JPH0751567B2 - 6-Substituted acyclopyrimidine nucleoside derivative and antiviral agent containing the derivative as an active ingredient - Google Patents

Description

TECHNICAL FIELD 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 Prior Art and Invention]

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

In addition, 2 ', 3'-dideoxyribonucleoside is known as a nucleoside compound showing antiretroviral activity, but it is desired to develop a substance having higher activity and low toxicity to host cells (Mitsuya Hiroaki, Biological Defense, Volume 4, pages 213-223, 1987).

On the other hand, since acyclovir (acycloguanosine) was developed as an antiviral agent against herpes virus, various acyclonucleoside compounds have been synthesized [CKChu and SJCulter, J. Heterocyclic Ch
em., 23 , 289 (1986)], particularly a compound exhibiting effective activity against retroviruses has not yet been found.

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

Conventionally, as a 6-substituted acyclopyrimidine nucleoside, a 6-fluorine-substituted product, a 6-alkylamino-substituted product, etc. (East German Published Patent No. 232492), or a 6-methyl-substituted product (CA 107 , 129717 w (1987)) However, there is no description of antiviral activity.

[Means for solving problems]

As a result of intensive studies to obtain a compound having antiviral activity, in particular, antiretroviral activity, the present inventors have found that a specific 6-substituted acyclopyrimidine nucleoside compound can achieve the intended purpose. Has been completed.

That is, the gist of the present invention is the following general formula [I] [In the above formula, R ¹ is an alkyl group; a cycloalkyl group; an alkenyl group which may have one or more substituents selected from a phenyl group, a halogen atom, a cyano group, an alkoxycarbonyl group and a carbamoyl group; phenyl An alkynyl group which may be substituted with a group; an alkylcarbonyl group;
Arylcarbonyl group; arylcarbonylalkyl group; represents an arylthio group or an aralkyl group, and R ² is selected from 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 and an acyl group. Arylthio group, alkylthio group, cycloalkylthio group, arylsulfinyl group, alkylsulfinyl group, cycloalkylsulfinyl group, alkenyl group, alkynyl group, aralkyl group, arylcarbonyl group, aryl which may be substituted with one or more substituents Represents a carbonylalkyl group or an aryloxy group, R ³ is 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; Ring carbonyloxy group; formyloxy ; Alkylcarbonyloxy group;
Cycloalkylcarbonyloxy group; aralkylcarbonyloxy group; arylcarbonyloxy group; azido group; or even if substituted with one or more substituents selected from aryl group, halogen atom, alkyl group, alkoxy group and halogenated alkyl group Good alkoxycarbonyloxy group, N-alkylcarbamoyloxy group, N-
Represents an arylcarbamoyloxy group, an N-alkylthiocarbamoyloxy group, an N-arylthiocarbamoyloxy group, an alkoxy group, an aralkyloxy group, a branched alkyl group, a cycloalkyl group or an aryl group, Z is an oxygen atom; a sulfur atom or It represents a methylene group, and n represents an integer of 0 to 5. ), R ⁴ represents a hydrogen atom, X represents an oxygen atom or a sulfur atom,
Y represents an oxygen atom or a sulfur atom. However, when Z represents an oxygen atom or a methylene group, R ⁵ does not represent a hydroxyl group. ] A 6-substituted acyclopyrimidine nucleoside derivative represented by: or a pharmaceutically acceptable salt thereof, and an antiviral agent containing the derivative as an active ingredient.

Hereinafter, the present invention will be described in detail.

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

Specifically, R ¹ is an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, and an n-butyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,
Cycloalkyl groups such as cyclohexyl group and cycloheptyl group; alkenyl groups such as vinyl group, propenyl group, butenyl group, phenylvinyl group, bromovinyl group, cyanovinyl group, alkoxycarbonylvinyl group, carbamoylvinyl group; ethynyl group: propynyl group, Alkynyl groups such as phenylethynyl groups; acetyl groups, propionyl groups,
Represents an alkylcarbonyl group such as an isobutyryl group; an arylcarbonyl group such as a benzoyl group and a naphthoyl group; an arylcarbonylalkyl group such as a phenacyl group; an arylthio group such as a phenylthio group, a tolylthio group, a naphthylthio group; and an aralkyl group such as a benzyl group .

R ² is an arylthio group such as a phenylthio group or a naphthylthio group; a methylthio group, an ethylthio group, a propylthio group,
Butylthio group, pentylthio group alkylthio group; cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, etc. cycloalkylthio group; phenylsulfinyl group, etc. arylsulfinyl group; methylsulfinyl group, ethylsulfinyl group, butylsulfinyl group, etc. alkyl Sulfinyl group; cycloalkylsulfinyl group such as cyclopentylsulfinyl group, cyclohexylsulfinyl group; alkenyl group such as vinyl group, propenyl group, phenylvinyl group; alkynyl group such as ethynyl group, propynyl group, phenylethynyl group; aralkyl such as benzyl group Group; represents an arylcarbonyl group such as a benzoyl group, an arylcarbonylalkyl group such as a phenacyl group; or an aryloxy such as a phenyloxy group, and these groups are salts Atom, halogen atom such as bromine atom, fluorine atom, iodine atom, alkyl group such as methyl group, ethyl group, propyl group, butyl group, pentyl group, halogenated alkyl group such as trifluoromethyl group, methoxy group, ethoxy group It may be substituted with one or more substituents selected from an alkoxy group such as a propoxy group and a butoxy group, a hydroxyl group, a nitro group, an amino group, an acyl group such as a cyano group or an acetyl group.

