JP2577640B2 - New cyclobutane derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a cyclobutane derivative which is expected as a drug such as an antiviral drug or an anticancer drug. Conventionally, nucleic acid-related substances have an antiviral action or an anticancer action. Are known, and some of them are clinically provided as useful pharmaceuticals. For example, antiviral agents include Vidarabine (M. Privat de Garilhe)
and J.de Rubber, CRAcad.Soc.D (Paris) 259,2725 (1
964)), acyclovir (GBElion et al., Proc. Natl.
Acad. Sci. USA, 82, 7096 (1985)) and the like. Also, 5-fluorouracil, cytosine arabinoside and the like are known as anticancer agents.

Problems to be Solved by the Invention However, the above-mentioned antiviral drugs have a narrow application range,
In addition, the method of administration is limited due to the effects of solubility, oral absorption, metabolism and the like. Many problems remain, such as difficulty in long-term administration due to side effects such as bone marrow toxin. In addition, since malignant viral diseases such as acquired immunodeficiency syndrome (AIDS) and adult T-cell leukemia (ATL) tend to increase, development of new antiviral drugs is desired.

In addition, the above-mentioned anticancer drugs still have many problems in application range, side effects, and the like.

Means for Solving the Problems The present invention provides a method of formula (G) 9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine represented by the formula:

The compound of the present invention represented by the formula (G) has the general formula (IV) [Wherein B is a purine base and R ⁴ is a hydrogen atom or a protecting group.] The cyclobutane derivative represented by the following formula can be synthesized according to the following method.

That is, the general formula (V) [Wherein R ⁴ represents hydrogen or a protecting group, and X represents a leaving group]. A general formula (VI) obtained by reacting a compound represented by the formula: with a purine base such as guanine. Wherein R ⁴ represents hydrogen or a protecting group, and B ¹ represents a purine base. When a protecting group is present in this compound, if necessary, the protecting group is appropriately removed. Manufactured by removal with a protective reagent.

The holding group (R ⁴ ) in the general formulas (V) to (VI) is not particularly limited as long as it is generally used as a protecting group, and an ester-type protecting group such as an acyl group such as an acetyl group or a benzoyl group; A carbamoyl group such as a dimethylcarbamoyl group or a diphenylcarbamoyl group, or an ether-type protecting group such as a silyl group such as a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group or (C ₁ -C ₄ ) such as a methoxymethyl group; Examples include a methyl group substituted with one or more phenyl groups such as an alkoxy- (C ₁ -C ₄ ) alkyl group, a tetrahydropyranyl group, a benzyl group, a 4-methoxybenzyl group, and a trityl group. Examples of the leaving group (X) in the general formula (V) include a sulfonyloxy group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group;
Halogens such as chlorine, bromine and iodine;

In the reaction of the compound represented by the general formula (V) with a purine base such as guanine, the use ratio of the compound of the general formula (V) and the purine base such as guanine is about 0.5 equivalent to 1 equivalent of the former. -10 equivalents, preferably about 1-5 equivalents are good.
The reaction between the two is carried out in the presence or absence of a base catalyst. As a base catalyst, potassium carbonate, lithium hydride, sodium hydride, or the like is used, and N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMS
O), in a solvent such as 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamide (HMPA),
0 ° C. to the reflux temperature of the solvent, preferably from around room temperature to 17 ° C.
It is performed at about 0 ° C. The amount of the base catalyst used is 0 to 2 equivalents, preferably about 0.5 to 1.5 equivalents, more preferably about 0.8 to 1.2 equivalents, to purine bases such as guanine.

The removal of the protecting group (including the alkyl group) of the compound represented by the formula (VI) can be achieved by using an appropriate deprotecting reagent or a deprotecting method depending on the difference of the protecting group. Examples thereof include alkalis such as sodium hydroxide, sodium methylate, and ammonia, acids such as hydrochloric acid and sulfuric acid, fluorine reagents such as tetrabutylammonium fluoride, hydrogenolysis, and the like.

