WO2003068796A1 - Nucleosides de 4'-c-cyano-2'-desoxypurine - Google Patents

Nucleosides de 4'-c-cyano-2'-desoxypurine Download PDF

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WO2003068796A1
WO2003068796A1 PCT/JP2003/001218 JP0301218W WO03068796A1 WO 2003068796 A1 WO2003068796 A1 WO 2003068796A1 JP 0301218 W JP0301218 W JP 0301218W WO 03068796 A1 WO03068796 A1 WO 03068796A1
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compound
group
formula
cyano
nucleoside
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PCT/JP2003/001218
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English (en)
Japanese (ja)
Inventor
Satoru Kohgo
Kohei Yamada
Shinji Sakata
Hiroshi Ohrui
Eiichi Kodama
Masao Matsuoka
Hiroaki Mitsuya
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Yamasa Corporation
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Priority to JP2003567922A priority Critical patent/JPWO2003068796A1/ja
Priority to AU2003211483A priority patent/AU2003211483A1/en
Publication of WO2003068796A1 publication Critical patent/WO2003068796A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to 4'-C-cyano-1'-deoxypurine nucleosides and their pharmaceutical uses, particularly for the treatment of HIV infections (eg, AIDS (AIDS)).
  • HIV infections eg, AIDS (AIDS)
  • HART highly active antiretroviral therapy
  • HART highly active antiretroviral therapy
  • HART protein inhibitors
  • HIV-1 human immunodeficiency virus-1
  • AZT and 3TC It has been reported that almost two cases of HIV infection in both resistant HIV cases were rare in the early 1990s, compared to 42% between 1995 and 1996. (AIDS, 11, 1184 (1997)).
  • 4'-C-ethynyl nucleosides The general group synthesized 4'-C-ethynyl nucleosides and measured the anti-HIV activity of those compounds. As a result, 4'-C-eturyl nucleosides having a specific structure were found to be equivalent to AZT or to produce AZT. It has superior anti-HIV activity and is also effective against multidrug-resistant virus strains that are resistant to multiple anti-HIV drugs such as AZT, ddl, ddC, d4T, and 3TC (J Med. Chem., 43 (2000), 4516-4525).
  • 4'-C-cyanothymidine, 4'-C-cyano-12'-dexoxycytidine and the like have been synthesized as nucleosides having a cyano group at the 4-position, and their anti-HIV activity has been evaluated.
  • 4'-C (4'-C-cyan-1,2-deoxy-15-methylperidine) has been shown to have anti-HIV activity, but is highly toxic and has not yet been put into practical use as a pharmaceutical (Tetrahedron Letters. 33 (1992) , 37-40, U.S. Pat.
  • a method for synthesizing 4'-C-cyanopurine nucleoside As a method for synthesizing 4'-C-cyanopurine nucleoside, a method is generally used in which a sugar is used as a starting material and a nucleic acid base is condensed with a sugar having a cyano group introduced thereinto. It requires a number of steps and is not always a simple method. This difficulty in synthesizing has delayed the research and development of 4'-C-cyanopurine nucleosides.
  • the inventors of the present invention have pursued purine nucleosides as a starting material in the process of conducting research to find compounds that have antiviral activity equal to or higher than AZT and are also effective against drug-resistant HIV strains, which have recently become a problem.
  • a simple method for synthesizing 4'-C-cyanopurine nucleoside was established, various 4'-C-cyanopurine nucleosides were synthesized by the method, and the antiviral activity was measured.
  • C-Canopurine nucleoside has excellent anti-HIV activity and is effective against multiple drug-resistant virus strains that are resistant to multiple anti-HIV drugs such as AZT, ddl, ddC, d4T, and 3TC In addition, they found that the cytotoxicity was weak, and completed the present invention.
  • the present invention provides a compound of the formula [I]
  • the present invention also relates to a method for treating AIDS, which comprises administering the compound of the formula [I] or a pharmaceutical composition comprising the same to an animal containing human.
