Masao Matsuoka
Original assignee: Yamasa Corporation
Priority date: 2004-03-24
Filing date: 2006-09-22
Publication date: 2007-04-20

Abstract

A compound which has excellent anti-HIV activity, is effective also against polypharmacy-resistant HIV strains having resistance to two or more anti-HIV drugs, especially AZT, DDI, DDC, D4T, 3TC, etc., is lowly cytotoxic, and has resistance to deactivation by adenosine deaminase. It is a 4'-C-substituted 2-haloadenosine derivative represented by the following formula [I], [II], or [III]. Also provided is a medicinal composition comprising the derivative and a pharmaceutically acceptable support. [Chemical formula 1](In the formulae, X represents halogeno;R1 represents ethynyl or cyano;and R2 represents hydrogen or the atoms of a residue of phosphoric acid or a derivative thereof.)

Description

DERIVATIVE OF 2-HALOADENOSINE 4'-C REPLACED TECHNICAL FIELD The present invention relates to 2-haloadenosine derivatives 4'-c-substituted and use thereof as a medicine, in particular a medicine that is useful for the treatment of acquired immunodeficiency syndrome (AIDS).

BACKGROUND OF THE INVENTION The clinical setting for AIDS has been drastically modified through multiple drug combination therapy, which is sometimes called highly active antiretroviral therapy or HAART. Thanks to HAART, mortality rates from AIDS have decreased significantly worldwide. In HAART, nucleoside reverse transcriptase inhibitors (NRTIs) are used, such as zidovudine (AZT), didanosine (ddl), zalcitabine (ddc), stavudine (d4T), and lamivudine (3TC) in combination with protease inhibitors (Pl ). Although HAART has drastically reduced the number of deaths caused by AIDS, a mutant of HIV-1 (human immunodeficiency virus type 1) resistant to multiple drugs has emerged that shows cross-resistance with various drugs. For example, in the early 1990s, patients infected with HIV who had resistance to AZT and 3TC were very rare, while from 1995 to 1996, the percentage of patients with AIDS infected with said resistant HIV rose to 42. %. Ohrui, I went to. have synthesized 2'-deoxy-4'-C-ethynyl nucleosides and analyzed the anti-HIV activity thereof, and as a result, have found that a 2'-deoxy-4'-C-ethynyl nucleoside having a The specific structure has potent anti-HIV activity equal to or greater than that of AZT, and has an effective antiviral activity against a multiple drug-resistant viral strain that has resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC (non-patent documents 1 to 5 and patent documents 1 to 3). Non-Patent Document 1: Nucleic Acids Symp. Ser., Jan. 2000, (44): 105-5. Non-patent document 2: J. Méd. Chem., Nov. 2000, 43 (23): 4516-25 Non-Patent Document 3: Curr. Drug Targets Infecí. Disord, May 2001, 1 (1): 1-10 Non-patent document 4: Antimicrob. Agents Chemother., May 2001, 45: 1539-1546 Non-patent document 5: Nucleosides Nucleotides Nucleic Acids, May 2003, 22 (5-8): 887-9 Non-patent document 6: Chem. Pharm. Bull., 42 (1994), p1688 Non-patent document 7: J. Med. Chem., 39 (1996), p3847 Non-patent document 8: Bioorg. Méd. Chem. Lett., Nov. 2003, 13 (21): 3775-7 Patent Document 1: WO 00/69876 Patent Document 2: WO 00/68877 Patent Document 3: WO 03/68796 BRIEF DESCRIPTION OF THE INVENTION The inventors have evaluated the in vitro toxicity of 4'-C-ethynyl purine nucleoside derivatives and 4'-C-cyano purine nucleoside derivatives, which, among a variety of 4'-C-substituted nucleosides, present particularly a potent anti-HIV activity. As a result, the present inventors have discovered that: (1) 2,6-diamnopurine derivatives and guanine derivatives, which exhibit the most potent anti-HIV activity, exhibit toxicity in vitro and in vivo; and (2) the adenine derivatives, which exhibit less toxicity, are easily converted into hypoxanthine derivatives in blood through adenosine deaminase, thereby weakening the anti-HIV activity of the derivatives. In order to obtain a further improvement of the selectivity index; that is, (concentration at which toxicity is obtained) / (concentration at which anti-HIV activity is obtained) and to provide resistance to inactivation by adenosine deaminase, the inventors have synthesized a variety of derivatives through modification 2'-deoxyadenosine chemistry 4'-C-substituted (a lead compound), which, among various purine nucleoside 4'-C-substituted, presents a potent anti-HIV activity and less toxicity. As you knowWhen a halogen atom, which has electron attraction, is introduced into position 2 of the base portion of an adenosine derivative, the resulting derivative has a certain level of resistance to inactivation by adenosine deaminase (non-patent documents 6 and 7). However, it is still unknown if the selectivity index can be improved or not through the introduction of a halogen atom. Only one literature discloses that the introduction of an ethinyl group to the 4 'position of d4T (stavudine: 2', 3'-dideshydro-3'-deoxythymidine) improves the selectivity index of d4T (Non-Patent Document 8). However, it is not expected to obtain effects similar to those of d4T in an adenosine derivative, which is a nucleoside purine, whose base structure differs considerably from that of d4T, and therefore, this bibliography does not provide useful information for the purposes of the inventors of the present. The inventors of the present have carried out studies on the anti-HIV activity, etc., of the newly synthesized derivatives, and have found that 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine - which is obtained by introducing a fluorine atom at position 2 of the base portion of 2'-deoxy-4'-C-ethynyladenosine (ie, lead compound) - exhibits resistance to inactivation by adenosine deaminase, has potent antiviral activity against a virus strain resistant to multiple drugs that exhibits resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC, and exhibits improved anti-HIV activity and considerably reduced cytotoxicity. Based on this discovery, the inventors have synthesized a variety of 4'-C-substituted 2-haloadenosine derivatives, each formed of 2-haloadenine (base portion) and a sugar moiety having an ethynyl group or cyano in position 4, and have analyzed the biological activities of the derivatives thus synthesized. The present invention has been made on the basis of the test results. Accordingly, the present invention provides a 4'-C-substituted 2-haloadenosine derivative represented by the following formula [I], [II], or [III], and a pharmaceutical composition containing the 2-haloadenosine derivative 4 '-C-substituted and a pharmaceutically acceptable carrier therefor.

ID (wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). The present invention provides a method for treating AIDS, which comprises administering, to a mammal or an animal, the substituted 4'-C-2-haloadenosine derivative or a pharmaceutical composition containing the derivative. As shown in the test examples presented below, the compounds of the present invention (for example, 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine) exhibit resistance to inactivation by adenosine deaminase, have potent activity antiviral against a multi-drug resistant virus strain that exhibits resistance to various anti-HIV drugs such as AZT, ddl, ddC, d4T, and 3TC, exhibit unexpectedly improved anti-HIV activity; specifically, higher anti-HIV activity by a factor of 144 than that of 2'-deoxy-4'-C-ethynyladenosine (ie, lead compound), and have a considerably reduced cytotoxicity. Therefore, surprisingly, the compounds of the present invention have a selectivity index of 110,000, which is considerably higher than 1, 630 of 2'-deoxy-4'-C-ethynyladenosine (EdAdo). As described above, the compounds of the present invention exhibit excellent anti-HIV activity, particularly against a multi-drug resistant HIV strain having resistance to various anti-HIV drugs such as AZT, DDI, DDC, D4T, and 3TC, present less cytotoxicity, and exhibit resistance to inactivation by adenosine deaminase. Therefore, the compounds of the present invention are useful as pharmaceuticals, particularly drugs for treating AIDS.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows stability of compounds against deamidation reaction induced by adenosine deaminase. The black squares show the results obtained from 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (a compound of the present invention), while the black circles show the results obtained from 2'- deoxy-4'-C-ethynyladenosine (a known compound); Figure 2 shows stability of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (a compound of the present invention) under acidic conditions; Figure 3 shows stability of 2 ', 3'-dideoxyadenosine (ddAdo, a known compound) under acidic conditions; and Figures 4A-4B show changes in body weight of mice, measured after administration of 2'deoxy-4'-C-ethynyl-2-fluoroadenosine (a compound of the present invention). In Figure 4A, the results obtained from oral administration are shown, and Figure 4B shows the results obtained from intravenous injection. In both graphs, the white circles show the results of administration of placebo, and the triangles and tables correspond to a dose of 30 mg / kg and 100 mg / kg, respectively.

DETAILED DESCRIPTION OF THE INVENTION (1) Compounds The compounds of the present invention are represented by the formulas [I], [II], or. { III]. Examples of the phosphate residue represented by R 2 in these formulas include a monophosphate residue, a diphosphate residue, a triphosphate residue, and a phosphonate; and examples of the phosphate derivative residue include phosphate polyesters (e.g., a phosphate diester and a phosphate triester), phosphate amidates (e.g., a phosphate monoamidate and a phosphate diamidate), phosphorothioate, phosphoroselenoate, and phosphorusboronate. Examples of halogen atoms represented by X include bromine, iodine, fluorine, and chlorine. Of these compounds, preferred are those that meet one or more of the following requirements: (a) R2 is hydrogen or phosphonate; (b) X is fluorine or chlorine; and (c) R1 is an ethynyl group. Specific examples of preferred compounds are given below.

Compounds represented by the formula \\] 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, 4'-C-cyano-2'-deoxy-2-fluoroadenosine, 2-chloro-2'-deoxy-4 '-C-etinyladenosine, and 5'-H-phosphonate of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine.

Compounds represented by the formula [II] 2 ', 3'-didehydro-2', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine, 2 ', 3'- dideshydro-2', 3'-dideoxy 4'-C-cyano-2-fluoroadenosine, 2 ', 3'-dideshydro-2', 3'-dideoxy-4'-C-ethynyl-2-chloroadenosine and 5'-H-phosphanate 2 ' , 3'-didehydro-2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine.