In addition, the compound represented by the general formula (IV) can be obtained by reacting the compound represented by the reaction formula (3) [Wherein, R ⁴ represents hydrogen or a protecting group, X represents a leaving group, B represents a purine base, and B ² represents a substituent which can be converted to B in one step or multiple steps] For example, an amine derivative represented by the general formula (XXII) is synthesized by a conventional method such as treating the compound represented by the general formula (V) with an azide ion such as sodium azide and then reducing the compound, and synthesizing the amine derivative represented by the general formula (XXII) The compounds represented are prepared by known methods (R. Vince et al., J. Med. Chem. 27, 1358).
(1984), R. Vince et al., J. Med. Chem., 30, 2026 (198
7), YFShealy and CAO Dell, J. Heterocyclic Che
m., 13, 1015 (1976), YFShealy et al., J. Heterocycli
c Chem., 18, 383 (1981), etc.) to obtain a compound represented by the general formula (IV) via an intermediate represented by the general formula (XXIII).

Further, the compound represented by the general formula (III) is very useful for producing the compound represented by the general formula (V) and further the compound represented by the general formula (IV). The general formula (II
Since the compound represented by I) can be produced optically active, the compound represented by the general formula (IV) can also be produced optically active.

That is, the reaction formula (4) [In the formula, R ¹ represents an alkyl group having 1 to 5 carbon atoms, an aralkyl group or a cyclic alkylene group having 2 to 3 carbon atoms in which two R ¹ are bonded, and R ² represents hydrogen, alkyl having 1 to 5 carbon atoms. R ³ represents hydrogen, a C ₁ -C ₅ lower alkyl group, a C ₁ -C ₅ lower alkoxy group, or an aralkyloxy group. A represents a linear or branched alkylene group having 2 to 5 carbon atoms, Y represents an oxygen or sulfur atom, and Z represents a substituted or unsubstituted methylene group or an oxygen or sulfur atom. When the compound represented by the formula (I) is reacted with the compound represented by the general formula (II) using a condensation catalyst, a racemic or optically active cyclobutane represented by the general formula (III) is obtained depending on the type of the catalyst. The compound is obtained in high yield. Examples of the condensation catalyst in this reaction include a Lewis acid or a combination of a Lewis acid and an equivalent or excess amount of a ligand. As Lewis acids,
Examples include titanium compounds such as titanium tetrachloride and dichlorodiisopropoxytitanium; tin compounds such as tin dichloride, tin tetrachloride and divalent tin triflate; and aluminum compounds such as dimethylaluminum chloride and diethylaluminum chloride. As the ligand, sterically crowded diols are preferable, for example, (2S, 3S) -2,3-O-
(1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A), (2S,
3S) -2,3-O-benzylidene-1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound C), (2S,
3S) -2,3-O- (1-phenylethylidene) -1,1,4,4
-Tetrakis (4-methoxyphenyl) -1,2,3,4-butanetetraol (compound E), etc., which has a 5- or more-membered ring in the molecule, preferably a 5- to 8-membered ring, And a group having a hydroxyl group bonded on both sides thereof. The use ratio of the compound represented by the general formula (I) to the compound represented by the general formula (II) is 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents per 1 equivalent of the former. The amount of the condensation catalyst to be used is 0.001 to 2 equivalents, preferably 0.01 to 1.2 equivalents, per 1 equivalent of the compound of the formula (I). In this reaction, the reaction may proceed more efficiently by adding a dehydrating agent such as Molecular Sieves 4A to the reaction system. Examples of the solvent for the reaction include hydrocarbon solvents such as pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, trimethylbenzene and triisopropylbenzene, halogenated carbon solvents such as freon, ethers such as ether and tetrahydrofuran. Examples thereof include a system solvent, a solvent such as acetonitrile, and a mixed solvent thereof. The reaction temperature is preferably about the boiling point to the freezing point of the reaction solvent, and more preferably about -50 ° C to about 30 ° C. For example, R ² is a methoxycarbonyl group, A is CH ₂ CH ₂ ,
A compound of the general formula (I) wherein Y is oxygen and Z is oxygen (1 equivalent); and a general formula (II) wherein R ¹ is a methyl group and R ³ is hydrogen.
(1.25 equivalents) of dichlorodiisopropoxytitanium (0.05 equivalents) and (2S, 3S) -2,3-
O- (1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A)
(0.055 equivalents), molecular sieves 4A were added, and the mixture was dissolved in a mixed solvent of hexane and toluene.
(2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane with high chemical yield and high optical yield. Obtained at a rate.