  • the compound of the present invention is represented by the above formula [I], and the base represented by B in the formula represents a purine base including azapurine and deazapurine.
  • Such purine bases include a halogen atom, an alkyl group, a haloalkyl group, an alkeninole group, a haloalkenyl group, an alkynyl group, an amino group, an alkylamino group, a hydroxyl group, a hydroxyamino group, an aminoxy group, an alkoxy group, and a mercapto group. And it may have a substituent such as an alkylmercapto group, an aryl group, an aryloxy group or a cyano group, and the number and position of the substituent are not particularly limited.
  • Examples of the halogen atom as a substituent include chlorine, fluorine, iodine, and bromine.
  • Examples of the alkyl group include lower alkyl groups having 1 to 7 carbon atoms, such as methyl, ethyl and propyl.
  • Examples of the haloalkyl group include a haloalkyl group having an alkyl having 1 to 7 carbon atoms, such as fluoromethyl, difluoromethinole, trifluoromethyl, bromomethyl, and bromoethyl.
  • Examples of the alkenyl group include alkenyl groups having 2 to 7 carbon atoms, such as butyl and aryl.
  • haloalkenyl group examples include a haloalkenyl group having a C2-7 anolekenyl such as bromobutyl and chlorovinyl.
  • alkynyl group examples include alkynyl groups having 2 to 7 carbon atoms, such as ethur and propynyl.
  • alkylamino group examples include an alkylamino group having 1 to 7 carbon atoms such as methylamino and ethylamino.
  • alkoxy group examples include alkoxy groups having 1 to 7 carbon atoms such as methoxy and ethoxy.
  • examples of the alkyl mercapto group include alkyl mercapto groups having alkyl having 1 to 7 carbon atoms, such as methyl mercapto and ethyl mercapto.
  • aryl group examples include a phenyl group; an alkylphenyl group having 1 to 5 carbon atoms such as methinolephenyl and ethenylphenyl; Groups; alkylaminophenyl groups having 1 to 5 carbon atoms, such as dimethylaminophenyl and dimethylaminophenyl; and halogenophenyl groups such as octaphenyl, bromophenyl and the like.
  • purine bases include purine, 6-aminopurine (adenine), 6-hydroxypurine, 6-fluoropurine, 6-chloropurine, 6-methinorea minopurine, 6-dimethylaminopurine, 6- Trifluoromethylaminopurine, 6-Benzoylaminopurine, 6-Acetylaminopurine, 6-Hydroxyaminopurine, 6-Aminoxypurine, 6-Methoxypurine, 6-Acetoxypurine, 6 _Benzoyloxypurine, 6-methylpurine, 6-ethylpurine, 6-trifluoromethylpurine, 6-phenylpurine, 6 _mercaptopurine, 6-methylmercaptopurine, 6-aminopurine 1-oxide, 6-hi 1-oxide, 2-amino- 6-hydroxypurine (guanine), 2,6-diaminopurine, 2-hydroxy 6-chloro-purine, 2-amino-6-odopurin, 2-amino-purine, 2-
  • purine bases a purine base not having an amino group at the 2-position is preferable.
  • preferable compounds of the present invention include, for example, 4′-C-Cyano 2′-deo. Xydenosine, 4'-C-cyano 2, -deoxyinosine or their 5'-phosphate esters.
  • the compound of the present invention may be in the form of a salt, hydrate or solvate.
  • Such salts include acid adducts such as hydrochloride or sulfate when R is a hydrogen atom;
  • R is a phosphate residue
  • a pharmaceutically acceptable salt such as an alkaline metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or an ammonium salt is used. Any salt is exemplified.
  • Examples of the hydrate or solvate include those in which 0.1 to 3.0 molecules of water or a solvent are attached to one molecule of the compound of the present invention or a salt thereof. Furthermore, the compounds of the present invention may include various isomers such as tautomers.
  • the compound of the present invention can be produced by the steps described below.