Compounds represented by the formula 2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine, 2', 3'-dideoxy-4'-C-cyano-2-fluoroadenosine, 2 ', 3'-dideoxy 4'-C-ethynyl-2-chloroadenosine and 5'-H-phosphonate 2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine. The compounds of the present invention can be salts, hydrates, or solvates. When R2 is hydrogen, examples of salts include acidic adducts such as hydrochlorides and sulfates; and when R2 is a phosphate residue, examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts, such as calcium salts; and ammonium salts, and any of these salts can be used as long as they are pharmaceutically acceptable.

Examples of hydrates or solvates include adducts formed by combining a molecule of the compound of the present invention or a salt thereof. same and 0.1-3.0 molecules of water or a solvent. In addition, the compounds of the present invention encompass a variety of isomers thereof such as tautomers. (2) Production method The compounds [I] of the present invention can be produced through the following steps described below.

First step: In the first step, hydroxyl groups are protected at the 3 'and 5' positions of a compound represented by the formula [IV], to thereby produce a compound represented by the formula [V]: [IV] [V] (wherein P represents a protecting group, and R1 represents an ethynyl group or a cyano group). Of the starting compounds represented by the formula [IV], those in which R1 is an ethynyl group are described in J. Med. Chem., 43, 4516-4525 (2000), and those in which R1 is a group cyano, are described in WO 03/68796) and therefore, these compounds are known compounds. The protecting groups represented by P, which protect the hydroxyl groups at the 3 'and 5' positions, can be those groups which are generally employed to protect a hydroxyl group. Examples of types of protecting groups include an ether type, an acyl type, a silyl type, and an acetal type. Specific examples of the protecting groups which may be employed include ether-like protecting groups such as methyl ether, tert-butyl ether, benzyl ether, methoxybenzyl ether, and trityl ether; acyl-type protecting groups such as acetyl, benzoyl, and pivaloyl; silyl protecting groups such as t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl and triethylsilyl; and acetal type protecting groups such as isopropylidene, ethylidene, methylidene, benzylidene, tetrahydropyranyl and methoxymethyl. The introduction of a protective group is carried out by conventional methods. For example, in organic solvent such as pyridine, acetonitrile or dimethylformamide, the compound [IV] is allowed to react with a protective agent (alkyl halide, acid halide, acid anhydride or alkylaryl halide) in the presence of a base such as an alkoxide of metal, triethylamine, 4-dimethylaminopyridine or imidazole, between -10 and 100 ° C.

Second step: In the second step, the amino group at position 2 of the compound [V] is converted to a halogen atom, to thereby produce a compound represented by the formula [VI]: (wherein P represents a protecting group, X represents a halogen atom, and R1 represents an ethynyl group or a cyano group). The compound [VI] can be synthesized by the following procedure: after the amino group at the 2-position of the compound Vj is treated with a nitrite derivative, the halogen atom is introduced at the 2-position of the base portion by using a halogen reagent; or the amino groups at positions 2 and 6 are treated under the same conditions, thereby forming a 2,6-dihalopurine derivative, and the halogen atom at the 6-position of the base portion is converted to an amino group through treatment with ammonia. Examples of reagents for substituting the amino group in portion 2 of compound [V] by fluorine include sodium nitrite in tetrafluoroboric acid; and an ester of nitrous acid (e.g., t-butyl nitrite) in hydrogen fluoride-pyridine. The reaction conditions vary depending on the reagent used. For example, when t-butyl nitrite is used in hydrogen fluoride-pyridine, t-bityl nitrite (1 to 3 moles) is added to the compound [V] in hydrogen fluoride-pyridine which serves as a solvent, and the The resulting mixture is allowed to react between -50 ° C and room temperature for about 15 minutes to about 5 hours. When the compound [alpha] f is formed into a 2,6-difluoropurine derivative, the resulting derivative is treated with aqueous ammonia in an organic solvent such as dioxane or methanol. Examples of reagents for replacing the amino group in the 2-position of the compound [V] by chlorine include a combination of antimony trichloride and t-butyl nitrite, and a combination of acetyl chloride and benzyltriethylammonium nitrite, combinations of which used in an organic solvent such as dichloromethane. The reaction conditions vary depending on the reagent used. For example, when a combination of acetyl chloride and benzyltriethylammonium nitrite is used as the reagent, in an organic solvent such as dichloromethane, the benzyltriethylammonium nitrite (1 to 5 moles) is treated with acetyl chloride (1 to 5 moles) between -50 ° C and room temperature for about 30 minutes to about 3 hours, and the resulting mixture is allowed to react with the compound [Vj (1 mole) between -50 ° C and room temperature for one hour to a few days. When the compound [Vj is formed in a 2,6-dichloropurine derivative, the resulting derivative is treated with aqueous ammonia in an organic solvent such as dioxane or methanol. The protective groups of the compound [VI] thus obtained are removed, to thereby produce the compound of the present invention in which R2 is hydrogen and if desired, the compound is phosphorylated: (wherein P represents a protecting group, X represents a halogen atom, R represents an ethynyl group or a cyano group, and R 2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). Protective groups can be removed through a technique which is suitably selected from traditional techniques (for example, hydrolysis under acidic conditions, hydrolysis under alkaline conditions, treatment with tetrabutylammonium fluoride and catalytic reduction) according to the protective groups used. (wherein X represents a halogen atom, R1 represents an ethyl group or a cyano group, and R2 represents hydrogen). In order to produce the 5'-H-phosphonate derivative [VII] (the compound of the present invention), the compound [I] in which R2 is hydrogen and phosphoric acid are subjected to condensation in an organic solvent by the use of a suitable condensation agent. Examples of the organic solvent that can be employed include pyridine, and dimethylformamide in the presence of a base such as triethylamine. Examples of the condensation agent that can be employed include carbodiimides such as dicyclohexyl carbodiimide, diisopropyl carbodiimide and water-soluble carbodiimide; sulfonic acid halides such as toluenesulfonyl chloride; and phosphate chlorides such as diphenyl phosphate chloride. The reaction conditions vary depending on the reagent used. For example, when dicyclohexyl carbodiimide is used in pyridine, phosphonic acid (1 to 5 moles) and dicyclohexyl carbodiimide (1 to 10 moles) are added to 1 mole of compound [1] and the resulting mixture is allowed to react between 0 ° and 50 °. C for about one to about 24 hours.

When a compound in which R2 is a monophosphate is to be produced, a compound in which R2 is hydrogen is reacted with a phosphorylating agent; for example, phosphorous oxychloride or tetrachloropyrophosphoric acid, which selectively phosphorylates the 5 'position of a nucleoside. When a compound is going to be produced in which R2 is a diphosphate or triphosphate, the corresponding 5'-monophosphate compound is activated in the form of phosphoimidazolide, phosphomorpholide, or anhydrous diphenyl phosphate, and the thus activated compound is reacted with phosphoric acid, pyrophosphoric, or a suitable salt thereof, to thereby produce an objective compound in a salt or free acid form. The compounds [II] of the present invention can be produced through the steps described below.

First step: In the first step, the hydroxyl group in the 5 'position of a compound represented by the formula [I] in which R2 is hydrogen, is selectively protected, to thereby produce a compound represented by the formula [Vlll]: M [Vlll] (wherein P represents a protecting group, X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen). The protecting group represented by P, which protects the hydroxyl group at the 5 'position, can be a protecting group which is generally employed to selectively protect a primary hydroxyl group. Specific examples of the protecting group include a trimethoxytrityl group, a dimethoxytrityl group, a methoxytrityl group, a trityl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and a benzoyl group. The introduction of the protecting group can be carried out in a manner similar to that used for the compound [V].

Second step: In the second step, the hydroxyl group in the 3 'position of the compound [HIV] is subjected to dehydration, forming a double bond 2', 3'- carbon-carbon, to thereby produce a compound represented by the formula [ IX].

[Vlll] [IX] (wherein P represents a protecting group, X represents a halogen atom, and R1 represents an ethynyl group or a cyano group). In order to produce the compound [IX] through dehydration of the hydroxyl group at the 3 'position of the compound [Vlll], the hydroxyl group at the 3 'position of the [HIV] compound is converted to a removable functional group such as a sulfonate group (eg, a methanesulfonate group, a chloromethanesulfonate group, a toluenesulfonate group, or a trifluoromethanesulfonate group) or an atom of halogen, and the group thus converted is removed through treatment with a base. The reaction conditions vary depending on the reagent used. For example, in the case of reaction through formation of a trifluoromethanesulfonate, trifluoromethanesulfonic anhydride (1 to 5 moles) and a base (eg, pyridine or triethylamine) (5 to 10 moles) are added to the compound [HIV] in a organic solvent such as dichloromethane or pyridine, and the resulting mixture is allowed to react between -78 ° C and room temperature for about one to about 24 hours. The protecting group of the compound [IX] thus obtained is removed, to thereby produce the compound of the present invention in which R2 is hydrogen, and if desired, the compound is phosphorylated: [IX] (wherein X represents a halogen atom, P represents a protecting group, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). The protecting group can be removed through a technique which is suitably selected from traditional techniques (eg, hydrolysis under acidic conditions, hydrolysis under alkaline conditions, treatment with tetrabutylammonium fluoride, and catalytic reduction) according to the protective group employed . A compound in which R2 is a phosphate residue or a derivative thereof can be synthesized in a manner similar to that of compound [I]. The compounds [III] of the present invention can be produced through the steps described below.

