JPH03279366A - 6-substituted acyclopyrimidine nucleoside derivative and antiviral agent containing the derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H, halogen, alkyl, alkenyl, etc.; R<2> is arylthio, alkylthio, cycloalkylsulfinyl, etc.; R<3> is H, methyl, alkyl, etc.; R<4> is H, alkyl or aralkyl; X is O or S; Y is O or S; etc.) or its salt. EXAMPLE:1-[(2-Acetoxyethoxy)methyl]-6-phenylthio-2-thiothymine. USE:An antiviral agent exhibiting effective activity especially against retrovirus and having low toxicity to host cell. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II with an organic alkali metal (e.g. lithium diisopropylamide) and reacting the product with an electrophilic reagent (e.g. diaryl disulfide).

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel 6-substituted acyclopyrimidine nucleoside derivative and an antiviral agent containing the derivative as an active ingredient.

[Problems to be solved by conventional technology and invention]

In recent years, human acquired immunodeficiency virus (HIV) infection, which is a type of retrovirus, has become a major social problem. Currently, 3'-deoxy-3'-azidothymidine is known as a nucleoside compound that is used clinically for the purpose of treating HIV infection. However, since it is highly toxic to host cells, side effects have become a problem.

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

On the other hand, since acyclovir (acycloguanosine) was developed as an antiviral agent against herpesviruses, various acyclonucleoside compounds have been synthesized (C, K, Chu and S, J, C).
utter, J., Heter.

cyclic Chem, 23,289 (198
6) No compound has yet been found that exhibits particularly effective activity against retroviruses.

Therefore, the present inventors focused on 6-substituted acyclopyrimidine nucleoside compounds, and aimed to provide a novel 6-substituted acyclopyrimidine nucleoside compound in order to provide an antiviral agent, particularly an antiviral agent that exhibits effective activity against retroviruses. We synthesized various cyclopyrimidine nucleoside compounds, and especially searched for compounds with antiretroviral activity.

Conventionally, 6-substituted acyclopyrimidine nucleosides include 6-fluorine substituted products, 6-alkylamino substituted products (East German Published Patent Application No. 232492), or 6-methyl substituted products (C, A, f, 129717 w ( 19
87)), but there is no description of antiviral activity.

[Means for solving problems]

The present inventors have conducted intensive studies to obtain metal compounds having antiviral activity, particularly antiretroviral activity, and have discovered that the desired objective can be achieved with a specific 6-substituted acyclopyrimidine nucleoside compound. The invention was completed.

That is, the gist of the present invention is the following general formula (1) [In the above formula, R1 is a hydrogen atom; a halogen atom; an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group; an alkylcarbonyl group; an arylcarbonyl group; an aryl Carbonylalkyl group; represents an arylthio group or an aralkyl group, R1 is a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a nitro group,
An arylthio group, an alkylthio group, a cycloalkylthio group, an arylsulfinyl group, an alkylsulfinyl group, a cycloalkylsulfinyl group, an alkenyl group, an alkynyl group, which may be substituted with one or more substituents selected from an amino group, a cyano group, and an acyl group. group, an aralkyl group, an arylcarbonyl group, an arylcarbonylalkyl group or an aryloxy group, and R3 is a hydrogen atom;
Methyl group; branched alkyl group or -CH, -Z-(
CH,)ゎ-R5 (wherein R5 is a hydrogen atom; a halogen atom; a hydroxyl group; a heterocyclic carbonyloxy group; a formyloxy group; an alkylcarbonyloxy group; a cycloalkylcarbonyloxy group; an aralkylcarbonyloxy group; an arylcarbonyloxy group) Group; an alkoxycarbonyloxy group optionally substituted with one or more substituents selected from an azide group or an aryl group, a halogen atom, an alkyl group, an alkoxy group, and a halogenated alkyl group;
Represents an N-alkylcarbamoyloxy group, N-arylcarbamoyloxy group, N-alkylthiocarbamoyloxy group, N-arylthiocarbamoyloxy group, alkoxy group, aralkyloxy group, branched alkyl group, cycloalkyl group or aryl group, Z represents an oxygen atom: a sulfur atom or a methylene group, and n is 0 to 5
), R4 represents a hydrogen atom; represents an alkyl group or an aralkyl group; When represents an oxygen atom, R% does not represent a hydroxyl group. ) or a 6-substituted acyclopyrimidine nucleoside derivative represented by the following general formula [I']3 (in the above formula, R1, R2, R3 and Y are as defined for the above general formula (1)), or Antiviral agents include pharmaceutically acceptable salts and derivatives thereof as active ingredients.

Hereinafter, the present invention will be explained in detail.

The 6-substituted acyclopyrimidine nucleoside derivative of the present invention is represented by the general formula (I) or [VI].

Specifically, R1 is a hydrogen atom; a chlorine atom, an iodine atom,
Halogen atoms such as bromine and fluorine; alkyl groups such as methyl, ethyl, n-propyl, i-propyl, and n-butyl; cyclopropyl, cyclobutyl,
Cycloalkyl groups such as cyclopentyl group, cyclohexyl group, cycloheptyl group; Alkenyl groups such as vinyl group, propenyl group, butenyl group, phenylvinyl group, bromvinyl group, cyanovinyl group, alkoxycarbonylvinyl group, carbamoylvinyl group; ethynyl group: Alkynyl groups such as propynyl and phenylethynyl; alkylcarbonyl groups such as acetyl, propionyl and isobutyryl; arylcarbonyl groups such as benzoyl and naphthoyl; arylcarbonylalkyl groups such as phenacyl; phenylthio and tolylthio groups , an arylthio group such as a naphthylthio group; or an aralkyl group such as a benzyl group.

R1 is a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom, an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a halogenated alkyl group such as a trifluoromethyl group, or a methoxy phenylthio, which may be substituted with one or more substituents selected from alkoxy groups such as ethoxy groups, propoxy groups, butoxy groups, hydroxyl groups, nitro groups, amino groups, acyl groups such as cyano groups or acetyl groups. arylthio groups such as naphthylthio groups; alkylthio groups such as methylthio, ethylthio, propylthio, butylthio, and pentylthio groups; cycloalkylthio groups such as cyclopentylthio, cyclohexylthio, and cyclohebutylthio;
Arylsulfinyl group of phenylsulfinyl 11;
Alkylsulfinyl groups such as methylsulfinyl group, ethylsulfinyl group, methylsulfinyl group; cycloalkylsulfinyl groups such as cyclopentylsulfinyl group, cyclohexylsulfinyl group; alkenyl groups such as vinyl group, propenyl group, phenylvinyl group: ethynyl group, propynyl group , an alkynyl group such as a phenylethynyl group; an aralkyl group such as a benzyl group; an arylcarbonyl group such as a benzoyl group, an arylcarbonylalkyl group such as a phenacyl group; or an aryloxy such as a phenyloxy group.

