JPH0762005B2 - 6-Substituted acyclopyrimidine nucleoside derivatives and antiviral agents containing said derivatives as active ingredients - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel 6-substituted acyclopyrimidine nucleoside derivatives, antiviral agents containing said derivatives as active ingredients, and methods for producing said derivatives.

[Prior Art and Problems of the Invention] In recent years, infection with the human acquired immunodeficiency virus (HIV), a type of retrovirus, has become a major social problem. 3'-Deoxy-3'-azidothymidine is a known nucleoside compound currently used clinically for the treatment of HIV infection. However, its side effects are problematic due to its strong toxicity to host cells.

Furthermore, 2',3'-dideoxyribonucleosides are known as nucleoside compounds that exhibit antiretroviral activity, but there is a need to develop substances with even higher activity and lower toxicity to host cells (Hiroaki Mitsuya, Biodefense, Vol. 4, pp. 213-223, 1987).

On the other hand, since acyclovir (acycloguanosine) was developed as an antiviral agent against herpes viruses, various acyclonucleoside compounds have been synthesized [CK Chu and SJ Culter, J. Heterocyclic C
hem., 23 , 289 (1986)], but no compound has yet been found that exhibits effective activity against retroviruses in particular.

Therefore, the present inventors focused on 6-substituted acyclopyrimidine nucleoside compounds and synthesized various novel 6-substituted acyclopyrimidine nucleoside compounds, searching for compounds having antiretroviral activity in particular, in order to provide antiviral agents, particularly antiviral agents that exhibit effective activity against retroviruses.

Conventionally, 6-substituted acyclopyrimidine nucleosides such as 6-fluorine-substituted and 6-alkylamino-substituted nucleosides (East German Patent Publication No. 232492), and 6-methyl-substituted nucleosides (CA 107 , 129717w (1987)) have been known, but there has been no description of their antiviral activity.

As a result of extensive research into obtaining a compound having antiviral activity, particularly antiretroviral activity, the present inventors have found that the desired object can be achieved by using a specific 6-substituted acyclopyrimidine nucleoside compound, thereby completing the present invention.

[Summary of the Invention] That is, the gist of the present invention is a compound represented by the following general formula [I]: (wherein R ¹ represents a hydrogen atom; a halogen atom; a C ₁ to _{C 10} alkyl group; a C ₂ to C ₅ alkenyl group optionally substituted with one or more substituents selected from a halogen atom, a C 2 to C 6 alkoxycarbonyl group, a phenyl group, a carbamoyl group, and a cyano group; a C ₂ to C ₅ alkenyl group optionally substituted with a phenyl _{group )}
an alkynyl group of _C2 to _C5 ; an alkylcarbonyl group of _C7 to
a _C11 arylcarbonyl group; a _C8 to _C12 arylcarbonylalkyl group; a _C6 to _C10 arylthio group; or a _C7
^R2 represents a C8 to _C13 aralkyl group optionally substituted by one or more substituents selected from a chlorine atom, a methyl group, a methoxy group, and a methylcarbonyl group; a _C6 to _C10 arylthio group optionally substituted by one or more substituents selected from a halogen atom, a _C1 to _C5 alkyl group, a _C1 to _C5 alkoxy group, a _C2 to _C6 alkylcarbonyl group, a halogenated methyl group, an amino group, a nitro group, a cyano group, and a hydroxyl group; _{a C1 to C5} alkylthio group; _{a C3} to _C10 cycloalkylthio group; _{a C6 to C10} arylsulfoxide group; a _C1 to _{C5 alkylsulfoxide group; a C3 to C10 cycloalkylsulfoxide group ;
R1} represents an aralkyl group having ₁₂ carbon atoms, an arylcarbonyl group having ₇ to ₁₁ carbon atoms, or an aryloxy group having ₆ to ₁₀ carbon atoms, or an alkenyl group having ₂ to ₅ carbon atoms or an alkynyl group having ₂ to ₅ carbon atoms, each of which may be substituted with one or more substituents selected from a halogen atom, an alkyl group having 1 to ₅ carbon atoms, an alkoxy group having 1 to ₅ carbon atoms, a _C2 to C6 alkylcarbonyl group, a halogenated methyl group, an amino group, a nitro group, a cyano group, a phenyl group, a naphthyl group, and a _{hydroxyl group; R3 represents a hydroxyalkyl group having 2} ^to _{6 carbon} atoms, the alkyl moiety of which may be connected via an oxygen atom; _X represents an oxygen atom;
wherein Y represents a sulfur atom or an amino group, Y represents an oxygen atom or a sulfur atom, and A represents ═N— or —NH—), or a pharmaceutically acceptable salt thereof, an antiviral agent containing the derivative as an active ingredient, and a method for producing the derivative.

[Detailed Description of the Invention] The 6-substituted acyclopyrimidine nucleoside derivative of the present invention is represented by the above general formula [I]: In the formula, the groups represented by ^R1 to ^R3 may be substituted with a substituent.

Specifically, R ¹ is a hydrogen atom; a halogen atom such as a chlorine atom, an iodine atom, a bromine atom, or a fluorine atom; an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, or an n-butyl group; a vinyl group, a propenyl group, a butenyl group,
Phenyl vinyl group, bromo vinyl group, cyano vinyl group,
Alkenyl groups such as an alkoxycarbonylvinyl group and a carbamoylvinyl group; alkynyl groups such as an ethynyl group, a propynyl group and a phenylethynyl group; alkylcarbonyl groups such as an acetyl group, a propionyl group and an isobutyryl group; arylcarbonyl groups such as a benzoyl group and a naphthoyl group;
It represents an arylcarbonylalkyl group such as a phenacyl group; an arylthio group such as a phenylthio group, a tolylthio group, or a naphthylthio group; or an aralkyl group such as a benzyl group.

^R2 is an arylthio group such as a phenylthio group or a naphthylthio group; a methylthio group, an ethylthio group, a propylthio group,
alkylthio groups such as butylthio and pentylthio; cycloalkylthio groups such as cyclopentylthio, cis-hexylthio and cycloheptylthio; arylsulfoxide groups such as phenylsulfoxide; alkylsulfoxide groups such as methylsulfoxide, ethylsulfoxide and butylsulfoxide; cycloalkylsulfoxide groups such as cyclopentylsulfoxide and cyclohexylsulfoxide; aralkyl groups such as benzyl; arylcarbonyl groups such as benzoyl and aryloxy groups such as phenyloxy (these groups may contain a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom or an iodine atom; a C1-C5 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group or a pentyl group; a _C1 - _C5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group or a pentyloxy group; a _C2 - _C6 alkyl group such as an acetyl group, a propionyl group or an isobutyryl group) _. alkylcarbonyl groups of ₁ to 6, halogenated methyl groups such as trichloromethyl groups, amino groups, nitro groups, cyano groups, and hydroxyl groups); alkenyl groups such as vinyl groups, propenyl groups, and phenylvinyl groups, and alkynyl groups such as ethynyl groups, propynyl groups, and phenylethynyl groups (these groups may contain halogen atoms such as chlorine atoms, bromine atoms, fluorine atoms, and iodine atoms; _C1 to _C5 alkyl groups such as methyl groups, ethyl groups, propyl groups, butyl groups, and pentyl groups; methoxy groups, ethoxy groups, propoxy groups, butoxy groups, and pentyloxy groups).
_C1 - _C5 alkoxy group, acetyl group, propionyl group,
_C2 to _C6 alkylcarbonyl groups such as isobutyryl groups, halogenated methyl groups such as trichloromethyl groups, amino groups,
_C8 - _C13 arylcarbonylalkyl groups such as phenacyl group (which may be substituted with one or more substituents selected from nitro group, cyano group, phenyl group, naphthyl group and hydroxyl group); and phenacyl group (which may be substituted with one or more substituents selected from chlorine atom, methyl group,
methoxy group, and methylcarbonyl group).