  • the first step is a step of protecting the 3′-hydroxyl group of the compound represented by the formula [II] to obtain a compound represented by the formula [IV].
  • B represents a purine (including azapurine or azapurine) base
  • R 2 represents a protecting group
  • the compound represented by the formula [IV] protects the 5'-hydroxyl group of the compound represented by the formula [II], and then protects the 3'-hydroxyl group with a protecting group whose removal method is different from that of the 5'-protecting group. Subsequently, the protective group at the 5′-position hydroxyl group can be selectively removed to obtain the compound.
  • the protecting group for the 5′-hydroxyl group represented by the formula may be any one that is commonly used as a protecting group for the 5′-hydroxyl group of a nucleoside.Specifically, dimethoxytrityl, methoxytrityl, tritinole, t- Examples thereof include butyldimethylsilyl, t-butinoresiphenylphenylsilyl, and benzoyl group.
  • the protecting group for the hydroxyl group at the 3′-position represented by R 2 may be any of those commonly used for a hydroxyl group and the like, such as an ether-based protecting group, an acyl-based protecting group, a silyl-based protecting group, and an acetal-based protecting group. Protecting groups and the like can be exemplified.
  • the ether protecting groups include methyl ether and tertiary butyl. Athenole, benzinooleate / re, methoxy pentinoleatenore, tritinoleatenore, etc .; acetyl-protecting groups such as acetyl, benzoyl, and vivaloyl; silyl-protecting groups such as t-butyldimethylsilyl; —Butyl diphenylsilyl, trimethylsilyl, triethylsilyl and the like, and acetylidene, ethylidene, methylidene, benzylidene, tetrahydrobilanyl, methoxymethyl and the like as acetal protecting groups can be used.
  • the subsequent removal of the 5′-protecting group is appropriately selected from ordinary processing methods such as acidic hydrolysis, alkaline hydrolysis, tetrabutylammonium fluoride treatment, and catalytic reduction, depending on the protecting group used. Just do it.
  • the second step is a step of introducing a hydroxymethyl group at the 4′-position of the compound represented by the formula [IV] to obtain a compound represented by the formula [V].
  • B represents a purine (including azapurine or azapurine) base
  • R 2 represents a protecting group
  • the compound represented by the formula [V] is obtained by converting the 5'-hydroxymethyl group of the compound represented by the formula [IV] to an aldehyde group, and then converting the compound to the 4'-position by an aldol reaction with formaldehyde. It can be synthesized through introduction of a hydroxymethyl group and reduction of an aldehyde group.
  • the oxidizing agent for converting the 5′-hydroxymethyl group of the compound represented by the formula [IV] to an aldehyde includes chromic anhydride, a complex reagent of pyridine and acetic anhydride, pyridine chlorochromate, and pyridine dichromate.
  • Chromium-based oxidizing agents such as dimethyl sulfoxide and acetic anhydride
  • high-valent iodine oxidizing agents such as Dess-Martin reagent Examples thereof include dimethylsulfoxide-based oxidizing agents which are used in combination with oxalyl chloride or dicyclohexylcarbodiimide.
  • reaction conditions vary depending on the oxidizing agent used.
  • oxidizing using 1-ethyl-3- (dimethylaminopropyl) carbodiimid hydrochloride and dimethyl sulfoxide, if necessary, in a mixed solvent of an organic solvent such as toluene and dimethyl sulfoxide. argon, an inert gas atmosphere such as nitrogen, to pair the formula [IV] compound 1 mol 1- Echiru 3 - (dimethyl ⁇ amino propyl) Karubojiimi de hydrochloride 1
  • the reaction can be carried out by using 5 moles and reacting at 10 to 50 ° C for about 1 to 2 hours.
  • introduction of a hydroxymethyl group at the 4'-position can be carried out by an aldol reaction between the obtained aldehyde compound and formaldehyde.
