JPH0748374A - Acyclic nucleosides - Google Patents

Abstract

(57) [Summary] [Objective] To provide novel acyclic nucleosides having antiviral activity. [Structure] An acyclic nucleoside derivative represented by the following general formula (1) or a salt thereof. However, R ¹ , R ² ,
Each R ³ is independently a hydrogen atom, R ⁴ O (CH ₂ ) _m −, or (R ⁵ O) ₂ P (O) CH ₂ O (CH ₂ ) _n −, and at least one is R ⁴ Represents O (CH ₂ ) _m -or (R ⁵ O) ₂ P (O) CH ₂ O (CH ₂ ) _n- ,
X, Y and Z each independently represent a hydrogen atom, a hydroxyl group, an amino group, a mercapto group, an alkylthio group, a halogen atom, a protected hydroxyl group or a protected amino group, and R ⁴ is a hydrogen atom or a hydroxyl group. Represents a protecting group, R ⁵
Represents a hydrogen atom or an alkyl group, and m and n each independently represent an integer of 1 to 3. [Chemical 1]

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to acyclic nucleosides having pharmacological activity such as antiviral activity.

[0002]

BACKGROUND OF THE INVENTION Nucleosides, nucleotides and their derivatives are antiviral as so-called antimetabolites that antagonize essential metabolites such as viruses and malignant tumor cells and suppress cell growth. It is widely used for pharmaceuticals such as drugs and antitumor agents, agricultural chemicals and other applications.

[0003] In particular, acyclic nucleosides have attracted attention as antiviral agents and anti-AIDS agents, and have been actively studied in recent years. However, many of them are preexisting acyclovir (Schaeffer.HJ, et al. Nature, 2
72 583-585,1978) and its derivatives (JP-A-60-228).
(See Japanese Patent Laid-Open No. 480, JP-A-2-73086, etc.)
Is. Such a derivative has a drawback in that it has no effect on acyclovir-resistant virus because acyclovir is the center of physiological activity.

Due to these problems, the development of nucleic acid derivatives having a new skeleton has been expected. However, there are few examples of derivatives having such a novel skeleton, for example, 9-
Only [3- (isopropoxymethoxy) propoxy] guanine (JP-A-3-118382) and the like are known.

[0005]

Means for Solving the Problems As a novel skeleton, the present inventors have focused their attention on acyclic nucleosides having a carbon-carbon double bond, and as a result of diligent studies, they are represented by the following general formula (1). It has been discovered that the acyclic nucleosides having excellent antiviral activity.
The present invention provides the acyclic nucleosides and salts thereof,
And an antiviral agent containing these compounds as active ingredients.

[0006]

[Chemical 2] [In the general formula (1), R ^{1 to} R ³ , X, Y, and Z are as follows. R ¹ , R ² , R ³ : each independently a hydrogen atom, R ⁴ O
(CH _{2) m} -, or _{^{(R 5 O) 2 P (}} O) CH 2 O (CH 2) n - and is, and at least one of _{^{R 4 O (CH 2) m}} - or (R ⁵ O) ₂ P (O) CH ₂ O (C
H ₂ ) _n- . X, Y, Z: each independently a hydrogen atom, a hydroxyl group, an amino group, a mercapto group, an alkylthio group, a halogen atom, a protected hydroxyl group, or a protected amino group.

However, the above R ⁴ , R ⁵ , and m, n
Indicates the following: R ^4: a hydrogen atom or a protecting group of a hydroxyl group,. R ⁵ : hydrogen atom or alkyl group. m and n: integers of 1 to 3 each independently. ]

In the present invention, the compound represented by the general formula (1) is not limited to the compound represented by the chemical formula and may be a tautomer thereof as long as the identity as a compound is maintained. It may be. That is, if one of the tautomers is a compound represented by the general formula (1), it is the compound of the present invention. For example, when X is a hydroxyl group and Y is an amino group, the formula (1) represents a guanine derivative represented by a lactim form, and this compound is a tautomeric guanine derivative represented by a lactam form. Is the same compound as.