^R3 represents a hydroxyalkyl group such as a (2-hydroxyethoxy)methyl group, a (3-hydroxypropoxy)methyl group, a (2,3-dihydroxypropoxy)methyl group, a 1-(2-hydroxyethoxy)ethyl group, a [2-hydroxy-1-(hydroxymethyl)ethoxy]methyl group, or a (2-hydroxy-1-methylethoxy)methyl group, preferably an ω-hydroxyalkoxyalkyl group.

X represents an oxygen atom, a sulfur atom or an amino group.

Y represents an oxygen atom or a sulfur atom.

A represents -N= or -NH-.

In the compound of the present invention, R ¹ is preferably a hydrogen atom, a halogen atom, a C ₁ to C ₅ alkyl group, or a C ₂ to C ₅ alkenyl group, particularly preferably a C ₁ to C ₅ alkyl group, and R ² is preferably a
_C6 to _C10 arylthio group, _C3 to _C10 cycloalkylthio group or _C7 to _C11 aralkyl group, in particular _C6 optionally substituted with a substituent selected from _C1 to _C5 alkyl group, _C1 to _C5 alkoxy group, halogen atom or nitro group.
Preferably, _R3 is ^a _C2 to _C6 hydroxyalkoxyalkyl group, particularly _a 2 _- hydroxyethoxymethyl group; and preferably, _X and _Y are oxygen atoms or sulfur atoms.

Specific examples of the compound of the present invention include those shown in Table 1 below.

The compound of the present invention can be synthesized, for example, according to the following reaction scheme (1) or (2).

(wherein R ¹ , R ² , X, Y and A are as defined above; W
represents a hydroxyalkyl group, and represents a substituent in which the hydroxyl group of ^R3 is protected, and the alkyl portion may be connected via an oxygen atom. Furthermore, ^X1 and ^X2 represent a halogen atom, an arylthio group, an alkoxy group, etc., and M represents an alkali metal.) In the formula, the protecting group for W can be any of those commonly used as protecting groups for alcohols, as long as it does not cleave under alkaline conditions.

Specific examples include aralkyl groups such as benzyl, trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl groups; silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and dimethylphenylsilyl groups; and substituted alkyl groups such as tetrahydropyranyl and methoxymethyl groups, with silyl groups being particularly preferred.

First, the compound represented by the general formula [II] or [IV] and an organic alkali metal are mixed in a solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran, at −80° C.
The reaction is carried out at a temperature of 0.2 to 10° C. for 0.2 to 10 hours. Examples of organic alkali metals include potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, and lithium alkylamides, and particularly lithium diisopropylamide (LDA), lithium 2,
2,6,6-tetramethylpiperidide (LTMP) is preferred. It is preferable to use such lithium alkylamides prepared immediately before the reaction. For example, a secondary amine such as diisopropylamine and an alkyllithium such as n-butyllithium are reacted in a solvent such as diethyl ether, dioxane, tetrahydrofuran, or dimethoxyethane.
In the presence of an inert gas, such as argon gas,
The reaction is preferably carried out at 10°C with stirring for 0.2 to 5 hours.

The organic alkali metal is usually used in an amount of 2 to 5 moles per mole of the compound represented by the general formula [II] or [IV].

Subsequently, various electrophilic reagents, i.e. ^, compounds represented by the general formula ^R2X1 or ^{R1X2 ,} are added in an amount of about 1 to 5 moles per mole of the compound represented by the general formula [II] or [IV], and reacted under the same reaction conditions as those for the organic alkali metals.

The electrophilic reagent contains ^R2 or ^R1 as defined above, and examples thereof include various diaryl disulfides, arylsulfenyl chlorides, dialkyl disulfides, dicycloalkyl disulfides, alkyl halides, aralkyl halides such as benzyl bromide, acid halides of organic acids such as benzoic acid and isobutyric acid, acid anhydrides or esters thereof, arylcarbonyl alkyl halides such as phenacyl chloride, and halogens.

The compound represented by the general formula [II] can be prepared in accordance with a known method. For example, a starting compound represented by the general formula [II] can be obtained by condensing a trimethylsilylated uracil derivative with (2-acetoxyethoxy)methyl bromide, hydrolyzing the condensed uracil derivative, and then introducing the above-mentioned protecting group (for details, see Can. J. Chem., 60 , 547 (1988)).
See 2) etc.

The introduction of a protecting group can be carried out by a conventional method.

For example, the introduction of a silyl protecting group can be carried out in a solvent such as pyridine, picoline, diethylaniline, dimethylaniline,
A silylating agent such as trimethylsilyl chloride, t-chloride, etc. is used in a solvent such as triethylamine, dimethylformamide, acetonitrile, or tetrahydrofuran, either singly or in a mixture thereof.
butyldimethylsilyl in 1 to 10 moles, reaction temperature 0 to 50
The reaction can be carried out at .degree.

The compound represented by the general formula [IV] is synthesized according to the above reaction formula (1) (R ¹ =H).

Next, the compound represented by the general formula [VI] thus obtained is separated and purified, if necessary, by a conventional separation and purification means for nucleosides, such as recrystallization, adsorption and ion exchange chromatography, and then the protecting group of the hydroxyl group is removed.

The protecting group can be removed by a known method appropriately selected depending on the protecting group used, such as acid hydrolysis, ammonium fluoride treatment, catalytic reduction, etc.

The compound of the present invention represented by the general formula [I] thus obtained can be separated and purified by a conventional method for separating and purifying nucleosides, for example, by recrystallization,
The separation and purification can be carried out by appropriately selecting an adsorption or ion exchange chromatography method.

Among the compounds obtained by the above methods (1) and (2), those having a nitro group on the benzene ring can be converted to an amino group by hydrogenation as shown in the following reaction formula (3). Hydrogenation is carried out in the presence of a catalyst such as palladium on carbon in an organic solvent such as alcohol or acetic acid at an appropriate temperature between room temperature and 80°C.

(The symbols in the above formula are as defined above.) As shown in the following reaction formula (4), an arylthio group,
The alkylthio group and cycloalkylthio group can be converted to the corresponding arylsulfoxide group, alkylsulfoxide group, and cycloalkylsulfoxide group with an oxidizing agent such as hydrogen peroxide or metachloroperbenzoic acid.

(In the above formula, ^R4 represents an aryl group, an alkyl group, or a cycloalkyl group. The other symbols are as defined above.) As shown in the following reaction formula (5), a phenyl sulfoxide derivative and an arylthio sodium salt or an aryloxy sodium salt having various substituents on the benzene ring are reacted in an organic solvent such as tetrahydrofuran, alcohol, dimethylformamide, or acetonitrile at room temperature to 100
By reacting at an appropriate temperature of 0.degree. C., the compound can be converted to the corresponding substituted arylthio group.

(In the above formula, B represents S or O, and ^R5 and ^R6 represent a halogen atom such as a chlorine atom, bromine atom, fluorine atom, or iodine atom; an alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group; a halogenated alkyl group such as a trichloromethyl group; an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group; a hydroxyl group; a nitro group; an amino group; a cyano group; or an acyl group such as an acetyl group. The other symbols are as defined above.) The compound of the present invention can also be synthesized, for example, according to the following reaction formula (6).