Examples of the alkyl group having 1 to 5 carbon atoms represented by R ¹ , R ² , and R ³ include an alkyl group such as a methyl group, an ethyl group, and a butyl group. Examples of the aralkyl group include a benzyl group and 4- Examples include an alkyl group substituted with an aromatic ring such as a methoxybenzyl group. Examples of the protected hydroxyalkyl group include a benzyloxymethyl group, an acetyloxymethyl group, a t-butyldiphenylsilyloxymethyl group, and the like. Examples of the protected carboxyl group include a methoxycarbonyl group,
Examples include an alkoxycarbonyl group such as an ethoxycarbonyl group, and an aralkyloxycarbonyl group of a benzyloxycarbonyl group. Examples of the alkoxy group having 1 to 5 carbon atoms include a methoxy group and an allyloxy group, and examples of the aralkyloxy group include a benzyloxy group, a 4-methoxybenzyloxy group and a t-butyldiphenylsilyloxy group. Can be

As the compound represented by the general formula (III), for example, a compound represented by the general formula (III) And the like.

However, two R ¹ of the compound represented by the general formula (III) may be the same or different.

The compound represented by the general formula (V) can be obtained, for example, by using the reaction formula (5) Wherein R ¹ is the same as in the general formula (III), R ¹⁰ and R ¹¹ represent hydrogen or an alkyl group or an aralkyl group having 1 to 5 carbon atoms, R ⁴ represents hydrogen or a protecting group, X represents a leaving group] from the compound represented by the general formula (III) (where R ² is a protected carboxyl group and R ³ is hydrogen) Can be.

First, for example, a compound represented by the general formula (III) (where R ² is a protected carboxyl group and R ³ is hydrogen) is dissolved in an alcoholic solvent such as methanol or ethanol in magnesium methoxide or sodium ethoxy. Preferably, the reaction is carried out at -78 ° C to near the boiling point of the solvent with a corresponding metal alkoxide such as a solvent at a temperature of room temperature or lower, or in an alcoholic solvent such as methanol or ethanol.
By solvolysis in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid or a base such as triethylamine or sodium hydroxide, R ¹⁰ and R ^{11 in the} general formula (VII) are obtained.
Is a group other than hydrogen, and the corresponding ester is hydrolyzed in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid or a base such as sodium hydroxide or potassium carbonate to give a compound of the general formula (VII). A carboxylic acid is obtained in which R ¹⁰ and R ¹¹ are hydrogen. General formula (VII) obtained here
Is reduced using a metal hydride such as lithium aluminum hydride, di (isobutyl) aluminum hydride, sodium borohydride, lithium borohydride, diborane, etc., and represented by the general formula (VIII). Get alcohol. Further, the dithioketal moiety of the compound represented by the general formula (IX) obtained by protecting the hydroxyl group of the compound represented by the general formula (VIII) is converted into, for example, iodine, N-bromosuccinimide, N- Hydrolysis using halogenating agents such as chlorosuccinimide, sulfuryl chloride, or heavy metal compounds such as silver nitrate, silver oxide, silver perchlorate, mercury chloride, copper chloride, copper oxide, or a combination of these compounds To a ketone represented by the general formula X).