The salt of the compound represented by the above general formula (1) includes a salt of a compound in which R ⁵ is a hydrogen atom (a derivative having a phosphorous acid moiety) and an acid addition salt of a purine base moiety. . As the salt-forming base or acid, a pharmaceutically acceptable inorganic or organic base or acid is used. Examples of the salt of the phosphorous acid derivative include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and ammonium salts such as triethylamine and cyclohexylamine. Examples of acid addition salts include salts of inorganic acids such as hydrochloric acid and sulfuric acid and salts of organic acids such as acetic acid.

In the present invention, the protected hydroxyl group is protected by a known protecting group such as triorganosilyl group (organic group is alkyl, aryl or aralkyl), acyl group, aralkyl group and the like. The preferred hydroxyl group is, specifically, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-
A hydroxyl group protected by a butyldiphenylsilyl group, an acetyl group, a benzoyl group, a benzyl group, a trityl group, a methoxytrityl group, a dimethoxytrityl group or the like is preferable. The protected amino group may be a known protecting group such as a triorganosilyl group (organic group is alkyl, aryl, aralkyl, etc.), an acyl group, an aralkyl group, or another protected amino group. A group is preferable, and specifically, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, an acetyl group, a benzoyl group, a benzyl group, a trityl group, a methoxytrityl group, a dimethoxytrityl group, An amino group protected with a dimethylaminomethylene group or the like is preferable.

In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The alkylthio group is an alkylthio group which may have a straight chain or a branched chain, for example, a lower alkylthio group having 4 or less carbon atoms is preferable, and specifically, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group. and so on. The alkyl group represented by R ⁵ is a linear or branched alkyl group, for example, an alkyl group having 1 to 8 carbon atoms is preferable, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group. , A butyl group and the like, and lower alkyl groups having 4 or less carbon atoms.

Specific examples of the compound of the present invention include, but are not limited to, the following compounds.

(E or Z) -9- (3-hydroxypropenyl) guanine, (E or Z) -9- (3-hydroxypropenyl) -2-amino-6-chloro-9H-
Purine, (E or Z) -9- (3-hydroxy-2-
Hydroxymethylpropenyl) guanine, (E or Z) -9- (3-hydroxy-2-hydroxymethylpropenyl) -2-amino-6-benzyloxy-9H-
Purine, (E or Z) -9- [3- (diethylphosphonomethoxy) propenyl] guanine, (E or Z)-
9- [3- (diethylphosphonomethoxy) propenyl]
-2-amino-6-benzyloxy-9H-purine,
(E or Z) -9- [3- (phosphonomethoxy) propenyl] guanine or a salt thereof, (E or Z) -9
-[3- (phosphonomethoxy) propenyl] -2-amino-6-benzyloxy-9H-purine or a salt thereof.

The compound of the present invention can be prepared, for example, by the following production method 1 or production method 2.

[Production Method 1] The compound represented by the general formula (2) is reacted with the compound represented by the general formula (3) in the presence of a base in an aprotic solvent to give the compound represented by the general formula (4). A method of obtaining a compound represented by the general formula (5) by further reacting with a base after obtaining the compound.

[0016]

[Chemical 3]

[Chemical 4]

[Chemical 5]

However, in the formula, R ^{6 to} R ¹² are as follows. R ⁶ , R ⁷ and R ⁸ are each R ¹ in the general formula (1),
A group corresponding to R ² and R ³ , each independently being R
¹³ O (CH ₂ ) _m -or (R ¹⁴ O) ₂ P (O) CH ₂ O (CH ₂ ) _n- and at least one is R ¹³ O (CH ₂ ) _m -or (R ¹⁴ O) ₂ P (O) CH ₂
O (CH ₂ ) _n −, and m and n are the same as m and n in the general formula (1). R ⁹ is a group that forms a leaving group in cooperation with an oxygen atom, and is, for example, a group such as an alkylsulfonyl group or an arylsulfonyl group, and specifically, a methanesulfonyl group, a benzenesulfonyl group, p-toluenesulfonyl group. Group, imidazosulfonyl group and the like.

R ¹⁰ , R ¹¹ and R ¹² are each independently
It is a hydrogen atom, a protected hydroxyl group, a protected amino group, or a halogen atom, and the protected hydroxyl group means a hydroxyl group protected by a protecting group similar to the above-mentioned hydroxyl protecting group. The protected amino group-protecting group means an amino group protected by the same protecting group as the aforementioned amino-group protecting group.