(The symbols in the above formula are as defined above.) The compound of the present invention can also be synthesized, for example, according to the following reaction formula (7).

(In the above formula, ^R7 represents an alkyl group such as a methyl group or an ethyl group; an aryl group such as a phenyl group or a toluyl group; or a protecting group such as a silyl group, and the other symbols are as previously defined.) The reactions of the above formulas (6) and (7) can be carried out in the presence of a palladium catalyst using an amine such as diethylamine or triethylamine as a solvent at an appropriate temperature between room temperature and 70°C. The addition of a solvent such as acetonitrile can make the reaction more uniform. As a catalyst, a palladium catalyst such as bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium(O), or bis(diphenylphosphino)ethane palladium dichloride can be used in combination with cuprous iodide.

Furthermore, the compounds of the present invention can be synthesized, for example, by using an olefin compound _H2C =CH- ^R8 (where ^R8 represents an alkoxycarbonyl group, a nitrile group, a carbamoyl group, etc.) instead of the acetylene compound in the above reaction formulas (6) and (7) according to the following reaction formulas (8) and (9).

(The symbols in the above formula are as defined above.) (The symbols in the above formula are as defined above.) The palladium catalyst is as explained in the above reaction formulas (6) and (7).

The compound of the present invention can be synthesized, for example, by the following reaction formula (10).

(In the above formula, ^X3 represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom. The other symbols are as defined above.) The compound of the present invention can also be produced, for example, by the reaction shown in the following reaction formulas (11) and (1
2) can be synthesized according to

(The symbols in the above formula are as defined above.) (The symbols in the above formulae are as defined above.) That is, in the above reaction formulae (1) and (2), R ¹ X ² or
Instead of R ² X ¹ The above method using (wherein ^R9 and ^R10 represent a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, or a propyl group, or an aryl group such as a phenyl group) is a method in which an intermediate obtained by a similar reaction treatment is dehydrated using a dehydrating reagent (methyl chloride, tosyl chloride, thionyl chloride, etc.) to introduce an alkenyl group.

The alkynyl group of the compound having an alkynyl group synthesized by the above reaction formulas (6) and (7) can be converted to a reactive alkenyl group or alkyl group, and the alkenyl group of the compound having an alkenyl group synthesized by the reaction formulas (8) to (12) can be converted to the corresponding alkyl group by hydrogenation. Reduction to an alkenyl group can be carried out by palladium-
The reaction can be carried out using a catalyst such as barium sulfate, palladium-calcium carbonate, palladium-calcium carbonate-lead acetate, or palladium-barium sulfate-quinoline under a hydrogen gas atmosphere at a suitable temperature between room temperature and 80°C.

Reduction of an alkenyl group or alkynyl group to an alkyl group can be carried out using palladium-carbon or palladium hydroxide as a catalyst under the same conditions as for reduction to an alkenyl group.

Furthermore, the 6-substituted acyclouridine and acyclothymidine derivatives obtained by these reactions can be converted into 4-thio derivatives that react with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide by heating in toluene or xylene, as shown in the following reaction scheme (13).

(The symbols in the above formula are as defined above.) The 4-thio derivatives are obtained by converting uridine or thymidine derivatives into 5-thio derivatives.
It is obtained by converting it into a 4-chloro form using phosphorus chloride or phosphorus oxychloride, and then reacting it with sodium hydrogen sulfide.

As shown in the following reaction formula (14), acyclouridine and acyclothymidine derivatives are reacted with 1-(2-mesitylenesulfonyl)-3-nitro-1,2,4-triazole in an organic solvent such as pyridine in the presence of diphenylphosphate to give the corresponding 4-(3-nitro-1,2,4-triazole) derivative. Then, aqueous ammonia is added and the reaction is continued at an appropriate temperature from room temperature to 100°C to give the corresponding 4-(3-nitro-1,2,4-triazole) derivative.
-amino derivatives are obtained.

(The symbols in the above formula are as defined above.) The compounds of the present invention described above may be converted into pharmaceutically acceptable salts thereof in a conventional manner. Examples of such salts include:
Examples include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts, and alkyl ammonium salts such as ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts and tetramethyl ammonium salts.

The compounds of the present invention can be administered to humans by any route, such as oral, enteral, parenteral, or topical administration, for the prevention or treatment of infection with retroviruses, etc. The dosage is determined appropriately depending on the age, health condition, body weight, etc. of the patient, but generally, an appropriate dosage is selected from the range of 1 to 100 mg/kg body weight, preferably 5 to 50 mg/kg body weight, per day, and is administered in a single dose or in multiple divided doses.

When the compound of the present invention is formulated, it is usually used as a composition containing commonly used pharmaceutical carriers, excipients, and other additives. The carrier may be solid or liquid. Examples of solid carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride, etc.

Liquid carriers include, for example, glycerin, peanut oil,
Examples include polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water.

The dosage form can take various forms. When a solid carrier is used, it can be in the form of tablets, powders, granules, capsules, suppositories,
When a liquid carrier is used, examples thereof include syrup, emulsion, soft gelatin capsule, cream, gel, paste, spray, and further, injection.

[Effects of the Invention] The novel 6-substituted acyclopyrimidine nucleoside derivatives of the present invention have effective activity against retroviruses and the like, and further have relatively low toxicity to host cells.
It can be effectively used as an antiviral agent.

[Examples] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples, and many variations and modifications are possible within the scope of the present invention.

The compound numbers used below correspond to the compound numbers in Table 1.

Reference Example 1 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]thymine (in the general formula [II], R ¹ =CH ₃ ,W
= 2-t-butyldimethylsilyl (TBDMS) -O(CH ₂ ) ₂ -
Preparation of a compound with O- _CH2- , A = -NH-, X = Y = O: 580 mg (4.18 mmol) of t-butyldimethylsilyl chloride and 556 mg (8.17 mmol) of imidazole were added to 476 mg (2.38 mmol) of 5-methylacyclouridine, and 10 ml of dimethylformamide was added to dissolve the compound, followed by stirring overnight. The reaction mixture was partitioned between 200 ml each of water and ethyl acetate, and the ethyl acetate layer was collected and concentrated under reduced pressure. The residue was adsorbed onto silica gel (30 g), washed with benzene, eluted with 10% methanol-chloroform, concentrated under reduced pressure, and then
Crystallize from water-ethanol to obtain 672 mg of the target compound
(Yield: 90%). Melting point: 137-138°C Example 1 (1) 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine (in the general formula [VI], R ¹ = CH ₃ , W=TBDMS-O- _CH2CH2 - _O - _CH2- ,A=-NH-,X=Y=
Preparation of Compound (O) 10 ml of tetrahydrofuran was cooled to -70°C, and then 0.263 ml (1.86 mmol) of diisopropylamine was added to the cooled tetrahydrofuran under an argon atmosphere.
Then, 1-1, n-butyllithium (1.86 mmol) were added successively to obtain a lithium diisopropylamide solution.
[(2-t-butyldimethylsilyloxyethoxy)methyl]thymine 229 mg (0.73 mmol) in 5 mL of tetrahydrofuran
This solution was added dropwise to the lithium diisopropylamide solution and reacted at -70°C for 1 hour. Next, 332 mg (1.52 mmol) of diphenyl disulfide was dissolved in 5 ml of tetrahydrofuran and added dropwise to the reaction solution while maintaining the temperature at -70°C, and the reaction was continued for 1 hour. After the reaction, 0.2 ml of acetic acid was added.
The mixture was cooled to room temperature after adding 1, and the mixture was partitioned between the chloroform layer and saturated aqueous sodium bicarbonate solution. The chloroform layer was concentrated to dryness. The residue was dissolved in a small amount of chloroform, adsorbed onto a silica gel column, and eluted with chloroform to obtain 226 mg of the target compound (yield 73%).