R3 is a hydrogen atom; a branched alkyl group such as a methyl group, i-propyl group, t-butyl group, or “CHz Z
(CHz)-R', R5 is a hydrogen atom; a halogen atom such as a fluorine atom, a chlorine atom, an iodine atom, a bromine atom;
Hydroxyl group; heterocyclic carbonyloxy group such as nicotinoyloxy group; formyloxy group; acetoxy group, propionyloxy group, n-butyryloxy group, i-butyryloxy group, valeryloxy group, hexanoyloxy group, heptanoyloxy group, deca Alkylcarbonyloxy groups that may be branched such as noyloxy groups; cycloalkylcarbonyloxy groups such as cyclohexylcarbonyloxy groups; aralkylcarbonyloxy groups such as benzylcarbonyloxy groups; benzoyloxy groups, toluoylcarbonyloxy groups, naphtho Arylcarbonyloxy group such as ylcarbonyloxy group; azide group or aryl group such as phenyl group, tolyl group, naphthyl group, halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n - Alkyl groups such as propyl group, i-propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t-butoxy group, etc. Methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, i-propoxycarbonyl group, which may be substituted with one or more substituents selected from halogenated alkyl groups such as alkoxy group and trifluoromethyl group. Alkoxycarbonyloxy groups such as oxy, n-butoxycarbonyloxy, and t-butoxycarbonyloxy; aryl groups such as phenyl, tolyl, and naphthyl; halogens such as fluorine, chlorine, bromine, and iodine; Atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group,
From alkyl groups such as t-butyl group, alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t-butoxy group, and halogenated alkyl groups such as trifluoromethyl group. N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-propylcarbamoyloxy group, N-butylcarbamoyloxy group, N-pentylcarbamoyloxy group, etc., which may be substituted with one or more selected substituents. N-
Alkylcarbamoyloxy group; aryl group such as phenyl group, tolyl group, naphthyl group, halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group,
Alkyl groups such as ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t- 1 selected from alkoxy groups such as butoxy groups and halogenated alkyl groups such as trifluoromethyl groups
N-arylcarbamoyloxy groups such as N-phenylcarbamoyloxy group and N-tolylcarbamoyloxy group, which may be substituted with the above substituents; phenyl group,
Aryl groups such as tolyl group and naphthyl group, fluorine atom,
Halogen atoms such as chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, i-propyl L
Alkyl groups such as n-butyl group and t-butyl group; alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, and t-butoxy group;
N-methylthiocarbamoyloxy group, N-ethylthiocarbamoyloxy group, N-propylthiocarbamoyloxy group, N-methylthiocarbamoyloxy group, N-ethylthiocarbamoyloxy group, which may be substituted with one or more substituents selected from halogenated alkyl groups such as trifluoromethyl group - N-alkylthiocarbamoyloxy groups such as butylthiocarbamoyloxy group and N-pentylthiocarbamoyloxy group; aryl groups such as phenyl group, tolyl group and naphthyl group, fluorine atom, chlorine atom, bromine atom,
Halogen atoms such as iodine atoms, methyl groups, ethyl groups, n
- Alkyl groups such as propyl group, t-propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-
propoxy group, i-propoxy group, n-butoxy group, t
-N-phenylthiocarbamoyloxy group, N-1-lylthiocarbamoyloxy group, which may be substituted with one or more substituents selected from alkoxy groups such as butoxy groups, and halogenated alkyl groups such as trifluoromethyl groups. N-arylthiocarbamoyloxy groups such as groups; aryl groups such as phenyl, tolyl, and naphthyl groups; halogen atoms such as fluorine, chlorine, bromine, and iodine;
Alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group , methoxy group, ethoxy group, n-propoxy group, i-propoxy group, which may be substituted with one or more substituents selected from alkoxy groups such as t-butoxy group, and halogenated alkyl groups such as trifluoromethyl group. group, alkoxy groups such as n-butoxy group, t-butoxy group, n-pentyloxy group, n-hexyloxy group; aryl group such as phenyl group, tolyl group, naphthyl group, fluorine atom, chlorine atom, bromine atom, Halogen atoms such as iodine atom, alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i- i-propyl group, i-propyl group, which may be substituted with one or more substituents selected from alkoxy groups such as propoxy group, n-butoxy group, and t-butoxy group, and halogenated alkyl group such as trifluoromethyl group; Branched alkyl groups such as butyl group, 5eC-butyl group, t-butyl group, i-heptyl group, i-hexyl group; aryl groups such as phenyl group, tolyl group, naphthyl group, fluorine atom, chlorine atom, bromine atom , halogen atoms such as iodine atoms, methyl groups, ethyl groups,
n-propyl group, i-propyl group, n-butyl group, t-
Alkyl groups such as butyl groups, methoxy groups, ethoxy groups, n
-propoxy group, i-propoxy group, n-butoxy group,
Cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, which may be substituted with one or more substituents selected from alkoxy groups such as t-butoxy group, and halogenated alkyl groups such as trifluoromethyl group. or aryl groups such as phenyl, tolyl, naphthyl, halogen atoms such as fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i- Alkyl groups such as propyl group, n-butyl group, t-butyl group, alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t-butoxy group, trifluoromethyl represents an aryl group such as a phenyl group which may be substituted with one or more substituents selected from halogenated alkyl groups such as halogenated alkyl groups.

R4 represents a hydrogen atom; an optionally branched alkyl group such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, or an aralkyl group such as benzyl group.

X represents an oxygen atom or a sulfur atom.

Y represents an oxygen atom or a sulfur atom. Z is an oxygen atom;
It represents a sulfur atom or a methylene group, and n represents an integer of 0 to 5.

However, in the above general formula [I], R4 is a hydrogen atom and Z
When represents an oxygen atom, R5 does not represent a hydroxyl group.

In the compound of the present invention, R1 is preferably a hydrogen atom; a halogen atom; a C1-C2 alkyl group; a C2-C3 alkenyl group, particularly a C2-C3 alkyl group, and R1 is preferably a C6-C1. arylthio group; C1~
Even if substituted with one or more substituents selected from a C3° cycloalkylthio group or a 07-C8 aralkyl group, especially a 01-C3 alkyl group, a C, -C, alkoxy group, a halogen atom, and a nitro group. A C6-C5° arylthio group, a C1-C8° cycloalkylthio group or a C1-C11 aralkyl group is preferred.

Also, R3 is a hydrogen atom; a methyl group or -CH, -
Z-(cHz)--R' is preferred, and RS is a hydrogen atom; a halogen atom; a hydroxyl group; a heterocyclic carbonyloxy group; a C1-COO alkylcarbonyloxy group; a C4-CIO cycloalkylcarbonyloxy group ;C6-C+Z aralkylcarbonyloxy group;C
1 to CI3 arylcarbonyloxy group; C, -C,
. alkoxycarbonyloxy group; CsNO3° aralkyloxycarbonyloxy group; C2 to C1 N-
Alkylcarbamoyloxy group: C7-Cl5ON-arylcarbamoyloxy group; C□-C, N-alkylthiocarbamoyloxy group; C1-CI! N-arylthiocarbamoyloxy group; CI''' Cr. alkoxy group, C,%C,, aralkyloxy group; azide group; C1-C3 branched alkyl group; C3-C1 cycloalkyl group; or aryl group, halogen atom,
C6 optionally substituted with one or more substituents selected from alkyl groups, alkoxy groups, and halogenated alkyl groups
An aryl group of ~C irises is preferred, Z is preferably an oxygen atom; a sulfur atom or a methylene group is preferred, and n is preferably an integer of 0 to 5. R4 is a hydrogen atom; preferably an alkyl group of C1 to CI3 or an aralkyl group of 07 to CI+, and X and Y are preferably an oxygen atom or a sulfur atom. However, when R4 is a hydrogen atom and Z is an oxygen atom, R5 does not represent a hydroxyl group.

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

In the compound of the present invention represented by the above formula (1), when R3 represents a methyl group or a branched alkyl group, f, -
R31) <-CHI -Z-(CH2), represents l-R', and Rs is a hydrogen atom, a halogen atom, an azide group,
In the case of an alkoxy group, an aralkyloxy group, or an aryl group that may have a substituent, the following reaction formula (1) is used.
It can be synthesized according to (2) or (3).