  • Aldolization is carried out in an organic solvent such as tetrahydrofuran or dioxane in the presence of 1 to 5 moles of a base such as sodium hydroxide.
  • the reaction can be carried out by using 1010 mol of formaldehyde and reacting.
  • Subsequent reduction of the aldehyde group is carried out in an organic solvent such as methanol, ethanol, getyl ether, tetrahydrofuran, etc. per mole of the aldehyde compound: from! To 5 moles of sodium borohydride, lithium aluminum hydride, etc. Using a reducing agent, the reaction may be carried out at a temperature of from 78 ° C to room temperature for about 15 minutes to 1 hour.
  • the third step is a step of introducing a protecting group at the 5′-position of the compound represented by the formula [V].
  • B represents a purine (including azapurine or azapurine) base
  • R 2 R 4 represents a protecting group
  • the compound represented by the formula [VII] is a compound represented by the formula [V] at the 4′-position After protecting the xymethyl group, the 5'-hydroxyl group is protected with a protecting group with a different removal method from the protecting group for the 4'-hydroxymethyl group, and then the protecting group for the 4'-hydroxymethyl group is selectively removed. Is obtained.
  • the protecting group of Kuraihi Dorokishimechiru group, 5 of the nucleoside' 4 represented by R 3 may be any those conventionally used as a position hydroxyl protecting group, specifically, examples before Symbol first step Can be used.
  • the removal of the protecting group for the hydroxymethyl group at the 4'-position is appropriately selected from ordinary treatment methods such as acidic hydrolysis, alkaline hydrolysis, tetrabutylammonium fluoride treatment, and catalytic reduction, depending on the protecting group used. Just do it.
  • the fourth step is a step of converting the 4′-hydroxymethyl group of the compound represented by the formula [VII] to a cyano group.
  • the compound represented by the formula [VIII] oxidizes the 4'-hydroxymethyl group of the formula [VII] to an aldehyde group, converts this to an oxime group, and subsequently dehydrates the obtained oxime compound. Can be synthesized.
  • the oxidizing agent used may be the one exemplified in the second step.
  • the reaction conditions vary depending on the oxidizing agent used.For example, when oxidizing using 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride and dimethyl sulfoxide, it is necessary in a mixed solvent of an organic solvent such as toluene and dimethyl sulfoxide. Under an inert gas atmosphere of argon, nitrogen, etc., using 1 to 5 mol of 1-ethyl-13- (dimethylaminopropyl) carbodiimide hydrochloride with respect to 1 mol of the compound of formula [VII], and 10 to 50 ° It can be carried out by reacting with C for about 1 to 2 hours.
  • the conversion of the aldehyde compound into the oxime compound can be carried out in an organic solvent such as pyridine using 1 to 5 moles of hydroxylamine hydrochloride per mole of the aldehyde compound at room temperature to 100 ° C for 30 minutes to 3 minutes. It can be carried out by reacting for a time.
  • organic solvent such as pyridine
  • a dehydrating agent such as phosgene, carbonyldiimidazole, methanesulfonyl chloride, or acetic anhydride in an organic solvent such as dichloromethane, acetonitrile, or tetrahydrofuran in the presence of a base such as pyridine, triethylamine, or sodium acetate.
  • a base such as pyridine, triethylamine, or sodium acetate.
  • Dehydration reaction conditions vary depending on the dehydrating agent used. For example, when dehydration is performed using methanesulfonyl chloride, methanesulfonyl chloride and triethylamine are added to 1 mol of the compound of formula [VII] in an organic solvent such as dichloromethane, tetrahydrofuran, pyridine or the like. Can be carried out by using 1 to 5 mol and 5 to 10 mol, respectively, and reacting at 50 ° C. to room temperature for about 15 minutes to 2 hours.
  • an organic solvent such as dichloromethane, tetrahydrofuran, pyridine or the like.
  • the protecting group of the compound [VIII] thus obtained is removed to obtain a compound of the present invention in which R is hydrogen, and phosphorylation as necessary to obtain a compound of the present invention.