First step: In the first step, the hydroxymethyl group in the 4-position of a compound represented by the formula [X] is oxidized to form an aldehyde group, which is adidonally converted to a triethylsilylethynyl or cyano group to produce in this way a compound represented by the formula [XI]: (wherein R 1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The compound [X] (ie, starting material) is a known compound (Biosci, Biotech, Biochem., 57, 1433-1438 (1993)). The compound [X] can be converted to a triethylsilylethynyl compound by the following procedure: the hydroxymethyl group in the 4-position of the compound [X] is oxidized to form a formyl group, and the formyl group is converted to a dibromovinyl group, followed by removal of a hydrogen bromide through treatment with a strong base. When the hydroxymethyl group in the 4-position of the compound [X] is converted to a formyl group, an oxidation agent is employed. Examples of the oxidizing agent that may be employed include chromium-containing oxidation agents such as mixed reagents of chromic anhydride-pyridine-acetic anhydride, pyridinium chlorochromate, and pyridinium dichromate; high valence iodine oxidation agents such as Dess-Martin reagent; and oxidizing agents based on dimethyl sulfoxide such as a combination of dimethyl sulfoxide and acetic anhydride, oxalyl chloride, or dicyclohexyl carbodiimide. The reaction conditions vary depending on the oxidation agent to be used. For example, when oxidation is carried out by the use of oxalyl chloride and dimethyl sulfoxide, the oxalyl chloride (1 to 5 mol) and dimethyl sulfoxide (1.5 to 6 mol) are added to 1 mol of the compound [ X] in an organic solvent (e.g., dichloromethane), optionally under an inert gas atmosphere (e.g., argon or nitrogen), and the resulting mixture is allowed to react between -100 ° C and 0 ° C for about 15 minutes at approximately two hours. Subsequently, a base such as triethylamine is added in an amount of 2 to 10 mol to the mixture, and the resulting mixture is further allowed to react at room temperature for about 15 minutes to about two hours. The aldehyde thus formed can be converted to a corresponding alkyne by the following procedure. The aldehyde is subjected to a carbon enhancing reaction (ie, a C-C bond formation); the resulting compound is treated with a strong base to thereby form a metal alkynyl compound; and a protecting group is introduced into the metal alkynyl compound. The increased carbon reaction is carried out in an organic solvent such as dichloromethane or dichloroethane,. optionally under an inert gas atmosphere (e.g., argon or nitrogen). Specifically, carbon tetrabromide (1 to 5 mol) and triphenylphosphine (2 to 10 mol) are added to 1 mol of the above-formed aldehyde, and the resulting mixture is allowed to react between 0 and 50 ° C for about 15 minutes at about three hours . The treatment with a strong base can be carried out in an organic solvent such as tetrahydrofuran, 1,4-dioxane, or dimethoxyethane, optionally under an inert gas atmosphere (eg, argon or nitrogen). Specifically, a lithium compound (eg, methyl lithium, n-butyl lithium or t-butyl lithium) (2 to 4 mol) is added to 1 mol of the compound obtained through the carbon enhancing reaction, and The resulting mixture is allowed to react between -100 and -20 ° C for about five to about 60 minutes. Further, when a silyl protecting group is introduced into the akinyl group of the compound thus obtained, the aforementioned strong base treatment is followed by the addition of a silylating agent such as a chlorotriethylsilane, and the resulting mixture is allowed to react. Meanwhile, the compound [X] can be converted to a cyano compound by the following procedure: the hydroxymethyl group in the 4-position of the compound [X] is oxidized to form a formyl group, and the formyl group is converted to an oxime group , followed by dehydration of the oxime group thus formed.

When the hydroxymethyl group in the 4-position of the compound [X] is converted to a formyl group, an oxidation agent is employed. Examples of the oxidizing agent that may be employed include chromium-containing oxidation agents such as mixed reagents of chromic anhydride-pyridine-acetic anhydride, pyridinium chlorochromate, and pyridinium dichromate; high valence iodine oxidation agents, such as Dess-Martin reagent; and oxidizing agents based on dimethyl sulfoxide such as a combination of dimethyl sulfoxide and acetic anhydride, oxalyl chloride or cyclohexyl carbodiimide. The reaction conditions vary depending on the oxidation agent to be used. For example, when oxidation is carried out by the use of an oxalyl chloride and dimethyl sulfoxide, the oxalyl chloride (1 to 5 mol) and dimethyl sulfoxide (1.5 to 6 mol) are added to 1 mol of the compound [X] in an organic solvent (e.g., dichloromethane) optionally under an atmosphere of inert gas (e.g., argon or nitrogen), and the resulting mixture is allowed to react between -100 ° C and 0 ° C for about 15 minutes at approximately two hours. Subsequently, a base such as triethylamine is added in an amount of 2 to 10 mol to the mixture, and the resulting mixture is further allowed to react at room temperature for about 15 minutes to about two hours. The aldehyde thus formed can be converted into a corresponding oxime by reacting 1 mol of the aldehyde with hydroxylamine hydrochloride (1 to 5 mol) in an organic solvent such as pyridine at room temperature at 100 ° C for about 30 minutes to about three hours. The dehydration of the oxime thus formed can be carried out by the use of a dehydrating agent (for example, phosgene, carbonyldiimidazole, methanesulfonyl chloride or acetic anhydride) in an organic solvent (for example, dichloromethane, acetonitrile, or tetrahydrofuran) in presence of a base (eg, pyridine, triethylamine, or sodium acetate) Dehydration conditions vary depending on the dehydration agent to be employed, eg, when dehydration is carried out using methanesulfonyl chloride, an organic solvent (such as dichloromethane, tetrahydrofuran, or pyridine), methanesulfonyl chloride (1 to 5 mol) and triethylamine (5 to 10 mol) are added to 1 mol of the oxime, and the resulting mixture is allowed to react to - 50 ° C at room temperature for about 15 minutes to about two hours.

Second step In the second step, the methylbenzylidene group protecting the hydroxyl groups at positions 3 and 5 of the compound [XI] is removed, to thereby produce a compound represented by the formula [XII]: P < 0 [XlO (wherein R 1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The protecting group can be removed through a technique that is appropriately selected from among typical techniques (eg, hydrolysis under acidic conditions and catalytic reduction). The reaction conditions vary depending on the technique to be used. For example, when the protecting group is removed by hydrolysis under acidic conditions, the compound [XI] is allowed to react in an aqueous solution of an organic acid (for example, formic acid or acetic acid) or mineral acid between 0 and 100. ° C for one to 24 hours.

Third step: In the third step, the hydroxyl group at the 5-position of the compound [XII] is selectively protected, to thereby produce a compound represented by the formula [Xlll]: [xifl peno (wherein P represents a protecting group, and R1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The protecting group represented P, which protects the hydroxyl group, in the 5-position, can be a protecting group which is generally used to selectively protect a primary hydroxyl group. Specific examples of the protecting group include a trimethoxytrityl group, a dimethoxytrityl group, a methoxytrityl group, a trityl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and a benzoyl group. The introduction of the protecting group can be carried out in a manner similar to that used for compound V.

Fourth step In the fourth step, the hydroxyl group in the 3-position of the compound [Xlll] is reduced, to thereby produce a compound represented by the formula [XIV]: eno [xiv] (wherein P represents a protecting group, and R1 represents an ethynyl group, a triethylsilylethynyl group, or a harm group). The deoxygenation of the hydroxyl group in the 3-position can be carried out by converting the compound having the hydroxyl group into a corresponding halide (iodide, bromide or chloride), phenoxythiocarbonate, thiocarbonylimidazole, or methyldithiocarbonate, or by reducing the compound thus converted by the use of a radical reducing agent in the presence of a radical initiator. For example, when deoxygenation is carried out through the formation of a phenoxythiocarbonyl compound, the conversion of the hydroxyl group to a phenoxythiocarbonyl group is carried out in an organic solvent (e.g., tetrahydrofuran, acetonitrile, or dichloromethane) in presence of a base such as dimethylaminopyridine or pyridine, optionally under an atmosphere of inert gas such as argon or nitrogen. Specifically, a phenyl chlorothionoformate derivative (1 to 10 mol, preferably 1 to 2 mol) is added to 1 mol of the aforementioned compound wherein only the protecting group for the hydroxyl group in the 3-position has been removed, and the mixture The resulting reaction is allowed to react under stirring at 0 to 50 ° C for about 0.5 to about five hours. Subsequently, a reduction is carried out in an organic solvent (for example, toluene or benzene) in the presence of a radical initiator such as azobisisobutyronitrile, optionally under an atmosphere of inert gas such as argon or nitrogen. Specifically, radical reducing agent such as tributyltin hydride or tris (trimethylsilyl) silane (1 to 10 mol, preferably 2 to 5 mol) is added to 1 mol of the aforementioned phenoxythiocarbonyl compound, and the resulting mixture is allowed to react under stirring between 50 and 150 ° C for about one to about 5 hours.

Fifth step In the fifth step, the isopropylidene group in positions 1 and 2 of the compound [XIV] is removed, and subsequently the hydroxyl groups thus formed are acetylated, to thereby produce a compound represented by the formula [XV]: [XIV] V] (wherein P represents a protecting group, and R represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). When the isopropylidene group in positions 1 and 2 is removed by hydrolysis under acidic conditions, the compound [XIV] is allowed to react in an aqueous solution of an organic acid (for example, formic acid or acetic acid) or mineral acid between 0 and 100 ° C during a 24 hours.

The introduction of acetyl groups to the hydroxyl groups, which follow the removal of the isopropylidene group, can be carried out by means of a usual technique. For example, acetyl groups are introduced to the hydroxyl groups through the reaction with an acetylating agent (eg, acetyl chloride or acetic anhydride) in an organic solvent such as pyridine, acetonitrile, or dichloromethane in the presence of a base such as pyridine or triethylamine. For example, in the case of reaction in pyridine by the use of acetic anhydride, acetic anhydride (2 to 10 mol) and, if desired, a catalytic amount of 4-dimethylaminopyridine are added to 1 mol of the compound from which the isopropylidene group has been removed, and the resulting mixture is allowed to react between 0 and 100 ° C for one to 24 hours.

