JPH0931091A - Arabinofuranosyl-5-fluoro-2-thiopyrimidines and antiviral agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound consisting of specific arabinofuranosyl-5-fluoro-2-thiopyrimidines, having excellent antiviral action, low side effects and high safety and useful in the field of pharmaceuticals as an antiviral agent, etc. SOLUTION: This new compound is 1-(β-D-arabinofuranosyl)-5-fluoro-2- thiocytosine (salt) expressed by formula I. It has excellent antiviral action, low side effects and high safety and is useful e.g. as an active component for antiviral agent. The compound can be produced by reacting a 2,2'- anhydronucleoside compound of formula II (R1 is a hydroxy-protective group) with hydrogen sulfide in the presence of a basic compound, acylating the 2' and 3'-hydroxyl groups of the sugar part of the resultant compound of formula III, aminating the 4-carbonyl group of the base part, deprotecting the 2' and 3'-protective groups of the sugar part and deprotecting the R1 group at the 5' site of the sugar part.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 1- (β-D-
It relates to arabinofuranosyl) -5-fluoro-2-thiopyrimidines or salts thereof. The compound of the present invention has an excellent antiviral effect and is useful in the field of medicine.

[0002]

Conventionally, as an antiviral agent, idoxuridine, cytarabine, vidarabine, and acyclovir have been clinically used.

[0003]

However, the above drugs have problems such as antiviral activity spectrum, emergence of drug resistant virus strains and various side effects, and further development of effective and safe antiviral drugs is strongly desired. There is. The present invention aims to provide a novel compound having an excellent antiviral effect.

[0004]

Means for Solving the Problems As a result of repeated studies to develop a novel compound having an excellent antiviral effect, the present inventors have found that 1- (β-D-arabinofuranosyl) -5-
The fluoro-2-thiopyrimidines and the compound are DN
The present invention was completed by discovering that it exhibits an excellent antiviral effect against A virus. That is, the first invention of the present invention is 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine represented by the following formula (I) or a salt thereof.

[0005]

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The second invention is 1-represented by the following formula (II)
(Β-D-arabinofuranosyl) -5-fluoro-2-
It is thiouracil.

[0007]

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The third invention comprises 1- (β-D-arabinofuranosyl) of the first invention comprising the following first to fourth steps.
It is a method for producing -5-fluoro-2-thiocytosine. Step 1: a compound represented by the following general formula (I) is reacted with hydrogen sulfide in the presence of a basic compound.
The compound represented by V) is prepared.

[0009]

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[In the formula (1), R ₁ represents a hydroxyl-protecting group. 2nd step: A hydroxyl group at the 2′-position and 3′-position of the sugar moiety of the compound represented by the following general formula (IV) obtained in the 1st step is acylated and represented by the following general formula (V) The compound is prepared.

[0011]

[Chemical 12]

[In the formula (2), R ₁ represents a hydroxyl-protecting group, and R ₂ represents an acyl group. 3rd step: Amination of the 4-position of the base part of the compound represented by the following general formula (V) obtained in the 2nd step and elimination of R ₂ groups at the 2′-position and 3′-position of the sugar part Protect and use the following general formula (VI)
The compound represented by is produced.

[0013]

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[In the formula (3), R ₁ represents a hydroxyl-protecting group, and R ₂ represents an acyl group. 4th step: 1- (β represented by the formula (I) by deprotecting R ₁ at the 5′-position of the sugar moiety of the compound represented by the following general formula (VI) obtained in the 3rd step -D-arabinofuranosyl) -5-fluoro-2-thiocytosine is prepared.

[0015]

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[In the formula (4), R ₁ represents a hydroxyl-protecting group. ] A fourth invention is a second invention comprising the following first step and second step.
It is a method for producing 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil of the present invention. Step 1: a compound represented by the following general formula (I) is reacted with hydrogen sulfide in the presence of a basic compound.
The compound represented by V) is prepared.

[0017]

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[In the formula (5), R ₁ represents a hydroxyl-protecting group. 2nd step; 1- (β represented by the formula (II) is obtained by deprotecting R ₁ at the 5′-position of the sugar moiety of the compound represented by the following general formula (IV) obtained in the 1st step. -D-arabinofuranosyl) -5-fluoro-2-thiouracil is prepared.

[0019]

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[In the formula (6), R ₁ represents a hydroxyl-protecting group. The fifth invention is 1- (β-D of the first invention or the second invention.
-Arabinofuranosyl) -5-fluoro-2-thiopyrimidines as an active ingredient. Hereinafter, the present invention will be described in detail.

In the present invention, 1- (β-D of the formula (I)
-Arabinofuranosyl) -5-fluoro-2-thiocytosine may be in the form of a salt, such as an inorganic salt such as hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid, or fumaric acid, Examples thereof include acid addition salts with organic acids such as tartaric acid, succinic acid, citric acid, methanesulfonic acid and toluenesulfonic acid. Further, any of the compounds of the present invention may be hydrates or solvates.

The compound of the present invention is a novel compound and can be produced by various methods.
1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine of formula (I) consisting of 4 steps of the invention and 1-of formula (II) consisting of 2 steps of the 4th invention (Β
It can be advantageously produced by the method for producing -D-arabinofuranosyl) -5-fluoro-2-thiouracil.

1- (β-D-arabinofuranosyl)-
Method for Producing 5-Fluoro-2-thiocytosine ○ Step 1 This step includes the step of reacting the compound of the general formula (II
In this step, the compound represented by the formula (IV) is reacted with hydrogen sulfide in the presence of a basic compound to decompose by hydrogen sulfide to produce a compound represented by the general formula (IV). In the 2,2′-anhydronucleosides represented by the above general formula (III), which is a raw material compound, R ₁ is a hydroxyl-protecting group and may be used as a usual nucleoside-protecting group.
Specifically, an arylalkyl group such as trityl, methoxytrityl and dimethoxytrityl, an acyl group such as an acetyl group, a propionyl group, a butyryl group and a benzoyl group, a trimethylsilyl group, a t-butyldimethylsilyl group and a phenyldimethylsilyl group. Examples of the organic silicon-based protecting group include As the basic compound used in this step, various compounds can be used as long as they show basicity, for example, amines such as trimethylamine, diethylamine and triethylamine, pyridines such as pyridine, picoline and lutidine, aniline and Examples thereof include anilines such as N, N-dimethylaniline and N, N-dimethylformamide. In this step, it is preferable to use amines, pyridines, and anilines among these basic compounds because the reaction rate is high and side reactions can be suppressed. In the reaction, it is preferable to use a suitable solvent. The solvent that can be used is not particularly limited, and examples thereof include amines, pyridines, anilines and N, N-dimethylformamide exemplified above as the basic compound, and dimethyl sulfoxide and the like.
Amines, pyridines, and anilines are preferable because they have a high solubility of the raw material compound and are themselves basic compounds and can enhance the reactivity of hydrogen sulfide. The solvent may be one kind or a mixture of two or more kinds. There are various methods for the reaction, but usually, a reaction mixture consisting of the compound represented by the general formula (III), hydrogen sulfide and a basic compound is put into a pressure resistant bomb and sealed to react. The reaction ratio of hydrogen sulfide may be equimolar or more to the compound represented by the general formula (III), and is usually reacted in excess. Further, the ratio of the basic compound is represented by the general formula (I
It may be added in excess to the compound represented by II) 1
A molar ratio of 0 times or more is preferable because the yield is excellent. The reaction temperature is not particularly limited, but it is preferably room temperature to 100 ° C. The reaction time varies depending on the type of the basic compound used in the reaction and the reaction temperature, but is several hours to several days,
For example, it is 5 days when the reaction is carried out in pyridine at room temperature. After completion of the reaction, the product represented by the general formula (IV) can be isolated from the reaction mixture by a conventional method.
For example, after completion of the reaction, hydrogen sulfide is vaporized and removed, the solvent is distilled off under reduced pressure, and the residue is purified by chromatography.

Second Step The second step is the general formula (I
This is a step of acylating and protecting the hydroxyl groups at the 2'-position and the 3'-position of the sugar moiety of the compound represented by V) to produce the compound represented by the general formula (V). This step can be performed by a conventional method. For example, with respect to 1 mol of the compound represented by the general formula (IV), an acylating agent is added in an amount of 2 times mol or more in a reaction solvent, and the reaction temperature is 0 to 50 ° C. It can be carried out by reacting under the conditions. The reaction solvent is not particularly limited, but for example, pyridine, picoline, dimethylformamide, acetonitrile, methylene chloride, chloroform and the like can be used. In addition, since the reaction time can be shortened in this reaction, it is preferable to add a tertiary amine such as dimethylaminopyridine or triethylamine. As the acylating agent, for example, acetic acid, propionic acid, butyric acid, acid anhydrides such as benzoic acid and substituted benzoic acid or acid chlorides thereof can be used, and in the compound represented by the general formula (V): , R ₂ groups are these residues. General formula obtained
The compound represented by (V) may be isolated by a usual separation and purification means.For example, the reaction solvent is distilled off, the residue is partitioned with ethyl acetate-water, and then purified by recrystallization or silica gel column chromatography. Methods and the like.

Third step The third step is a general formula as shown by the above formula (3).
The compound represented by the general formula (VI) is obtained by aminating the 4-position of the base moiety of the compound represented by (V) and deprotecting the R ₂ groups at the 2′-position and the 3′-position of the sugar moiety. This is a manufacturing process. The 4-position of the base moiety of the compound represented by the general formula (V) may be aminated by a conventional method.
A compound represented by (V), a triazole, and a chlorooxyphosphorus compound such as phosphorus oxychloride and p-chlorophenyl phosphorodichloridate are reacted in an organic solvent,
A method of introducing a triazole group at the 4-position of the base portion and then treating with ammonia is preferable. In this case, the reaction ratio of the triazole and the chlorooxyphosphorus compound is not less than equimolar with respect to 1 mol of the compound represented by the general formula (V), and at least 1.5 mol is obtained. It is preferable because the compound yield is excellent. The reaction rate of ammonia may be 3 mol or more per 1 mol of the compound represented by the general formula (V), and 3.5 mol or more is preferable because the yield of the obtained compound is excellent. The reaction for introducing a triazole group is preferably carried out in an aprotic organic solvent, and examples thereof include pyridine, acetonitrile, toluene, dioxane and chloroform.
The reaction temperature is not particularly limited, but the reaction can be performed at room temperature to 100 ° C. The reaction time depends on the reaction temperature,
Usually several hours to several days. In this step, it is preferable to add a tertiary amine such as trimethylamine, triethylamine, N, N-dimethylaniline and N, N-dimethylaminopyridine, because the reaction time can be shortened. Isolation of the obtained compound represented by the general formula (VI) may be carried out by an ordinary separation and purification means.For example, after completion of the reaction, the solvent is removed, the residue is partitioned with ethyl acetate and water, and the organic layer is separated. There are methods such as concentration. Furthermore, if necessary, the concentrate can be purified by column chromatography to enhance the purity. The compound obtained by introducing the triazole group at the 4-position of the base moiety obtained by the above method is easily aminated at the 4-position of the base moiety by treating with ammonia, and the 2'-position and the 3'-position of the sugar moiety are deprotected. Can be protected. The solvent and conditions for this reaction are not particularly limited, but for example, it can be carried out at room temperature in a mixed solvent of dioxane and 30% aqueous ammonia. The compound represented by the general formula (VI) thus obtained may be isolated by a usual separation and purification means. For example, after the reaction is completed, the solvent is removed and the residue is purified by column chromatography.

4th step In the 4th step, the R ₁ group at the 5′-position of the sugar moiety of the compound represented by the general formula (VI) obtained in the 3rd step is represented by the above formula (4). Is deprotected, and 1- (β-D- is represented by the formula (I).
Arabinofuranosyl) -5-fluoro-2-thiocytosine. This step can be carried out by appropriately selecting a usual deprotection treatment such as acidic hydrolysis, alkaline hydrolysis, or ammonium fluoride treatment, depending on the type of R ₁ group. For example, when the protecting group is an arylalkyl group such as a trityl group, a methoxytrityl group and a dimethoxytrityl group, an inorganic acidic substance such as hydrochloric acid or sulfuric acid, or acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trichloroacetic acid Deprotection is carried out by acidic hydrolysis using an organic acid such as fluoroacetic acid, methanesulfonic acid and toluenesulfonic acid. When the protecting group is an acyl group such as an acetyl group or a benzoyl group, ammonia,
Deprotection is carried out by usual alkaline hydrolysis using amines and alkoxides. The protecting group is a trimethylsilyl group,
In the case of an organosilicon-based protecting group such as t-butyldimethylsilyl group and phenyldimethylsilyl group, deprotection can be performed by treating with an ammonium fluoride salt such as tetrabutylammonium fluoride. The above-mentioned proportions of the inorganic acidic substance, organic acid, ammonia, amine, alkoxide, ammonium fluoride salt and the like may be used in the usual amounts used for deprotection in consideration of the reaction conditions. The reaction temperature is usually room temperature so that the reaction proceeds sufficiently and heating can be performed for the purpose of shortening the reaction time. The reaction time varies depending on the reaction temperature, the type of protecting group and the deprotection method selected, but it is usually completed in 1 to 20 hours. Isolation of the obtained 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine may be carried out by a usual separation and purification means. For example, after the reaction is completed, the solvent is removed, the residue is partitioned with chloroform and water, the aqueous layer is washed with chloroform, the organic layer is concentrated, and the concentrate is purified by column chromatography and HPLC. .

1- (β-D-arabinofuranosyl)-
Method for Producing 5-Fluoro-2-thiouracil ○ Step 1 This step is performed by the general formula (II) as shown by the above formula (5).
In this step, the compound represented by the formula (IV) is reacted with hydrogen sulfide in the presence of a basic compound to decompose by hydrogen sulfide to produce a compound represented by the general formula (IV). This step is based on the above 1-
(Β-D-arabinofuranosyl) -5-fluoro-2-
It can be performed by the same method as the first step in the method for producing thiocytosine.

Second step In the second step, the R ₁ group at the 5′-position of the sugar moiety of the compound represented by the general formula (IV) obtained in the second step is represented by the above formula (6). Is deprotected to produce 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil represented by the formula (II). In this step, the above 1- (β-D-
It can be performed by the same method as in the fourth step in the method for producing arabinofuranosyl) -5-fluoro-2-thiocytosine.

◎ Uses The compound of the present invention can be used for various purposes, but in particular, it exhibits an excellent antiviral action against DNA virus, and the drug containing it as an active ingredient is the antiviral agent of the fourth invention. Is useful as The compound of the present invention exhibits a particularly excellent effect against herpesviruses, and is particularly useful as an anti-herpesvirus agent.

The antiviral agent of the present invention is administered by any suitable route for the treatment of animals including humans. The route includes oral, rectal, nasal, topical (oral, sublingual and transdermal), vaginal, and parenteral (subcutaneous, muscular, intravenous and intradermal) and the like. The anti-herpesvirus agent of the present invention can be used by various methods such as oral administration, parenteral administration and topical application depending on the intended route, and is used in the following forms depending on each method. Oral Administration The antiviral agent of the present invention is administered as an aqueous solution, aqueous suspension, tablet, pill, granule, pellet, paste or the like. Parenteral administration The antiviral agent of the present invention is subcutaneously, intramuscularly, or intravenously injected as a sterile solution or suspension. O Topical application The antiviral agent of the present invention is applied to the skin as a cream, salve or spray. Vaginal administration The antiviral agent of the present invention is administered as a pessary, cream or foam. The route, form and amount of use of the antiviral agent of the present invention may be appropriately selected depending on the symptoms, weight, age and sex of the patient, the nature of infection and the selected active ingredient.

[0031]

The present invention will be described more specifically with reference to the following examples. ◎ Example 1 1- (β-D-arabinofuranosyl) -5-fluoro-
Synthesis of 2-thiocytosine ○ Step 1 Synthesis of 1- (5′-O-trityl-β-D-arabinofuranosyl) -5-fluoro-2-thiouracil In a pressure vessel, 2,2′-anhydro-1 was used. -(5'-O-
90 ml of a mixed solution of trityl-β-D-arabinofuranosyl) -5-fluorouracil (6.00 g = 12.3 mmol) and pyridine / hydrogen sulfide = 1/2 (volume ratio) was added, and the mixture was sealed and kept at 30 ° C. The reaction was carried out in a hot water bath for 10 days.
After the reaction, excess hydrogen sulfide gas was removed, and then the solvent in the reaction solution was distilled off under reduced pressure. The residue was dissolved in chloroform, column chromatography using silica gel as a carrier (chloroform / methanol = 98/2 to 85/15), and H
Purification by PLC gave 1.37 g of the title compound. The results of ¹ HNMR spectrum measurement of the obtained compound are shown below.

¹ H NMR (DMSO-d6) 13.19 (1H, br, 3-NH D ₂ O exchangeable) 7.68 (1H, d, J = 6.8
3Hz, 6-H) 7.44-7.26 (15H, m, trityl) 6.72 (1H, d, J = 2.45H
z, 1'-H) 5.60 (1H, d, J = 3.91Hz, 2'-OH D ₂ O exchangeable)
5.57 (1H, d, J = 4.4Hz, 3'-OH D ₂ O exchangeable) 4.17 (1
H, m, 3'-H) 4.05 (1H, m, 4'-H) 3.87 (1H, br s, 2'-H) 3.30
(1H, dd, J = 7.81, 10.25Hz, 5'-H) 3.21 (1H, dd, J = 3.90, 1
(0.25Hz, 5'-H)

Second step Synthesis of 5'-O-trityl-2 ', 3'-bis-O-acetyl-1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil 1- (5′-O-Trityl-β-D-arabinofuranosyl) -5-fluoro-2-thiouracil (1.37 g =
2.63 mmol) was dissolved in anhydrous pyridine, and after cooling to 0 ° C., acetic anhydride (1.24 ml = 13.2 mmol) and dimethylaminopyridine (30 mg) were added. After the addition was completed, the mixture was returned to room temperature and stirred for 15 hours. The solvent of the obtained reaction liquid was distilled off under reduced pressure, ethyl acetate and water were added to the residue for partitioning, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in chloroform and purified by column chromatography using silica gel as a carrier (chloroform / methanol = 97 / 3-8 / 2) to obtain the title compound (1.21 g = 76%). The results of ¹ HNMR spectrum measurement of the obtained compound are shown below.

¹ H NMR (CDCl ₃ ) 7.81 (1H, d, J = 6.35Hz, 6-H) 7.48-7.22 (15H, m, trityl) 6.
83 (1H, dd, J = 1.46, 4.39Hz, 1'-H) 5.66 (1H, dd, J = 1.46,
4.39Hz, 2'-H) 5.21 (1H, dd, J = 1.95, 3.42Hz, 3'-H) 4.21 (1
H, m, 4'-H) 3.52 (1H, dd, J = 3.42, 10.25Hz, 5'-H) 3.40 (1
H, dd, J = 5.86, 10.25Hz, 5'-H) 2.12 (3H, s, COCH ₃ ) 1.86 (3
H, s, COCH ₃ )

Third step: Synthesis of 5'-O-trityl-1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine 5'-O-trityl-2 ', 3'-bis -O-acetyl-1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil (1.10 g = 1.82 mmol)
Was dissolved in 18 ml of anhydrous pyridine and cooled to 0 ° C. with an ice bath. P-Chlorophenyl phosphorodichloridate (0.8 ml = 4.91 mmol) was added dropwise to this solution and stirred for 10 minutes, after which 1,2,4-triazole (0.70) was added.
g = 9.82 mmol) was added and stirred for 20 minutes. The reaction solution was returned to room temperature and further stirred for 2 days. After distilling off the solvent in the reaction solution under reduced pressure, ethyl acetate and water were added to the residue for partitioning, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated. P-Dioxane (20 ml) was added to the residue to dissolve it, 28% aqueous ammonia (20 ml) was added, and the mixture was stirred at room temperature for 15 hours. After distilling off the solvent under reduced pressure and dissolving the residue in chloroform, column chromatography using silica gel as a carrier (chloroform / methanol = 99)
/ 1-95 / 5) and the title compound (516 mg = 7
7%). The results of ¹ HNMR spectrum measurement of the obtained compound are shown below.