R ³ is i- propyl, t- butyl alkyl or -CH ₂ -Z- (CH ₂₎ branched groups such represent _n -R ^5, R ⁵ is a hydrogen atom; a fluorine atom, a chlorine atom, iodine Atom, halogen atom such as bromine atom; hydroxyl group: heterocyclic carbonyloxy group such as nicotinoyloxy group; formyloxy group;
Alkylcarbonyloxy group which may be branched such as acetoxy group, propionyloxy group, n-butyryloxy group, i-butyryloxy group, valeryloxy group, hexanoyloxy group, heptanoyloxy group, decanoyloxy group; cyclohexylcarbonyl Cycloalkylcarbonyloxy groups such as oxy groups; aralkylcarbonyloxy groups such as benzylcarbonyloxy groups; arylcarbonyloxy groups such as benzoyloxy groups, toluoylcarbonyloxy groups, naphthoylcarbonyloxy groups;
Aryl group such as azido group or phenyl group, toluyl group and naphthyl group, halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n- Halogenated alkyl groups such as butyl and t-butyl groups, methoxy groups, ethoxy groups, n-propoxy groups, i-propoxy groups, n-butoxy groups, alkoxy groups such as t-butoxy groups, and trifluoromethyl groups. A methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, an i-propoxycarbonyloxy group, an n-butoxycarbonyloxy group, t, which may be substituted with one or more substituents selected from alkyl groups. -Alkoxycarbonyloxy groups such as butoxycarbonyloxy group; phenyl group, toluyl group, sodium An aryl group such as a chill group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group and the like. One or more substituents selected from alkyl groups, methoxy groups, ethoxy groups, n-propoxy groups, i-propoxy groups, n-butoxy groups, alkoxy groups such as t-butoxy groups, and halogenated alkyl groups such as trifluoromethyl groups. Optionally substituted with a group,
N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-propylcarbamoyloxy group, N
-N-alkylcarbamoyloxy groups such as butylcarbamoyloxy group and N-pentylcarbamoyloxy group;
Aryl groups such as phenyl group, toluyl group, naphthyl group,
Fluorine atom, chlorine atom, bromine atom, halogen atom such as iodine atom, methyl group, ethyl group, n-propyl group, i-
Alkyl group such as propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-
An N-phenylcarbamoyloxy group which may be substituted with one or more substituents selected from a propoxy group, an n-butoxy group, an alkoxy group such as a t-butoxy group, and a halogenated alkyl group such as a trifluoromethyl group, N-arylcarbamoyloxy groups such as N-tolylcarbamoyloxy group; aryl groups such as phenyl group, toluyl group and naphthyl group, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, ethyl group, Alkyl group such as 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-butoxy group, etc. N, which may be substituted with one or more substituents selected from halogenated alkyl groups such as alkoxy group and trifluoromethyl group. Methyl thiocarbamoyl group,
N-alkylthiocarbamoyloxy groups such as N-ethylthiocarbamoyloxy group, N-propylthiocarbamoyloxy group, N-butylthiocarbamoyloxy group, N-pentylthiocarbamoyloxy group; phenyl group,
Toluyl group, aryl group such as naphthyl group, fluorine atom,
Halogen atom such as chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group,
alkyl groups such as n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, alkoxy groups such as t-butoxy group, trifluoromethyl group, etc. N, which may be substituted with one or more substituents selected from halogenated alkyl groups
-N-arylthiocarbamoyloxy groups such as phenylthiocarbamoyloxy group and N-tolylthiocarbamoyloxy group; aryl groups such as phenyl group, toluyl group and naphthyl group, fluorine atom, chlorine atom, bromine atom, iodine atom and the like Alkyl group such as halogen atom, 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, alkoxy group such as t-butoxy group, methoxy group, ethoxy group, n-propoxy group, which may be substituted with one or more substituents selected from halogenated alkyl groups such as trifluoromethyl group, Alkoxy such as i-propoxy group, n-butoxy group, t-butoxy group, n-pentyloxy group, n-hexyloxy group Aryl groups such as phenyl group, toluyl group, naphthyl group, halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group ,
From alkyl groups such as t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, alkoxy groups such as t-butoxy group, halogenated alkyl groups such as trifluoromethyl group A benzyloxy group, which may be substituted with one or more selected substituents,
Aralkyloxy group such as phenethyloxy group; aryl group such as phenyl group, toluyl group, naphthyl group, halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, i -Alkyl group such as propyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, alkoxy group such as t-butoxy group, trifluoro It may be substituted with one or more substituents selected from halogenated alkyl groups such as methyl group,
i-propyl group, i-butyl group, sec-butyl group, t-
Branched alkyl groups such as butyl group, i-heptyl group and i-hexyl group; aryl groups such as phenyl group, toluyl group and naphthyl group, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl Group, ethyl group, n-propyl group, i-propyl group, n-butyl group, alkyl group such as t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, Cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl 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. Groups such as cycloalkyl groups; or aryl groups such as phenyl groups, toluyl groups, naphthyl groups, etc., fluorine atoms, chlorine atoms, bromine atoms A halogen atom such as iodine atom, a methyl group, an ethyl group, n- propyl group, i- propyl radical, n
-Alkyl group such as butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, alkoxy group such as t-butoxy group, halogen such as trifluoromethyl group Represents an aryl group such as a phenyl group which may be substituted with one or more substituents selected from the following alkyl groups.

R ⁴ represents a hydrogen atom.

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], when Z represents an oxygen atom or a methylene group, R ⁵ does not represent a hydroxyl group.

In the compound of the present invention, R ¹ is preferably a C _{1 to} C ₅ alkyl group; a C _{2 to} C ₅ alkenyl group, particularly a C _{1 to} C ₅ alkyl group, and R ² is preferably C ₆ to C ₁₀ arylthio group; C
Cycloalkylthio group or an aralkyl group C ₇ -C ₁₁ of ₃ -C _10, especially alkyl groups of C ₁ -C _5, alkoxy groups C ₁ ~C _{5, 1} or more substituents selected from halogen atom and a nitro group in an arylthio group which have good C ₆ -C ₁₀ be substituted, an aralkyl group having C ₃ cycloalkylthio group or C ₇ -C ₁₁ of -C ₁₀ are preferred. Further, as R ³ , -CH ₂ -Z-
(CH ₂ ) _n —R ⁵ is preferable, and R ⁵ is a hydrogen atom; a halogen atom; a hydroxyl group; a heterocyclic carbonyloxy group; a C _{2 to} C ₁₁ alkylcarbonyloxy group; a C _{4 to} C ₁₀ cyclo group. aralkyloxycarbonyl group of C ₈ -C _10; alkoxycarbonyloxy group C ₂ -C _11; alkylcarbonyloxy group; a C ₇ -C ₁₃ arylcarbonyloxy group, C ₈ -C aralkylcarbonyloxy group _12; C
Of ₂ -C ₈ N-alkylcarbamoyl group; a C ₇ -C ₁₃ N-arylcarbamoyloxy group; a C ₂ -C ₈ N-alkylthiocarbamoyl group; a C ₇ -C ₁₃ N-arylthiocarbamoyl oxy Group; C _{1 to} C ₁₀ alkoxy group; C _{7 to} C ₁₃ aralkyloxy group; azido group; C _{3 to} C ₅
A branched alkyl group of C _{5 to} C ₇ cycloalkyl group; or C optionally substituted with one or more substituents selected from an aryl group, a halogen atom, an alkyl group, an alkoxy group and a halogenated alkyl group. an aryl group having ₆ -C ₁₀ are preferred, Z is an oxygen atom; a suitable sulfur atom or a methylene radical, n is preferably an integer of 0 to 5. R ⁴ is preferably a hydrogen atom, and X and Y are preferably an oxygen atom or a sulfur atom. However, when Z represents an oxygen atom, R ⁵ does not represent a hydroxyl group.