3 3 3 (In the formula, R', R", R3, R', First, the compound of the general formula (It) or (IV) and an organic alkali metal are mixed in a solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran, at a temperature of -80 to -10°C. ,0.2~1
React for 0 hours. As organic alkali metals, mention may be made, for example, of potassium bistrimethylsilylamide, sodium bistrimethylsilylamide and lithium alkylamide, but in particular lithium diisopropylamide (LDA), lithium 2,2,6.6-titramethylpiberi Zido (LTMP) is preferred. The lithium alkylamide is preferably prepared immediately before the reaction. A secondary amine such as diisopropylamine and an alkyl lithium such as n-butyllithium are mixed in a solvent such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane. , 0.2 at -80 to -10°C in the presence of an inert gas, e.g. argon gas.
It is preferable to react with stirring for ~5 hours.

This organic alkali metal has general formula (n) or (IV)
It is usually used in an amount of 1 to 5 mol per mol of the compound.

Subsequently, various electrophiles, namely those of the general formula R1XI
or R1) (the compound represented by Z is represented by the general formula [11])
Alternatively, it is added in an amount of about 1 to 5 mol per mol of the compound (IV), and reacted under the same reaction conditions as the organic alkali metal.

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

Incidentally, the compound of general formula (II) can be prepared according to a known method.

The compound of general formula (IV) is synthesized according to the above reaction formula (1) (R' = H).

CH.

(■) 3 (In the formula, R', R", R', R', ) In other words, the compound represented by (VI) is dissolved in a suitable solvent,
For example, in alcohol such as methanol, ethanol, or water, with an acid such as hydrochloric acid or hydrochloric acid at 100°C from room temperature.
The compound of general formula (■) is obtained by reacting at an appropriate temperature.

Next, the compound of general formula (■) is dissolved in a suitable solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, or tetrahydrofuran in the presence of a suitable base such as sodium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate, etc. A compound of general formula (■) is reacted at a temperature from room temperature to the boiling point of the solvent to obtain a compound of general formula (1).

The compound of general formula (Vl) which is a starting material can be synthesized according to the reaction formula (1) or (2).

In addition, when R5 in the compound of the present invention is a hydroxyl group or an intermediate having a hydroxyl group, a starting material in which the hydroxyl group is protected with an appropriate protecting group can be used instead of the compound of general formula (n) or (IV). After using the compound and reacting in the same manner according to reaction formula (1) or (2), the protecting group is removed to obtain the target compound.

The above-mentioned hydroxyl group-protecting group may be any of those commonly used as hydroxyl group-protecting groups as long as it does not desorb under alkaline conditions.

Specifically, for example, aralkyl groups such as benzyl group, trityl group, monomethoxytrityl group, dimethoxytrityl group, trimethoxytrityl group, trimethylsilyl group, triethylsilyl group, t-betyldimethylsilyl group,
Examples include silyl groups such as t-butyldiphenylsilyl group and dimethylphenylsilyl group, and substituted alkyl groups such as tetrahydropyranyl group and methoxymethyl group, with silyl groups being particularly preferred.

Introduction of a protecting group can be carried out according to a conventional method.

For example, the introduction of a silyl protecting group can be carried out using a silylating agent, in the presence of a solvent such as a base such as pyridine, picoline, diethylaniline, dimethylaniline, triethylamine, imidazole, etc. alone or in a mixed solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, etc. For example, the reaction can be carried out by reacting trimethylsilyl chloride and t-butyldimethylsilyl chloride in 1 to 10 times the mole at a reaction temperature of 0 to 50°C.

The protective group can be removed by known methods depending on the protective group used.
For example, acid hydrolysis, ammonium fluoride treatment, catalytic reduction, and the like can be selected and carried out as appropriate.

Among the compounds obtained by the method of (1), (2) or (3) above, those in which the 6-position is substituted with a phenylthio group and have a nitro group on the benzene ring are represented by the following reaction formula (
As shown in 4), it can be converted to an amino group by hydrogenation.

Hydrogenation is carried out in an organic solvent such as alcohol or acetic acid at a suitable temperature from room temperature to 80° C. in the presence of a catalyst such as palladium on carbon.

(The substituents in the above formula are as defined above.

In addition, as shown in reaction formula (5) below, an arylthio group,
An alkylthio group and a cycloalkylthio group can be converted into the corresponding arylsulfinyl group, alkylsuf L, finyl group, and cycloalkylsulfinyl group using an oxidizing agent such as hydrogen peroxide or metachloroperbenzoic acid.

) 3 (In the above formula, R6 represents an aryl group, an alkyl group, or a cycloalkyl group. The other substituents are as defined above.) In addition, as shown in the following reaction formula (6), a phenyl sulfoxide derivative and a benzene ring An arylthiosodium salt or an aryloxysodium salt having various substituents on the top thereof is dissolved in an organic solvent such as tetrahydrofuran, alcohol, dimethylformamide, acetonitrile, etc. from room temperature for 10 min.
By reacting at an appropriate temperature of 0°C, it can be converted to the corresponding substituted arylthio group.

(In the above formula, A represents a sulfur atom or an oxygen atom, and R7
and R@ is a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom, an iodine atom; a methyl group, an ethyl group, a propyl group,
Alkyl groups such as butyl groups; halogenated alkyl groups such as trichloromethyl groups; alkoxy groups such as methoxy, ethoxy, propoxy, and butoxy groups; hydroxyl groups;
Nitro group; amino group; cyano group; acyl group such as acetyl group, etc. Other substituents are as defined above. ) Furthermore, the compound of the present invention can be expressed, for example, by the following reaction formula (7) or (
8).

(7) 3 3 (8) 3 3 (In the above formula, R9 is an alkyl group such as a methyl group or an ethyl group;
It represents an aryl group such as a phenyl group or a tolyl group; a protecting group such as a silyl group, and the other substituents are as defined above. ) The reactions of the above reaction formulas (7) and (8) can be carried out in the presence of a palladium catalyst, using an amine such as diethylamine or triethylamine as a solvent, and at an appropriate temperature from room temperature to 70°C. The reaction can be made more uniform by adding a solvent such as acetonitrile. As a catalyst, a palladium solvent such as bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium(0), bis(diphenylphosphino)ethane palladium dichloride, etc., and cupric iodide can be used in combination. .

Further, the compounds of the present invention can be used, for example, in the above reaction formulas (7) and (8).
) instead of the acetylene compound, an olefin compound H1C=CH-R1'' (where RI6 represents an alkoxycarbonyl group, nitrile group, carbamoyl group, etc.)
can be synthesized according to the following reaction formula (9) and 0ω.

3 3 (The substituents in the above formula are as defined above.

) 00) 3 3 (The substituents in the above formula are as defined above.

) For palladium catalysts, the above reaction formulas (7) and (8)
As explained in .

Further, the compound of the present invention can be synthesized, for example, by the following reaction formula 〇〇.

D 3 3 (In the above formula, X4 represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, etc. The other substituents are as defined above.) The compound of the present invention can be used, for example, according to the following reaction formula 02. ) or can be synthesized according to the side.

3 3 3 3 (The substituents in the above formula are as defined above.

) That is, in the reaction formula (1) or (2), R'
"Dashi, RI 1 and R" represent a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, 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 (mesyl chloride, tosyl chloride, thionyl chloride, etc.) and an alkenyl group is introduced.