Step Six: In the passage step the compound [XV] and 2,6-diaminopurine are subjected to condensation, to thereby produce a compound represented by the formula [XVI]: (wherein P represents a protecting group, and R1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group) The condensation of the compound [XV] and 2,6-diaminopurine can be carried out by reacting the compound [XV] with 2, 6-diaminopurine in the presence of a Lewis acid. In this case, 2,6-diaminopurine can be silylated, and said silylation of 2,6-diaminopurine can be carried out by a known technique. For example, 2,6-diaminopurine is silylated under reflux in a mixture of hexamethyldisilazane and trimethylchlorosilane, or silylated under reflux by the use of bis (trimethylsilyl) acetamide in an organic solvent such as acetonitrile or 1,2-dichloroethane. Examples of Lewis acids to be employed include trimethylsilyl trifluoromethanesulfonate, tin tetrachloride, zinc chloride, zinc iodide, and anhydrous aluminum chloride. The condensation reaction can be carried out in an organic solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, or toluene, optionally under an atmosphere of inert gas such as argon or nitrogen. Specifically, 2,6-diaminopurine (1 to 10 mol) and Lewis acid (0.1 to 10 mol) are added to 1 mol of compound [XV], and the resulting mixture is allowed to react between -20 to 150 ° C for about 30 minutes to approximately 24 hours.

Seventh step In the seventh step, the amino group in the 2-position of the compound [XVI] is converted to a halogen atom, to thereby produce a compound represented by the formula [XVII]: pcvij rxvii] (wherein P represents a protective group, X represents a halogen atom, and R represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The compound [XVII] can be synthesized by the following procedure: after the amino group in the 2-position of the compound [XVI] is treated with a nitrite derivative, the halogen atom is introduced in the 2-position of a base portion by the use of a halogen reagent; or the amino groups at positions 2 and 6 are treated under the same conditions, thereby forming a 2,6-dihalopurine derivative, and the halogen atom at the 6-position of the same base portion is converted to an amino group through of the treatment with ammonia. Examples of reagents for substituting the amino group at the 2-position of the compound [XVI] by fluorine include sodium nitrite in tetrafluoroboric acid, and nitrous acid ester (for example, t-butyl nitrite) in hydrogen fluoride-pyridine. The reaction conditions vary depending on the reagent used. For example, when t-butyl nitrite is used in hydrogen fluoride-pyridine, t-butyl nitrite (1 to 3 mol) is added to compound [XVI] in hydrogen fluoride-pyridine which serves as a solvent, and The resulting mixture is allowed to react between -50 ° C and 0 ° C for about 15 minutes to about five hours. When the compound [XVI] is formed in a 2,6-difluoropurine derivative, the resulting derivative is treated with aqueous ammonia in an organic solvent such as dioxane or methanol. Examples of reagents for replacing the amino group at the 2-position of the compound [XVI] by chlorine include a combination of antimony trichloride and t-butyl nitrite, and a combination of acetyl chloride and benzyltriethylammonium nitrite, the combinations of which are used in an organic solvent such as dichloromethane. The reaction conditions vary depending on the reagent used. For example, when a combination of acetyl chloride and benzyltriethylammonium nitrite is used as the reactant, in an organic solvent such as dichloromethane, benzyltriethylammonium nitrite (1 to 5 mol) is treated with acetyl chloride (1 to 5 mol) at -50 ° C at room temperature for about 30 minutes to about three hours, and the resulting mixture is allowed to react with 1 mole of compound [XVI] at -50 ° C at room temperature for one hour for a few days. When the compound [XVI] is formed into a 2,6-dichloropurine derivative, the resulting derivative is treated with aqueous ammonia in an organic solvent such as dioxane or methanol.

Eighth step: In the eighth step, the acetyl group protecting the hydroxyl group in position 2 of compound [XVII] is removed, to thereby produce a compound represented by formula [XVIII]: [XVII] rxviii] (wherein P represents a protecting group, X represents a halogen atom, and R1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The acetyl group can be removed by the use of an appropriate base or acid catalyst. For example, when the removal of the acetyl group is carried out in a mixture of water solvent and an alcohol (e.g., ethanol), a base catalyst such as sodium hydroxide, potassium hydroxide, triethylamine or aqueous ammonia can be employed.

For example, the acetyl group can be removed by allowing the compound [XVII] to react by using aqueous ammonia in methanol between 0 and 100 ° C for one to 24 hours.

Ninth step: In the ninth step, the hydroxyl group in the 2 'position of the compound [XVIII] is reduced, to produce a compound represented by the formula [XIX]: [XVIII] [XIX] (where P represents a protecting group, X represents a halogen atom, and R1 represents an ethynyl group, a triethylsilylethynyl group, or a cyano group). The deoxygenation of the hydroxyl group in the 2 'position can carried out by converting the compound having the hydroxyl group into the corresponding halide (iodide, bromide or chloride), phenoxythiocarbonate, thiocarbonylimidazole, or methyldithiocarbonate, and by reducing the compound thus converted by the use of a radical reducing agent in the presence of a radical initiator.

For example, when the deoxygenation is carried out through the formation of a phenoxythiocarbonyl compound, the conversion of the hydroxyl group to a phenoxythiocarbonyl group is carried out in an organic solvent (for example tetrahydrofuran, acetonitrile or dichloromethane) in the presence of a base as dimethylaminopyridine or pyridine, optionally under an inert gas atmosphere such as argon or nitrogen. Specifically, a phenyl chlorothionoformate derivative (1 to 10 moles, preferably 1 to 2 moles) is added to 1 mole of the above-mentioned compound wherein only the protecting group for hydroxyl group in the 2 'position has been removed, and the mixture The resultant is left to react under stirring at 0 to 50 ° C for about 0.5 to about 5 hours. Subsequently, the reduction is carried out in an organic solvent (for example toluene or benzene) in the presence of a radical initiator such as azobisisobutyronitrile, optionally under an inert gas atmosphere such as argon or nitrogen. Specifically, a radical reducing agent such as tributyltin hydride or tris (trimethylsilyl) silane (1 to 10 moles, preferably 2 to 5 moles) is added to 1 mole of the phenoxythiocarbonyl compound mentioned above, and the resulting mixture is allowed to react under stirring from 50 to 150 ° C for about one to about 5 hours. The protecting group for the hydroxyl group of the compound thus obtained [XIX] is removed, in order to generate the compound of the present invention in which R2 is hydrogen, and if desired, the compound is phosphorylated: * j NH 2 i "2 1 I i"? . | PO N X R "0 or * N X R1 - R XE I [NI (wherein P represents a protecting group, X represents a halogen atom, R1 represents an ethyl group, a triethylsilylethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue or a phosphate-derived residue). The protecting group can be removed by a technique that is appropriately selected from among typical techniques (eg hydrolysis under acidic conditions, hydrolysis under alkaline conditions, treatment with tetrabutylammonium fluoride and catalytic reduction) in accordance with the protecting group employed. A compound wherein R2 is a phosphate residue or a derivative thereof can be synthesized in a manner similar to that of compound [I]. The compounds of the present invention can be isolated and purified by conventional methods, in appropriate combination, which are used to isolate and purify nucleosides and nucleotides; for example recrystallization, column chromatography with ion exchange and chromatography on adsorption column. The compounds thus obtained can also be converted to salts thereof according to the needs. (3) Use As shown in the test examples described below the compounds of the present invention show excellent antiviral activity against retroviruses. Thus, the compositions of the present invention containing one of the compounds of the present invention as an active ingredient find utility in the field of therapeutic drugs. Specifically, the compositions of the present invention are useful for the treatment of infectious diseases caused by a retrovirus, in particular AIDS which is caused by HIV infection. The dose of the compounds of the present invention depends on and is determined by considering conditions such as the age, body weight and type of disease of the patient, the severity of the disease; tolerance to the drug; and the administration route; however, the daily dose is determined as typically within 0.00001-1,000 mg / kg, preferably 0.0001-100 mg / kg. of body weight. The compounds are administered in a single dose or in divided doses. Any route of administration can be employed and the compounds can be administered orally, parenterally, enterally or topically.

When a pharmacist is prepared from the compounds of the present invention, the compounds are typically mixed with customarily employed additives, such as a carrier and an excipient. Examples of solid carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin and sodium chloride. Examples of liquid carriers include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol and water. The product form is arbitrarily selected. When the carrier is solid, examples of product forms include tablets, powder, granules, capsules such as suppositories and pills, while when liquid, examples include syrup, emulsion, soft gelatin capsules, cream, gel, paste, aspersion and injection.

EXAMPLES The present invention will now be described in detail by examples including synthetic examples, test examples and examples of drug preparation, which should not be construed as restrictive of the invention.