  • R represents a hydrogen atom or a phosphate residue
  • R 2 and R 4 represent protecting groups.
  • the removal of the protecting group may be appropriately selected from ordinary treatment methods such as acidic hydrolysis, hydrolysis by hydrolysis, tetrabutylammonium fluoride treatment, and catalytic reduction, depending on the protecting group used.
  • deaminate the amino group in the base a variety of deaminase such as adenosine deaminase and cytidine deaminase can be used in a conventional manner. It is also possible to deaminate.
  • a compound in which R is a phosphate residue such as a monophosphate residue or a diphosphate residue
  • a compound in which R is a hydrogen atom is converted to a nucleoside such as phosphorus oxychloride or tetrachloropyrroline acid.
  • a phosphorylating agent used for selective phosphorylation at the 5′-position By reacting the compound with a phosphorylating agent used for selective phosphorylation at the 5′-position, a free acid type or salt type target compound can be obtained.
  • the functional group in the purine base can be protected by a usual method and then deprotected, if necessary.
  • the compound of the present invention can be separated and purified by appropriately combining the methods used for isolating and purifying general nucleosides and nucleotides (for example, recrystallization, ion exchange column chromatography, adsorption column chromatography, etc.). .
  • the compound thus obtained can be in the form of a salt, if necessary.
  • the composition of the present invention containing these as an active ingredient is useful as a medicament. It is useful for the use, specifically for the treatment of lethal oral virus infections, in particular for the treatment of HIV infections (eg AIDS) resulting from human immunodeficiency virus (HIV) infection.
  • HIV infections eg AIDS
  • HIV human immunodeficiency virus
  • Animals other than humans in which the pharmaceutical composition of the present invention can be effectively used include livestock, poultry, and experimental animals.
  • the dose of the compound of the present invention varies depending on the patient's age, body weight, disease, severity of the disease, tolerability to the drug, administration method, and the like, and is appropriately determined based on a combination of these conditions.
  • a certain force S usually selected from the range of 0.001 to 1000 mg / kg body weight per day, preferably within the range of 0.001 to 10 mg / kg body weight, Is administered in multiple divided doses.
  • the method of administration may be oral, parenteral, transdermal, enteral, topical, or any other route.
  • the compound is generally used as a composition containing commonly used carriers, excipients and other additives.
  • Carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, tanolek, agar, pectin, Examples include solid carriers such as stearic acid, magnesium stearate, lecithin and sodium chloride, and liquid carriers such as glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water. Can be.
  • the dosage form can be in any form, such as tablets, powders, granules, capsules, suppositories, troches, buccals, patches, etc. as solid preparations, and syrups as liquid preparations And emulsions, soft gelatin capsules, creams and pastes, gels, sprays, ribosomes, injections, and the like.
  • the description may be a so-called functional book that describes the use, efficacy, administration method, etc. No.
  • the compound of the present invention and the pharmaceutical composition thereof can be administered in combination with other antiviral agents such as AZT, ddl, ddc, d4, and 3TC.
  • A is adenine
  • a BZ is N 6 -benzoyl-adenine
  • H is inosine
  • G is guanine
  • DAP is 2,6-diaminopurine
  • DAP BZ2 is 2,6-dibenzamide doblin
  • DMT r is Dimethoxytrityl
  • TBS stands for t-butyldimethylsilyl.
  • N 6 Benzyru 2 ′ —Doxy 5 ′ —O—Dimethoxytrityl adenosine (2.00 g, 3.04 mmo1) was dissolved in dimethylformamide (6.00 ml), and imidazole (0.83 g, 12.2 mmo1), tert- Butinochlorodimethylsilane (0.92 g, 6.10 mmol) was added, and the mixture was stirred at room temperature overnight.
  • reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and dried (anhydrous magnesium sulfate). After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform (70. 0 ml), and a solution of toluene sulfonic acid monohydrate (2. 00 g) in methanol (30.0 ml) was added dropwise under ice cooling. Then, the mixture was stirred at the same temperature for 30 minutes.