The alkynyl group of the alkynyl group-containing compound synthesized by reaction formula (7) or (8) above is replaced with the corresponding alkenyl group or alkyl group, and the alkynyl group of the alkenyl group-containing compound synthesized by reaction formula (9) to 0■. The alkenyl group can be converted into the corresponding alkyl group by a hydrogenation reaction. Reduction to alkenyl groups is carried out in alcohol or acetic acid, palladium-
Using a catalyst such as barium sulfate, palladium-calcium carbonate, palladium-calcium carbonate-lead acetate, or palladium-barium sulfate-quinoline, the reaction can be carried out at an appropriate temperature from room temperature to 80°C in a hydrogen gas atmosphere.

Further, the reduction of an alkenyl group or an 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 the reduction to an alkenyl group.

Furthermore, the benzyl derivative at the 6-position in the compound of the present invention can be synthesized by the following reaction formula 04).

3 3 (The substituents in the above formula are as defined above.

That is, the above method using 1 HCR'' instead of RI This is a method in which the hydroxyl group of the intermediate obtained by the reaction treatment is replaced with hydrogen using an appropriate reducing agent. Examples of the reduction method include a method using hydrogen in the presence of palladium on carbon or palladium hydroxide.

In addition, the 6-i11F-substituted acyclouridine and acyclothymidine derivatives obtained by these reactions are converted into 2゜4-bis(4-methoxyphenyl)-1, 3-dithia-2,4-
It can be converted into the corresponding 4-thio derivative by heating with diphosphethane-2,4-disulfide.

) 3 (The substituents in the above formula are as defined above.

In addition, 4-thio derivatives include uridine and thymidine derivatives.
It can also be obtained by reacting the 4-chloro compound with phosphorus chloride or phosphorus oxychloride and then with sodium hydrogen sulfide.

In addition, as shown in the following reaction formula 06), acyclouridine and acyclothymidine derivatives are reacted with 1-(2-mesitylenesulfonyl)3- in the presence of diphenylphosphoric acid.
By reacting nitro-1,2,4-)riazole with an organic solvent such as pyridine, the corresponding 4-(3-nitro-1,2-)
, 4-) lyazole) derivative, and then add ammonia water and react at a suitable temperature from room temperature to 100°C to obtain the corresponding 4-amino derivative.

3 R3 (The substituents in the above formula are as defined above.

The compound of the above general formula (I') is synthesized by the above reaction.

Starting from the compound in which R4 is a hydrogen atom obtained as above, R'
(excluding hydrogen atoms) can be introduced.

) 07) 3 (In the above formula, X5 represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, or a sulfonyloxy group such as a toluenesulfonyloxy group or a mesyloxy group. The other substituents are as defined above. ) The above reaction is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, alcohol, etc. in the presence of 1 to 2 times the amount of base at a suitable temperature from room temperature to the boiling point of the solvent. As the base, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate, sodium hydride, etc. can be used.

In the compounds obtained by reaction formula (1) to 0'I), R5
When is a hydroxyl group, it can be induced into a corresponding substituted hydroxyl group as shown in the following reaction formula (21).

(In the above formula, R14 is an optionally branched alkyl group,
It represents an aryl group or a heterocyclic substituent which may have a substituent, and Xk represents a halogen atom such as chlorine, bromine, 1 iodine, or 10CR+'.

Other substituents are as defined above. ) The above reaction is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform, etc. in the presence of 1 to 2 times the amount of base at a suitable temperature from room temperature to the boiling point of the solvent. As the base, triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydride, etc. can be used.

(In the above formula, RIS is an optionally branched alkyl group,
or represents an aralkyl group, and X represents a halogen atom such as chlorine, 1 bromine, or iodine, or 1000R15. Other substituents are as defined above. ) The above reaction is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform, etc. in the presence of 1 to 2 times the amount of base at a suitable temperature from room temperature to the boiling point of the solvent. As the base, triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydride, etc. can be used.

(In the formula, R1 & represents an optionally branched alkyl group or aralkyl group, and X8 represents a halogen atom such as chlorine, bromine, or iodine, or a sulfonyloxy group such as toluenesulfonyloxy group or mesyloxy group.Other substitutions (The groups are as defined above.) The above reaction is carried out in an appropriate solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform, etc. in the presence of 1 to 2 times the amount of base from room temperature to the boiling point of the solvent. It is carried out at a suitable temperature. As the base, triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydride, etc. can be used.

(In the above formula, RI'? represents an optionally branched alkyl group or allyl group, and X9 represents an oxygen atom or a sulfur atom.Other substituents are as defined above.) The above reaction is performed using tetrahydrofuran. , acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform, etc., at a suitable temperature from room temperature to the boiling point of the solvent.

The compound of the present invention represented by the general formula (1) thus obtained can be separated and purified by appropriately selecting a conventional nucleoside separation and purification method, such as recrystallization, adsorption, or ion exchange chromatography.

The above-mentioned compounds of the present invention may be converted into pharmaceutically acceptable salts thereof according to conventional methods. Such salts include, for example,
Examples include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts, and alkylammonium salts such as ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, and tetramethylammonium salts.

The compounds of the present invention can be administered to humans by any route such as oral, enteral, parenteral or local administration for the prevention or treatment of infections such as retroviruses. The dosage is determined appropriately depending on the patient's age, health condition, weight, etc., but - the appropriate dosage for boat fishing is 1 to 100 seconds per day.
+g/kg body weight, preferably selected from the range of 5 to 50+ag/kg body weight, and administered in one or more divided doses.

When formulating the compound of the present invention, 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, white china clay (kaolin), and C! Examples include sugar, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, and sodium chloride.

Examples of liquid carriers include glycerin, peanut oil,
Examples include polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.

The dosage form can take various forms. When using solid carriers, tablets, powders, granules, capsules, suppositories,
Examples include lozenges and the like. In addition, when a liquid carrier is used, examples include syrup, emulsion, soft gelatin capsule, cream, gel, paste, spray, and further injection solution.

〔Effect of the invention〕

The novel 6-substituted acyclopyrimidine nucleoside derivatives of the present invention have effective activity against retroviruses and the like, and have relatively low toxicity to host cells, so they can be effectively used as antiviral agents.

〔Example〕

Hereinafter, the present invention will be specifically explained with reference to Examples.

However, the present invention is not limited to these embodiments, and many variations and modifications are possible within the scope of the present invention.

The compounds used below correspond to compound Nα in Table-1.

In addition, 1-((2-hydroxyethoxy)methyl]6-phenylthio-2-thiothymine, 1-((2-hydroxyethoxy)methyl)-6-phenylthiothymine, 1-[(2- hydroxyethoxy)methyl]-6-(m
, m'-dimethylphenylthio)thymine, 1-((2-
hydroxyethoxy)methyl]-6-(m,m'-dimethylphenylthio)-2-thiothymine, 1-[(2-hydroxyethoxy)methyl]-6-(m
, m'-dichlorophenylthio)thymine, 1-((2-
hydroxyethoxy)methyl]-6-benzylthymine, 1-[(2-hydroxyethoxy)methyl]-6-convex hexylthiothymine, 1-((2-hydroxyethoxy)methyl]-6-m-
Starting materials such as 1lylthiothymine were obtained by the method described in the Examples of WO39109213.

Example 1 Production of 1-[(2-acetoxyethoxy)methyl]-6-phenylthio-2-thiothymine (compound Nα1) 1-[(2-hydroxyethoxy)methyl-6-phenylthio2 was added to 2 mf of pyridine under a nitrogen atmosphere. - Add 0.31 g of thiothymine (1,0 mm) and 0.10 mf of acetic anhydride (1,1 s + moj), react for 2 hours at room temperature, concentrate to dryness under reduced pressure, and crystallize from ethanol-water to obtain the target compound. 0.62 g (yield: 88 g) was obtained.