EXAMPLE OF SYNTHESIS 1 Synthesis of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (compound 4) (1) Synthesis of 9- (3,5-di-O-acetyl-2-deoxy-4-C-ethynyl-β-D-riboprophennosyl) -2,6-diaminopurine (compound 2) 1 2 Compound 1 (0.33 g, 1.14 mmol) was suspended in acetonitrile (10.0 ml), and acetic anhydride (0.23 ml, 2.43 mmol), triethylamine (0.67 g, 4.81 mmol), and a small amount of 4-dimethylaminopyridine were added to the resulting suspension, followed by stirring at room temperature overnight. The crystals thus precipitated were filtered and dried, in order to generate compound 2 (0.40 g, 1.07 mmol, 93.9%). 1 H-NMR (DMSO-d 6) d 7.94 (1 H, s, H-8), 6.76 (2 H, bs, NH 2), 6.27 (1 H, t, H-1 J = 7.00), 5.84 (2 H, bs, NH2), 5.60 (1 H, dd, H-3 \ J = 4.00, 6.80), 4.46 (1 H, d, H-5'a, J = 11.5), 4.21 (1H, d,. 5'b, J = 11.5), 3.74 (1 H, s, ethynyl) 3.12 (1 H, m, H-2'a), 2.52 (1 H, m, H-2'b), 2.12, 2.03 ( each 3H, s, acetyl) (2) Synthesis of 3'.5'-di-O-acetyl-2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (compound 3) 3 Compound 2 (450 mg, 1.20 mmol) was dissolved in 70% hydrogen fluoride-pyridine (5.00 ml), and t-butyl nitrite (0.194 ml, 1.63 mmol) was added to the resulting solution, followed by stirring at room temperature. -10 ° C for one hour. Distilled water was added to the resulting mixture and the resulting mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. A mixture of chloroform and methanol (50: 1) was added to the resulting residue and the crystals thus precipitated were filtered and dried, to thereby generate compound 3 (240 mg, 0.64 mmol, 53.3%). 1 H-NMR (DMSO-d 6) d 8.34 (1 H, s, H-8), 7.94, 7.99 (each 1 H, bs, NH 2), 6.35 (1 H, t, H-1 J = 6.80), 5.68 (1H, dd, H-3 \ J = 5.10, 7.05), 4.41 (1 H, d, H-5'a, J = 11.6), 4.21 (1H, d, H-5 ', J = 11.6), 3.42 (1 H, s, ethynyl), 3.14 (1 H, m, H-2'a), 2.63 (1 H, m, H-2'b), 2.12, 2.00 (each 3H, s, acetyl). (3) Synthesis of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (compound 4) 3. 4 Compound 3 (200 mg, 0.53 mol) was dissolved in methanol (7.00 ml), and 28% aqueous ammonia (5.00 ml) was added to the resulting solution, followed by stirring at room temperature for 4 hours. The resulting reaction mixture was concentrated under reduced pressure and a mixture of chloroform and methanol (20: 1) was added to the resulting residue. The crystals thus precipitated were recorded and then the resulting crystals were recrystallized from water, to thereby generate compound 4 (113 mg, 0.39 moles, 73.6%). 1 H-NMR (DMSO-ds) d 8.30 (1 H, s, H-8), 7.87, 7.84 (every 1 H, bs, NH 2), 6.24 (1 H, dd, H-1 ', J = 5.05, 7.15), 5.57 (1 H, d, 3'-OH, J = 5.50), 5.30 (1 H, t, 5'-OH, J = 6.40), 4.57 (1 H, m, H-3 '), 3.65 (1 H, m, H-5'a), 3.55 (1 H, m, H-5'b), 3.51 (1 H, s, ethynyl), 2.70 (1 H, m, H-2'a), 2.44 (1H, m, H-2'b).

EXAMPLE OF SYNTHESIS 2 Synthesis of 4'-c-cyano-2'-deoxy-2-fluoroadenosine (compound 8) (1) Synthesis of 9- (3,5-di-O-acetyl-4-C-cyano-2-deoxy-3-D-riboporopuranosyl) -2,6-diaminopurine (compound 6) Compound 5 (122 mg, 0.418 mol) was suspended in acetonitrile (5.00 ml), and acetic anhydride (118 1, μ1.25 mol), triethylamine (352 μl, 2.51 mol), and a small amount of 4 dimethylaminopyridine were added to the resulting suspension, followed by stirring at room temperature overnight. The crystals thus precipitated were filtered and dried, to thereby generate compound 6 (128 mg, 0.341 moles, 81.6%). 1 H-NMR (CDCl 3) d 7.54 (1 H, s, H-8), 6.31 (1 H, t, H-1 ', J = 7.00), 6.06 (1 H, dd, H-3', J = 5.00, 6.50), 5.31 (2H, bs, NH2), 4.59 (1 H, d, H-5'a, J = 11.5), 4.80 (2H, bs, NH2), 4.37 (1 H, d, H- 5'b, J = 12.0), 3.43 (1 H, m, H-2'a), 2.63 (1 H, m, H-2'b), 2.23, 2.1.2 (each 3H, s, acetyl) . (2) Synthesis of 3'.5'-di-O-acetyl-4'-C-cyano-2'-deoxy-2-fluoroadenosine (compound 7) 7 Compound 6 (118 mg, 0.314 mol) was dissolved in 70% hydrogen fluoride-pyridine (2.30 ml) and t-butyl nitrite (50.0 μl, 0.427 mol) was added to the resulting solution, followed by stirring at - 10 ° C for three hours. To the resulting mixture was further added t-butyl nitrite (10.0 μl, 85 μmol) additionally and the mixture was stirred adidonally at -10 ° C for one hour. After a saturated aqueous solution of sodium bicarbonate was added to the resulting mixture, the resulting mixture was subjected to extraction with ethyl acetate and the resulting organic layer was washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethanol under heating, followed by cooling. The crystals thus precipitated were filtered and dried to thereby generate compound 7 (53.7 mg, 0.14 moles, 45.2%). 1 H-NMR (DMSO-de) d8.35 (1 H, s, H-8), 8.00, 7.92 (every 1 H, bs, NH 2), 6.54 (1 H, t, H-1 ', J = 7.00), 5.83 (1 H, dd, H-3 ', J = 4.00, 6.50), 4.63 (1 H, d, H-5'a, J = 11.5), 4.44 (1 H, d, H- 5'b, J = 12.0), 3.26 (1 H, m, H-2'a), 2.73 (1 H, m, H-2'b), 2.18, 2.05 (each 3H, s, acetyl). (3) Synthesis of 4'-C-cyano-2'-deoxy-2-fluoroadenosine (compound 8) 7 s Compound 7 (53.7 mg, 0.142 mmol) was dissolved in methanol (1.90 ml) and 28% aqueous ammonia (1.30 ml) was added to the resulting solution, followed by stirring at room temperature for 30 minutes. The resulting reaction mixtures were concentrated under reduced pressure and then the resulting residue was purified by column chromatography with silica gel (silica gel 10 ml, hexane / ethyl acetate (5: 1), ethyl acetate, ethyl acetate methanol (10: 1)), to thereby generate compound 8 (30.2 mg, 0.10 mmol, 72.3%). 1 H-NMR (DMSO-d 6) d 8.31 (1 H, s, H-8), 7.93, 7.82 (every 1 H, bs, NH 2), 6.43 (1 H, t, H-1'J, J = 7.00), 6.36 (1H, bs, 3'-OH), 5.74 (1 H, bs, 5'-OH), 4.70 (1 H, t, H-3 ', J = 5-50), 3.80 ( 1 H, d, H-5'a, J = 12.0), 3.65 (1 H, d, H-5'b, J = 12.0), 2.93 (1 H, m, H-2'a), 2.47 ( 1 H, m, H-2'b).

EXAMPLE OF SYNTHESIS 3 Synthesis of 2-chloro-2'-deoxy-4'-C-ethynyladenine (compound 9) 2 9 Benzyltriethylammonium nitrite (1.04 g, 4.36 mmol) was dissolved in dichloromethane (24.0 ml) and acetyl chloride (0.40 ml, 5.63 mmol) was added to the resulting solution, followed by stirring at 0 ° C for 30 minutes. To the resulting solution was added a solution of compound 2 (340 mg, 0.91 mol) in dichloromethane (6.00 ml) and the resulting mixture was stirred at 0 ° C for three hours. The resulting reaction mixture was diluted with chloroform and then the resulting organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue was added 28% aqueous ammonia (10.0 m!) And methanol (15.0 ml) and the resulting mixture was stirred at room temperature overnight. After this, the resulting reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (silica gel 50 ml, chloroform: methanol = 20: 1 a : 1). The residue thus purified was further purified by ODS column chromatography (ODS 50 ml, 5 to 10 to 15 to 20% acetonitrile), to thereby generate compound 9 (39.2 mg, 0.13 mmol, 14.3%). 1 H-NMR (DMSO-d 6) d 8.34 (1 H, s, H-8), 7.84 (2 H, bs, NH 2), 6.27 (1 H, dd, H-1 ', J = 5.00, 7.00), 5.60 (1 H, d, 3'-OH, J = 5.00), 5.33 (1 H, t, 5'-OH, J = 6.00), 4.56 (1 H, m, H-3 '), 3.64 (1 H , m, H-5'a), 3-56 (1 H, m, H-5'b), 3-52 (1 H, s, ethynyl), 2.68 (1H, m, H-2'a) 2.45 (1 H, m, H-2'b).

EXAMPLE OF SYNTHESIS 4 Synthesis of 5'-H-phosphonate of S'-deoxy ^ '- C-ethynyl ^ -fluoroadenosine (compound 10) 4 10 Compound 4 (50.0 mg, 0.171 mmol) was dissolved in pyridine (2.00 ml), and phosphoric acid (21.0 mg, 0.25 mmol) and dicyclohexyl carbodiimide (106 mg, 0.51 mmol) were added to the resulting solution, followed by stirring at room temperature. room temperature for five hours. The resulting precipitate was removed through filtrate and then the filtrate was concentrated under reduced pressure. The resulting residue was partitioned with water and chloroform. The resulting aqueous layer was concentrated under reduced pressure and the residue thus obtained was purified by preparative thin layer chromatography (isopropanol, 28% aqueous ammonia: water = 7: 1: 2). The resulting residue was boiled together with acetonitrile and then treated with methanol and ether to generate a powdery compound (compound 10, 6.3 mg, 17.6 μmol, 10.3%). 1 H-NMR (D 2 O) d 8.13 (1 H, s, H-8), 6.49 (1 H, d, HP, J = 645), 6.25 (1 H, dd, H-1 ', J = 5.00, 7.50), 3.96 (2H, m, H-50 '), 2.75, 2.59 (every 1 H, m, H-2'). 31 P-NMR (D20) d 6.45.