  • the compound (2.55 g .5.43mmo 1) was dissolved in toluene (10.0 ml) and dimethyl sulfoxide (150 ml), and 1-ethyl-3- (3-dimethyl) was dissolved.
  • (Aminopropyl) carbodiimide hydrochloride (3.12 g, 16.3 mmol), pyridine (0.41 ml), trifluoroacetic acid (0.21 ml) are added, and the mixture is stirred at room temperature for 2 hours. did. After diluting the reaction solution with ethyl acetate, the organic layer was washed with water and dried (magnesium sulfate anhydride).
  • the reaction solution was neutralized with sulfuric acid, diluted with ethyl acetate, washed with water and dried. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (25.0 ml). Under water cooling, sodium borohydride (0.21 g, 5.55 mm 1) was added and stirred for 30 minutes. The reaction solution was neutralized with acetic acid, diluted with ethyl acetate, washed with water, and dried (anhydrous magnesium sulfate).
  • the compound (1.00 g 5.43 mmo 1) was dissolved in toluene (3.0 ml) and dimethyl sulfoxide (600 ml), and 1-ethyl-3- (3-dimethylaminopropyl) was dissolved.
  • Carbohydrate carbodiimide hydrochloride (0.94 g, 4.90 mmol)
  • pyridine (0.13 m1)
  • calorie 1 hour at room temperature Stirred.
  • the organic layer was washed with water and dried (anhydrous magnesium sulfate).
  • the compound (26.2 g, 10 Ommo 1) was azeotroped twice with pyridine, then suspended in pyridine (400 mL), and chlorotrimethylsilane (88 mL, 70 Ommo 1) was added at 0 ° C. It was added dropwise over 10 minutes. After stirring at 0 ° C. for 30 minutes, benzoinole chloride (82 m 1, 70 Ommo 1) was added dropwise over 20 minutes, and the mixture was further stirred at room temperature for 2 hours. Ice water (200 ⁇ 1) was slowly poured into the reaction solution at 0 ° C, and the mixture was stirred for 15 minutes. Then, concentrated ammonia water (300 ml) was added dropwise at the same temperature, and the mixture was stirred for 30 minutes.
  • the solvent was distilled off, and the residue was subjected to silica gel column chromatography (silica gel 300 g, black form to black form: methanol: 200: 1 to 500: 1 to 50: 1). And purified.
  • the obtained residue (69. 9 g) was azeotropically dehydrated twice with dimethylformamide, then dissolved in dimethylformamide (37 Om1), and imidazole (8.8 g, 12 dimethylsilane (16.5 g, 10.9 mmo 1) was added thereto, followed by stirring at room temperature.
  • the precipitated crystals (a part of the formyl body) were collected by filtration, and the organic layer of the filtrate was recovered. The organic layer was washed twice with water and once with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue and the collected crystals were combined to obtain a crude aldehyde.
  • the crude aldehyde was dissolved in dioxane (240 ml), a 37% aqueous solution of formaldehyde (45 ml) and a 2N aqueous solution of sodium hydroxide (45 ml) were added at room temperature, and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was neutralized with glacial acetic acid (8.6 ml) and extracted with ethyl acetate (700 ml). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, the obtained residue was dissolved in ethanol (360 ml), sodium borohydride (3.2 g, 85. Ommo 1) was added at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes. . Glacial acetic acid (2.5 ml) was added to the reaction solution to stop the reaction, and the mixture was extracted with chloroform-methanol (10: 1) (1.1 L).
  • the crude oxime is dissolved in dichloromethane (20.0 ml), and under ice cooling, triethylamine (0.76 ml, 5.45 mm'o1), methanesulfonyl chloride (0.32 ml, 4.13 mm) o 1) was added and stirred for 30 minutes. After the reaction solution was diluted with chloroform, it was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate and then dried under reduced pressure.