Examples 2 to 6 In Example 1, 1-[(2-hydroxyethoxy)
methyl]-6-phenylthio 2-thiothymine, 1-[(2-hydroxyethoxy)methylco6-
Phenylthiothymine, 1-[(2-hydroxyethoxy)methyl] -6-(m,m'-dimethylphenylthio)thymine, 1-[(2-hydroxyethoxy)methyl]
-6-(m,m'-dimethylphenylthio)-2-thiothymine, 1-[(2-hydroxyethoxy)methyl]
-6-(m,m'-dichlorophenylthio)thymine, 1
-[(2-Hydroxyethoxy)methyl]-6-benzylthymine was used, but in the same manner as in Example 1, compounds 2 to N116 in Table 1 were obtained.

Examples 7 to 13 Example 2 except that ethyl formate, isobutyryl chloride, pivaloyl chloride, decanoyl chloride, cyclohexane carbonyl chloride, benzoyl chloride, and nicotinyl chloride were used instead of acetic anhydride in Example 2.
Compounds Nα7 to 13 in Table 1 were obtained in the same manner as above.

Example 14 Compound No. 14 was obtained in the same manner as in Example 2 except that t-butoxycarbonyl chloride was used instead of acetic anhydride.

Example 15 In Example 2, 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine was replaced with 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine.
-hydroxyethoxy)methyl]-6-cyclohexylthiothymine and benzyloxycarbonyl chloride instead of acetic anhydride were used in the same manner to obtain compound NCL15.

Example 16 Preparation of 1-[(2-phenylcarbamoyloxyethoxy)methyl]-6-m-)lylthiothymine (compound 16) 1-[(2-hydroxyethoxy)methyl was added to 2 ml of pyridine under a nitrogen atmosphere. ]-6-m-Tolylthiothymine 0.32 g (1,0++ uwol) and phenyl isocyanate 0.12 all (1,1 mmoi) were added and reacted at room temperature for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure and crystallized from acetone-water to obtain 0.24 g (yield 54%) of the target compound.

Examples 17-18 Compound Nos, 17.1 was prepared by another similar method using ethyl isocyanate or phenylthioisocyanate in place of phenyl isocyanate in Example 16.
I got 8.

Example 19 1-[(2-benzyloxyethoxy)methyl]-6-
Preparation of phenylthiothymine (compound Nα19) 0.17 g (4,2++u++of) of sodium hydride was added to 4 tan of tetrahydrofuran under a nitrogen stream and stirred. 0.62 of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine was added to this suspension.
g (2, Os + 2 tons of tetrahydrofuran
The all solution was slowly added and reacted at room temperature for 45 minutes. To this was added 0.24 ml of benzyl bromide (2,0
mvaol”) and tetrabutylammonium iodide7.
4 mg (20 μl) was added and reacted for 15 hours.

After neutralizing the reaction mixture with acetic acid, it was partitioned between chloroform and a saturated aqueous sodium bicarbonate solution, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of chloroform, adsorbed on a silica gel column, eluted with 1% methanol-chloroform, concentrated, and crystallized from diethyl ether-hexane to obtain 0.64 g of the target compound (yield 80%).
) was obtained.

Examples 20 to 2 Compound Nos, 20.21 was obtained in the same manner as in Example 19 except that methyl bromide and bromopentane were used instead of benzyl bromide.

Example 22 Preparation of 1-(methoxymethyl)-6-phenylthiothymine (compound 22) To 250 II methylene chloride, 25 g (0,20 s+oj) of thymine and 109 van (0,44 mof) of bistrimethylsilylacetamide were added under nitrogen atmosphere. )
was added and stirred at room temperature for 2 hours and 30 minutes. Next, add 24 g (0,30 moj of chloromethane) and 0.59 g (1,
6 m5 iof) was added thereto, and the mixture was refluxed for 1 hour and 30 minutes. Add 400s+j of methanol to the reaction mixture! and 100 mf of water were slowly added and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1-(methoxymethyl)-thymine.

Then, in 335 ml of tetrahydrofuran under a nitrogen stream,
A solution of lithium diisopropylamide in tetrahydrofuran (2,1 M) at −70 °C was added to 119 tag (0,2
5 mof), then 1-(methoxymethyl)thymine 1
1. og (0.10 moj of tetrahydrofuran 1
07mj! The suspension was added dropwise over 30 minutes. -70°
After reacting for 2 hours and 30 minutes at C, a solution of 43.6 g of diphenyl disulfide in 49 mf of tetrahydrofuran was
The mixture was added dropwise over 0 minutes and reacted for 20 minutes. Add 35wf of acetic acid to the reaction mixture, return to room temperature, and add 1! added. After washing with 100 mf of water five times and twice with saturated sodium bicarbonate, it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 20 g (yield 73%) of the target compound.

Examples 23 to 26 1-(ethoxymethyl)thymine, 1-[(2-azidoethoxy)methyl]thymine, 1-[(2-fluoroethoxy)methyl instead of 1-(methoxymethyl)thymine in Example 22 ] Thymine and 1-[(2-chloroethoxy)methyl]thymine were used in the same manner to obtain compounds Nos, 23-26.

Example 27 Production of lophenylthiothymine (compound 27) Concentrated hydrochloric acid 100mj! , 1-(methoxymethyl)-6-
17.2 g (62 mmof) of phenylthiothymine was added and reacted at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and crystallized from ethanol to obtain 3.8 g of the target compound.
(yield 26%).

Example 28 1-Methyl-6-phenylthiothymine (compound Nα28
) to 1 m12 of dimethyl sulfoxide, under nitrogen atmosphere, 6
- phenylthiothymine 20 mg (85 gmoE),
Methyl iodide 2.5μ! (40 μm) and 12 mg (85 umol) of potassium carbonate were added and reacted at 80°C for an hour. The reaction mixture was concentrated under reduced pressure and adsorbed on a silica gel column, and then eluted with 1% methanol-chloroform. Crystallization from ether gave 5.0 mg (yield 51%) of the target compound.

Examples 29-30 Compound Nos, 29.30 was obtained in the same manner as in Example 28 except that ethyl tosylate and n-butyl iodide were used instead of methyl iodide.

Example 31 Production of 1-(4-hydroxybutyl)-6-phenylthiothymine (compound 31) 468 mg of 6-phenylthiothymine (2, Ovataol) was added to 2 ml of dimethyl sulfoxide under a nitrogen atmosphere.
) 4-(t-Butyldimethylsiloxy)-butyl P-toluenesulfonate 358mg (1,0umol2
) and 276 mg (2.0 mmof) of potassium carbonate were added and heated at 80°C for 4 hours. The reaction mixture was distilled off under reduced pressure, and methanol was added to the residue. This was filtered, the filtrate was distilled off under reduced pressure, and 20ml of tetrahydrofuran! and IN
1 lll of hydrochloric acid was added and stirred for 90 minutes. The reaction mixture was evaporated under reduced pressure, adsorbed on a silica gel column, eluted with 2% methanol/chloroform, and crystallized from acetone/hexane to obtain 12.0 mg (yield: 4%) of the target compound.

Example 32 1-(Methylthiomethyl)-6-phenylthiothymine (
Preparation of Compound 32) To 4 ears of dimethylformamide, add 0.17 ml of chloromethyl methyl sulfide (2,
0 mmof), 6-phenylthiothymine 0.47 g (2
,0 mmof) and triethylamine 0.56 ml
(2.0 tamol) was added, and the mixture was reacted at room temperature for 22 hours, and then concentrated under reduced pressure. The residue was adsorbed on a silica gel column, eluted with chloroform, and then crystallized from ethyl acetate to obtain 45 mg (yield: 8%) of the target compound.