EXAMPLE OF SYNTHESIS 5 Synthesis of 2 ', 3'-didehydro-2', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine (compound 13) 4 11 NH2 NH2H.,:] R "" "'N GB DPS O- or f' ^" F HO -, or N "" H '"T 12 13 Compound 4 (0.28 g, 0.95 mmol) was dissolved in dimethylformamide (7.00 ml), and t-butylchlorodiphenylsilane (0.50 ml, 1.92 mmol) and imidazole (0.26 g, 3.82 mmol) were added to the resulting solution, followed by stirring at room temperature. room temperature overnight. After methanol was added to the resulting reaction mixture, the resulting mixture was concentrated under reduced pressure and the resulting residue was partitioned with ethyl acetate and water. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (silica gel 100 ml, chloroform: methanol = 20: 1), in order to generate a crude compound 11 (0.38 g). The crude compound 11 (0.38 g) was dissolved in dichloromethane (10.0 ml), and trifluoromethanesulfonic anhydride (0.14 ml, 0.83 mmol) and pyridine (0.14 g, 1.71 mmol) were added to the resulting solution at -10 ° C, followed by stirring at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the resulting reaction mixture and then the resulting mixture was subjected to extraction with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crude triflate thus obtained was used in the next reaction without purification thereof. The crude triflate was dissolved in dry tetrahydrofuran (20.0 ml), and a solution of 1-M sodium hexamethyldisilazide in tetrahydrofuran (2.50 ml, 2.50 mmol) was added to the resulting solution under an argon atmosphere at -78 ° C, followed by by stirring at the same temperature for 2 hours. After this, the resulting reaction mixture was allowed to warm to room temperature and then stirred overnight. Water was added to the resulting reaction mixture and then the resulting mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (silica gel 50 ml, chloroform: methanol = 50: 1 to 20: 1), in order to generate a crude compound 12 (0.20 g). The crude compound thus obtained 12 was dissolved in tetrahydrofuran (10.0 ml), and a solution of tetrabutylammonium fluoride 1-M in tetrahydrofuran (0.59 ml, 0.59 mmole) was added to the resulting solution, followed by stirring at room temperature for 30 minutes. . The resulting reaction mixture was concentrated under reduced pressure and then a mixture of chloroform and methanol (10: 1) was added to the mixture thus concentrated. The crystals thus precipitated were filtered to yield compound 13 (52.0 mg, 0.19 mmol, 20.0% of compound 4). 1 H-NMR (DMSO-de) d 8,08 (1 H, s, H-8), 7.84 (2 H, bs, NH 2), 6.90 (1 H, t, H-1 ', J = 1.50), 6.43 (1 H , dd, H-3 ', J = 2.00, 6.00), 6.27 (1H, dd, H-3', J = 1.00, 6.00), 5.37 (1 H, t, 5'-OH, J = 6.00), 3.71 (1 H, s, ethynyl), 3.67 (1 H, dd, H-5'a, J = 6.00, 12.0), 3.57 (1 H, dd, H-5'b, J = 6.00, 12.0).

EXAMPLE OF SYNTHESIS 6 Synthesis of 5'-H-phosphonate 2 ', 3'-dideshdrone-2', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine (compound 14) Compound 13 was dissolved (13.0 mg, 0.047 mmol) in pyridine (0.7 ml), and phosphonic acid (7.7 mg, 0.094 mmol) and dicyclohexylcarbodiimide (29.2 mg, 0.14 mmol) were added to the resulting solution, followed by stirring at room temperature for one hour. The resulting reaction mixture was concentrated under reduced pressure and the residue thus obtained was purified by means of ODS column chromatography (ODS 10 ml, acetonitrile at 0-1%). The resulting residue was applied to a Dowex 50Wx8 column (Na type) and eluted. The elution product was concentrated and the resulting residue was treated with methane and ether, to thereby yield a powdery compound (compound 14, 4.3 mg, 12 μmol, 25.5%). 1 H-NMR (MeOD) d8.30 (1 H, s, H-8), 6.69 (1 H, d, HP, J = 6.25), 7.02 (1H, bt, H-1 '), 6.48 (1H, dd, H-2 ', J = 2.00, 5.50), 6.22 (1 H, dd, H-3 \ J = 1.00, 5.50), 4.18 (1H, dd, H-5'a, J = 7.50, 11.0) , 3.99 (1H, dd, H-5'b, J = 7.50, 11.0). 31P-NMR (MeOD) d4.11.

EXAMPLE OF SYNTHESIS 7 Synthesis of 2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine (compound 23) (1) Synthesis of 1,2-O-isopropylidene-4-C-triethylsilyletyl-a-D-xl-pentofuranose (compound 16) fifteen Oxalyl chloride (0.54 ml, 6.19 mmol) was dissolved in dichloromethane (10.0 ml) and dimethyl sulfoxide (0.90 ml, 12.7 mmol) was added dropwise to the resulting solution at -60 ° C, followed by stirring thereto. temperature for 15 minutes. A solution of compound 15 (1.06 g, 3.13 mmol, Biosci, Biotech, Biochem, 57, 1433-1438 (1993)) in dichloromethane (15.0 ml) was added dropwise to the resulting mixture, followed by stirring at -60. ° C for 30 minutes. After adding triethylamine (1.86 ml, 13.3 mmol) thereto, the resulting reaction mixture was allowed to warm to room temperature, followed by stirring for 30 minutes. The reaction mixture was eluted with chloroform and then washed with water. The organic layer thus obtained was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crude aldehyde thus obtained was used in the next reaction without purification thereof.