  • the compound (1.00 g, 1.37 mmo 1) was dissolved in methanol (10.0 ml), a 40% aqueous methylamine solution (10.0 ml) was added, and the mixture was stirred at room temperature for 3 days. .
  • the precipitated crystals (0.25 g, 0.48 mm o 35.0%) were dissolved in tetrahydrofuran (9.0 ml), and tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was dissolved. , 1.0 m 1, 1.0 Ommo 1) and stirred at room temperature for 15 minutes.
  • Synthesis Example 4 Synthesis of 4'-C-cyano-2'-dexoxyguanosine (compound 17)
  • Compound 16 (70.0 mg, 0.24 mmo 1) was dissolved by heating in 50 mM Tris-HC1 buffer (pH 7.50, 13.3 ml), and adenosine kinase (0. 13 ml, 58.5 units) and stirred at 40 ° C for 1 hour. The precipitated crystals were recrystallized from water to obtain Compound 17 (56.0 mg, 0.19 mmol, 79.2%).
  • a tablet is prepared from the above composition by a conventional method.
  • a capsule is prepared from the above composition by a conventional method.
  • the above composition is dissolved in purified water for injection to prepare an injection.
  • Test examples are shown below. In the test, the following two compounds of the present invention and two known compounds were used as drugs.
  • HIV Human immunodeficiency virus
  • HIV Human immunodeficiency virus
  • Tables 1 and 2 show the average of 2 to 5 measurements.
  • the compound of the present invention is also effective for a multidrug-resistant HIV strain having excellent anti-HIV activity, particularly resistance to a plurality of anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC. Because of its low cytotoxicity, it is useful as a pharmaceutical, especially for the treatment of HIV infection.

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Abstract

L'invention concerne des nucléosides de 4'-C-cyano-2'-désoxypurine représentés par la formule générale suivante (I), qui possèdent un excellent effet anti-VIH, et sont notamment efficaces sur des souches de VIH multirésistantes aux médicaments qui présentent une résistance à de nombreux médicaments tels que l'AZT, la ddI, la ddC, la d4T et la 3TC, sans engendrer de problème de cytotoxicité ; et des compositions thérapeutiques contenant ce composé et un excipient pharmaceutiquement acceptable. Dans la formule, B représente une base purine et R représente hydrogène ou phosphate.
PCT/JP2003/001218 2002-02-15 2003-02-06 Nucleosides de 4'-c-cyano-2'-desoxypurine WO2003068796A1 (fr)

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JP2003567922A JPWO2003068796A1 (ja) 2002-02-15 2003-02-06 ４’−ｃ−シアノ−２’−デオキシプリンヌクレオシド
AU2003211483A AU2003211483A1 (en) 2002-02-15 2003-02-06 4'-c-cyano-2'-deoxypurine nucleosides

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WO2005090349A1 (fr) * 2004-03-24 2005-09-29 Yamasa Corporation Derive de 2-haloadénosine 4'-c substitue
US7339053B2 (en) 2004-03-24 2008-03-04 Yamasa Corporation 4′-C-substituted-2-haloadenosine derivative
US7625877B2 (en) 2004-03-24 2009-12-01 Yamasa Corporation 4′-c-substituted-2-haloadenosine derivative
US8039614B2 (en) 2004-03-24 2011-10-18 Yamasa Corporation 4' -C-substituted-2-haloadenosine derivative
WO2018092728A1 (fr) 2016-11-16 2018-05-24 国立研究開発法人国立国際医療研究センター Dérivé nucléosidique ayant des activités physiques comprenant une activité antivirale
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WO2018110643A1 (fr) * 2016-12-14 2018-06-21 ヤマサ醤油株式会社 Dérivé de nucléoside présentant une activité antivirale
JPWO2018110643A1 (ja) * 2016-12-14 2019-12-12 ヤマサ醤油株式会社 抗ウイルス活性を示すヌクレオシド誘導体

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