Melting point: 89-90°C (2) 1-[(2-hydroxyethoxy)methyl]-6
Preparation of 6-phenylthiothymine (Compound No. 1): 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine obtained in (1) above.
98 mg of the product was dissolved in 2 ml of tetrahydrofuran, and 2 ml of acetic acid and 1 ml of water were added, followed by reaction at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and then adsorbed onto a silica gel (20 g) column to obtain a 1%
After eluting with methanol-chloroform and concentrating, the target compound was crystallized from ethyl acetate-methanol to give 65 mg (yield
91%).

Melting point: 123-124°C Examples 2-5 (1) In the same manner as in Reference Example 1, acyclouridine derivatives having a protecting group (in the general formula [II], R ¹ = F, Cl, B
r or H,W=TBDMS-O- _CH2CH2 - _O - _CH2 -A=-NH
After obtaining the compound (X=Y=O), the compound was reacted and treated in the same manner as in Example 1 to obtain Compounds Nos. 2 to 5 in Table 1.

Examples 6 to 27 Compounds Nos. 6 to 20 and 22 to 28 in Table 1 were obtained in the same manner as in (1) and (2) of Example 1, except that various disulfide derivatives were used in place of diphenyl disulfide in Example 1.

Example 28 1-[(2-hydroxyethoxy)methyl]-6-(4
-acetylphenyl-1-thio)thymine (Compound No. 2
0) (1) 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine 576 mg (1.3
7 mmol) was dissolved in 10 ml of chloroform, 235 mg (1.37 mmol) of metachloroperbenzoic acid was added, and the mixture was reacted at room temperature for 20 hours. After the reaction, the mixture was concentrated to dryness, dissolved in a small amount of chloroform, adsorbed onto a silica gel column, and eluted with 10% n-hexane-chloroform.
[(2-t-butyldimethylsilyloxyethoxy)methyl]thymin-6-yl-phenylsulfoxide 177m
g (40% yield).

(2) 39 mg (0.25 mmol) of 4-acetylthiophenol was dissolved in 2 ml of tetrahydrofuran, and 0.25 mmol of sodium hydride was added and reacted at room temperature for 1 hour. To this reaction solution, 87.5 mg (0.2 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]thymin-6-yl-phenylsulfoxide obtained in (1) was added, and the mixture was refluxed for 2 hours.
To this reaction mixture were added 5 ml of acetic acid, 3 ml of tetrahydrofuran and 1.5 ml of water, and the mixture was reacted at room temperature overnight.
After the reaction, the reaction mixture was concentrated to dryness, dissolved in a small amount of chloroform, and adsorbed onto a silica gel column. After elution with 3% methanol-chloroform, the mixture was concentrated to dryness to obtain 42 mg of the target compound (yield 61%).
obtained.

Melting point: 107-108°C Example 29 1-[(2-hydroxyethoxy)methyl]-6-(6
-hydroxynaphthyl-2-thio)thymine (Compound No. 2
Preparation of 9) 314 mg (1 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]thymine was reacted and treated with 1.16 g (2 mmol) of 2,2'-t-butyldimethylsilyloxy-6,6'-dinaphthyl disulfide in the same manner as in (1) of Example 1, and then reacted and treated in the same manner as in (2) of Example 1 to obtain 1-
[(2-hydroxyethoxy)methyl]-6-(6-t
This was dissolved in 37 ml of tetrahydrofuran, and 1 ml of water and 2 ml of a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution were added, followed by a reaction at room temperature for 30 minutes. After the reaction, the mixture was concentrated to dryness, and the residue was dissolved in a small amount of chloroform and adsorbed onto a silica gel column.
Elution with 100% methanol-chloroform, concentration to dryness,
The target compound was crystallized from ethyl acetate to give 315 mg (yield 42.8%).
%) was obtained.

Melting point: 188°C. Examples 30-34: In place of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]thymine in Example 1, 1-[(3-t-
1-[(2-t-butyldimethylsilyloxypropoxy)methyl]thymine, 1-[(2-t-butyldimethylsilyloxypropoxy)methyl]thymine
-methylethoxy)methyl]thymine, 1-[(2-t-
butyldimethylsilyloxy-1-t-butyldimethylsilyloxymethylethoxy)methyl]thymine, 1-
[(2,3-di-t-butyldimethylsilyloxypropoxy)methyl]thymine or 1-[1-(2-t-butyldimethylsilyloxyethoxy)ethyl]uracil was treated in the same manner as in (1) and (2) of Example 1, and the resulting mixture was treated with 1-[(2,3-di-t-butyldimethylsilyloxypropoxy)methyl]thymine or 1-[1-(2-t-butyldimethylsilyloxyethoxy)ethyl]uracil in the same manner as in (1) and (2) of Example 1, and the resulting mixture was treated in the same manner as in Table 1.
Compounds Nos. 30 to 34 of Compound 1 were obtained.

Example 35 1-[(2-hydroxyethoxy)methyl]-6-(2
(-aminophenyl-1-thio)thymine (Compound No. 35)
Preparation of 1-[(2-hydroxyethoxy)methyl]-6-(2
(-nitrophenyl-1-thio)thymine (Compound No. 16)
100 mg (0.57 mmol) of this compound was dissolved in 12 ml of acetic acid and 5 ml of ethanol, and 50 mg of 5% palladium-carbon was added. The mixture was reacted at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 6 hours. After filtering off the palladium-carbon, the mixture was concentrated to dryness and crystallized from toluene-ethanol to obtain the target compound.

Melting point: 140°C Example 36 1-[(2-hydroxyethoxy)methyl]-6-(3
(-aminophenyl-1-thio)thymine (Compound No. 36)
Preparation Example 35 of 1-[(2-hydroxyethoxy)methyl]
-6-(2-nitrophenyl-1-thio)thymine,
A similar reaction was carried out using (3-nitrophenyl-1-thio)thymine, followed by crystallization from toluene-ethanol.
The target compound was obtained.

Melting point 235-238°C Example 37 1-[(2-hydroxyethoxy)methyl]thymine-6
Preparation of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (100 mg) was dissolved in 2 ml of acetic acid and 3 ml of ethanol, and 0.7 ml of 30% aqueous hydrogen peroxide was added. The mixture was allowed to react at room temperature for one week. The ethyl acetate layer was partitioned into an aqueous layer, and the ethyl acetate layer was concentrated to dryness. Crystallization from ethanol-toluene afforded 28.3 mg of the desired compound (yield 26.5%).

Melting point 130°C Example 38 1-[(2-hydroxyethoxy)methyl]-6-(2
(1) 3.14 g (10 mmol) of 1-[2-t-butyldimethylsilyloxyethoxymethyl]thymine was reacted and treated in the same manner as in Example 1 (1), except that iodine (20 mmol) was used instead of diphenyl disulfide, to obtain 1-
3.11 g (70.6% yield) of [(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine was obtained.

(2) 1-[(2-t-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine obtained in (1)
0 mg (1 mmol) of methyl methyl ketone was dissolved in 10 ml of triethylamine and 3 ml of acetonitrile, and 70.2 mg of bis(triphenylphosphine)palladium dichloride, 19 mg of cuprous iodide, and 0.33 ml of phenylacetylene were added, followed by a reaction at 60°C for 1.5 hours. The mixture was returned to room temperature and concentrated to dryness, after which it was partitioned between the chloroform layer and the water layer, and the chloroform layer was concentrated to dryness. The residue was dissolved in a small amount of chloroform, adsorbed onto a silica gel column, and eluted with 30% n-hexane-chloroform. After concentration, the residue was dissolved in 5 ml of tetrahydrofuran and 5 ml of acetic acid were added.
The reaction mixture was concentrated and then crystallized from toluene-ethanol to give target compound 25.
0 mg (yield 84%).