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

In the compound of the present invention represented by the above formula [I], when R ³ represents a branched alkyl group, R ³ represents —CH ₂ —Z— (C
H ₂ ) _n —R ⁵ and R ⁵ is a hydrogen atom, a halogen atom, an azido group, an alkoxy group, an aralkyloxy group, an aryl group which may have a substituent or the like, the following reaction formula (1 ), (2) or (3).

(In the formula, R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined above. Further, X ¹ and X ² represent a halogen atom, an arylthio group, an alkoxy group or the like, and M is an alkali. First, the compound of the general formula [II] or [IV] and an organic alkali metal are mixed in a solvent such as an ether solvent such as diethyl ether or tetrahydrofuran at a temperature of -80 to -10 ° C. Incubate for 0.2-10 hours. Examples of the organic alkali metal include potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, and lithium alkylamide, and particularly lithium diisopropylamide (LDA) and lithium 2,2,6,6-tetramethylpiperidin (LTMP) is preferred. It is preferable to use the lithium alkylamide prepared immediately before the reaction. For example, a secondary amine such as diisopropylamine and an alkyllithium such as n-butyllithium in a solvent such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, an inert gas,
For example, 0.2 to 5 at -80 to -10 ° C in the presence of argon gas.
Those that are reacted with stirring for a period of time are preferred.

This organic alkali metal is usually used in the range of 1 to 5 mol per 1 mol of the compound of the general formula [II] or [IV].

Subsequently, various electrophiles, that is, compounds represented by the general formula R ² X ¹ or R ¹ X ² are added to the general formula [II] or [IV].
1 to 5 mol per 1 mol of the compound described above and reacted under the same reaction conditions as the above-mentioned organic alkali metal.

The electrophile contains R ² or R ¹ defined above, and includes, for example, various diaryl disulfides, arylsulfenichlorides, 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, arylcarbonylalkyl halides such as phenacyl chloride, and halogens. .

The compound of general formula [II] can be prepared according to a known method.

The compound of the general formula [IV] is synthesized in the same manner as in the above reaction formula (1) (R ¹ → H).

(In the formula, R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined above, and X ³ is a halogen atom such as chlorine, bromine or iodine, or a sulfonyl group such as a toluenesulfonyloxy group or a mesyloxy group. An oxy group.) That is, the compound represented by (VI) is treated with an acid such as hydrochloric acid or hydrobromic acid at room temperature to 100 ° C. in a suitable solvent such as alcohol such as methanol or ethanol, or water. Reaction at temperature gives compounds of general formula (VII).

Then, the compound of general formula (VII) in a suitable solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran in the presence of a suitable base such as sodium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate and the like. The compound of general formula (VIII) is reacted at a temperature from room temperature to the boiling point of the solvent to obtain the compound of general formula (I).

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

When R ⁵ is a hydroxyl group or an intermediate having a hydroxyl group in the compound of the present invention, a starting material obtained by protecting the hydroxyl group with an appropriate protecting group instead of the compound of the general formula (II) or (IV) In the same manner as in the reaction formula (1) or (2), and then the protecting group is removed to obtain the target compound.

The protecting group for the hydroxyl group may be any of those commonly used as a protecting group for a hydroxyl group, as long as it does not leave under alkaline conditions.

Specifically, for example, an aralkyl group such as a benzyl group, a trityl group, a monomethoxytrityl group, a dimethoxytrityl group, and a trimethoxytrityl group, a trimethylsilyl group, a triethylsilyl group, a t-betyldimethylsilyl group, a t-butyldiphenyl group. Examples thereof include a silyl group, a silyl group such as a dimethylphenylsilyl group, and a substituted alkyl group such as a tetrahydropyranyl group and a methoxymethyl group, and a silyl group is particularly preferable.

The protecting group can be introduced according to a conventional method.

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

Removal of the protecting group is a known method depending on the protecting group used,
For example, an acid hydrolysis method, ammonium fluoride treatment, a catalytic reduction method or the like can be appropriately selected and carried out.

Among the compounds obtained by the above method (1), (2) or (3), those in which the 6-position is substituted with a phenylthio group and which has a nitro group on the benzene ring are represented by the following reaction formula (4). Thus, it can be converted to an amino group by hydrogenation. Hydrogenation is carried out in the presence of a catalyst such as palladium carbon in an organic solvent such as alcohol or acetic acid at a suitable temperature from room temperature to 80 ° C.

(The substituents in the above formula are as defined above.) As shown in the following reaction formula (5), an arylthio group,
The alkylthio group and the cycloalkylthio group can be converted into the corresponding arylsulfinyl group, alkylsulfinyl group and cycloalkylsulfinyl group by an oxidizing agent such as hydrogen peroxide and metachloroperbenzoic acid.

(In the above formula, R ⁶ represents an aryl group, an alkyl group or a cycloalkyl group. Other substituents are as defined above.) Further, as shown in the following reaction formula (6), the phenyl sulfoxide derivative and the benzene ring Arylthiosodium salt or aryloxysodium salt having various substituents in tetrahydrofuran, alcohol, dimethylformamide, acetonitrile or the like organic solvent at room temperature to 100
It can be converted into the corresponding substituted arylthio group by reacting at a suitable temperature of ° C.

(In the above formula, A represents a sulfur atom or an oxygen atom, R ⁷ and R ⁸ are halogen atoms such as chlorine atom, bromine atom, fluorine atom and iodine atom; alkyl such as methyl group, ethyl group, propyl group and butyl group. Group; halogenated alkyl group such as trichloromethyl group; alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; hydroxyl group; nitro group; amino group; cyano group; acyl group such as acetyl group. Other substituents are as defined above.) The compound of the present invention can be synthesized, for example, according to the following reaction formula (7) or (8).

(In the above formula, R ⁹ represents an alkyl group such as a methyl group and an ethyl group; an aryl group such as a phenyl group and a toluyl group; a protecting group such as a silyl group, and the other substituents are as defined above.) The reactions of the 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 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 the catalyst, cuprous iodide can be used in combination with a palladium solvent such as bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium (O), bis (diphenylphosphino) ethane / palladium dichloride and the like. .