The crude aldehyde was dissolved in dichloromethane (40.0 ml) and carbon tetrabromide (2.08 g, 6.27 mmol) and triphenylphosphine (3.28 g, 12.5 mmol) were added to the resulting solution at 0 ° C, followed by stirring at room temperature for one hour. hour. Triethylamine (2.60 ml, 18.7 mmol) was then added to the resulting reaction mixture, the resulting mixture was diluted with chloroform and the resulting organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by means of silica gel column chromatography (silica gel 10 ml, hexane: ethyl acetate = 3: 1), to thereby produce a crude dibromoethene (1.42 g). The crude dibromoethene (1.42 g, 2.89 mmol) was dissolved in dry tetrahydrofuran (20.0 ml) and a solution of 2.2 M methyl lithium in ether (4.49 ml, 9.88 mmol) was added to the resulting solution under an argon atmosphere a - 10 ° C, followed by stirring at the same temperature for five minutes. Chlorotriethylsilane (0.95 ml, 5.66 mmol) was added to the resulting mixture and the mixture was stirred further for 30 minutes. After a saturated aqueous solution of ammonium chloride was added to the resulting reaction mixture, the resulting mixture was stirred and then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to thereby produce a crude alkyne. The crude alkyl was dissolved in acetic acid (80.0 ml) and water (20.0 ml) was added to the resulting solution, followed by stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the resulting residue was boiled together with toluene. The resulting residue was purified by means of silica gel column chromatography (silica gel 50 ml, hexane: ethyl acetate = 3: 1), to thereby yield compound 16 (0.70 g, 2.13 mmol, 64.4%). 1 H-NMR (CDCl 3) d 6.00 (1 H, d, H-1, J = 3.50), 4.60 (1 H, d, H-2, J = 4.00), 4.58 (1 H, d, H-3 , J = 5.00), 3.96-3.91 (3H, m, H-5 and 3-OH), 2.50 (1 H, t, 5-OH), 1.64, 1.33 (each 3H, s, acetonide), 0.97 (9H , t, Et, J = 8.00), 0.59 (6H, q, Et, J = 8.00). (2) Synthesis of d-O-t-butyldiphenylsilyl-l ^ -O-isopropylidene-C-triethylsilylethynyl-a-D-xylo-pentofuranose (compound 17) 16 17 Compound 16 (0.70 g, 2.13 mmol) was dissolved in dimethylformamide (3.50 ml) and t-butylchlorodiphenylsilane (0.66 ml, 2.54 mmol) and imidazole (0.35 g, 5.14 mmol) were added to the resulting solution, followed by stirring overnight. After methanol was added to the resulting reaction mixture and the resulting mixture was concentrated under reduced pressure, the residue thus obtained was dissolved in ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by means of silica gel column chromatography (silica gel 100 ml, hexane: ethyl acetate = 5: 1), to thereby yield compound 17 (1.10 g, 1.94 mmol, 91.9%). 1 H-NMR (CDCl 3) d7.72-7.36 (10H, s, aromatic), 6.02 (1 H, d, H-1, J = 3.50), 4.66 (1 H, d, H-3, J = 5.50) , 4.63 (1 H, d, H-1, J = 4.00), 4.05 (1 H, d, H-5a, J = 10.5), 3.99 (1H, d, 3-OH, J = 5.50), 3.93 ( 1 H, d, H-5'b, J = 10.5), 1.65, 1.35 (each 3H, s, acetonide), 1.06 (9H, s, t-Bu), 0.93 (9H, t, Et, J = 8.00 ), 0.56 (6H, q, Et, J = 8.00). (3) Synthesis of 5-Q-t-butyl-phenylsilyl-3-deoxy-1,2-O-isopropylidene-4-C-tritylsilylethynyl-α-D-xylo-pentofuranose (compound 18) Compound 17 (1.10 g, 1.94 mmol) was dissolved in acetonitrile (20.0 ml) and phenyl chlorothionoformate (0.40 ml, 2.89 mmol) and 4-dimethylaminopyridine (0.71 g, 5.81 mmol) were added to the resulting solution, followed by stirring at room temperature for 3 hours. The resulting reaction mixture was diluted with ethyl acetate and then the resulting organic layer was washed with 0.1N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude thiocarbonate thus obtained was used in the next reaction without purification thereof. The crude thiocarbonate was boiled three times together with toluene and then dissolved in toluene (30.0 ml), followed by degassing under reduced pressure. Tributyltin hydride (2.61 ml, 9.70 mmol) and a small amount of azobis (isobutyronitrile) were added to the resulting solution under an argon atmosphere at 80 ° C and the resulting mixture was stirred under the same conditions for 1 hour. The resulting reaction mixture was concentrated under reduced pressure and then the residue thus obtained was purified by means of silica gel column chromatography (silica gel 100 ml, hexane: ethyl acetate = 10: 1), to thereby produce the compound 18 (1.07 g, 1.94 mmoles, quant.). 1 H-NMR (CDCl 3) d7.69-7.38 (10H, m, aromatic), 5.90 (1 H, d, H-1, J = 4.00), 4.85 (1 H, t, H-2, J = 5.00) , 3.82 (1 H, d, H-5a, J = 11.0), 3.58 (1 H, d, H-5b, J = 10.5), 2.64 (1H, dd, H-3a, J = 6.00, 14.0), 2.40 (1 H, d, H-3b, J = 14.0), 1 .68, 1.36 (each 3H, s, acetonide), 1.04 (9H, s, t-Bu), 0.92 (9H, t, Et, J = 8.00), 0.54 (6H, q, Et, J = 8.00). (4) Synthesis of 1,2-di-O-acetyl-5-Q-t-butyldiphenylyl-3-deoxy-4-C-triethylsilylethyl-D-xylo-pentofuranose (compound 19) 18 19 Compound 18 (1.07 g, 1.94 mmol) was dissolved in 80% acetic acid (100 ml) and trifluoroacetic acid (10.0 ml) was added to the resulting solution, followed by stirring at 40 ° C for three hours. The resulting reaction mixture was concentrated under reduced pressure and the residue thus obtained was then boiled together with toluene. The resulting residue was purified by means of silica gel column chromatography (silica gel 100 ml, hexane: ethyl acetate = 4: 1). The resulting residue was dissolved in pyridine (20.0 ml) and acetic anhydride (0.49 ml) was added to the resulting solution, followed by stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the residue thus obtained was then boiled, together with toluene. The resulting residue was purified by means of silica gel column chromatography (silica gel 100 ml, hexane: ethyl acetate = 5: 1), to yield compound 19 (0.75 g). 1 H-NMR (CDCl 3) d 7.17-7.37 (10H, m, aromatic), 6.44 (0.3H, d, H-1-alpha, J = 4.50), 6.20 (0.7H, s, H-1-beta), 5.36 (0.3H, m, H-2-alpha), 5.19 (0.7H, d, H-2-beta, J = 5.50), 3.77, 3.74 (each 0.7H, d, H-5-beta, J = 10.0), 3.76, 3.62 (each 0.3H, d, H-5-alpha, J = 11.0), 2.86 (0.3H, dd, H-3a-alpha, J = 8.50, 12.5), 2.72 (0.7H, dd , H-3a-beta, J = 5.50, 14.0), 2.39 (0.3H, dd, H-3b-alpha, J = 10.0, 12.5), 2.33 (0.7H, d, H-3b-beta, J = 14.0 ), 2.11, 2.08 (each 0.9H, s, acetyl-alpha), 2.10, 1.80 (each 2.1H, s, acetyl-beta), 1.074 (6.3H, s, t-Bu-beta), 1.067 (2.7H , s, t-Bu-alpha), 0.97 (6.3H, t, Et-beta, J = 8.00), 0.94 (2.7H, t, Et-alpha, J = 8.00), 0.58 (4.2H, q, Et -beta, J = 8.00), 0.54 (1.8H, q, Et-alpha, J = 8.00). (5) Synthesis of 9- (2-O-acetyl-5-O-t-butyldiphenylsilyl-3-deoxy-4-C-triethylsilylethynyl-β-D-xylo-pentofuransl) -2,6-diaminopurine (compound 20) 2,6-Diaminopurine (1.21 g, 8.06 mmol) was suspended in acetonitrile (24.0 mL), and N, O-bis (trimethylsilyl) acetamide (11.9 mL, 48.1 mmol) was added to the resulting suspension, followed by stirring at 80 ° C for 3 hours. The resulting solution was concentrated under reduced pressure and the residue thus obtained was boiled three times together with 1,2-dichloromethane. To the resulting residue, a solution of compound 19 (2.39 g, 4.02 mmol) in 1,2-dichloroethane (24.0 ml), and trimethylsilyl trifluoromethanesulfonate (3.05 ml, 16.9 mmol) was added and the resulting mixture was stirred under a Argon at 50 ° C for 5 hours and at 80 ° C for 10 hours. A saturated aqueous solution of sodium bicarbonate was then added to the resulting mixture and stirred under the mixture, the resulting solution was filtered through Celite. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by means of silica gel column chromatography (silica gel 300 ml, chloroform: methanol = 20: 1). The thus purified residue was crystallized from hexane and ethyl acetate, to thereby yield compound 20 (1.60 g, 2.34 mmol, 58.2%). 1 H-NMR (CDCl 3) d 7.67-7.33 (10H, m, aromatic), 6.13 (1 H, d, H-1 '-J = 3.50), 5.77 (1 H, md, H-2'), 5.28 ( 2H, bs, NH2), 4.49 (2H, bs, NH2), 3.67 (1 H, d, H-5'a, J = 10.5), 3.79 (1 H, d, H-5'b, J = 11.0 ), 3.18 (1 H, dd, H-3'a, J = 7.50, 14. 0), 2.37 (1 H, dd, H-3'b, J = 3.00, 14.0), 1.06 (9H, s, t-Bu), 0.99 (9H, t, Et, J = 8.00), 0.61 (6H, q, Et, J = 8.00) (6) Synthesis of 5'-O-t-butyldimethylsilyl-3'-deoxy-4'-C-triethylsilylethynyl-2-fluoroadenosine (compound 21) Compound 20 (100 mg, 0.146 mmol) was dissolved in pyridine (3.00 ml), and hydrogen fluoride-pyridine (7.00 ml) and t-butyl nitrite (160 μl, 1.34 mmol) were added to the resulting solution a- 15 ° C, followed by stirring at the same temperature for 30 minutes. After water was added to the resulting reaction mixture, the resulting mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained in this way was purified by means of silica gel column chromatography (silica gel 300 ml, chloroform: methanol = 100: 1 to 20: 1). The resulting residue (48.9 mg) was dissolved in dichloromethane (1.30 ml), and butyldenethylsilyl trifluoromethanesulfonate (36.0 μl, 0.157 mmol) and collidine (44.1 μl, 0.0331 mmol) were added to the resulting solution at 0 ° C, followed by stirring at the same temperature for 50 minutes. Water was added to the resulting reaction mixture and the resulting mixture was extracted with chloroform. The resulting organic layer was washed with 0.01-N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in dioxane (3.00 ml), and 28% aqueous ammonia (0.30 ml) was added to the resulting solution, followed by stirring at room temperature for 30 minutes. The resulting reaction mixture was concentrated under reduced pressure, and then the residue obtained in this manner was dissolved in methanol (1.20 ml), and 28% aqueous ammonia (0.80 ml) was added to the resulting solution followed by stirring at room temperature. environment for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and the crystals obtained in this way were recovered by filtration, to thereby produce compound 21 (34.0 mg, 0.0652 mmol, 44.7%). 1 H-NMR (CDCl 3) d 8.04 (1 H, s, H-8), 5.99 (1 H, d, H-1 ', J = 4.00), . 80 (2H, bs, NH2), 4.73 (1 H, m, H-2 '), 4.23 (1 H, d, 2'-OH, J = 5.00), 3.88 (1 H, d, H-5' a, J = 11.0), 3.70 (1 H, d, H-5'b, J = 11.0), 2.82 (1 H, dd, H-3'a, J = 7.50, 13.0), 2. 42 (1 H, dd, H-3'b, J = 6.50, 13.0), 1.01 (9H, t, Et, J = 8.00), 0.80 (9H, s, t-Bu), 0. 64 (6H, q, Et, J = 8.00), 0.039, -0.013 (every 3H, s, Me). (7) Synthesis of 5'-O-t-butyldimethylsilyl-2 ', 3'-dideoxy-4'-C-triethylsilylethynyl-2-fluoroadenosine (compound 22) 21 Compound 21 (32.0 mg, 0.61 mmol) was co-boiled three times with acetonitrile, and then dissolved in acetonitrile (1.00 ml). To the resulting solution were added phenyl chlorothionoformate (12.7 μl, 0.092 mmol) and 4-dimethylaminopyridine (22.5 mg, 0.180 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was dissolved with ethyl acetate, and then the organic layer obtained in this way was washed with 0.01-N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure, and the crude thiocarbonate obtained in this manner was employed in the next reaction without purification thereof. The crude thiocarbonate was co-boiled with toluene 3 times, and then dissolved in toluene (1.00 ml), followed by degassing under reduced pressure. To the resulting solution were added Tris (trimethylsilyl) silane (94.6 μl, 0.306 mmol) and a small amount of azobis (isobutyronitrile) under an argon atmosphere at 80 ° C, and the resulting mixture was stirred under the same conditions for 1 hour. hour. The resulting reaction mixture was concentrated under reduced pressure, and then the residue thus obtained was purified by means of silica gel column chromatography (silica gel 10 ml, chloroform: methanol = 200: 1 to 100: 1) , to thereby produce compound 22 (26.1 mg, 0.0516 mmole, 84.6%). 1 H-NMR (CDCl 3) d 8.24 (1 H, s, H-8), 6.36 (1 H, dd, H-1 J = 2.50, 7.00), 5.91 (2 H, bs, NH 2), 4.04 (1 H , d, H-5'a, J = 11.0), 3.81 (1 H, d, H-5'b, J = 11.00), 2.83 (1 H, m, H-2'a), 2.54 (1 H , m, H-3'a), 2.37 (1 H, m, H-2'b), 2.11 (1H, m, H-3'b), 1.00 (9H, t, Et, J = 8.00), 0.93 (9H, s, t-Bu), 0.62 (6H, q, Et, J = 8.00), 0.13 (6H, s, Me). (8) Synthesis of 2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine (compound 23) 22 23 Compound 22 (101 mg, 0.200 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of 1-M tetrabutylammonium fluoride in tetrahydrofuran (0.42 ml, 0.42 mmol) was added to the resulting solution, followed by stirring at room temperature for 5 minutes. After acetic acid (24 μl) was added to the resulting reaction mixture, the resulting mixture was concentrated under reduced pressure. The residue obtained in this way was purified by means of column chromatography on silica gel (silica gel 15 ml, chloroform: methanol = 40: 1 to 20: 1), to thereby produce compound 23 (53.0 mg, 0.191 mmol, 95.7%). 1 H-NMR (MeOD) d 8.23 (1 H, s, H-8), 6.22 (1 H, dd, H-1 ', J = 4.00, 7.00), 3.77 (1 H, d, H-5'a, J = 12.5), 3.61 (1 H, d, H-5 * b, J = 12.0), 2.94 (1 H, s, ethynyl), 2.66 (1 H, m, H-2'a), 2.54 (1 H, m, H-3'a), 2.42 (1 H, m, H-2'b), 2.11 (1 H, m, H-3'b) EXAMPLE OF SYNTHESIS 8 Synthesis of 5'-H-phosphonate of 2 ', 3, -dideoxy-4'-C-et? nyl-2-fluoroadenosine (compound 24) 23 24 Compound 23 (20.0 mg, 0.07 mmol) was dissolved in pyridine (1 ml), and phosphonic acid (11.8 mg, 0.144 mmol) and dicyclohexyl carbodiimide (44.7 mg, 0.216 mmol) were added to the resulting solution, followed by stirring at room temperature for five hours. The resulting reaction mixture was concentrated under reduced pressure, and the residue obtained in this way was purified by ODS column chromatography (ODS 10 ml, 0 to 1% acetonitrile). The resulting residue was applied to a Dowex 50Wx8 column (Na type) and eluted. The eluted product was concentrated, and the resulting residue was treated with methanol and ether, to thereby produce a powdery compound (compound 24, 4.7 mg, 13 μmol, 18. 6%). 1 H-NMR (MeOD) d8.37 (1 H, s, H-8), 6.77 (1 H, d, H-P, J = 6.25), 6. 32 (1 H, dd, H-1 ', J = 4.00, 6.50), 4.09 (1 H, m, H-5'), 2.71 (2H, m, H-2'a, H-3'a) , 2.52 (1 H, m, H-2'b), 2.29 (1 H, m, H-3'b). 31p-NMR (MeOD) d4.52.