R ¹³ and R ¹⁴ are each R in the general formula (1).
⁴ , a group corresponding to R ⁵ , R ¹³ represents a hydroxyl-protecting group, and R ¹⁴ represents an alkyl group. The hydroxyl-protecting group represents the same protecting group as described above, and the alkyl group also represents the same alkyl group as described above.

As the above base, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4,3,0] -7-nonene (DBN), 1,8-
Diazabicyclo [5,4,0] -7-undecene (DB
Known organic amine bases such as U) are preferred.

These reactions are carried out in an aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dioxane and acetonitrile within a temperature range of 0 ° C. to the reflux temperature of the solvent. Is preferred.

[Production Method 2] The compound represented by the general formula (6) is reacted with the compound represented by the general formula (7) in the presence of a base in an aprotic solvent to give the compound represented by the general formula (8). The compound of formula (9) is obtained by reacting the compound of formula (9) with a halogenating reagent in a basic solvent.

[0023]

[Chemical 7]

[Chemical 8]

[Chemical 9]

[Chemical 10]

However, in the formula, R ^{15 to} R ²⁰ are as follows. R ¹⁵ , R ¹⁶ and R ¹⁷ are each R ¹ in the general formula (1),
A group corresponding to R ² and R ³ , each independently being R
²¹ O (CH ₂ ) _m -or (R ²² O) ₂ P (O) CH ₂ O (CH ₂ ) _n- and at least one is R ²¹ O (CH ₂ ) _m -or (R ²² O) ₂ P (O) CH ₂
O (CH ₂ ) _n −, and m and n are the same as m and n in the general formula (1).

R ¹⁸ , R ¹⁹ and R ²⁰ are each independently
A hydrogen atom, a protected hydroxyl group, a protected amino group, or a halogen atom, and the protected hydroxyl group and the protected amino group are as described above. R ²¹ and R ²² are groups corresponding to R ⁴ and R ⁵ in the general formula (1), R ²¹ represents a hydroxyl-protecting group, and R ²² represents an alkyl group.

The base used in the reaction between the compound represented by the general formula (6) and the compound represented by the general formula (7) includes sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like. An inorganic base is preferable, and the aprotic solvent described above is preferable as the aprotic solvent. The reaction is preferably carried out within the temperature range of 0 ° C to the solvent reflux temperature.

Examples of the halogenating reagent used in the step of dehydrating the hydroxyl group of the general formula (8) include phosphonyl chloride, thionyl chloride, sulfuryl chloride, thionyl bromide,
Known halogenating agents such as sulfuryl bromide are preferred, and the reaction is preferably carried out in a known amine solvent such as pyridine, N-ethylpiperidine and triethylamine within a temperature range of 0 ° C. to solvent reflux temperature.

The compound represented by the general formula (5) and the compound represented by the general formula (9) obtained by the above-mentioned production method 1 and production method 2 are deprotected as necessary and represented by the general formula (1). The present invention compound can be used.

The present invention will be specifically described below with reference to reference examples and examples, but the present invention is not limited to these examples.

[0030]

【Example】

[Reference Example 1] Synthesis of 1-O-benzoyl-2,3-O-di-p-toluenesulfonylglycerol

2.64 g of dimethyldioxolane methanol
(20.0 mmol) was dissolved in pyridine (20 ml), 2.32 ml (20 mmol) of benzoyl chloride was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate under ice cooling and chloroform 60 was added.
Extracted twice with ml. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give a residue, which was mixed with 80% acetic acid (30
ml) was added and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was evaporated under reduced pressure, azeotroped with 30 ml of ethanol 6 times, and dried under reduced pressure. 20 ml of pyridine was added to this residue, 8.39 g (44 mmol) of p-toluenesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature.
It was stirred for 14 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate under ice cooling, extracted twice with 60 ml of chloroform, dried over magnesium sulfate, filtered and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography using a mixed solvent of hexane / ethyl acetate, 9.9 g of the title compound (19.9
mmol) was obtained. NMR (CDCl ₃ ) δ 7.9-7.2 (13H, m); 4.8-5.0 (1H, m); 4.2-
4.5 (4H, m); 2.39 (3H, s); 2.36 (3H, s)

Reference Example 2 Synthesis of 1-O-diethylphosphonomethyl-2,3-O-isopropylideneglycerol

1.2 g (30.3 mmol) of 60% sodium hydride
DMF solution (20 ml) of dimethyldioxolanemethanol 4.0 g (30.3 mmol) was added dropwise to the DMF suspension solution (10 ml) under ice-cooling and stirred at room temperature for 30 minutes, and the resulting solution was diethylphosphonomethyl-p-toluene. Sulfonate 9.8g (3
A DMF solution (20 ml) of 0.3 mmol) was added dropwise under ice cooling. 80
After stirring at 0 ° C for 2 hours, the reaction solution was poured into water and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography using a hexane / ethyl acetate mixed solvent and then a chloroform / methanol mixed solvent to obtain 6.5 g of the title compound. Obtained. NMR (CDCl ₃ ) δ 4.0-4.4 (6H, m); 3.7-3.9 (3H, m); 3.62
(2H, d, J = 5.6Hz); 1.42 (3H, s); 1.3-1.4 (9H, m)

Reference Example 3 Synthesis of 1-O- (diethylphosphonomethyl) glycerol

6.5 g of the dioxirane derivative obtained in Reference Example 2
(23 mmol) was dissolved in 30 ml of 80% acetic acid, and the mixture was heated with stirring at 80 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained by azeotroping with 15 ml of ethanol four times was purified by silica gel column chromatography using a mixed solvent of chloroform / methanol to obtain 2.22 g of the title compound. . NMR (CDCl ₃ ) δ 4.1-4.2 (5H, m); 3.8-3.9 (2H, d, J = 12H
z); 3.6-3.7 (4H, m); 1.36 (6H, m)

Reference Example 4 Synthesis of 1-O- (dimethylphosphonomethyl) -2,3-O-di-p-toluenesulfonylglycerol

2.22 g (9.17 mmo) of the diol obtained in Reference Example 3
l) is dissolved in 20 ml of pyridine, p-toluenesulfonic acid chloride 3.85 g (20.17 mmol) is added under ice cooling, and the mixture is allowed to stand at room temperature for 2 hours.
The mixture was stirred for 1 hour at 40 ° C. The reaction solution is concentrated under reduced pressure,
The residue was diluted with chloroform and poured into saturated aqueous sodium hydrogen carbonate, and the organic layer was separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography using a mixed solvent of toluene / ethyl acetate to obtain 1.83 g of the title compound. NMR (CDCl ₃ ) δ 7.75 (4H, dd, J = 9.4Hz); 7.32 (4H, d, J = 9.
4Hz); 4.6-4.7 (1H, m); 4.1-4.2 (6H, m); 3.7-3.8 (4H, m);
2.47 (6H, s); 1.32 (6H, t, J = 7Hz)

Reference Example 5 Synthesis of 1,3-O-di-t-butyldimethylsilyl-2-methylene-1,3-propanediol

2-methylene-1,3-propanediol
0.6 g (6.82 mmol) and imidazole 2.79 g (40.9 mmol)
Was added dropwise to a DMF solution (5 ml) of t-butyldimethylchlorosilane (2.57 g, 17.05 mmol) under ice cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with chloroform and then washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography using a mixed solvent of hexane / ethyl acetate to obtain 1.97 g of the title compound. NMR (CDCl ₃ ) δ 5.09 (2H, s); 4.1 (4H, s); 0.83 (18H, s);
0.09 (12H, s)

Reference Example 6 Synthesis of 2- (t-butyldimethylsiloxymethyl) -2-propenol oxide-t-butyldimethylsilyl ether

O-di-t-butyldimethylsilyl-2-methylene-1,3-propanediol obtained in Reference Example 1.
To 97 g (6.17 mmol) of a dichloromethane solution (20 ml) was added m-chloroperbenzoic acid under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated, and the residue obtained was purified by silica gel column chromatography using a mixed solvent of hexane / ethyl acetate to obtain 946 mg of the title compound. NMR (CDCl ₃ ) δ 3.73 (4H, s); 2.67 (2H, s); 0.83 (18H,
s); 0.06 (12H, s)

Reference Example 7 2-Amino-6-chloro-9- (3-benzoyloxy-
Synthesis of 2-p-toluenesulfonyloxypropyl) -9H-purine

2-amino-6-chloropurine (1.7 g, 10 mmol) was added to a suspension of 60% sodium hydride (0.4 g, 10 mmol) in DMF (10 ml) under ice cooling and the mixture was stirred at room temperature for 30 minutes. A solution of 5.1 g (10 mmol) of di-p-toluenesulfonate obtained in Reference Example 1 in DMF (10 ml) was added dropwise to the solution under ice cooling, and the mixture was stirred at 90 ° C. for 1 hour. The reaction solution was poured into water and extracted 3 times with 50 ml of chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography using a mixed solvent of chloroform / methanol to obtain 3.5 g of the title compound. NMR (CDCl ₃ ) δ 7.0-8.0 (12H, m); 5.1-5.2 (1H, m); 4.5-
4.8 (2H, m); 4.3-4.4 (2H, m); 2.38 (3H, s)

[Example 1] 2-amino-6-chloro-9- (3-benzyloxy-
Synthesis of 1-propenyl) -9H-purine

0.7 g (1.4 mmol) of the p-toluenesulfonate compound obtained in Reference Example 7 was dissolved in 14 ml of acetonitrile,
Diazabicycloundecene (DBU) 0.4 ml (2.8 mmo
l) was added and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform / methanol to give 0.43 g of the title compound. NMR (CDCl ₃ ) δ 7.43-8.00 (6H, m); 7.24 (1H, d, J = 14.9H
z); 6.72 (1H, dt, J = 14.9Hz, 7.63Hz); 5.03 (2H, d, J = 7.63H
z)

Example 2 Synthesis of 9- (3-hydroxypropenyl) guanine

The benzoyl compound obtained in Example 1 0.2 g (0.6
mmol) was dissolved in dioxane (2.0 ml), and 2N- was added thereto.
Sodium hydroxide (2.0 ml) was added and the mixture was heated under reflux for 2 hours. The reaction solution was neutralized with 2N-hydrochloric acid and then concentrated under reduced pressure,
The residue was purified by C-18 silica gel column chromatography to obtain 63 mg of the title compound. NMR (CD ₃ OD) δ 8.04 (1H, s); 7.24 (1H, d, J = 15.9Hz); 6.
57 (1H, dt, J = 15.9Hz, 6.6Hz); 4.32 (2H, d, J = 6.6Hz)

Reference Example 8 Synthesis of 6-O-benzyl-9- [3- (diethylphosphonomethoxy) -2-p-toluenesulfonyloxypropyl] guanine

60% sodium hydride 145 mg (3.64 mmol)
6-O-benzylguanine was added to the DMF suspension solution (5 ml) in Example 3 under ice-cooling, and the solution was obtained by stirring at room temperature for 30 minutes, and 0.88 g (3.64 mm) of the di-p-toluenesulfonyl compound obtained in Reference Example 4 was obtained.
ol) in DMF solution (5 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 24 hours and then at 50 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with chloroform and washed twice with water.
The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography using a mixed solvent of chloroform / methanol to obtain 1.1 g of the title compound. NMR (CDCl ₃ ) δ 7.3-7.5 (10H, m); 7.03 (2H, d, J = 8.1Hz);
5.55 (2H, s); 4.8-4.9 (1H, m); 4.84 (2H, s); 4.1-4.3 (6
H-m); 3.8-3.9 (2H, m); 2.56 (3H, s); 1.3-1.4 (6H, m)

Example 3 Synthesis of 6-O-benzyl-9- [3- (diethylphosphonomethoxy) -1-propenyl] guanine

P-Toluenesulfonyl derivative obtained in Reference Example 8
Dissolve 977 mg (1.58 mmol) in 30 ml of acetonitrile, and then diazabicycloundecene (DBU) 0.24 ml (1.58 mmol)
Was added and the mixture was heated with stirring at 80 ° C. for 24 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform / methanol to give 1.1 g of the title compound.

NMR (CDCl ₃ ) δ [E-form of olefin]: 7.78 (1H, s); 7.3-7.5 (5H, m);
7.12 (1H, d, J = 14.6Hz); 6.4-6.5 (1H, m); 5.57 (2H, s); 4.8
9 (2H, s); 4.1-4.3 (6H, m); 3.84 (2H, d, J = 8.6Hz); 1.36 (6
H, m) [Z-form of olefin]: 7.80 (1H, s); 7.3-7.5 (5H, m);
6.92 (1H, d, J = 11.8Hz); 5.7-5.8 (1H, m); 5.57 (2H, s); 4.8
9 (2H, s); 4.21-4.3 (6H, m); 3.8 (2H, d, J = 8.6Hz); 1.2-1.
3 (6H, m)

Example 4 Synthesis of 9- [3- (phosphonomethoxy) -1-propenyl] guanine 45.4 mg (0.102 mmol) of the ester obtained in Example 3 was dissolved in 1 ml of acetonitrile and bromo under ice-cooling. Trimethylsilane
0.13 ml (1.02 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (0.5 ml) was added to the reaction mixture and the mixture was concentrated under reduced pressure.
Purification using silica gel column chromatography gave 25.2 mg of the title compound.

NMR (CD ₃ OD) δ [E-form of olefin]: 9.40 (1H, s); 7.36 (1H, d, J = 13.7
Hz); 6.9-7.1 (1H, m); 4.4-4.5 (2H, m); 3.92 (2H, d, J = 8.1H
z) [Z-form of olefin]: 9.20 (1H, s); 7.02 (1H, d, J = 9.1H
z); 6.2-6.3 (2H, m); 4.4-4.5 (2H, m); 3.81 (2H, d, J = 8.1H
z)

Reference Example 9 6-O-benzyl-9- [2-hydroxy-2- (t-
Synthesis of butyldimethylsiloxymethyl) -3- (t-butyldimethylsiloxy) propyl] guanine

Epoxide obtained in Reference Example 6 946 mg (2.83 mm
ol), 6-O-benzylguanine 530 mg (2.18 mmol),
A solution of potassium carbonate 902mg (6.54mmol) in DMF (5ml)
Was heated and stirred at 140 ° C. for 5 hours. The reaction mixture was poured into water, extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography using a mixed solvent of toluene / ethyl acetate. 578 mg of the title compound
Got NMR (CDCl ₃ ) δ 7.95 (1H, s); 7.3-7.4 (5H, m); 5.55 (2H,
s); 4.37 (2H, s); 3.43 (4H, dd, J = 9.7Hz, 10.5Hz); 2.80 (1
H, bs); 0.8-0.9 (18H, m); 0.03 (12H, m)

[Reference Example 10] 2-N-monomethoxytrityl-9- [2-hydroxy-2- (t-butyldimethylsiloxymethyl) -3-
Synthesis of (t-butyldimethylsiloxy) propyl] guanine

Alcohol obtained in Reference Example 9 578 mg (1 mmo
l) and 0.14 ml of triethylamine in dichloromethane (4 ml) under ice cooling monomethoxytrityl chloride 309 mg
(1 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate, the layers are separated, the organic layer is dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by silica gel column chromatography using a mixed solvent of toluene / ethyl acetate. This gave 570 mg of the title compound. NMR (CDCl ₃ ) δ 7.62 (1H, s); 7.2-7.3 (14H, m); 6.75 (2
H, d, J = 8.9Hz); 4.10 (2H, bs); 3.76 (3H, s); 3.43 (4H, dd,
J = 6.2Hz, 7.0Hz); 0.88-0.90 (18Hm); 0.02-0.03 (12H, m)

Example 5 Synthesis of 2-N-monomethoxytrityl-9- [2- (t-butyldimethylsiloxymethyl) -3- (t-butyldimethylsiloxy) -1-propenyl] guanine

531 mg (0.63 mmo) of the compound obtained in Reference Example 10
l) was dissolved in pyridine (15 ml), 0.13 ml (1.25 mmol) of thionyl chloride was slowly added dropwise under ice cooling, and the mixture was stirred under ice cooling for 3.5 hours. The reaction solution was poured into ice-saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer is dried over magnesium sulfate,
The residue obtained by filtration and concentration was purified by silica gel column chromatography using a mixed solvent of toluene / ethyl acetate to obtain 131 mg of the title compound. NMR (CDCl ₃ ) δ 7.82 (1H, s); 7.2-7.3 (14H, m); 6.74 (1
H, s); 4.34 (2H, s); 4.15 (2H, s); 3.76 (3H, s); 0.8-0.9
(18H, m); 0.02-0.03 (12H, m)

Example 6 Synthesis of 9- (2-hydroxymethyl-3-hydroxy-1-propenyl) guanine

131 mg (0.158) of the disilyl compound obtained in Example 5
mmol) was dissolved in acetonitrile (3 ml), 0.21 ml (1.58 mmol) of bromtrimethylsilane was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. 1 ml of water was added to the reaction solution, and the mixture was concentrated under reduced pressure, and the residue was purified by C-18 silica gel column chromatography to obtain 31 mg of the title compound. NMR (CD ₃ OD) δ 9.22 (1H, s); 6.99 (1H, s); 4.45 (2H, s);
4.28 (2H, s)

[Evaluation of antiviral activity] Test viruses As test viruses, varicella zoster virus CaQu strain (VZV) and human cytomegalovirus AD169.
HEL cells (human fetal lung-derived fibroblasts) were used as a host cell for each virus. Antiviral activity evaluation method In the antiviral activity evaluation test, a plaque reduction effect (PRE) test is conducted.
The 50% effective concentration (PRE ₅₀ ) was determined. The results are shown in Table 1.

[0064]

[Table 1]

[0065]

INDUSTRIAL APPLICABILITY The novel acyclic nucleosides of the present invention have higher antiviral activity than the known acyclic nucleoside acyclovir.

[Chemical 6]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshitomi Morisawa 1150 Hazawa-machi, Kanagawa-ku, Yokohama, Kanagawa Prefecture Asahi Glass Co., Ltd. Central Research Laboratory (72) Inventor Sumi Ikeuchi 1-16-13 Kitakasai, Edogawa-ku, Tokyo Ichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor Shogo Shinko 1-16-13 Kitakasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor Hiroyuki Takase Edogawa-ku, Tokyo Kitakasai 1-16-13 Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center (72) Inventor Yoichi Murakami 1-16-13 Kitakasai, Tokyo Edogawa-ku Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center

Claims (4)

[Claims] 1. An acyclic nucleoside derivative represented by the general formula (1) or a salt thereof. [Chemical 1] [In the general formula (1), R ^{1 to} R ³ , X, Y, and Z are as follows. R ¹ , R ² , R ³ : each independently a hydrogen atom, R ⁴ O
(CH _{2) m} -, or _{^{(R 5 O) 2 P (}} O) CH 2 O (CH 2) n - and is, and at least one of _{^{R 4 O (CH 2) m}} - or (R ⁵ O) ₂ P (O) CH ₂ O (C
H ₂ ) _n- . X, Y, Z: each independently a hydrogen atom, a hydroxyl group, an amino group, a mercapto group, an alkylthio group, a halogen atom, a protected hydroxyl group, or a protected amino group. However, the above R ⁴ , R ⁵ , and m and n are as follows. R ^4: a hydrogen atom or a protecting group of a hydroxyl group,. R ⁵ : hydrogen atom or alkyl group. m and n: integers of 1 to 3 each independently. ] 2. (E or Z) -9- (3-hydroxypropenyl) guanine, (E or Z) -9- (3-hydroxypropenyl)-
2-Amino-6-chloro-9H-purine, (E or Z) -9- (3-hydroxy-2-hydroxymethylpropenyl) guanine, (E or Z) -9- (3-hydroxy-2-hydroxymethyl) Propenyl) -2-amino-6-benzyloxy-9H-purine or salts thereof. 3. (E or Z) -9- [3- (diethylphosphonomethoxy) propenyl] guanine, (E or Z) -9- [3- (diethylphosphonomethoxy) propenyl] -2-amino- 6-benzyloxy-
9H-purine, (E or Z) -9- [3- (phosphonomethoxy) propenyl] guanine, (E or Z) -9- [3- (phosphonomethoxy) propenyl] -2-amino-6-benzyl Oxy-9H-purine or a salt thereof. 4. An antiviral agent comprising the compound according to claim 1, 2 or 3 as an active ingredient.