Example 33 Preparation of 1-[(2-hydroxyethoxy)methyl]-3-benzyl-6-phenylthiothymine (compound NQ, 33) 1-[(2-hydroxyethoxy)methyl]-6 in dimethylformamide 2 rsl -Phenylthiothymine 0.
62 g (2,0++v+of), benzyl bromide 0.26 sj! (2,2mmof!,) and ethyldiisopropylamine 0.38 tan (2,2s
+o+or! , ) were added thereto, and the mixture was reacted at room temperature under a nitrogen atmosphere for 5 days, and then concentrated to dryness under reduced pressure. The residue was adsorbed on a silica gel column and eluted with 1% methanol-chloroform to obtain 0.248 of the target compound (yield 30%).

Example 34 Compound 34 was obtained in the same manner as in Example 33 except that methyl iodide was used instead of benzyl bromide.

Example 35 Production of 1-ethoxymethyl-5-ethyl-6-phenylthiouracil (compound Nα247) Methylene chloride 100
5-ethyluracil 5.1 g in a+f under nitrogen atmosphere
(40s+mof) and 22 mfl (88 mmof) of bistrimethylsilylacetamide were added, and the mixture was stirred at room temperature for 40 minutes. Next, chloromethyl ethyl ether 4
．． Add 1 mf (88 mmof) and 0.15 g (0.4 woof) of tetrabutylammonium iodide;
It was refluxed for 5 hours. The reaction mixture was carefully poured into 50 mf of saturated sodium bicarbonate water and filtered through Celite. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 6.4 g (81%) of 1-ethoxymethyl-5-ethyluracil.

Next, 2.2 mj2 (4,4 +
n+of), and then a solution of 0.40 g (2.0 mmof!) of 1-ethoxymethyl-5-ethyluracil in 3 vbfl of tetrahydrofuran was added dropwise over 15 minutes. After reacting at −70° C. for 1 hour, 0.57 g (2.6 mmoffi) of diphenyl disulfide was added to the tetrahydrofuric acid and reacted for 30 minutes. Add 1 rr+ of acetic acid to the reaction mixture
1, return to room temperature, and add 3 On/L of ethyl acetate.
! added. Water 3 w. i! The mixture was washed five times with water and twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel chromatography (ethyl acetate/hexane = 3:17) and crystallized from ethyl acetate to obtain 1-ethoxymethyl-5-ethyl-6-phenylthiouracil (0-610-61%).

Example 36 Compound 357 was prepared in the same manner as in Example 35 except that 3.3',5.5'-tetramethyldiphenyl disulfide was used instead of diphenyl disulfide.
I got it.

Example 37 1-ethoxymethyl-5-ethyl-6-phenylthio-
Production of 2-thiouracil (compound Nct35B) 100 mjl of methylene chloride! 5. 2-thiouracil under nitrogen atmosphere. 1 g (40 mmof) and 22 ml (88 mmof) of bistrimethylsilylacetamide
mmof) and stirred at room temperature for 40 minutes. Next, chloromethyl ethyl ether 8.2 tal (8 8
mmoj2) and tetrabutylammonium iodide 0.
15 g (0.4 mmof) was added and refluxed for 15 hours.

The reaction mixture was carefully poured into 50 mf of saturated sodium bicarbonate water and filtered through Celite. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate and 1
-Ethoxymethyl-2-thiouracil 1.1 g (15
%)Obtained.

Then tetrahydrofuran 911i. Then, add 3.3 ml of 2.1M lithium diisopropylamide tetrahydrofuran solution (6.6III
IIIO and then 0.56 g (3.0 mmof) of 1-ethoxymethyl-2-thiouracil in tetrahydrofuran 3 va 12. The solution was added dropwise over 15 minutes.

After reacting at −70°C for 1 hour, a solution of 0.85 g (3.9 + u+of) of diphenyl disulfide in 1 rag of tetrahydrofuran was added dropwise over 10 minutes.
The reaction was allowed to proceed for 0 minutes. Add 1111 ml of acetic acid to the reaction mixture, return to room temperature, and add 30 ml of ethyl acetate! added. Water 3■! The mixture was washed five times with water and twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexane = 3:17) and crystallized from ethyl acetate to give 0.64 g (7
3%).

Then tetramethylpiperidine 0.57 van (3
, 4 months mob) of tetrahydrofuran 8■I! , 2.1 van (3.4 mmoi) of butyllithium hexane solution (1.6 M) was added to the solution at -70°C under nitrogen atmosphere.
The mixture was then heated to -50°C and stirred for 20 minutes. 17 again
After returning to 0°C, 0.44 g of 1-ethoxymethyl-6-phenylthio-2-thiouracil (1,5
A solution of n) in 4 vans of tetrahydrofuran was added dropwise over 15 minutes. After 1 hour, add ethyl iodide to 1.2@l (
15ms+of) and stirred for 19 hours. 1 tag of acetic acid was added to the reaction mixture, the mixture was warmed to room temperature, 30 ml of ethyl acetate was added, the mixture was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel chromatography (ethyl acetate/hexane = 3:17),
Crystallization from ethyl acetate yielded 96+gg (20
%) was obtained.

Example 38 Compound Nct359 was prepared in the same manner as in Example 37 except that 3.3′,5.5′-tetramethyldiphenyl disulfide was used instead of diphenyl disulfide.
I got it.

Example 39 Compound 360 was obtained in the same manner as in Example 35 except that benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 40 A compound was prepared in the same manner as in Example 35 except that benzyl chloromethyl ether was used instead of chloromethyl ethyl ether and 3,3'5,5'-tetramethyldiphenyl disulfide was used instead of diphenyl disulfide. Nl1361 was obtained.

Example 41 Compound Hi362 was obtained in the same manner as in Example 35 except that thymine was used instead of 5-ethyluracil and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 42 Compound 41 was obtained in the same manner as in Example 22 except that chloromethyl propyl ether was used instead of chloromethyl methyl ether.

Example 43 Compound No. 485 was obtained in the same manner as in Example 22 except that butyl chloromethyl ether was used instead of chloromethyl methyl ether.

Example 44 Compound 365 was obtained in the same manner as in Example 35 except that 3.3',5.5'-tetrachlorodiphenyl disulfide was used instead of diphenyl disulfide.

Example 45 In Example 35, 5-ethyl-2-thiouracil was used instead of 5-ethyluracil, and 3.3', 5.5' tetrachlorodiphenyl disulfide was used instead of diphenyl disulfide. obtained compound N[L366 by a similar method.

Example 46 In Example 35, 5-ethyluracil was replaced with 5-
Compound 496 was obtained in the same manner except that isopropyl uracil was used.

Example 47 In Example 35, 5-ethyluracil was replaced with 5-
Compound Nl1497 was obtained in the same manner except that isopropyl-2-thiouracil was used.

Example 48 In Example 35, 5-ethyluracil was replaced with 5-
Compound NO.574 was obtained by the same method except that cyclopropyluracil was used.

Example 49 In Example 35, 5-ethyluracil was replaced with 5-
Compound 575 was obtained by the same method except that cyclopropyl-2-thiouracil was used.

Example 50 Compound 675 was obtained in the same manner as in Example 35 except that chloromethyl isopropyl ether was used instead of chloromethyl ethyl ether.

Example 51 In Example 35, 5-ethyluracil was replaced with 5-
Compound 676 was obtained in the same manner except that ethyl-2-thiouracil was used and chloromethyl isopropyl ether was used in place of chloromethyl ethyl ether.