Melting point 214°C Example 39 1-[(2-hydroxyethoxy)methyl]-6-(1
Preparation of (-propynyl)thymine (Compound No. 39) The target compound (yield 53%) was obtained by the same reaction and treatment as in Example 38 (2), except that methylacetylene was used instead of phenylacetylene.

Melting point: 169°C Example 40 Preparation of 1-[(2-hydroxyethoxy)methyl]-6-ethynylthymine (Compound No. 40) Using 0.82 ml (6 mmol) of trimethylsilylacetylene instead of phenylacetylene in (2) of Example 38, 1-
880 mg (2 mmol) of [(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine was treated in the same manner to give 1-[(2-hydroxyethoxy)methyl]-6-(2-trimethylsilylethynyl)thymine. This was dissolved in 100 ml of methanol, and 1 ml of 1N aqueous sodium hydroxide was added. After reacting at room temperature for 2 minutes, the mixture was neutralized with hydrochloric acid and concentrated. This mixture was partitioned between the ethyl acetate layer and the aqueous layer. The ethyl acetate layer was concentrated to dryness and then crystallized from toluene and ethanol to give 170 mg (38% yield) of the target compound.

Melting point: 154°C Example 41 1-[(2-hydroxyethoxy)methyl]-6-(2
Preparation of 1-[(2-hydroxyethoxy)methyl]-6-(2-phenylvinyl)thymine (Compound No. 41)
-phenylethynyl)thymine (Compound No. 38) 120 mg (0.
After the reaction was completed, 17 mg of 10% palladium-barium sulfate was added and the mixture was stirred at room temperature for 2 minutes in a hydrogen atmosphere at 1 atmosphere pressure.
The barium sulfate was removed by filtration, and the filtrate was concentrated to dryness and crystallized from toluene to obtain 106 mg (yield 88%) of the target compound.

Melting point: 144°C Example 42 1-[(2-hydroxyethoxy)methyl]-6-(1
Preparation of 1-[(2-hydroxyethoxy)methyl]-6-(1-propynyl)thymine (Compound No. 39) was used in place of Compound No. 38 in Example 41, and the reaction and treatment were carried out in the same manner as in Example 41 to give the target compound.

Melting point: 97°C Example 43 Preparation of 1-[(2-hydroxyethoxy)methyl]-6-vinylthymine (Compound No. 43) 1-[(2-hydroxyethoxy)methyl]-6-ethynylthymine (Compound No. N) was used instead of Compound No. 38 in Example 41.
o.40) was used and the reaction and treatment were carried out in the same manner to obtain the target compound.

Melting point: 114°C Example 44 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-iodo-6-phenylthiouracil (Compound No. 44) (1) After cooling 35 ml of tetrahydrofuran to -70°C, 2,2,6,6-tetramethylpiperidine (2,2,6,6-tetramethylpiperidine) was added to the cooled tetrahydrofuran under an argon atmosphere.
2.1 g (15 mmol) of the solution and n-butyllithium (15 mmol) were added successively to obtain a lithium tetramethylpiperidide solution. Next, 2.04 g (15 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil were added.
l) was dissolved in 20 ml of tetrahydrofuran, and this was added dropwise to the lithium tetramethylpiperidide solution.
The mixture was allowed to react at -70°C for 1 hour. Next, 3.81 g (15 mmol) of iodine dissolved in 20 ml of tetrahydrofuran was added dropwise to the reaction mixture while maintaining the temperature at -70°C, and the mixture was allowed to react for 1 hour. After the reaction, 0.8 ml of acetic acid was added, and the mixture was returned to room temperature.
The mixture was partitioned with saturated aqueous sodium bicarbonate, and the chloroform layer was concentrated to dryness. The residue was crystallized from petroleum ether to give 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil.
1.835 g (62.8% yield) was obtained.

Melting point: 84-85°C (2) 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-
Phenylthiouracil was reacted and treated in the same manner as in Example 1 (2) to obtain the target compound.

Melting point: 180-182°C Example 45 1-[(2-hydroxyethoxy)methyl]-5-(2
Preparation of (2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil (Compound No. 45) [0123] Except for 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine in (2) of Example 38, 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil was used, the reaction was carried out under the same conditions as in Example 38, and the product was crystallized from ethyl acetate to give the desired compound.

Melting point: 146-148°C Example 46 1-[(2-hydroxyethoxy)methyl]-5-(1
-propynyl)-6-phenylthiouracil (Compound N
Preparation of o.46) Methylacetylene was used in place of phenylacetylene in Example 45, and the reaction and treatment were carried out under the same conditions, followed by crystallization from ethyl acetate to obtain the desired compound.

Melting point: 165-166.5°C Example 47 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-ethynyl-6-phenylthiouracil (Compound No. 47) The procedure of Example 40 was repeated, except that 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine was replaced with 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil to give 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-(2-trimethylsilylethynyl)-6-phenylthiouracil. This was dissolved in tetrahydrofuran and desilylated with tetrabutylammonium fluoride to give the desired compound.

Melting point: 163-165°C Example 48 1-[(2-hydroxyethoxy)methyl]-5-(2
Preparation of (2-phenylvinyl)-6-phenylthiouracil (Compound No. 48)
-6-(2-phenylethynyl)thymine instead of 1-
[(2-hydroxyethoxy)methyl]-5-(2-phenylethynyl)-6-phenylthiouracil was used,
The same reaction was carried out for 2 days, and the reaction mixture was similarly worked up and crystallized from ethyl acetate-n-hexane to obtain the desired compound.

Melting point: 141-145°C Example 49 1-[(2-hydroxyethoxy)methyl]-5-(1
-propenyl)-6-phenylthiouracil (Compound N
o.49) Preparation of Example 41, 1-[(2-hydroxyethoxy)methyl]
-6-(2-phenylethynyl)thymino instead of 1-
The same reaction and treatment were carried out using [(2-hydroxyethoxy)methyl]-5-(1-propynyl)-6-phenylthiouracil, and the target compound was obtained by crystallization from isopropyl ether.

Melting point: 76-77°C Example 50 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-vinyl-6-phenylthiouracil (Compound No. 50) 1-[(2-hydroxyethoxy)methyl]
1-(2-phenylethynyl)thymine instead of 6-(2-phenylethynyl)thymine
The same reaction and treatment were carried out using [(2-hydroxyethoxy)methyl]-5-ethynyl-6-lenylthiouracil, and the target compound was obtained by crystallization from ethyl acetate-n-hexane.

Melting point: 100-103°C Example 51 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-benzyl-6-phenylthiouracil (Compound No. 51) The same procedure as in Example 44 was repeated except that benzyl bromide was used instead of iodine.
The same reaction and treatment were carried out, and the target compound was obtained by crystallization from isopropyl ether.

Melting point: 126-128°C. Example 52: Preparation of 1-[(2-hydroxyethoxy)methyl]-5,6-diphenylthiouracil (Compound No. 52). The same reaction and treatment were carried out as in Example 44, except that diphenyl disulfide was used instead of iodine, and the target compound was obtained by crystallization from toluene.