EXAMPLE OF DRUG PREPARATION 1 Tablets Compound of the present invention 30.0 mg Cellulose micro-powder 25.0 mg Lactose 39.5 mg Starch 40.0 mg Talc 5.0 mg Magnesium stearate 0.5 mg The tablets are prepared from the above composition by means of a customary method.

EXAMPLE OF DRUG PREPARATION 2 Capsules Compound of the present invention 30.0 mg Lactose 40.0 mg Starch 15.0 mg Talc 5.0 mg The capsule drugs are prepared from the above composition by means of a customary method.

EXAMPLE OF DRUG PREPARATION 3 Inventions Compound of the present invention 30.0 mg Glucose 100.0 mg The injections are prepared by dissolving the above composition in purified water to prepare injections.

Next, the test examples will be described. In the The following five compounds of the present invention and four known compounds were used.

Compounds of the invention: Compound 4: 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine; Compound 8: 4'-C-cyano-2'-deoxy-2-fluoroadenosine Compound 9: 2-chloro-2'-deoxy-4'-C-ethynyladenine; Compound 10: 5'-H-phosphonate of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine; Y Compound 13: 2 ', 3'-didehydro-2', 3-d'-deoxy-4'-C-ethynyl-2-fluoroadenosine Known compounds AZT: Azidothymidine; EdAdo: 2'-deoxy-4'-C-ethynyladenosine; EdDAP: 9- (4-C-ethynyl-2-deoxy-ribopentofuranosyl) -2,6-diaminopurine; and ddAdo: 2 ', 3'-dideoxydenosine.

EXAMPLE OF TEST 1 Test methods Activity of the anti-human immunodeficiency virus (HIV) 1) MTT method using MT-4 cells 1. A test agent (100 μl) is diluted in a 96-well microplate. MT4 cells infected with HIV-1 (I I Ib strain, 100 TCID50) and uninfected MT-4 cells are added to the microplate, so that the number of cells in each well is 10,000. The cells are cultured at 37 ° C for five days. 2. MTT (20 μl, 7.5 mg / ml) is added to each well, and the cells are further cultured for 2 to 3 hours. 3. The cultivated medium (120 μl) is sampled, and an MTT termination solution (isopropanol containing 4%) is added to the sample.

Triton X-100 and 0.04 N HC1). The mixture is stirred to dissolve the formed formazan. The absorbance at 540 nm of the solution is measured. As the absorbance is proportional to the number of viable cells, the concentration of the test agent in which a mean value of the absorbance is measured in a test using infected MT-4 cells, represents EC50, while the concentration of the test agent in which a mean value of the absorbance is measured in a test using uninfected MT-4 cells, represents CC5o- 2) MAGI assay using HeLa CD4 / LTR-beta-Gal 1 cells. HeLa CD4 / LTR-beta-Gal cells were added to 96 wells, in such a way that the number of cells in each well is 10,000. After 12 to 24 hours, the culture medium is removed, and a diluted test agent (100 μl) is added. 2. A variety of strains of HIV are added (natural strain: WT, drug-resistant strain: MDR and M184V, each being equivalent to 50 TCID50), and the cells are further cultured for 48 hours. 3. The cells are fixed for 5 minutes using PBS supplemented with 1% formaldehyde and 0.2% glutaraldehyde. 4.- After washing the fixed cells three times with PBS, the cells are stained with 0.4 mg / ml X-Gal for one hour, and the number of cells stained blue is counted under a stereomicroscope. The concentration of the test agent at which the stained blue cells decrease by 50% in number represents EC50.

Results Activity and toxicity of the anti-human immunodeficiency virus (HIV) 1. - MTT method using MT-4 cells TABLE 1 2. - MAGI assay using HeLa CD4 / LTR-beta-Gal cells TABLE 2 EXAMPLE OF TRIAL 2 Test methods Stability of compound 4 against adenosine deaminase Adenosine deaminase derived from calf intestine (unit 0.01) was added to 0.5 ml of 0.5-mM compound 4 (50 mM Tris-HCl pH regulated solution (pH 7.5)), and the mixture was incubated at 25 ° C. A 5-μl aliquot of the reaction mixture was removed each minutes, followed by analysis by means of HPLC (high performance liquid chromatography). The peak area of a test drug at reaction time 0 was taken as 100%, and the curve was monitored over time. HPLC analysis was performed under the following conditions. Column: YMC-Pack ODS-A (250 x 6.0 mm) Eluent: 15% MeCN-50mM TEAA Flow rate: 1 ml / min. Temperature: 30 ° C Detection: 260 nm Results As shown in Figure 1, 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, which is compound 4 of the present invention, was not completely demeaned, in contrast to the case where the Conventional 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (EdAdo) was deaminated, which means that the compound of the present invention has resistance to adenosine deaminase.

EXAMPLE OF TEST 3 Test methods Stability of compound 4 under acidic conditions Compound 4 (2.9 mg) or 2 ', 3'-dideoxydenosine (ddAdo: 2.4 mg) was dissolved in 10 ml of a test solution at 37 ° C (which had been prepared by adding 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid in water to make a solution of 1, 000 ml), followed by incubation at the same temperature (37 ° C). An aliquot of 100 μl of the reaction mixture was removed therefrom, and neutralized with an aqueous solution of 0.1 N sodium hydroxide followed by 5 μl analysis by means of HPLC. The conditions of the HPLC analysis are the same as those used in test example 2.

Results Approximately 98% of ddAdo, which is a conventional compound, was degraded in approximately five minutes under the above conditions (see Fig. 3), while 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, which is the compound 4 of the present invention, it was degraded very slowly, verifying that the compound of the present invention is relatively stable under acidic conditions (see Fig. 2).

EXAMPLE OF TEST 4 Test methods Acute acute toxicity test of compound 4 To groups of ICR mice (6 weeks of age, males), each group consisted of 8 mice, were given a test drug (compound 4, dissolved or suspended in a saline solution) orally or by intravenous injection in amounts of up to 100 mg / kg. The occurrence of death and the body weight of each mouse was monitored for seven days.

Results All mice given Compound 4 at up to 100 mg / kg in a single dose survived regardless of the oral or intravenous route of administration (Table 3). Also, as can be seen in figs. 4A-4B, no weight loss or pathological symptoms such as diarrhea were observed. Thus, it was now confirmed that 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (compound 4) of the present invention does not exhibit acute toxicity in mice.

TABLE 3

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A 4'-C-substituted 2-haloadenosine derivative represented by the following formulas [I], [llj or [III]: (wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate-derived residue).

2. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that the phosphate residue or the phosphate derivative residue represented by R2 is a monophosphate; a diphosphate; a triphosphate; a phosphonate; or a phosphate-derived residue, such as a polyester phosphate (for example, a phosphate diester or a phosphate triester), a phosphate amidate (for example a phosphate monoamidate or a phosphate diamidate), phosphorothioate, phosphoroselonate or phosphorus borane.

3. - The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that the halogen atom represented by X is a fluorine or chlorine atom.

4. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that R1 is an ethynyl group.

5. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine.

6. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 4'-C-cyano-2'-deoxy-2-fluoroadenosine.

7. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2-chloro-2'-deoxy-4'-C-ethynyladenosine.

8. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 5'-H-phosphonate of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine.

9. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'-dideshdrone-2', 3'-dideoxy-4'-C- ethynyl-2-fluoroadenosine.

10. - The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'- dideshydro-2', 3'-dideoxy-4'-C-cyano-2- fluoroadenosine.

11. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'-didehydro-2', 3'-dideoxy-4'-C-ethynyl-2. -chloroadenosine.

12. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'-dideoxy-4'-C-ethynyl-2-fluoroadenosine.

13. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'-dideoxy-4'-C-cyano-2-fluoroadenosine.

14. The 4'-C-substituted 2-haloadenosine derivative according to claim 1, further characterized in that it is 2 ', 3'-dideoxy-4'-C-ethynyl-2-chloroadenosine.

15. A pharmaceutical composition containing a 4'-C-substituted 2-haloadenosine derivative as claimed in any of claims 1 to 14, and a pharmaceutically acceptable carrier therefor.

16. The pharmaceutical composition according to claim 15, further characterized in that it is an anti-HIV drug.

17. - The pharmaceutical composition according to claim 15, further characterized in that it is a drug for the treatment of AIDS.

18. The use of a 4'-C-substituted 2-haloadenosine derivative according to any of claims 1 to 14, or a pharmaceutical composition containing the derivative, in the manufacture of a medicament for the treatment of AIDS in a human or animal.