A compound represented by the general formula (X) is used as a reducing agent, for example, lithium aluminum hydride, lithium tri (t-butoxy) aluminum, sodium borohydride, lithium tri (s-butyl) boron, borohydride Using a metal hydride complex such as lithium or a metal hydride such as diisobutylaluminum hydride or diborane, as a solvent, for example, a hydrocarbon-based solvent such as pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, a chloride, etc. Methylene, a halogenated carbon-based solvent such as chloroform, ether, an ether-based solvent such as tetrahydrofuran, an alcohol-based solvent such as methanol and ethanol, water and a mixed solvent thereof, and the reaction temperature is -100 ° C to 50 ° C, Preferably, -80
Reduction from about 30 ° C. to about 30 ° C. yields a compound represented by the general formula (XI). At the time of this reduction reaction, one of the stereoisomers can be preferentially obtained by selecting the type of reducing agent to be used and the reaction conditions. For example, the reaction formula (6) [Wherein R ⁴ represents hydrogen or a protecting group] Cyclobutanone, which is 2,3-trans represented by the general formula (Xa) as shown in the following formula, for example, is reduced with a relatively sterically unreduced reducing reagent. Then, an alcohol represented by the general formula (XIb), which is 1,2-trans, is selectively obtained. For example, by treating with a reducing agent having a large steric hindrance, an alcohol represented by the general formula (XI The alcohols represented by a) are preferentially obtained. That is, (2S, 3S) -2,3-
Bis (t-butyldiphenylsilyloxymethyl) -1
Reduction of cyclobutanone with less sterically hindered lithium tri (t-butoxy) aluminum or sodium borohydride gives (1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) Cyclobutanol can be selectively obtained (isolation yields 88% and 80%, respectively) and reduced with lithium tertiary tri (s-butyl) hydride or di (isobutyl) aluminum borohydride (1S , 2S, 3S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) cyclobutanol is preferentially obtained (75% and 82% isolation yield, respectively). The results are shown in the following table.

The stereoisomer obtained here, that is, the general formula (XI
After isolation, the compound represented by a) and the compound represented by formula (XIb) can be easily converted to other isomers mutually. For example, a compound represented by the general formula (XIa) or a compound represented by the general formula (XIb) is converted into a metal oxidizing agent such as chromic acid / acetic acid, chromic acid / pyridine, dimethyl sulfoxide (DMSO) -acetic anhydride / acetic acid. , DMSO-oxalyl chloride-triethylamine / DMSO oxidation such as methylene chloride, etc., a method of subjecting the ketone represented by the general formula (Xa) to oxidation again by a usual oxidation reagent or oxidation method, and further subjected to selective reduction, or The method of inverting the configuration of the 1-position carbon having a hydroxyl group in the compound represented by the general formula (XIa) and the compound represented by the general formula (XIb) using, for example, a Mitsunobu reaction. No. For example, a compound represented by the general formula (XIa) or a compound represented by the general formula (XIb) is converted to a trivalent phosphorus compound such as triphenylphosphine, trimethyl phosphite, and triethyl phosphite, acetic acid, and benzoic acid. Carboxylic acid such as, and azodicarboxylic acid ester such as diethyl azodicarboxylate, as a solvent, for example, pentane,
Using hydrocarbon solvents such as hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, etc .; halogenated carbon solvents such as methylene chloride and chloroform; ether solvents such as ether and tetrahydrofuran; Is from -100 ° C to 50
C., preferably at about -50 ° C. to about 30 ° C. to form an ester, for example, potassium carbonate, sodium hydroxide, sodium methylate, alkali such as ammonia,
Hydrolysis with an acid such as hydrochloric acid or sulfuric acid, or a metal hydride complex compound such as lithium aluminum hydride, lithium tri (s-butyl) borohydride, lithium borohydride, or a metal hydride such as diisobutylaluminum hydride or diborane To obtain a compound represented by the general formula (XIb) or a compound represented by the general formula (XIa). For example, (1R, 2S, 3S) -2,3-bis (t
-Butyldiphenylsilyloxymethyl) cyclobutanol is reacted with triphenylphosphine / benzoic acid / diethylazodicarboxylate in benzene to give (1
After leading to (S, 2S, 3S) -1-benzoyl-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane, reducing with diisobutylaluminum hydride in toluene to remove the benzoyl group, 1S, 2S, 3S)
-2,3-Bis (t-butyldiphenylsilyloxymethyl) cyclobutanol is obtained. The compound represented by the general formula (V) is produced by leading the secondary hydroxyl group of the compound represented by the general formula (XI) thus obtained to a leaving group.