Melting point: 146-148°C Example 53 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-benzoyl-6-phenylthiouracil (Compound No. 53) The same procedure as in Example 44 was repeated except that benzoyl chloride was used instead of iodine.
The same reaction and treatment were carried out, and the target compound was obtained by crystallization from ethyl acetate.

Melting point: 150-151°C Example 54 1-[(2-hydroxyethoxy)methyl]-5-isobutyroyl-6-phenylthiouracil (Compound No. 5
4) Preparation of Example 44: Isobutyroyl chloride was used instead of iodine, and the same reaction and treatment were carried out, followed by crystallization from ethyl acetate to give the desired compound.

Melting point: 144-145°C Example 55 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-phenacyl-6-phenylthiouracil (Compound No. 55) The same procedure as in Example 44 was repeated except that phenacyl bromide was used instead of iodine.
The same reaction and treatment were carried out, and the target product was obtained by crystallization from ethyl acetate.

Melting point: 151.5-153.5°C. Example 56: Preparation of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiocytosine (Compound No. 56) 200 mg (0.49 m) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil
2,4,6-trimethylbenzene-1-sulfonyl-(3-nitro-1,2,4-triazole) (727 mg, 2.45 mmol) and 1,1-diphenylphosphate (61.3 mg, 0.245 mmol) were added and the mixture was allowed to react at room temperature overnight. After the reaction, 1 ml of water and 1 ml of ethanol were added, and the mixture was stirred at room temperature for 20 minutes.
The residue was left standing for 1 minute, then concentrated to dryness. The residue was dissolved in a small amount of chloroform, adsorbed onto a silica gel column, eluted with 30% hexane-chloroform, and concentrated. This residue was dissolved in 5 ml of dioxane, and 3 ml of concentrated aqueous ammonia was added. The mixture was reacted at room temperature for 30 minutes and concentrated to dryness. The residue was dissolved in a small amount of chloroform, adsorbed onto a silica gel column, eluted with 4% methanol-chloroform, and concentrated. This residue was dissolved in 1 ml of tetrahydrofuran, and then added with 1 ml of acetic acid and 0.5 ml of water.
After adding 1, the mixture was allowed to react at room temperature overnight. After concentrating to dryness, the mixture was crystallized from ethanol to obtain 70.3 mg of the target compound (yield 49%).

Melting point: 202°C. Example 57 Preparation of 1-[(2-hydroxyethoxy)methyl]-5-methyl-6-phenylthiocytosine (Compound No. 57) Using 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine instead of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil in Example 56, the reaction and treatment were carried out in the same manner as above, and the product was crystallized from ethanol to give the desired compound.

Melting point: 220°C Example 58 Preparation of 1-[(2-hydroxyethoxy)methyl]-2-thio-6-phenylthiouracil (Compound No. 58) (1) 3.84 g (30 mmol) of 2-thiouracil was suspended in 75 ml of methylene chloride, and the suspension was added with 17.8 ml (72 mmol) of bis(trimethylsilyl)acetamide and 2-acetoxyethoxyacetic acid.
7.2 g (45 mmol) of methyl was added, and the mixture was allowed to react at room temperature for 20 minutes.
The mixture was cooled to °C and 4.5 ml (45 mmol) of stannic chloride was added.
The mixture was allowed to cool to room temperature and react overnight, after which ice and sodium bicarbonate were added. The precipitated solid was removed by filtration and partitioned between the methylene chloride layer and the water layer. The methylene chloride layer was concentrated to dryness, and the residue was dissolved in a small amount of chloroform and adsorbed onto a silica gel column. It was eluted with 2.5% methanol-chloroform and concentrated. This residue was dissolved in 5 ml of ethanol, and 5 ml of 1N aqueous sodium hydroxide solution was added. The mixture was reacted at room temperature for 10 minutes. After the reaction, the residue was transferred to Dowex-50 cation exchange resin (H ⁺ type).
The residue was dissolved in 15 ml of dimethylformamide, and 600 mg (4 mmol) of t-butyldimethylsilyl chloride and 270 mg (4 mmol) of imidazole were added, followed by a reaction at room temperature for 1 hour.
The precipitated solid was collected by filtration, dried, and recrystallized from toluene-hexane to give 716 mg (yield 7.5%) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thiouracil.

Melting point: 121°C (2) 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thio-6-phenylthiouracil (in general formula [VI], R ¹ =H, W =TBDMS-O-CH ₂ CH ₂
O−CH ₂ −, Preparation of a compound where A=-NH-, X=S, Y=O: 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thiouracil obtained in (1) was used in place of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]thymine in Example 1 (1) and treated in the same manner as in Example 1 to give 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thio-6-phenylthiouracil.

Melting point: 105°C (3) Instead of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine in (2) of Example 1, 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thio-
123 mg of 6-phenylthiouracil was added to the solution (2) of Example 1.
The residue was crystallized from water-ethanol to obtain the target compound (Compound No. 58).

Melting point: 146°C. Example 59: Preparation of 1-[(2-hydroxyethoxy)methyl]-2-thio-6-phenylthiothymine (Compound No. 59) To 2 ml of tetrahydrofuran was added 0.09 ml (0.52 mmol) of 2,2,6,6-tetramethylpiperidine. The mixture was cooled to -70°C, and then n-butyllithium (0.52 mmol) was added under an argon stream to give a lithium 2,2,6,6-tetramethylpiperidide solution.
Next, 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-2-thio-6-phenyluracil
0 mg (0.24 mmol) was dissolved in 2 ml of tetrahydrofuran.
This was added dropwise to the lithium 2,2,6,6-tetramethylpiperidide solution and reacted for 1 hour at -70°C. Next, 0.07 ml (1.2 mmol) of methyl iodide was added to the reaction solution and reacted for 1 hour. Next, the same post-reaction treatment as in Example 1 (1) was carried out, followed by the same reaction and treatment as in Example 1 (2). The residue was crystallized from toluene to obtain the target compound.
39 mg (yield 60%) was obtained.

Melting point: 107°C Example 60 Preparation of 1-[(2-hydroxyethoxy)methyl]-4-thio-6-phenylthiouracil (Compound No. 60) 294 mg (1 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiouracil was dissolved in 5 ml of pyridine, and 0.17 ml (1.5 mmol) of benzoyl chloride was added and reacted at room temperature for 2 hours. After the reaction, the ethyl acetate layer was partitioned with water, and the ethyl acetate layer was concentrated to dryness and crystallized from toluene to give 1.
-[(2-benzoyloxyethoxy)methyl]-6-
340 mg of phenylthiouracil was obtained (85% yield). This was suspended in 5 ml of toluene, and 449 mg (1.11 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added, followed by a reaction at 100°C for 3 hours. After the reaction, the mixture was partitioned between the ethyl acetate layer and water, and the ethyl acetate layer was concentrated to dryness. The residue was dissolved in tetrahydrofuran.
The resulting mixture was dissolved in 2 ml of ethanol and 5 ml of ethanol, and 2.25 ml of 1N aqueous sodium hydroxide solution was added and reacted at room temperature for 1 hour. After the reaction, the mixture was neutralized with hydrochloric acid, concentrated to dryness, and partitioned between the ethyl acetate layer and water. The ethyl acetate layer was concentrated to dryness, dissolved in a small amount of chloroform, and adsorbed on a silica gel column. The column was eluted with 2.5% methanol-chloroform, concentrated to dryness, and crystallized from toluene to obtain 141 mg of the target compound (yield 53%).

Melting point: 156°C. Example 61 Preparation of 1-[(2-hydroxyethoxy)methyl]-4-thio-6-phenylthiothymine (Compound No. 61) The same reaction and treatment were carried out as in Example 56, except that 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiothymine was used instead of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil, and the target compound was obtained by crystallization from toluene.

Melting point: 114°C Compounds No. 21 and No. 62 to No. 202 in Table 1 above can also be synthesized in the same manner as described in the above Examples.

Example 62 (Preparation of tablets) 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine 10 g, Corn starch 65 g, Carboxycellulose 20 g, Polyvinylpyrrolidone 3 g, Calcium stearate 2 g , Total 100 g. The above ingredients were thoroughly mixed and the mixture was compressed by direct compression into tablets of 100 mg each.
Each tablet contained 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine.
Contains 10mg.

Example 63 (Preparation of powder and capsules) 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine 20 g Microcrystalline cellulose 80 g Total 100 g The two powders were thoroughly mixed to obtain a powder.
The mixture was filled into No. 5 hard capsules to obtain capsules.

Example 64 (Preventive effect against HIV infection) 3 x 10 MT-4 cells (human T cell clone that dies when infected with HIV) were infected with HIV in an RPMI1640DM medium containing 20 mM Hepes buffer, 10% fetal bovine serum, and ²⁰ μg/ml gentamicin at a concentration 100 times the amount of HIV that infects 50% of the cells. Immediately afterwards, a predetermined amount of a sample prepared at 50 mg/ml with dimethyl sulfoxide was added, and the cells were cultured at 37°C.

After 5 days of culture, the number of viable cells was counted, and the compound concentration required to prevent 50% of MT-4 cell death was determined.
The results are shown in Table 2.

Example 65 (HIV proliferation inhibitory effect) In the same medium as that for MT-4 cells, HUT-78 cells (human T cell clones that release HIV without dying even after infection with HIV) were infected with 0.4 HIV per cell, and then 1-
[(2-hydroxyethoxy)methyl]-6-phenylthiothymine was added at a predetermined concentration, and the cells were cultured at 37°C.

Three-quarters of the culture medium was replaced every four days, and after 12 days, the number of HIV antigen-positive cells was measured by indirect immunofluorescence using HIV antisera (positive for envelope and core proteins) obtained from HIV-infected patients. The compound of the present invention completely inhibited HIV antigen expression at 20 μM, and the concentration required for 50% inhibition was 5.2 μM. Furthermore, no toxicity to HUT-78 cells was observed at 100 μM.

For comparison, similar measurements were carried out using 2',3'-dideoxyadenosine. The concentration required to completely inhibit HIV antigen expression was similar to that of the compound of the present invention, but it was toxic to HUT-78 cells at a concentration of 100 μM.

──────────────────────────────────────────────────── Continued from the front page (72) Inventor: Walker, Richard Thomas 50 Middle Park Road, Selly Oak, Birmingham, England (72) Inventor: Ubazawa Ken Machida Coop, 1-13-1 Ogawa, Machida, Tokyo Town 17-203

Claims (17)