Example 52 Compound Nα685 was obtained in the same manner as in Example 35 except that chloromethyl cyclohexyl ether was used instead of chloromethyl ethyl ether.

Example 53 In Example 35, 5-ethyluracil was replaced with 5-
Compound NcL686 was obtained by the same method except that ethyl-2-thiouracil was used and chloromethyl cyclohexyl ether was used instead of chloromethyl ethyl ether.

Example 54 Compound 689 was obtained in the same manner as in Example 35 except that chloromethyl cyclohexyl methyl ether was used instead of chloromethyl ethyl ether.

Example 55 In Example 35, 5-ethyluracil was replaced with 5-
Compound N1169 was prepared by the same method except that ethyl-2-thiouracil was used and chloromethyl cyclohexyl methyl ether was used instead of chloromethyl ethyl ether.
I got 0.

Example 56 In Example 35, 5-ethyluracil was replaced with 5-
Compound Nα512 was obtained in the same manner except that isopropyl uracil was used and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 57 In Example 35, 5-ethyluracil was replaced with 5-
Compound Nα513 was obtained by the same method except that isopropyl-2-thiouracil was used and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 58 Compound 748 was obtained in the same manner as in Example 35 except that chloromethyl phenethyl ether was used instead of chloromethyl ethyl ether.

Example 59 In Example 35, 5-ethyluracil was replaced with 5-
Compound Is 749 was obtained by the same method except that ethyl-2-thiouracil was used and chloromethyl phenethyl ether was used instead of chloromethyl ethyl ether.

Example 60 In Example 35, 5-ethyluracil was replaced with 5-
Compound 1t3 was prepared by the same method except that ethyl-2-thiouracil was used and chloromethyl (4-methylbenzyl) ether was used instead of chloromethyl ethyl ether.
I got 72.

Example 61 In Example 35, 5-ethyluracil was replaced with 5-
Compound 704 was obtained in the same manner except that ethyl-2-thiouracil was used and 4-chlorobenzyl chloromethyl ether was used in place of chloromethyl ethyl ether.

Example 62 Production of 6-benzyl-1-ethoxymethyl-5-ethyluracil (compound NL1472) Methylene chloride 100+
+/! 5.1 g of 5-ethyluracil under nitrogen atmosphere
(40 swoj and bistrimethylsilylacetamide were added and stirred at room temperature for 40 minutes. Next, chloromethyl ethyl ether iodide tetrabutylammonium 0.15 g (0.4 +
+nof) was added and refluxed for 15 hours. The reaction mixture was diluted with 50 mj of saturated sodium bicarbonate water! and filtered through Celite.

The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 6.4 g (81%) of 1-ethoxymethyl-5-ethyluracil.

Next, 2.2 mL of lithium diisopropylamide tetrahydrofuran solution (2.1 M) was added to 6 Ill of tetrahydrofuran at -70°C under a nitrogen atmosphere. (4,4wb
mol), then 1-ethoxymethyl-5-ethyluraciltrahydrofuran 9 copper! The solution was added dropwise over 15 minutes. After reacting at -70℃ for 1 hour, benzaldehyde 0
．． 27 g (2.6 ugly-ol) of tetrahydrofuran 2
w. The il solution was added dropwise over 10 minutes, and the reaction was allowed to occur for 30 minutes. Add 1 ml of acetic acid to the reaction mixture, return to room temperature, and add ethyl acetate to 301111! added. After washing with 3 L of water five times and twice with saturated sodium bicarbonate solution, it was dried over magnesium sulfate and concentrated under reduced pressure.

This was dissolved in ethanol 10-2, 20s+g of 20% palladium hydroxide-carbon was added, and the mixture was reacted with stirring at 55°C for one day in a hydrogen atmosphere, and then the catalyst was removed by filtration and concentrated. The residue was crystallized from hexane to give 6-benzyl-1-ethoxymethyl-
0.28 g (85%) of 5-ethyluracil was obtained.

Example 63 3.5 in place of benzaldehyde in Example 62
Compound 474 was obtained by the same method except that -dimethylbenzaldehyde was used.

Example 64 1-Butyl-5-ethyl-6-phenylthiouracil (
Preparation of compound NQ252) 5-ethyluracil 5.6 g (40 su++o
5.5 g (40 mmof) of potassium carbonate and 2.3 ml (20 mmof) of n-iodobutane were added to 60 mj2 of dimethylformamide solution of f), and the mixture was stirred at 120°C for 2 hours.The reaction mixture was concentrated under reduced pressure, and dichloromethane and chloride were added. After partitioning with an ammonium aqueous solution, the organic layer was concentrated under reduced pressure.The residue was adsorbed on a silica gel column to give a 30%
By elution with ethyl acetate/hexane, 2.7 g (yield 69%) of 1-butyl-5-ethyluracil was obtained.

Next, 392 mg of 1-butyl-5-ethyluracil (
2. 0 m-of ) of tetrahydrofuran 9 copper! Lithium diisopropylamide (4.4 sv+offi) in tetrahydrofuran 2.8 copper! in solution at -70°C under nitrogen atmosphere! The solution was added dropwise over 10 minutes and heated to -70°C.
The mixture was stirred at -25°C for 70 minutes and for 5 minutes at -25°C. Return to -70℃, diphenyl disulfide 567■ (2.6mm
Add 3 liters of solution of tetrahydrofuran and 2 oz.
After stirring for 0 minutes, 1 sf of acetic acid was added, the mixture was returned to room temperature, washed with saturated brine, and concentrated under reduced pressure.

The residue was adsorbed on a silica gel column, eluted with 10% ethyl acetate/hexane, and crystallized from hexane to give 40 g of 1-butyl-5-ethyl-6-phenylthiouracil.
(yield 7%).

Example 65 In Example 35, 5-ethyluracil was replaced with 5-
Compound N111.363 was obtained in the same manner except that ethyl-2-thiouracil was used and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 66 In Example 35, 5-ethyluracil was replaced with 5-
Ethyl-2-thiouracil was used, benzyl chloromethyl ether was used instead of chloromethyl ethyl ether, and 3.3', 5.
Compound N113 6 4 was obtained in the same manner except that 5'-tetramethyldiphenyl disulfide was used.

NCL35 to 40 listed in Table 1 above. 42 ~
246, 248-251, 253-269.271-3
56, 367-371, 373-471, 473, 47
5-484, 486-495, 498-511, 514
~573,576~674.677~684.687,
688.691-703.

Compounds 705-747 and 750-803 can also be synthesized in the same manner according to the methods described in the Examples above.

Example 67 5-(2(dan)bromovinyl)-1-(ethoxymethyl)-6-(phenylthio)uracil (compound Nα270
) Production of 4.76 g (20 mmol) of 5-iodouracil was suspended in 50 mj2 of dichloromethane, and 11 ml (45 mmol) of bistrimethylsilylacetamide was added to the suspension.
was added and stirred at room temperature for 15 minutes to obtain a homogeneous solution.

Add to this 2.0 dllIf of chloromethyl ethyl ether (
22 mmol) and 60 μl of tetra-n-butylammonium iodide were added and heated under reflux for 3 hours. After distilling off the solvent, water was added to the residue, and the resulting crystals were collected by filtration. The crystals were suspended washed with hot methanol, cooled, and collected by filtration, yielding 5.43 g.
1-(ethoxymethyl)-5-iodouracil was obtained.

Then, 1-(ethoxymethyl)-5-iodouracil 1
．． 184 g (4 mmol), ethyl acrylic acid ester 870 μf (8 mmol), palladium acetate 45 μf and triethylamine 0.6 mf in DMF40d
The mixture was heated and stirred at 70°C for 5 hours.