¹ H NMR (DMSO-d6) 8.30 (1H, br s, 4-NH D ₂ O exchangeable) 7.93 (1H, br s, 4
-NH D ₂ O exchangeable) 7.45-7.25 (15H, m, trityl) 6.90
(1H, m, 1'-H) 5.54 (1H, d, J = 4.4Hz, 3'-OH D ₂ O exchangeab
le) 5.43 (1H, d, J = 4.88Hz, 2'-OH D ₂ O exchangeable) 4.2
0 (1H, m, 3'-H) 4.03 (1H, m, 4'-H) 3.84 (1H, br s, 2'-H) 3.
30 (1H, dd, J = 7.32, 10.25Hz, 5'-H) 3.19 (1H, dd, J = 3.91,
(10.25Hz, 5'-H)

4th step 1- (β-D-arabinofuranosyl) -5-fluoro-
Synthesis of 2-thiocytosine 5'-O-trityl-1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine (142 mg =
0.273 mmol) was dissolved in methylene chloride (5 ml) and cooled to 0 ° C. 5 ml of a 6% trifluoroacetic acid / methylene chloride solution was slowly added dropwise to this, and the mixture was stirred for 30 minutes. The solvent of the obtained reaction solution was distilled off under reduced pressure in an ice bath, water and chloroform were added to the residue for partitioning, the aqueous layer was washed with chloroform and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel as a carrier (chloroform / methanol = 8/2) and HPLC to give the title compound 6
5 mg were obtained. The ¹ H NMR spectrum and the UV spectrum measurement result of the obtained compound are shown below.

¹ H NMR (DMSO-d6) 8.28 (1H, br, 4-NH D ₂ O exchangeable) 7.99 (1H, d, J = 8Hz,
6-H) 7.91 (1H, br, 4-NHD ₂ O exchangeable) 6.83 (1H, d, J =
3.2Hz, 1'-H) 5.47 (1H, d, J = 3.2Hz, 2'-OH D ₂ O exchangeab
le) 5.43 (1H, d, J = 5.6Hz, 3'-OH D ₂ O exchangeable) 5.14
(1H, t, J = 5.6Hz, 5'-OH D ₂ O exchangeable) 4.26 (1H, m, 2 '
-H) 3.90 (1H, m, 3'-H) 3.83 (1H, m, 4'-H) 3.63 (2H, dt, J = 5.
6, 2.4Hz, 5'-H) ・ UV (H ₂ O, nm) λmax: 272.6, 239.6, 225.4 λmim: 256.8, 229.1

Example 2 1- (β-D-arabinofuranosyl) -5-fluoro-
Synthesis of 2-thiouracil ○ First step Synthesis of 1- (5′-O-trityl-β-D-arabinofuranosyl) -5-fluoro-2-thiouracil In a pressure vessel, 2,2′-anhydro-1 was used. -(5'-O-
A mixed solution of trityl-β-D-arabinofuranosyl) -5-fluorouracil (170 mg = 0.35 mmol), diethylamine (1 ml), DMF (9 ml) and hydrogen sulfide (20 ml) was added, and the mixture was sealed at 30 ° C. The reaction was carried out for 3 hours. After the reaction, excess hydrogen sulfide gas was removed, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol = 95/5).
~ 85/15) and HPLC to give 75 mg of the title compound. As a result of measuring ¹ HNMR spectrum of this compound, it was found to be the same as the product obtained in the first step of Example 1.

Second step 1- (β-D-arabinofuranosyl) -5-fluoro-
Synthesis of 2-thiouracil 1- (5′-O-trityl-β-D-arabinofuranosyl) -5-fluoro-2-thiouracil (80 mg =
0.15 mmol) in 5 ml of methylene chloride,
Cooled to ° C. A methylene chloride solution (5 ml) of 6% trifluoroacetic acid was added dropwise thereto, and the mixture was stirred for 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure in an ice bath, water and chloroform were added to the residue for partitioning, the aqueous layer was washed with chloroform and concentrated under reduced pressure. The residue was column chromatographed on silica gel (chloroform / methanol = 85/1).
5) and purified by HPLC to give the title compound (32m
g = 75%) was obtained. The ¹ H NMR spectrum and the UV spectrum measurement result of the obtained compound are shown below.