[Claims] Claim 1: A compound represented by the following general formula [I] (wherein R ¹ represents a hydrogen atom; a halogen atom; a C ₁ to _{C 10} alkyl group; a C ₂ to C ₅ alkenyl group optionally substituted with one or more substituents selected from a halogen atom, a C 2 to C 6 alkoxycarbonyl group, a phenyl group, a carbamoyl group, and a cyano group; a C ₂ to C ₅ alkenyl group optionally substituted with a phenyl _{group )}
an alkynyl group of _C2 to _C5 ; an alkylcarbonyl group of _C7 to
a _C11 arylcarbonyl group; a _C8 to _C12 arylcarbonylalkyl group; a _C6 to _C10 arylthio group; or a _C7
^R2 represents a C8 to _C13 aralkyl group optionally substituted by one or more substituents selected from a chlorine atom, a methyl group, a methoxy group, and a methylcarbonyl group; a _C6 to _C10 arylthio group optionally substituted by one or more substituents selected from a halogen atom, a _C1 to _C5 alkyl group, a _C1 to _C5 alkoxy group, a _C2 to _C6 alkylcarbonyl group, a halogenated methyl group, an amino group, a nitro group, a cyano group, and a hydroxyl group; _{a C1 to C5} alkylthio group; _{a C3} to _C10 cycloalkylthio group; _{a C6 to C10} arylsulfoxide group; a _C1 to _{C5 alkylsulfoxide group; a C3 to C10 cycloalkylsulfoxide group ;
R1} represents an aralkyl group having ₁₂ carbon atoms, an arylcarbonyl group having ₇ to ₁₁ carbon atoms, or an aryloxy group having ₆ to ₁₀ carbon atoms, or an alkenyl group having ₂ to ₅ carbon atoms or an alkynyl group having ₂ to ₅ carbon atoms, each of which may be substituted with one or more substituents selected from a halogen atom, an alkyl group having 1 to ₅ carbon atoms, an alkoxy group having 1 to ₅ carbon atoms, a _C2 to C6 alkylcarbonyl group, a halogenated methyl group, an amino group, a nitro group, a cyano group, a phenyl group, a naphthyl group, and a _{hydroxyl group; R3 represents a hydroxyalkyl group having 2} ^to _{6 carbon} atoms, the alkyl moiety of which may be connected via an oxygen atom; _X represents an oxygen atom;
wherein R represents a sulfur atom or an amino group, Y represents an oxygen atom or a sulfur atom, and A represents ═N— or —NH—, or a pharmaceutically acceptable salt thereof. [Claim 2] ^R1 is a hydrogen atom; a halogen atom; a _C1 to _C5 alkyl group; an alkenyl group optionally substituted with one or more substituents selected from a halogen atom, a _C2 to _C4 alkoxycarbonyl group, a phenyl group, a carbamoyl group, and a cyano group; a _C2 to _C5 alkynyl group optionally substituted with a phenyl group; a _C2 to _C5 alkylcarbonyl group; a _C7 to _C11 arylcarbonyl group; _{a C8} to _C12 arylcarbonylalkyl group; a _C6 to _C10 arylthio group; or a _C7 to _C12
^R2 represents an aralkyl group of the formula: _R6 - _C10 arylthio group optionally substituted with one or more substituents selected from a halogen atom, a _C1 - _C5 alkyl group, a _C1 - _C5 alkoxy group, a _C2 - _C5 alkylcarbonyl group, a trifluoromethyl group, an amino group, a nitro group, a cyano group, and a hydroxyl group; a _C1 - _C5 alkylthio group; a _C3 - _C10 cycloalkylthio group optionally substituted with one or more substituents selected from a halogen atom, a _C1 - _C5 alkyl group, a _C1 -C5 alkoxy group, a _C2 - _C5 alkylcarbonyl group, a trifluoromethyl group, and an amino group; a _C6 - _C10 arylthio group optionally substituted with one or more substituents selected from a halogen atom, a _C1 - _C5 alkyl group, a C1-C5 alkoxy group, _{a C2} - _C5 alkylcarbonyl group, and an amino group _;
a C3 to _C10 arylsulfoxide group; a _C1 to _C5 alkylsulfoxide group; a _C3 to _C10 cycloalkylsulfoxide group optionally substituted with one or more substituents selected from a halogen atom, a _C1 to _{C5 alkyl group, a C1 to C5} alkoxy group, a _C2 to _C5 alkylcarbonyl group, and an amino group; a halogen atom, _{a C1} to _C5 alkoxy group, _{a C2} to _C5
an alkylcarbonyl group of _C2 to _C5, optionally substituted with one or more substituents selected from a phenyl group, a naphthyl group, and an amino group; a halogen atom, a _C1 to _C5 alkyl group,
a _C2 - _C5 alkynyl group optionally substituted with one or more substituents selected from a halogen atom, a C1-C5 alkyl group, a _C1 - _C5 alkoxy group, a _C2 - _C5 alkylcarbonyl group, a phenyl group, a naphthyl group, and an amino group; a C7-C12 aralkyl group optionally substituted with one or more substituents selected from a halogen atom, a C1-C5 alkyl group, a _C1 - _C5 alkoxy group, and a _C2 - _C5 alkylcarbonyl group; a halogen atom, a _C1 - _C5 alkyl group, a C1-C5 aralkyl group optionally substituted with one or more substituents selected from a halogen atom, a C1-C5 alkyl group, a _C1 - _C5 alkoxy group, and a C2 _-C5 alkylcarbonyl group;
and optionally substituted with one or more substituents selected from a C2 to _C5 alkoxy group and a _C2 to _C5 alkylcarbonyl group.
a _C7 - _C11 arylcarbonyl group; or a halogen atom, a _C1 - _C5 alkyl group, a _C1 - _C5 alkoxy group, a _C2-
The compound according to claim 1, wherein R represents a _C6 to _C10 aryloxy group optionally substituted with one or more substituents selected from a _C5 alkylcarbonyl group, a trifluoromethyl group, and a nitro group; ^R3 represents a _C2 to _C6 hydroxyalkoxyalkyl group; X represents an oxygen atom, a sulfur atom, or an amino group; Y represents an oxygen atom or a sulfur atom; and A represents =N- or -NH-. [Claim 3] ^R1 is a hydrogen atom; a halogen atom; a _C1 to _C5 alkyl group; a _C2 to C5 alkenyl group optionally substituted with one or more substituents selected from a halogen atom, a C2 to _C4 alkoxycarbonyl group, a phenyl group, a carbamoyl group, and a cyano group; a _C2 to _C5 alkenyl group optionally substituted with a phenyl _group .
_C5 alkynyl group; _C2 - _C5 alkylcarbonyl group; _C7
a _C8 - _C10 arylcarbonyl group; _{a C6} - _C10 arylthio group or a _C7
^R2 represents a C6- _C10 aralkyl group, and R3 represents a _C6 - _C10 arylthio group optionally substituted with one or more substituents selected from a halogen atom, a _C1 - _C5 alkyl group, a _C1 - _C5 alkoxy group, a _C2 - _C5 alkylcarbonyl group, a trifluoromethyl group, an amino group, a nitro group, a cyano group, and a hydroxyl group; a _C1 - _C5 alkylthio group; a _{C3 - C10} cycloalkylthio group optionally substituted with one or more substituents selected from a halogen atom, a _{C1 - C3} alkyl group, a _C1 - _C3 alkoxy group, a _C2 - _C5 alkylcarbonyl group, and a trifluoromethyl group;
an arylsulfoxide group of _C1 to _C5 ; an alkylsulfoxide group of C3 to _C10 ; a cycloalkylsulfoxide group of _C2 to C5; an alkenyl group of C2 to _C5 optionally substituted with one or more phenyl groups; an alkynyl group _{of C2} to _C5 optionally substituted with one or more phenyl groups; an aralkyl group of _C7 to _{C11 ;}
an arylcarbonyl group having a carbon number of 1 to ₁₁ ; or a halogen atom, C
The compound according to claim 2, wherein R represents a C6 to _C10 aryloxy group optionally substituted by one or more substituents selected from _{a C1 to C5} alkyl group, _{a C1} to _C5 alkoxy group, a C2 to _C5 alkylcarbonyl group, a trifluoromethyl group _, and a nitro group; ^R3 represents a _C2 to _C6 hydroxyalkoxyalkyl group; X represents an oxygen atom, a sulfur atom, or an amino group; Y represents an oxygen atom or a sulfur atom; and A represents =N- or -NH-. [Claim 4] ^R1 represents a hydrogen atom, a halogen atom, a _C1 - _C5 alkyl group, or a _C2 -C5 alkenyl group; ^R2 represents a halogen atom, a _C1 - _C5 alkyl group, a C1-C5 alkoxy group, a C6- _C10 arylthio group optionally substituted with one or more substituents selected from a nitro group, a C3- _C10 arylthio group optionally substituted with one or more substituents selected from a nitro group, a _C1 -C5 ... alkyl group optionally substituted with one or more substituents selected from a nitro group, a _C6 - _C10 arylthio group optionally substituted with one or more substituents selected from a nitro group, a C1-C5 arylthio group optionally substituted with one or more substituents selected from a nitro group, a _C1 - _C
The compound according to claim 3, wherein R represents a cycloalkylthio group or a _C7 to _C11 aralkyl group; ^R3 represents a _C2 to _C6 hydroxyalkoxyalkyl group; X and Y represent an oxygen atom or a sulfur atom; and A represents =N- or -NH-. [Claim 5] The compound according to claim 4, wherein ^R1 represents a _C1 to _C3 alkyl group, ^R2 represents a phenylthio group substituted with one or more substituents selected from a chlorine atom, a _C1 to _C3 alkyl group, and a _C1 to _C3 alkoxy group, ^R3 represents a _C2 to _C5 ω-hydroxyalkoxyalkyl group, X and Y represent an oxygen atom or a sulfur atom, and A represents -NH-. [Claim 6] The compound according to claim 5, wherein ^R1 represents a methyl group, ^R2 represents a phenylthio group substituted with one or more substituents selected from a chlorine atom, a methyl group, and a methoxy group, ^R3 represents a (2-hydroxyethoxy)methyl group, X and Y represent an oxygen atom or a sulfur atom, and A represents -NH-. 7. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine. 8. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl-1-thio)thymine. 9. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-(3-chlorophenyl-1-thio)thymine. 10. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-(2-methoxyphenyl-1-thio)thymine. 11. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-(3-methoxyphenyl-1-thio)thymine. 12. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-(3-nitrophenyl-1-thio)thymine. 13. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-6-cyclohexylthiothymine. 14. The compound according to claim 6, which is 1-[(2-hydroxyethoxy)methyl]-2-thio-6-phenylthiothymine. 15. An antiviral agent comprising the 6-substituted acyclopyrimidine nucleoside derivative or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. Claim 16: A compound represented by the following general formula [II] (Wherein W represents a group ^R3 in which a hydroxyl group is protected,
^R1 , ^R3 , X, Y and A have the meanings given in claim 1.
^{2. A} method for producing a 6-substituted acyclopyrimidine nucleoside derivative according to claim ^{1, characterized in that the protecting group is removed by a deprotection reaction after reacting an acyclopyrimidine nucleoside derivative represented by the formula (I) with an organic alkali metal and a compound represented by the following general formula [III] R2X1} ... [III] (wherein ^X1 represents a halogen atom, an arylthio group or an alkoxy group, and R2 has the meaning as defined in claim 1). Claim 17: A compound represented by the following general formula [IV] (Wherein W represents a group ^R3 in which a hydroxyl group is protected,
^R2 , ^R3 , X, Y and A have the meanings given in claim 1.
2. ^A method for producing a ⁶ -substituted acyclopyrimidine nucleoside derivative according to claim ¹ , characterized in that the method comprises reacting an acyclopyrimidine nucleoside derivative represented by the formula (I) with an organic alkali metal and a compound represented by the following general formula [V] R 1 X 2 ... [V] (wherein X ² represents a halogen atom, an arylthio group or an alkoxy group, and R 1 has the meaning as defined in claim 1), followed by removing the protecting group by a deprotection reaction.