After distilling off the solvent, it was adsorbed onto a silica gel column, eluted with a dichloromethane-ethyl acetate (1:1 v/v) solution, the desired fractions were collected, and the solvent was distilled off to obtain 5- (2-(dan)
-carboethoxyvinyl)-1=(ethoxymethyl)uracil 798 ml was obtained as crystals.

Next, add 0.16 cal of water to 0.16 cal of sodium hydroxide at room temperature.
g (4,0+mmol) and 5- (2-(E)-
Add 0.54 g (2.0+mol) of carboethoxyvinyl)-1-(ethoxymethyl)uracil, and add 4.5
Stir for hours. After neutralization with 1N hydrochloric acid, dimethylformamide 10+/l! was added to make a homogeneous system.

Next, add 0.62 g of potassium carbonate (4.5s
a+o1) and stirred at room temperature for 5 minutes to form a homogeneous system. After that, 0.36 g of N-promosuccinimide (2
The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. After partitioning between chloroform and an aqueous ammonium chloride solution, the organic layer was concentrated under reduced pressure. The residue was adsorbed on a silica gel column, eluted with 20% ethyl acetate/hexane, the desired fraction was collected, and the solvent was distilled off to obtain 5-(2-(E)
-bromovinyl)1-(ethoxymethyl)uracil 0.15 g (yield 28%) was obtained.

Next, 1.22 mmol of lithium diisopropylamide
5-(2-(dan)-bromovinyl)- in 2.3mf of tetrahydrofuran solution at -70°C under nitrogen atmosphere
1-(ethoxymethyl)uracil 0.15g (0,5
7mmol) of tetrahydrofuran 1.7mf solution
After stirring for 40 minutes, a solution of 0.16 g (0.73 mmol) of diphenyl disulfide in 1 ml of tetrahydrofuran was added, and the mixture was further stirred for 1 hour.

The reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was adsorbed onto a silica gel column and 15% ethyl acetate/
The desired fractions were collected by elution with hexane, and the solvent was distilled off to obtain the desired compound 11 (yield: 5%).

m, p, 143-148°C Example 68 (manufacture of tablets) 1-1: (2-acetoxyethoxy) Methyl-6-phenylthiothymine 10g Cornstarch Carboxycellulose Polyvinylpyrrolidone Calcium stearate 5g 0g 3g 3g Mix the above ingredients well Mix and make 100 tablets by direct compression method.
mg tablets were prepared. One tablet of this tablet is 1-((2-
acetoxyethoxy) methyl-6-phenylthiothymine to 1. Contains Otag.

Example 69 (Production of powders and capsules) 1-((2
-acetoxyethoxy) Methyl-6-phenylthiothymine 20g Crystalline cellulose 80g Total amount
100 g of both powders were mixed well to obtain a scattering. Further, 100 mg of this powder was filled into No. 5 hard capsules to obtain capsules.

Example 70 (Effect of preventing HIV infection) 20+M Hepes buffer, 10% beef tallow serum and 2
RPMI containing 0 μg/all gentamicin
Add 50 MT-4 cells (a human T cell clone that dies when infected with HIV) to 3 x 10' cells in 1640DM medium.
% cells were infected with 100 times the amount of HIV, and immediately treated with dimethyl sulfoxide at 50 mg/++.
+j! A predetermined amount of the sample prepared above was added and cultured at 37°C.

After 5 days of culture, the number of viable cells was measured, and the compound concentration required to prevent 50% of MT-4 cell death was determined. Also,
Culture was performed in the same manner as above except that HIV was not infected, and M
The compound concentration required to kill 50% of T-4 cells was determined. Both results are shown in Table-3.

Table-3

Claims (4)

[Claims] (1) The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the above formula, R^1 is a hydrogen atom; a halogen atom; an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group ; Alkylcarbonyl group; Arylcarbonyl group; Arylcarbonylalkyl group; represents an arylthio group or an aralkyl group, and R^2 is a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a nitro group, an amino group, a cyano group; Arylthio group, alkylthio group, cycloalkylthio group, arylsulfinyl group, alkylsulfinyl group, cycloalkylsulfinyl group, alkenyl group, alkynyl group, aralkyl group, which may be substituted with one or more substituents selected from groups and acyl groups. , represents an arylcarbonyl group, an arylcarbonylalkyl group or an aryloxy group,
R^3 is a hydrogen atom; a methyl group; a branched alkyl group or -CH_2-Z-(CH_2)_n-R^5 (in the formula,
R^5 is a hydrogen atom; a halogen atom; a hydroxyl group; a heterocyclic carbonyloxy group; a formyloxy group; an alkylcarbonyloxy group; a cycloalkylcarbonyloxy group; an aralkylcarbonyloxy group; an arylcarbonyloxy group; an azide group or an aryl group; Alkoxycarbonyloxy group, N-alkylcarbamoyloxy group, N-arylcarbamoyloxy group, N-
It represents an alkylthiocarbamoyloxy group, an N-arylthiocarbamoyloxy group, an alkoxy group, an aralkyloxy group, a branched alkyl group, a cycloalkyl group, or an aryl group, Z represents an oxygen atom; a sulfur atom or a methylene group, and n represents Represents an integer from 0 to 5. ), R^4 represents a hydrogen atom; an alkyl group or an aralkyl group, X represents an oxygen atom or a sulfur atom, and Y
represents an oxygen atom or a sulfur atom. However, when R^4 is a hydrogen atom and Z represents an oxygen atom, R^5 does not represent a hydroxyl group. ] A 6-substituted acyclopyrimidine nucleoside derivative or a pharmaceutically acceptable salt thereof. (2) The following general formula [I ′] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I ′] [In the above formula, R^1 is a hydrogen atom; a halogen atom; an alkyl group; a cycloalkyl group; an alkenyl group; Alkynyl group; alkylcarbonyl group; arylcarbonyl group; arylcarbonylalkyl group; represents an arylthio group or an aralkyl group, R^2 is a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a nitro group, an amino group , an arylthio group, an alkylthio group, a cycloalkylthio group, an arylsulfinyl group, an alkylsulfinyl group, a cycloalkylsulfinyl group, an alkenyl group, an alkynyl group, which may be substituted with one or more substituents selected from a cyano group and an acyl group, represents an aralkyl group, an arylcarbonyl group, an arylcarbonylalkyl group or an aryloxy group,
R^3 is a hydrogen atom; a methyl group; a branched alkyl group or -CH_2-Z-(CH_2)_n-R^5 (in the formula,
R^5 is a hydrogen atom; a halogen atom; a hydroxyl group; a heterocyclic carbonyloxy group; a formyloxy group; an alkylcarbonyloxy group; a cycloalkylcarbonyloxy group; an aralkylcarbonyloxy group; an arylcarbonyloxy group; an azide group or an aryl group; Alkoxycarbonyloxy group, N-alkylcarbamoyloxy group, N-arylcarbamoyloxy group, N-
It represents an alkylthiocarbamoyloxy group, an N-arylthiocarbamoyloxy group, an alkoxy group, an aralkyloxy group, a branched alkyl group, a cycloalkyl group, or an aryl group, Z represents an oxygen atom; a sulfur atom or a methylene group, and n represents Represents an integer from 0 to 5. ), and Y represents an oxygen atom or a sulfur atom. ] A 6-substituted acyclopyrimidine nucleoside derivative or a pharmaceutically acceptable salt thereof. (3) An antiviral agent comprising the 6-substituted acyclopyrimidine nucleoside derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. (4) An antiviral agent comprising the 6-substituted acyclopyrimidine nucleoside derivative according to claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient.