KR0140021B1 - Pyrimidine acyclonucleoside derivatives - Google Patents

Abstract

The present invention relates to a novel pyrimidine acyclonucleoside derivative represented by the following structural formula (I) and an antiviral agent comprising the same as an active ingredient.

In the above formula, R ¹ is an ethyl group or isopropyl group, R ² is a substituted or unsubstituted phenyl selenenyl group, the substituent is one or more selected from alkyl groups and halogen atoms of C ₁ ~ C ₂ , R ³ is hydrogen An atom, a C ₁ to C ₃ alkyl group, a C ₁ to C ₃ hydroxyalkyl group, an acyloxyalkyl group or a substituted or unsubstituted phenyl group may be selected from the group consisting of C ₁ to C ₃ alkyl group and C ₁ to C ₃ alkoxy group Or a halogen atom, X is an oxygen atom or a sulfur atom.

Description

Pyrimidine Acyclonucleoside Derivatives

The present invention relates to a novel pyrimidine acyclonucleoside derivative represented by the following structural formula (I) and an antiviral agent comprising the same as an active ingredient.

In the above formula, R ¹ is an ethyl group or isopropyl group, R ² is a substituted or unsubstituted phenyl selenenyl group, the substituent is one or more selected from alkyl groups and halogen atoms of C ₁ ~ C ₃ , R ³ is hydrogen An atom, a C ₁ to C ₃ alkyl group, a C ₁ to C ₃ hydroxyalkyl group, an acyloxyalkyl group or a substituted or unsubstituted phenyl group may be selected from the group consisting of C ₁ to C ₃ alkyl group and C ₁ to C ₃ alkoxy group Or a halogen atom, X is an oxygen atom or a sulfur atom.

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (hereinafter referred to as HIV) and is one of the most serious health problems in the world.

3 '= deoxy-3'-azidothymidine (hereinafter referred to as AZT), known as a conventional AIDS therapeutic, is a compound that improves the clinical and immune status of patients with AIDS and AIDS-related complexes. Although well known, serious side effects such as anemia and leukopenia are problematic for clinical use.

Recently, 2, '3'-dideoxyinosine (hereinafter referred to as DDI) and 2', 3 'dideoxycytidine (hereinafter referred to as DDC) have been recognized as useful for patients who are not resistant to AZT. However, these compounds also have side effects such as peripheral neuropathy and pancreatitis.

Therefore, there is an urgent need for the development of new compounds having strong antiviral activity and low cytotoxicity against host cells.

In addition, various pyrimidine acyclonucleosides containing a substituted or unsubstituted phenylthio group or a substituted or unsubstituted benzyl group at the 6th carbon position of pyrimidine as an effective antiviral activity against retroviruses Derivatives have been developed (International Patent Publication No. 89/09213, European Patent 420,763 A2, European Patent 449,726 A1).

In addition, several pyrimidine acyclonucleoside derivatives substituted with 6-phenylselenyl group have been prepared [J. Med. Chem., (1991) 34,3305-3309, Antiviral Chem. Chemother, 1992, 3 (5), 263-266], had limitations on antiviral activity against retroviruses.

Accordingly, the inventors of the present invention, in order to solve the problems of the conventional invention, a novel pyri having an ethyl group or an isopropyl group on the fifth carbon of the pyrimidine, and a phenyl selenenyl group substituted or unsubstituted on the sixth carbon of pyrimidine The midine acyclonucleoside derivatives were prepared, and it was found that most of the pyrinidine acyclonucleoside derivatives have excellent antiretroviral activity to complete the present invention.

It is an object of the present invention to provide a novel pyridinidine acyclonucleoside derivative, a pharmaceutically acceptable salt thereof, and an antiviral agent having the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention is characterized by pyrimidine acyclonucleoside derivatives represented by the following structural formula (I).

Wherein R ¹ , R ² , R ³ and X are as defined above.

Referring to the present invention in more detail as follows.

The present invention relates to a pyrimidine acyclonucleoside derivative represented by the above formula (I) having excellent antiviral activity, and is preferably as follows for the compound of the above formula (I).

R ¹ is an ethyl group or an isopropyl group. R ² is a substituted or unsubstituted phenylselenyl group, and examples of the substituent include C ₁ to C ₃ alkyl groups such as methyl, ethyl, propyl or isopropyl groups; Or halogen atoms such as fluorine, chlorine, bromine or iodine atoms. R ³ is a hydrogen atom; C ₁ to C ₃ alkyl groups such as methyl, ethyl or propyl groups; C ₁ to C ₃ hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl or hydroxypropyl groups; Acyloxyalkyl groups such as acetyloxymethyl, acetyloxyethyl, acetyloxypropyl, propionyloxymethyl, propionyloxyethyl or propionyloxypropyl groups; Or as a substituted or unsubstituted phenyl group, substituents include C ₁ to C ₃ alkyl groups such as methyl, ethyl, propyl or isopropyl groups; C ₁ to C ₃ alkoxy groups such as methoxy, ethoxy, propoxy or isopropoxy groups; Or halogen atoms such as fluorine, chlorine, bromine or iodine atoms. X is an oxygen atom or a sulfur atom.

Representative examples of the pyrimidine acyclonucleoside compound represented by the above formula (I) according to the present invention are shown in Table 1 below.

The preparation process of the compound represented by the above formula (I) according to the present invention is shown in the following scheme.

[Scheme]

Wherein R ¹ , R ² , R ³ and as defined above.

In the above reaction scheme, the compound represented by the above formula (II) used as the starting material of the present invention can be easily prepared and used by known methods as known compounds. Chem. Soc., Chem. Commun., 684 (1989); Bull. Inst. Chem. Res., Kyoto Univ., 68,199 (1990)].

In order to prepare the target compound of the present invention, first, the compound represented by the formula (II) is refluxed for 3 to 72 hours with an aqueous solution of potassium hydroxide in an ethanol solvent to an acid compound represented by the formula (III). After conversion, oxalyl chloride was added to the compound of formula III, and N, N-dimethylformamide (hereinafter referred to as DMF) was catalyzed in a benzene solvent at a temperature of 0 to 80 ° C. for 1 to 24 hours. Reaction gives an acid chloride represented by the above formula (IV).

The compound of formula (IV) was refluxed for 0.5 to 5 hours in a benzene solvent with silver cyanate or ammonium thiocyanate, and then amine was added thereto and reacted for 0.5 to 5 hours at a temperature of -78 to 40 ° C. To obtain acryloyl urea represented by the structural formula (Va) or acryloylthiourea represented by the structural formula (Vb).

The compound represented by the above formula (Va) is 6-methylthiouracil represented by the above formula (VI) by cyclization reaction for 1 to 24 hours at a temperature of 60 ~ 100 ℃ with 0.1 ~ 0.3 molar ratio of methanesulfonic acid in acetic acid solvent To prepare, it was refluxed for 1 to 24 hours in a benzene solvent with m-chloroperbenzic acid (mCPBA, referred to as MCPBA) to obtain 6-methylsulfonyluracil represented by the formula (VII).

In addition, the compound represented by the above formula (Vb) is cyclized reaction at 15 ~ 30 ℃ temperature for 5 minutes to 15 minutes with a 1 to 3 molar ratio of methanesulfonic acid in acetic acid solvent to prepare a compound represented by the above formula (VII) This was refluxed for 1 to 5 hours in a methanol solvent with an aqueous solution of sodium periodate in a 3 to 10 molar ratio to obtain 6-methylsulfinyl-2-thiouracil represented by the above formula.

Finally, the compound represented by the structural formula (VII) or the compound represented by the structural formula (VII) is reacted at a temperature of 15 to 30 ° C. for 5 minutes to 5 hours in a 1 to 2 molar ratio of aryl selenol and sodium hydroxide solution. The compound represented by said structural formula (I) is manufactured. At this time, aryl selenol is used that includes the R ² group defined above.

Separation and purification of the compound represented by Structural Formula (I), which is the target compound of the present invention prepared by the above production process, is carried out by conventional methods, that is, by column chromatography and recrystallization.

In addition, the pyrimidine acyclonucleoside derivatives according to the invention can be prepared into pharmaceutically possible salts by conventional methods. Examples of such salts include alkali metal salts such as sodium salts and potassium salts; Alkaline earth metal salts such as magnesium salts; Ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, tetramethylammonium salt and the like.

In addition, the pyrimidine acyclonucleoside derivative according to the present invention is injected into a patient by a conventional method for the purpose of preventing the transmission of a retrovirus or the like, or for treating an infectious disease caused by such a virus. There are oral, parenteral or topical methods.

Effective dosages of the pyrimidine acyclonucleoside derivatives according to the present invention may vary greatly depending on the age, physical condition, weight, etc. of the patient, but are generally added within the range of 1 to 100 mg / kg (weight) per day. Preferably it is 5-50 mg / kg (weight) 1 day. Then, within the effective daily dose range, one dose per day or several times per day.

The compounds prepared by the invention also prepare pharmaceutical compositions with suitable carriers, excipients and other additives. At this time, carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, pectin, agar, stearic acid, magnesium stearate, lecithin, sodium chloride, glycerin, peanut oil, polyvinylpyrrolidone, Liquid carriers such as olive oil, ethanol, benzyl alcohol, propylene glycol and water are used.

In addition, the antiviral agent of the present invention can be prepared in various forms, for example, when using a solid carrier can be prepared as tablets, capsules, powders, granules, suppositories, troches, etc., when using a liquid carrier, It can be formulated as a syrup, soft gelatin capsules, gels, pastes, injections and the like.

The novel pyrimidine acyclonucleoside derivatives according to the present invention have a strong activity against viruses, especially retroviruses, and have relatively low toxicity to host cells, which is very useful as an active ingredient of antiviral agents.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Ethyl 3,3- (dimethylthio) -2-ethylacrylate (300 mmol) and 2NKOH (300 mL) were added to ethanol (300 mL), refluxed for 3 hours, and concentrated to remove ethanol. Pour water (300 mL) and wash the aqueous layer with diethyl ether (200 mL × 2), add concentrated hydrochloric acid to acidify the solution to pH 3, and extract with diethyl ether (200 mL × 3). . The organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain a residue. The residue was recrystallized using hexane to obtain the title compound as a white solid.

Prepared by the same method as in Preparation Example 1, instead of ethyl 3,3- (dimethylthio) -2-ethyl acrylate, ethyl 3,3- (dimethylthio) -2-isopropyl acrylate was used for the target compound. Got it.

3,3- (dimethylthio) -2-ethylacrylic acid (100 mmol) prepared in Preparation Example 1 was added to anhydrous benzene (100 mL) and oxalyl chloride (10.5 mL, 120 mmol) at 0 ° C. under nitrogen stream was stirred. Frost is added drop by drop and 3 drops of DMF. After stirring for 3 hours at room temperature, the residue was evaporated to obtain a residue. The residue was distilled under reduced pressure to obtain a target compound of dark red oil.

Prepared in the same manner as in Preparation Example 3, using 3,3- (dimethylthio) -2-isopropylacrylic acid instead of 3,3- (dimethylthio) -2-ethylacrylic acid to obtain the target compound.

3,3- (dimethylthio) -2-ethylacryloyl chloride (3.50 g, 16.6 mmol) and AgOCN (2.61 g, 17.4 mmol) prepared in Preparation Example 3 were added to anhydrous benzene (30 mL). It is refluxed for 30 minutes under a nitrogen stream in a dark place. The temperature of the reaction solution was -78 ° C, and a solution of butylamine (1.81 ml, 18.3 mmol) dissolved in benzene (10 ml) was slowly added dropwise, and then the temperature of the reaction solution was gradually raised over 30 minutes. At room temperature. The reaction solution was filtered through Celite, the filtrate was collected and filtered again using a microfilter (0.22㎛), and then the filtrate was distilled off to obtain a residue. The residue was separated by silica gel column chromatography (ethyl acetate / hexane = 1/6) to obtain 4.21 g of the target compound.

Prepared by the same method as in Preparation Example 5, but using 3-phenyl-1-propylamine instead of butylamine to obtain the target compound.

Prepared by the same method as Preparation Example 5, but using 3,3- (dimethylthio) -2-isopropylacryloyl chloride instead of 3,3- (dimethylthio) -2-ethylacryloyl chloride The compound was obtained.

Prepared by the same method as Preparation Example 5, using 3,3- (dimethylthio) -2-isopropylacryloyl chloride instead of 3,3- (dimethylthio) -2-ethylacryloyl chloride, 3-phenyl-1propylamine was used instead of butylamine to obtain the target compound.

3,3- (dimethylthio) -2-ethylacryloyl chloride (5.20 g, 24.7 mmol) and NH ₄ SCN (1.97 g, 25.9 mmol) prepared in Preparation Example 3 were added to anhydrous benzene (30 mL). Then reflux for 30 minutes in a dark place under nitrogen stream. The temperature of the reaction solution was 0 ° C, and a solution of 4-amino-1-butanol (2.50 ml, 27.2 mmol) dissolved in anhydrous benzene (10 ml) was added one by one to the frost, and then the temperature of the reaction bath was adjusted. Warm to room temperature and leave for 1 hour. Water (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The organic layer was washed with brine (50 mL), dried over anhydrous MgSO ₄ , filtered and evaporated to obtain a residue. The residue was separated by silica gel column chromatography (ethyl acetate / hexane: 1/2) to obtain 6.39 g of the target compound.

Prepared by the same method as Preparation Example 9, but using the butylamine instead of 4-amino-1-butanol to obtain the target compound.

Prepared by the same method as Preparation Example 9, but using 3,3- (dimethylthio) -2-isopropylacryloyl chloride instead of 3,3- (dimethylthio) -2-ethylacryloyl chloride The compound was obtained.

Prepared by the same method as Preparation Example 9, using 3,3- (dimethylthio) -2-isopropylacryloyl chloride instead of 3,3- (dimethylthio) -2-ethylacryloyl chloride, Butylamine was used instead of 4-amino-1butanol to obtain the target compound.

N-butyl-N '-[3,3- (dimethylthio) -2-ethylacryloyl] urea (0.50 g, 1.72 mmol) and methanesulfonic acid (25.0 mg, 0.26 mmol) prepared in Preparation Example 5 were prepared. It is suspended in acetic acid (10 ml), then heated at 80 ° C. for 1 hour and evaporated to obtain a residue. The residue was dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (25 mL), brine (25 mL), and dried over anhydrous MgSO ₄ to obtain a residue.

The residue was separated by silica gel column chromatography (ethyl acetate / hexane: 1/3) to obtain 0.40 g of the target compound.

Prepared by the same method as Preparation Example 13, except that N- [3,3- (dimethylthio)-in place of N-butyl-N '-[3,3- (dimethylthio) -2-ethylacryloyl] urea 2-ethylacryloyl] -N '-(3-phenylpropyl) urea was used to obtain the target compound.

Prepared by the same method as Preparation Example 13, except N-butyl-N '-[3,3- (dimethylthio) -2-ethylacryloyl] urea, but instead of N-butyl-N'-[3,3- The target compound was obtained using (dimethylthio) -2-isopropylacryloyl] urea.

Prepared by the same method as Preparation Example 13, except that N-[(3,3- (dimethylthio) instead of N-butyl-N '-[3,3- (dimethylthio) -2-ethylacryloyl] urea 2-isopropylacrylate] -N '-(3-phenylpropyl) urea was used to obtain the target compound.

1-Butyl-5-ethyl-6- (methylthio) uracil (1.50 g, 6.2 mmol) and 3-chloroperoxybenzoic acid (85%, 6.29 g, 31.0 mmol) prepared in Preparation Example 13 were used as benzene (50). ML) to reflux for 16 hours and then evaporate to obtain a residue. The residue was dissolved in water (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic layer was washed with saturated sodium bicarbonate solution (50 mL), washed with brine (50 mL), dried over anhydrous MgSO ₄ , and filtered. And evaporation to obtain a residue. The residue was separated by silica gel chromatography (ethyl acetate / hexane: 1/2) to obtain 1.67 g of the target compound.

Prepared by the same method as Preparation Example 17, but using 5-ethyl-6- (methylthio) -1- (3-phenylpropyl) uracil instead of 1-butyl-5-ethyl-6- (methylthio) uracil To obtain the target compound.

Prepared by the same method as Preparation Example 17, but using 1-butyl-5-isopropyl-6- (methylthio) uracil instead of 1-butyl-5-ethyl-6- (methylthio) uracil to prepare the target compound. Got it.

Prepared by the same method as Preparation Example 17, except 5-isopropyl-6- (methylthio) -1- (3-phenylpropyl) uracil instead of 1-butyl-5-ethyl-6- (methylthio) uracil To obtain the desired compound.

N- [3,3- (dimethylthio) -2-ethylacryloyl] -N '-(4-hydroxybutyl) thiourea (4.5 g, 14.0 mmol) prepared in Preparation Example 9 and methanesulfonic acid ( 1,35 g, 14.0 mmol) was suspended in acetic acid (50 mL), stirred at room temperature for 1.5 hours, and evaporated to obtain a residue, which was dissolved in dichloromethane (150 mL) and then saturated sodium hydrogencarbonate solution (50 mL). Washed with brine (50 mL), dried over anhydrous MgSO ₄ , filtered and evaporated to obtain a residue, which was separated by silica gel column chromatography (ethyl acetate / hexane: 4/1) to give the title compound 4.50 g. Got.

Prepared by the same method as Preparation Example 21, except for N- [3,3- (dimethylthio) -2-ethylacryloyl] -N '-[4hydroxybutyl] thiourea and N-butyl-N The target compound was obtained using '-[3,3- (dimethylthio) -2-ethylacryloyl] thiourea.

Prepared by the same method as Preparation Example 21, except N- [3,3- (dimethylthio) -2-ethylacryloyl] -N '-(4-hydroxybutyl) thiourea. The target compound was obtained using, 3- (dimethylthio) -2-isopropylacryloyl] -N '-(4-hydroxybutyl) thiourea.

Prepared by the same method as Preparation Example 21, except for N- [3,3- (dimethylthio) -2-ethylacryloyl] -N '-(4-hydroxybutyl) thiourea. The target compound was obtained using N '-[3,3- (dimethylthio) -2-isopropylacryloyl] thiourea.

1- (4-acetoxybutyl) -5,6-dihydro-6- (dimethylthio) -5-ethyl-2-thiouracil (1.46 g, 4.0 mmol) prepared in Preparation Example 21 was prepared using methanol (50). ㎖) and then a solution of NaIO ₄ (5.14 g, 24.0 mmol) dissolved in water (50 mL) while stirring at room temperature. The reaction solution was refluxed for 1,5 hours, filtered, the filtrate was concentrated to 50 ml and extracted with chloroform. The organic layer was dried over MgSO ₄ , filtered, and evaporated to obtain a residue. The residue was separated by silica gel chromatography (methanol / chloroform: 3/97) to obtain 0.77 g of the target compound.

Prepared by the same method as Preparation Example 25, except that 1- (4-acetoxybutyl) -5,6-dihydro-6- (dimethylthio) -5-ethyl-2-thiouracil was substituted with 1-butyl- 5,6-Dihydro-6- (dimethylthio) -5-ethyl-2-thiouracil was used to obtain the target compound.

Prepared by the same method as Preparation Example 25, except that 1- (4 instead of 1- (4-acetoxybutyl) -5,6-dihydro-6- (dimethylthio) -5-ethyl-2-thiouracil -Acetoxybutyl) -5,6-dihydro-6- (dimethylthio) -5-isopropyl-2-thiouracil was used to obtain the target compound.

Prepared by the same method as Preparation Example 25, except for 1- (acetoxybutyl) -5,6-dihydro-6- (dimethylthio) -5-ethyl-2-thiouracil, 1-butyl-5, 6-Dihydro-6- (dimethylthidio) -5-isopropyl-2-thiouracil was used to obtain the target compound.

1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil (0.33 g, 100 mmol) and benzene selenol (0.11 mL, 1.04 mmol) were added to ethanol (5 mL). After suspension, 1N NaOH methanol solution (3.00 ml) was added thereto at room temperature under a nitrogen stream, and stirred for 2 hours. 3N HCI ethanol solution (1.00 mL) was added to the reaction solution, and the residue was evaporated. The residue was separated by silica column chromatography (methanol / chloroform = 5/95) to obtain 0.23 g of the target compound.

Yield: 60%

Prepared in the same manner as in Example 1, using 3,5-dimethylphenyl selenol instead of benzene selenol to obtain the target compound.

Prepared by the same method as Example 1, except that 1- (4-acetoxybutyl) -5 instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil Isopropyl-6- (methylsulfinyl) -2-thiouracil was used to obtain the target compound.

Prepared by the same method as Example 1, except that 1- (4-acetoxybutyl) -5 instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil Isopropyl-6- (methylsulfinyl) -2-thiouracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared by the same method as Example 1, except 1-butyl-5-isopropyl-6- instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil (Mefilsulfinyl) -2-thiouracil was used to obtain the target compound.

Prepared by the same method as Example 1, except 1-butyl-5-isopropyl-6- instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil (Methylsulfinyl) -2-thiouracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared by the same method as in Example 1, except that 1-butyl-5-ethyl-6- (instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil Methylsulfonyl) uracil was used to obtain the target compound.

Prepared by the same method as in Example 1, except that 1-butyl-5-ethyl-6- (instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil Methylsulfonyl) uracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared in the same manner as in Example 1, except that 1-butyl-5-ethyl-6- (instead of 1- (4-acetoxybutyl) -5-ethyl-6-methylsulfinyl) -2-thiouracil Methylsulfinyl) -2-thiouracil was used to obtain the target compound.

Prepared by the same method as in Example 1, except that 1-butyl-5-ethyl-6- (instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil Methylsulfinyl) -2-thiouracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared by the same method as Example 1, except 5-ethyl-6- (methylsulfonyl) instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil -1- (3-phenylpropyl) uracil was used to obtain the target compound.

Prepared by the same method as Example 1, except 5-ethyl-6- (methylsulfonyl) instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil 1- (3-phenylpropyl) uracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared by the same method as Example 1, except 1-butyl-5-isopropyl-6 instead of 1- (4-acetoxybutyl) -5-isopropyl-6- (methylsulfinyl) -2-thiouracil The desired compound was obtained using-(methylsulfonyl) uracil.

Prepared by the same method as Example 1, except 1-butyl-5-isopropyl-6- instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil (Methylsulfonyl) uracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

Prepared by the same method as Example 1, except 5-isopropyl-6- (methylsulfonyl instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil ) -1- (3-phenylpropyl) uracil was used to obtain the target compound.

Prepared by the same method as Example 1, except 5-isopropyl-6- (methylsulfonyl instead of 1- (4-acetoxybutyl) -5-ethyl-6- (methylsulfinyl) -2-thiouracil ) -1 (3-phenylpropyl) uracil was used, and 3,5-dimethylphenyl selenol was used instead of benzene selenol to obtain the target compound.

The tablets were prepared by crushing and mixing the ingredients listed above and then by direct tableting method. The total amount of each tablet was 100 mg, of which 1-butyl-6-[(3,5-dimethylphenyl) selenyl] -5-isopropyluracil was 10 mg.

The powders were prepared by crushing and mixing the ingredients listed above, and 100mg of powder was put in a hard capsule five times to make a capsule.

1 × 10 ⁴ / well concentration in RPMI 1640 cultures containing 10% fetal bovine serum, 2 mM L-glutamine, 100 U / ml penicillin G and 100 μg / ml streptomycin, inactivated by heating on a wide-bottomed microdilution plate MT-4 cells were added. And it was infected with HIV-1 (HTLV-III _B strain) so that TCID ₅₀ is 500.

The drug to be tested immediately after virus infection was dissolved in a dimethyl sulfoxide solvent to prepare a stock solution, diluted with a predetermined ratio with the culture solution, and added to wells of four different microdilution plates. After 6 days of incubation at 37 ° C, the survival rate of mock-infected and HIV-infected cells was reduced to 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetra. It was measured by the solium bromide (MTT) method.

In addition, cytotoxicity by drugs of HIV-4 cells not infected with HIV was evaluated in parallel with the antiviral activity measurement of drugs in the same manner as described above. The results are shown in Table 2 below.

Claims (8)

A pyrimidine acyclonucleoside derivative represented by the following structural formula (I) and a pharmaceutically acceptable salt thereof. In the above formula, R ¹ is an ethyl group or isopropyl group, R ² is a substituted or unsubstituted phenyl selenenyl group, the substituent is one or more selected from alkyl groups and halogen atoms of C ₁ ~ C ₃ , R ³ is hydrogen An atom, a C ₁ to C ₃ alkyl group, a C ₁ to C ₃ hydroxyalkyl group, an acyloxyalkyl group or a substituted or unsubstituted phenyl group may be a C ₁ to C ₃ alkyl group or a C ₁ to C ₃ alkoxy group Or a halogen atom, X is an oxygen atom or a sulfur atom. The compound of formula (I) according to claim 1, wherein the compound represented by formula (I) is 1-butyl-6-[(3,5-dimethylphenyl) selenyl] -5-ethyluracil and a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound represented by formula (I) is 6-[(3,5-dimethylphenyl) selenyl] -5-ethyl-1- (3-phenylpropyl) uracil and its pharmaceutically acceptable Possible salts. The compound of formula (I) according to claim 1, wherein the compound represented by formula (I) is 1-butyl-6-[(3,5-dimethylphenyl) selenyl] -5-isopropyluracil and a pharmaceutically acceptable salt thereof. According to claim 1, wherein the compound represented by formula (I) is 6-[(3,5-dimethylphenyl) selenyl] -5-isopropyl-1- (3-phenylpropyl) uracil and pharmaceuticals thereof Acceptable salts. An antiviral agent containing a pyrimidine acyclonucleoside derivative represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Wherein R ¹ , R ² , R ³ and X are as defined in claim 1 above. An antiviral pharmaceutical composition comprising a pyrimidine acyclonucleoside derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient. Wherein R ¹ , R ² , R ³ and X are as defined in claim 1 above. A virus infection prevention or treatment agent of pyrimidine acyclonucleoside derivative represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof. Wherein R ¹ , R ² , R ³ and X are as defined in claim 1 above.