¹ H NMR (DMSO-d6) 13.17 (1H, br s, 3-NH D ₂ O exchangeable) 8.05 (1H, d, J =
7.6Hz, 6-H) 6.66 (1H, brs, 1'-H) 5.59 (1H, d, J = 5.6Hz, 2'-
OH D ₂ O exchangeable) 5.52 (1H, d, J = 4.0Hz, 3'-OH D ₂ O e
xchangeable) 5.18 (1H, t, J = 5.6Hz, 5'-OH D ₂ O exchangea
ble) 4.22 (1H, m, 2'-H) 3.91 (1H, m, 3'-H) 3.84 (1H, m, 4'-
H) 3.63 (2H, m, 5'-H) ・ UV (H ₂ O, nm) λmax: 274.5, 222.8 λmim: 253.7nm

Example 3 Herpes simplex virus type 1 (KOS strain, F strain) and herpes simplex virus 2 using RPM8226 cells as host cells
Type (G strain, lyon strain) and herpes zoster virus (V strain
ZV) to 1- (β-D-arabinofuranosyl)
The results of measuring the antiviral effect of -5-fluoro-2-thiocytosine are shown in Table 1 below. In Table 1,
The EC50 value and CC50 value are the concentrations of drugs that inhibit the growth of viruses and the growth of host cells by 50%, respectively.
The values represent their ratio (CC50 / EC50), ie the selectivity. As shown in Table 1, this drug has a strong anti-herpesvirus activity, is not cytotoxic, and has excellent selectivity.

[0043]

[Table 1]

[0044]

INDUSTRIAL APPLICABILITY The present invention is a novel compound, which shows an excellent antiviral action against a DNA virus, particularly against a herpes virus.

Claims (5)

[Claims] 1. 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine represented by the following formula (I) or a salt thereof. Embedded image 2. 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil represented by the following formula (II). Embedded image 3. The method for producing 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiocytosine according to claim 1, which comprises the following first to fourth steps. Step 1: a compound represented by the following general formula (I) is reacted with hydrogen sulfide in the presence of a basic compound.
The compound represented by V) is prepared. Embedded image [In Formula (1), R ₁ represents a protective group for a hydroxyl group. 2nd step: A hydroxyl group at the 2′-position and 3′-position of the sugar moiety of the compound represented by the following general formula (IV) obtained in the 1st step is acylated and represented by the following general formula (V) The compound is prepared. Embedded image [In the formula (2), R ₁ represents a hydroxyl-protecting group, and R _1
2 represents an acyl group. 3rd step: Amination of the 4-position of the base part of the compound represented by the following general formula (V) obtained in the 2nd step and elimination of R ₂ groups at the 2′-position and 3′-position of the sugar part Protect and use the following general formula (VI)
The compound represented by is produced. Embedded image [In the formula (3), R ₁ represents a hydroxyl-protecting group, and R _1
2 represents an acyl group. 4th step: 1- (β represented by the formula (I) by deprotecting R ₁ at the 5′-position of the sugar moiety of the compound represented by the following general formula (VI) obtained in the 3rd step -D-arabinofuranosyl) -5-fluoro-2-thiocytosine is prepared. [Chemical 6] [In Formula (4), R ₁ represents a protective group for a hydroxyl group. ] 4. The method for producing 1- (β-D-arabinofuranosyl) -5-fluoro-2-thiouracil according to claim 2, which comprises the following first step and second step. Step 1: a compound represented by the following general formula (I) is reacted with hydrogen sulfide in the presence of a basic compound.
The compound represented by V) is prepared. [Chemical 7] [In Formula (5), R ₁ represents a protective group for a hydroxyl group. 2nd step; 1- (β represented by the formula (II) is obtained by deprotecting R ₁ at the 5′-position of the sugar moiety of the compound represented by the following general formula (IV) obtained in the 1st step. -D-arabinofuranosyl) -5-fluoro-2-thiouracil is prepared. Embedded image [In Formula (6), R ₁ represents a protective group for a hydroxyl group. ] 5. 1- (β-D according to claim 1 or claim 2.
-Arabinofuranosyl) -5-fluoro-2-thiopyrimidines as an active ingredient.