Further, the compound of the present invention is, for example, an olefin compound H ₂ C═CH—R ¹⁰ (wherein R ¹⁰ is an alkoxycarbonyl group, a nitrile group, a carbamoyl group or the like instead of the acetylene compound in the above reaction formulas (7) and (8) .) Can be synthesized according to the following reaction formulas (9) and (10).

(The substituents in the above formula are as defined above.) (The substituents in the above formula are as defined above.) Regarding the palladium catalyst, the above reaction formulas (7) and (8) are used.
As described in.

The compound of the present invention can be synthesized, for example, by the following reaction formula (11).

(In the above formula, X ⁴ represents a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. The other substituents are as defined above.) The compound of the present invention can be represented by, for example, the following reaction formula (12). Alternatively, it can be synthesized according to (13).

(The substituents in the above formula are as defined above.) That is, instead of R ¹ X ² or R ² X ^{1 in} the above reaction formula (1) or (2). (However, R ¹¹ and R ^{12 each} 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.) The intermediate is dehydrated with a dehydrating reagent (mesyl chloride, tosyl chloride, thionyl chloride, etc.) to introduce an alkenyl group.

The compound having the alkynyl group of the compound having an alkynyl group synthesized by the above reaction formula (7) or (8) has the corresponding alkenyl group or alkyl group, and the alkenyl group synthesized by the reaction formulas (9) to (13). The alkenyl group can be converted to the corresponding alkyl group by a hydrogenation reaction. Reduction to an alkenyl group is carried out in alcohol or acetic acid using a catalyst such as palladium-barium sulfate, palladium-calcium carbonate, palladium-calcium carbonate-lead acetate, palladium-barium sulfate-quinoline system in a hydrogen gas atmosphere at room temperature to 80%. It can be carried out at a suitable temperature of ° C.

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

The 6-position benzyl derivative in the compound of the present invention can be synthesized by the following reaction formula (14).

(The substituents in the above formula are as defined above.) That is, in place of R ¹ X ^{2 in} the above reaction formula (1) (However, R ¹³ represents an aryl group such as a phenyl group which may have a substituent.) Can be obtained by using a suitable reducing agent from an intermediate obtained by a similar reaction treatment. This is a method of replacing a hydroxyl group with hydrogen. Examples of the reduction method include a method using hydrogen in the presence of palladium carbon or palladium hydroxide.

The 6-substituted acyclouridine or acyclothymidine derivative obtained by these reactions is 2,4-bis (4-methoxyphenyl) -1,2 in toluene or xylene as shown in the following reaction formula (15). It can be converted to the corresponding 4-thio derivative by heating with 3-dithia-2,4-diphosphetane-2,4-disulfide.

(Substituents in the above formula are as defined above.) The 4-thio derivative is a uridine or thymidine derivative.
It can also be obtained by converting the 4-chloro form with phosphorus chloride or phosphorus oxychloride and then reacting with sodium hydrogen sulfide.

In the compounds obtained by the reaction formulas (1) to (15), those in which R ⁵ is a hydroxyl group can be derived to the corresponding substituted hydroxyl group as shown in the following reaction formulas (16) to (19).

(16) (In the above formula, R ¹⁴ represents an alkyl group which may be branched, an aryl group which may have a substituent, or a substituent of a heterocycle, X ⁶ is a halogen such as chlorine, bromine or iodine. Atom or Represents The other substituents are as defined above. The above reaction is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform and the like in the presence of 1 to 2 times the amount of the 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 and the like can be used.

(17) (In the above formula, R ¹⁵ represents an alkyl group which may be branched, or an aralkyl group, X ⁷ is a halogen atom such as chlorine, bromine or iodine, or Represents The other substituents are as defined above. The above reaction is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane or chloroform at a suitable temperature from room temperature to the boiling point of the solvent in the presence of 1 to 2 times the amount of the base. As the base, triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydride and the like can be used.

(18) (In the formula, R ¹⁶ represents an alkyl group which may be branched or an aralkyl group, and X ⁸ represents a halogen atom such as chlorine, bromine or iodine, 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, dichloromethane, chloroform or the like from room temperature in the presence of 1 to 2 volumes of a base. It is carried out at a suitable temperature up to the boiling point. As the base, triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydride and the like can be used.

(19) (In the above formula, R ¹⁷ represents an optionally branched alkyl group or an allyl group, X ⁹ represents an oxygen atom or a sulfur atom, and the other substituents are as defined above.) It is carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane, chloroform or the like 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 [I] thus obtained can be separated and purified by an ordinary method for separating and purifying nucleosides, for example, recrystallization, adsorption or ion exchange chromatography.

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

The compound 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 retrovirus and the like. The dose is appropriately determined according to the age, health condition, weight, etc. of the patient, but generally a suitable dose is 1 to 100 mg / kg per day.
Body weight, preferably selected from the range of 5 to 50 mg / kg body weight, is administered once or in divided doses.

In formulating the compound of the present invention, it is usually used as a composition containing a commonly used carrier for formulation, an excipient, and other additives. The carrier may be solid or liquid. Examples of the solid carrier include lactose, white clay (kaolin), sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride and the like.

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

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

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The novel 6-substituted acyclopyrimidine nucleoside derivative of the present invention has effective activity against retroviruses and the like, and has relatively low toxicity to host cells, and therefore can be effectively used as an antiviral agent.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples. However, 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.

In addition, 1-[(2-hydroxyethoxy) methyl] -6-phenylthio-2-thiothymine, 1-[(2-hydroxyethoxy) methyl] -6-phenylthiothymine, 1-[(described in Examples. 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-cyclohexylthiothymine, 1-[(2-hydroxy Ethoxy) methyl] -6-m-
Starting materials such as tolylthiothymine were obtained by the method described in the examples of WO89 / 09213.

Example 1 Preparation of 1-[(2-acetoxyethoxy) methyl] -6-phenylthio-2-thiothymine (Compound No. 1) 1-[(2-hydroxyethoxy) methyl]-in 2 ml of pyridine under a nitrogen stream. 0.31 g (1.0 mmol) of 6-phenylthio-2-thiothymine and 0.10 ml (1.1 mmol) of acetic anhydride were added, the mixture was reacted at room temperature for 2 hours, concentrated to dryness under reduced pressure, and crystallized from ethanol-water to give the desired compound 0.62. g (88% yield)
Got

Examples 2 to 6 In Example 1, 1-[(2-hydroxyethoxy)
Instead of 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 was used to obtain compounds No. 2 to No. 6 in Table 1 by the same method as in Example 1.

Examples 7 to 13 Example 2 except that ethyl formate, isobutyryl chloride, pivaloyl chloride, decanoyl chloride, cyclohexanecarbonyl chloride, benzoyl chloride, nicotinyl chloride were used in place of acetic anhydride in Examples 2 to 13.
Compounds Nos. 7 to 13 in Table 1 were obtained by the same method as described above.

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

Example 15 Instead of 1-[(2-hydroxyethoxy) methyl] -6-phenylthiothymine in Example 2, 1-[(2
-Hydroxyethoxy) methyl] -6-cyclohexylthiothymine and a compound by the same method except that benzyloxycarbonyl chloride was used instead of acetic anhydride.
I got No.15.

Example 16 Preparation of 1-[(2-phenylcarbamoyloxyethoxy) methyl] -6-m-tolylthiothymine (Compound No. 16) 1-[(2-hydroxyethoxy) methyl in 2 ml of pyridine under nitrogen atmosphere. ] -6-m-tolylthiothymine 0.32 g
(1.0 mmol) and phenyl isocyanate 0.12 ml (1.1 mmo
l) was added and the mixture was 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 of the desired compound (yield 54%).

Examples 17 to 18 Compound Nos. 17 and 18 were obtained by the same method as in Example 16 except that ethyl phenyl and phenyl thioisocyanate were used instead of phenyl isocyanate.

Example 19 1-[(2-benzyloxyethoxy) methyl] -6-
Production of Phenylthiothymine (Compound No. 19) To 4 ml of tetrahydrofuran was added 0.17 g (4.2 mmol) of sodium hydride under a nitrogen stream, and the mixture was stirred. To this suspension was added 1-[(2-hydroxyethoxy) methyl] -6-phenylthiothymine, 0.62 g (2.0 mmol) of tetrahydrofuran.
A 2 ml solution was added slowly and the reaction was allowed to proceed for 45 minutes at room temperature.
To this, 0.24 ml (2.0 mmol) of benzyl bromide and 7.4 mg (20 μmol) of tetrabutylammonium iodide were added and reacted for 15 hours. The reaction mixture was neutralized with acetic acid, partitioned with chloroform-saturated aqueous sodium hydrogen carbonate solution, and the chloroform layer was concentrated to dryness under reduced pressure. Dissolve the residue in a small amount of chloroform, adsorb it on a silica gel column, and
Elute with methanol-chloroform, concentrate and crystallize from diethyl ether-hexane to give the desired compound 0.64 g.
(Yield 80%) was obtained.

Examples 20 to 21 Compound Nos. 20 and 21 were 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 No. 22) In 250 ml of methylene chloride, 25 g of thymine (0.20) under a nitrogen atmosphere.
mol) and bistrimethylsilylacetamide 109 ml (0.
44 mol) was added and the mixture was stirred at room temperature for 2 hours and 30 minutes. Next, add 24 g (0.30 mol) of chloromethyl methyl ether and 0.59 g (1.6 mmol) of tetrabutylammonium iodide and add 1
Refluxed for 30 minutes. 400 ml of methanol and 100 ml of water were slowly added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1- (methoxymethyl) -thymine. Then, 119 ml (0.25 mol) of lithium diisopropylamide tetrahydrofuran solution (2.1M) was added to 335 ml of tetrahydrofuran at -70 ° C under a nitrogen stream,
Next, a suspension of 17.0 g (0.10 mol) of 1- (methoxymethyl) thymine in 107 ml of tetrahydrofuran was added dropwise over 30 minutes. After reacting at -70 ° C for 2 hours and 30 minutes, a solution of 43.6 g of diphenyl disulfide in 49 ml of tetrahydrofuran was added dropwise over 20 minutes, and the reaction was performed for 20 minutes. Acetic acid in the reaction mixture 35
After adding ml, the mixture was returned to room temperature and 1 ethyl acetate was added.
The extract was washed 5 times with 100 ml of water and twice with saturated sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethanol to give 20 g of the target compound (yield 73
%) Was obtained.

Examples 23 to 26 In Example 22, 1- (ethoxymethyl) thymine, 1-[(2-azidoethoxy) methyl] thymine, 1-[(2-fluoroethoxy) methyl instead of 1- (methoxymethyl) thymine were used. ] Nos. 23 to 26 were obtained by the same method except that thymine and 1-[(2-chloroethoxy) methyl] thymine were used.

Example 27 Production of 6-phenylthiothymine (Compound No. 27) To 100 ml of concentrated hydrochloric acid, 17.2 g (62 mmol) of 1- (methoxymethyl) -6-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 No. 28)
Preparation of 6-phenylthiothymine 20 mg (85 μmol) and methyl iodide 2.5 μl in a nitrogen atmosphere in 1 ml of dimethyl sulfoxide.
(40 μmol) and potassium carbonate 12 mg (85 μmol) were added,
The reaction was carried out at 80 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, adsorbed on a silica gel column, and then eluted with 1% methanol-chloroform. This was crystallized from diisopropyl ether to obtain 5.0 mg of the target compound (yield 51%).

Examples 29 to 30 Compound Nos. 29 and 30 were 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 Preparation of 1- (4-hydroxybutyl) -6-phenylthiothymine (Compound No. 31) In 2 ml of dimethyl sulfoxide, under nitrogen atmosphere, 6-phenylthiothymine 468 mg (2.0 mmol), 4- (t- Butyldimethylsiloxy) -butyl p-toluene sulfonate 35
8 mg (1.0 mmol) and potassium carbonate 276 mg (2.0 mmol) were added, and it heated at 80 degreeC for 4 hours. The reaction mixture was evaporated under reduced pressure,
Methanol was added to the residue. This was filtered, the filtrate was evaporated under reduced pressure, tetrahydrofuran (20 ml) and 1N hydrochloric acid (1 ml) were added, and the mixture was 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 give the desired compound 1
2.0 mg (yield 4%) was obtained.

Example 32 Preparation of 1- (methylthiomethyl) -6-phenylthiothymine (Compound No. 32) 4 ml of dimethylformamide under a nitrogen atmosphere 0.17 ml (2.0 mmol) of chloromethyl methyl sulfide, 0.47 g of 6-phenylthiothymine (2.0 mmol) and triethylamine 0.
After adding 56 ml (2.0 mmol) and reacting at room temperature for 22 hours,
It was concentrated under reduced pressure. Adsorb the residue on a silica gel column,
After eluting with chloroform, it was crystallized from ethyl acetate to obtain 43 mg of the target compound (yield 8%).

Example 33 Preparation of 1-[(2-hydroxyethoxy) methyl] -3-benzyl-6-phenylthiothymine (Compound No. 33) 1-[(2-hydroxyethoxy) methyl] -6- in 2 ml of dimethylformamide. Phenylthiothymine 0.62 g (2.0
mmol), 0.26 ml (2.2 mmol) of benzyl bromide and 0.38 ml (2.2 mmol) of ethyldiisopropylamine were added, and the mixture was reacted at room temperature for 5 days under a nitrogen atmosphere, and then concentrated to dryness under reduced pressure. The residue is adsorbed on a silica gel column and eluted with 1% methanol-chloroform to give 0.24 g of the desired compound.
(Yield 30%) was obtained.

Example 34 Compound No. 34 was obtained in the same manner as in Example 33 except that methyl iodide was used instead of benzyl bromide.

Example 35 Preparation of 1-ethoxymethyl-5-ethyl-6-phenylthiouracil (Compound No.247) 5.1 g (40 mmol) of 5-ethyluracil and 22 ml (88 mmol) of bistrimethylsilylacetamide in 100 ml of methylene chloride under nitrogen atmosphere. Was added, and the mixture was stirred at room temperature for 40 minutes. Next, 4.1 ml (88 mmol) of chloromethyl ethyl ether and 0.15 g (0.4 mmol) of tetrabutylammonium iodide were added,
Refluxed for 15 hours. The reaction mixture was carefully poured into 50 ml of saturated aqueous sodium hydrogen carbonate, and filtered through Celite. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1-ethoxymethyl-5-ethyluracil.
6.4 g (81%) was obtained.

Then, in 6 ml of tetrahydrofuran, under nitrogen atmosphere, at -70
2.2 ml (4.4 mmol) of a lithium diisopropylamide tetrahydrofuran solution (2.1M) was added at 0 ° C, and then a tetrahydrofuran 3 ml solution of 0.40 g (2.0 mmol) of 1-ethoxymethyl-5-ethyluracil was added dropwise over 15 minutes. −70
After reacting at ℃ for 1 hour, diphenyl disulfide 0.57
A solution of g (2.6 mmol) in tetrahydrofuran (2 ml) was added dropwise over 10 minutes, and the reaction was carried out for 30 minutes. 1 ml acetic acid in the reaction mixture
Was added, the temperature was returned to room temperature, and 30 ml of ethyl acetate was added.
The extract was washed 5 times with 3 ml of water and twice with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane = 3: 17), crystallized from ethyl acetate and 1-ethoxymethyl-5-
0.61 g (32%) of ethyl-6-phenylthiouracil was obtained.

Example 36 Compound No. 357 was obtained in the same manner as in Example 35 except that 3,3 ′, 5,5′-tetramethyldiphenyldisulfide was used instead of diphenyldisulfide.

Example 37 1-Ethoxymethyl-5-ethyl-6-phenylthio-
Preparation of 2-thiouracil (Compound No. 358) 2-thiouracil in 100 ml of methylene chloride under nitrogen atmosphere
5.1 g (40 mmol) and bistrimethylsilylacetamide
22 ml (88 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. Next, 8.2 ml (88 mmol) of chloromethyl ethyl ether and 0.15 g (0.4 mmol) of tetrabutylammonium iodide were added, and 15
Reflux for hours. The reaction mixture was carefully poured into 50 ml of saturated aqueous sodium hydrogen carbonate, and filtered through Celite. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and 1.1 g of 1-ethoxymethyl-2-thiouracil was added.
(15%) obtained.

Then, in 9 ml of tetrahydrofuran, under nitrogen atmosphere, at -70
3.3 ml (6.6 mmol) of 2.1M lithium diisopropylamide terahydrofuran solution was added at 0 ° C., and then a solution of 0.56 g (3.0 mmol) of 1-ethoxymethyl-2-thiouracil in 3 ml of tetrahydrofuran was added dropwise over 15 minutes. After reacting at -70 ℃ for 1 hour, 0.85g of diphenyl disulfide (3.9mm
1 ml of tetrahydrofuran solution was added dropwise over 10 minutes and reacted for 20 minutes. 1 ml of acetic acid was added to the reaction mixture, the temperature was returned to room temperature, and 30 ml of ethyl acetate was added. 3 ml of water
5 times, and twice with saturated aqueous sodium hydrogen carbonate, 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 0.64 g (73%) of 1-ethoxymethyl-6-phenylthio-2-thiouracil.

Next, 2,2,6,6-tetramethylpiperidine 0.57 ml (3.4 mm
ol) in 8 ml of tetrahydrofuran under a nitrogen atmosphere,
2.1 ml of butyllithium-hexane solution (1.6M) (3.
4 mmol) was added, the temperature was raised to −50 ° C., and the mixture was stirred for 20 minutes. After returning to −70 ° C. again, a solution of 0.44 g (1.5 mmol) of 1-ethoxymethyl-6-phenylthio-2-thiouracil in 4 ml of tetrahydrofuran was added dropwise over 15 minutes. After 1 hour, 1.2 ml (15 mmol) of ethyl iodide was added and stirred for 19 hours. 1 ml of acetic acid was added to the reaction mixture, returned to room temperature, 30 ml of ethyl acetate was added, 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) and crystallized from ethyl acetate to give 96 mg (20%) of the title compound.
%) Was obtained.

Example 38 Instead of diphenyl disulfide in Example 37, 3,
Compound No. 359 was obtained by the same method except that 3 ', 5,5'-tetramethyldiphenyl disulfide was used.

Example 39 Compound No. 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 By the same method 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. Compound No. 361 was obtained.

Example 41 Compound NO.362 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 No. 41 was obtained in the same manner as in Example 22 except that chloromethylpropyl ether was used instead of chloromethyl methyl ether.

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

Example 44 Instead of diphenyl disulfide in Example 35,
Compound No. 365 was obtained by the same method except that 3,3 ′, 5,5′-tetrachlorodiphenyl disulfide was used.

Example 45 The same as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil, and 3,3 ′, 5,5′-tetrachlorodiphenyldisulfide was used instead of diphenyldisulfide. Compound No. 366
Got

Example 46 Compound No. 496 was obtained in the same manner as in Example 35 except that 5-isopropyluracil was used instead of 5-ethyluracil.

Example 47 Compound No. 497 was obtained in the same manner as in Example 35 except that 5-isopropyl-2-thiouracil was used instead of 5-ethyluracil.

Example 48 Compound No. 574 was obtained in the same manner as in Example 35 except that 5-cyclopropyluracil was used instead of 5-ethyluracil.

Example 49 Compound No. 575 was obtained by the same method as in Example 35 except that 5-cyclopropyl-2-thiouracil was used instead of 5-ethyluracil.

Example 50 Compound No. 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 Compound No. 676 was obtained in the same manner as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and chloromethylisopropyl ether was used instead of chloromethylethyl ether. .

Example 52 Compound No. 685 was obtained in the same manner as in Example 35 except that chloromethylcyclohexyl ether was used instead of chloromethyl ethyl ether.

Example 53 Compound No. 686 was obtained in the same manner as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and chloromethylcyclohexyl ether was used instead of chloromethyl ethyl ether. .

Example 54 Compound No. 689 was obtained in the same manner as in Example 35 except that chloromethylcyclohexyl methyl ether was used instead of chloromethyl ethyl ether.

Example 55 Compound No. 690 was obtained in the same manner as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and chloromethylcyclohexylmethyl ether was used instead of chloromethylethyl ether. It was

Example 56 Compound No. 512 was obtained by the same method as in Example 35 except that 5-isopropyluracil was used instead of 5-ethyluracil and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether.

Example 57 Compound No. 513 was obtained by the same method as in Example 35 except that 5-isopropyl-2-thiouracil was used instead of 5-ethyluracil and benzyl chloromethyl ether was used instead of chloromethyl ethyl ether. .

Example 58 Compound No. 748 was obtained by the same method as in Example 35 except that chloromethylphenethyl ether was used instead of chloromethylethyl ether.

Example 59 Compound No. 749 was obtained by the same method as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and chloromethylphenethyl ether was used instead of chloromethylethyl ether. .

Example 60 In Example 35, 5-ethyl-2-thiouracil was used in place of 5-ethyluracil, and chloromethyl (4-methylbenzyl) was used in place of chloromethyl ethyl ether.
Compound No. 372 was obtained by the same method except that ether was used.

Example 61 A compound No. was prepared in the same manner as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and 4-chlorobenzil chloromethyl ether was used instead of chloromethyl ethyl ether. I got .704.

Example 62 Preparation of 6-benzyl-1-ethoxymethyl-5-ethyluracil (Compound No. 472) 5.1 g (40 mmol) of 5-ethyluracil and 22 ml (88 mmol) of bistrimethylsilylacetamide were added to 100 ml of methylene chloride under a nitrogen atmosphere. The mixture was added and stirred at room temperature for 40 minutes. Next, 4.1 ml (88 mmol) of chloromethyl ethyl ether and 0.15 g (0.4 mmol) of tetrabutylammonium iodide were added,
Refluxed for 15 hours. The reaction mixture was carefully poured into 50 ml of saturated aqueous sodium hydrogen carbonate, and filtered through Celite. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1-ethoxymethyl-5-ethyluracil.
6.4 g (81%) was obtained.

Then, in 6 ml of tetrahydrofuran, under nitrogen atmosphere, at -70
2.2 ml (4.4 mmol) of a lithium diisopropylamide tetrahydrofuran solution (2.1M) was added at 0 ° C, and then a tetrahydrofuran 3 ml solution of 0.40 g (2.0 mmol) of 1-ethoxymethyl-5-ethyluracil was added dropwise over 15 minutes. −70
After reacting at ℃ for 1 hour, benzaldehyde 0.27g (2.6
2 ml of tetrahydrofuran) solution was added dropwise over 10 minutes and reacted for 30 minutes. 1 ml of acetic acid was added to the reaction mixture, the temperature was returned to room temperature, and 30 ml of ethyl acetate was added. 3 ml of water
5 times, and twice with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure.

This was dissolved in ethanol (10 ml), 20% palladium hydroxide-carbon (20 mg) was added, and the mixture was stirred and reacted at 55 ° C for 1 day in a hydrogen atmosphere, and the catalyst was filtered off and concentrated. The residue was crystallized from hexane to obtain 0.28 g (85%) of 6-benzyl-1-ethoxymethyl-5-ethyluracil.

Example 63 Compound No. 474 was obtained in the same manner as in Example 62 except that 3,5-dimethylbenzaldehyde was used instead of benzaldehyde.

Example 64 Preparation of 1-butyl-5-ethyl-6-phenylthiouracil (Compound No. 252) 5.5 g (40 mmol) of potassium carbonate and n-iodobutane were added to a solution of 5.6 g (40 mmol) of 5-ethyluracil in 60 ml of dimethylformamide. 2.3 ml (20 mmol) was added, and the mixture was stirred at 120 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure, partitioned with dichloromethane and an aqueous solution of ammonium chloride, and the organic layer was concentrated under reduced pressure. The residue was adsorbed on a silica gel column and eluted with 30% ethyl acetate / hexane to give 1-butyl-5-ethyluracil 2.7 g (yield 69%).

Next, 392 mg of 1-butyl-5-ethyluracil (2.0 mmo
l) in a solution of 9 ml of tetrahydrofuran in a nitrogen atmosphere,
At 70 ° C, a solution of lithium diisopropylamide (4.4 mmol) in 2.8 ml of tetrahydrofuran was added dropwise over 10 minutes, and -70
The mixture was stirred at 70 ° C for 70 minutes and at -25 ° C for 5 minutes. The mixture was returned to −70 ° C., a solution of 567 mg (2.6 mmol) of diphenyl disulfide in 3 ml of tetrahydrofuran was added, and after stirring for 20 minutes, 1 ml of acetic acid was added, the mixture was returned to room temperature, washed with saturated saline, 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 obtain 1 mg of butyl-5-ethyl-6-phenylthiouracil (yield 7%).

Example 65 Compound No. 363 was prepared in the same manner as in Example 35 except that 5-ethyl-2-thiouracil was used instead of 5-ethyluracil and dibenzyl chloromethyl ether was used instead of chloromethyl ethyl ether. Obtained.

Example 66 In Example 35, 5-ethyl-2-thiouracil was used in place of 5-ethyluracil, benzyl chloromethyl ether was used in place of chloromethyl ethyl ether, and 3,3 ', 5 ,, in place of diphenyl disulfide. 5'-
Compound No. 364 was obtained by the same method except that tetramethyldiphenyl disulfide was used.

No. 35 ~ 40, 42 ~ 246, 248 ~ 251, 253 ~ listed in Table 1 above
269,271 ~ 356,367 ~ 371,373 ~ 471,473,475 ~ 484,486 ~ 4
95,498 ~ 511,514 ~ 573,576 ~ 674,677 ~ 684,687,688,691
The compounds of -703,705 to 747,750 to 803 can be similarly synthesized according to the method described in the above-mentioned Examples.

Example 67 5- (2 ( E ) bromovinyl) -1- (ethoxymethyl) -6- (phenylthio) uracil (Compound No. 270)
Preparation of 5-iodouracil 4.76 g (20 mmol) of dichloromethane 5
It was suspended in 0 ml, 11 ml (45 mmol) of bistrimethylsilylacetamide was added thereto, and the mixture was stirred at room temperature for 15 minutes to obtain a uniform solution. 2.04 ml of chloromethyl ethyl ether
(22 mmol) and tetra-n-butylammonium iodide 60 mg were added, and the mixture was 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 in hot methanol, cooled, and filtered to obtain 5.43 g of 1- (ethoxymethyl) -5-iodouracil.

Then, 1- (ethoxymethyl) -5-iodouracil 1.
184g (4mmol), 870μl of ethyl acrylate (8m
mol), palladium acetate 45 mg and triethylamine 0.6 ml
Was dissolved in 40 ml of DMF, and the mixture was heated with stirring at 70 ° C. for 5 hours. After distilling off the solvent, it was adsorbed on a silica gel column and eluted with a dichloromethane-ethyl acetate (1: 1 v / v) solution to collect the target fractions, and the solvent was distilled off to give 5- (2- ( E )- Carboethoxyvinyl) -1- (ethoxymethyl) uracil 798m
g was obtained as crystals.

Next, in 8 ml of water at room temperature, 0.16 g of sodium hydroxide (4.0 mmo
l) and 5- (2- ( E ) -carboethoxyvinyl)-
0.54 g (2.0 mmol) of 1- (ethoxymethyl) uracil was added, and the mixture was stirred for 4.5 hours. After neutralization with 1N hydrochloric acid, 10 ml of dimethylformamide was added to make a homogeneous system.

Next, 0.62 g (4.5 mmol) of potassium carbonate was added to this solution,
After stirring at room temperature for 5 minutes and becoming a homogeneous system, 0.36 g (2.0 mmol) of N-bromosuccinimide was added and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, partitioned with chloroform and an aqueous solution of ammonium chloride, and the organic layer was concentrated under reduced pressure. Adsorb the residue on a silica gel column and elute with 20% ethyl acetate / hexane to collect the target fractions.
0.15 g (yield 28%) of-(2- ( E ) -bromovinyl) -1- (ethoxymethyl) uracil was obtained.

Next, in a solution of lithium diisopropylamide (1.22 mmol) in tetrahydrofuran (2.3 ml) at −70 ° C. under a nitrogen atmosphere at 5 ° C.
-(2- ( E ) -Bromovinyl) -1- (ethoxymethyl) uracil 0.15 g (0.56 mmol) of tetrahydrofuran
A 1.7 ml solution was added over 7 minutes, and after stirring for 40 minutes, a solution of 0.16 g (0.73 mmol) of diphenyl sulfide 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. Adsorb the residue on a silica gel column, elute with 15% ethyl acetate / hexane to collect the target fractions, and evaporate the solvent to yield 11 mg of the target compound.
(Yield 5%) was obtained.

mp143-148 ° C. Example 68 (Production of tablet) 1-[(2-acetoxyethoxy) methyl] -6-phenylthiothymine 10 g Corn starch 65 g Carboxycellulose 20 g Polyvinylpyrrolidone 3 g Calcium stearate 2 g Total amount 100 g Mixing the above ingredients well , 100 mg per tablet by direct compression method
Tablets were prepared. This 1 tablet contains 1-[(2-acetoxyethoxy) methyl] -6-phenylthiothymine.
Contains 1.0 mg.

Example 69 (Production of powder and capsule) 1-[(2-acetoxyethoxy) methyl] -6-phenylthiothymine 20 g Crystalline cellulose 80 g Total amount 100 g Both powders were well mixed to obtain a dispersion. Also this powder 100mg
Was filled in a No. 5 hard capsule to obtain a capsule.

Example 70 (Preventive effect against HIV infection) MT-4 cells (H-4) in RPMI 1640DM medium containing 20 mM Hepes buffer solution, 10% fetal bovine serum and 20 μg / ml gentamicin.
Human T cell clones that die when infected with IV) 3 × 10 ⁴
50% of the cells were infected with 100 times the amount of HIV, and immediately a predetermined amount of a sample prepared to 50 mg / ml with dimethyl sulfoxide was added, and the cells were cultured at 37 ° C.

After 5 days of culture, the number of surviving cells was measured to determine the compound concentration required to prevent 50% cell death of MT-4 cells. Also, HIV
The cells were cultured in the same manner as above except that the cells were not infected, and the compound concentration required for 50% of MT-4 cells to die was determined. Both results are shown in Table-3.

Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical location C07D 239/60 401/12 239 (72) Inventor Richard Thomas Walker Birmingham Serry Oak Middle Park Road 50 (72) ) Inventor Ken Uzawazawa Sanryo Kasei Co., Ltd. Research Institute, 1000 Kamoda-cho, Midori-ku, Yokohama-shi, Kanagawa

Claims (2)

[Claims] 1. The following general formula [I] [In the above formula, R ¹ is an alkyl group; cycloalkyl group: an alkenyl group which may have one or more substituents selected from a phenyl group, a halogen atom, a cyano group, an alkoxycarbonyl group and a carbamoyl group; a phenyl group An alkynyl group optionally substituted with; an alkylcarbonyl group; an arylcarbonyl group; an arylcarbonylalkyl group;
Represents an arylthio group or an aralkyl group, and R ² is substituted with one or more substituents selected from 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 and an acyl group. Represents an optionally substituted arylthio group, alkylthio group, cycloalkylthio group, arylsulfinyl group, alkylsulfinyl group, cycloalkylsulfinyl group, alkenyl group, alkynyl group, aralkyl group, arylcarbonyl group, arylcarbonylalkyl group or aryloxy group. , R ³ is a branched alkyl group or --CH
_{2 -Z- (CH 2) n -R} 5 ( wherein, R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a heterocyclic carbonyloxy group; a formyloxy group; alkylcarbonyloxy group; a cycloalkyl carbonyl group; aralkyl Carbonyloxy group; arylcarbonyloxy group; azido group; or an alkoxycarbonyloxy group which may be substituted with one or more substituents selected from an aryl group, a halogen atom, an alkyl group, an alkoxy group and a halogenated alkyl group, 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 represents an integer of 0 to 5. ), R ⁴ represents a hydrogen atom, X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom or a sulfur atom. However, when Z represents an oxygen atom or a methylene group, R ⁵ does not represent a hydroxyl group. ] A 6-substituted acyclopyrimidine nucleoside derivative represented by the following: or a pharmaceutically acceptable salt thereof. 2. An antiviral agent comprising the 6-substituted acyclopyrimidine nucleoside derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.