Effects The following experimental examples show that the compounds of the present invention exert broad and strong antiviral and anticancer effects.

Experimental Example 1. Herpes simplex virus type 1 virus (HSV-
I), antiviral activity against herpes simplex virus 2 (HSV-II) was tested by the following method.

(Method 1) Virus 100-150 PFU (P) was placed on a 6-well multiplate having a monolayer of Vero cells (derived from African green monkey kidney cells).
After infecting with a laque forming unit and adsorbing at 37 ° C for 1 hour, an agar medium containing each concentration of sample (Eagle MEM medium containing 1.5% agar) was overlaid, and 37 ° C, 5% (v / v) carbonic acid. After culturing for 48 hours in a gash egg container, the formation of plaque (Plaque) was measured, and a 50% inhibition value (IC ₅₀ ) was determined.

Experimental Example 2. DNA virus, human cytomegalovirus (HCM
The effect on V) was tested in the following manner.

(Method 2) The anti-cytomegalovirus activity was determined by infecting a 35-mm dish having a monolayer of human fetal fibroblasts with cytomegalovirus (A0169 strain) 100PFU (Plaque Forming Unit), and adsorbing for 1 hour. Medium containing the present compound (0.5
% Agarose, 2% fetal calf serum (fetal cal)
f serum)], and cultured for 10 days at 37 ° C in a 5% (v / v) carbon dioxide oocytes. Plaque formation was measured to determine the 50% inhibition value (IC ₅₀ ). Was.

Experimental Example 3 The effect on hepatitis B virus (HBV), a DNA virus, was tested by the following method.

(Method 3) A cultured hepatocyte cell line that produces and releases active hepatitis B virus
HB611 (Proc. Natl. Acad. Scl. USA, 84 , 444 (1987))
10% in modified Eagle medium (GIBCO) according to lbecco
The cells are cultured in the presence of fetal calf serum, 200 μg / ml G418, penicillin and streptomycin (100 u / ml each) at 37 ° C. using 5% CO ₂ . 5 × 10 ⁴ calls / hole (35m
m) and inoculated to 50% confluence 1-2 days later, when a certain amount of the compound is added and cultured, and thereafter, the culture is continued for 15 days while replacing the medium containing the drug at the same concentration every 3 days. Remove the medium. Transfer the cells to 0.5 ml Lysis buffer (10 mM TrisHCI pH7.8 / 5 mM Na ₂ EDT
A, 1% SDS / 0.1 mg / ml Pronase K) for 1 hour at 37 ° C to dissolve, and the resulting DNA was purified by RNase treatment and ethanol precipitation with phenol / chloroform treatment.

Next, 5 μg DNA was treated with Hind III, and then
^The DNA pattern was analyzed using ³² P-marked hepatitis B virus DNA as a probe.

Experimental Example 4. RNA (Human Immunode ficiency Vi
rus) was tested in the following manner.

(Method 4) Approximately 50,000 MT-4 cells / ml were placed in a 24-well tray, and 100 μg of a solution containing a fixed amount of the compound of the present invention was added.
After culturing for 2 hours in a 5% (v / v) CO2 egg container, H
IV10 ³ to 10 ⁴ infection units added, after 4 days of culture, and spread a part of the culture solution to the slide glass, after the acetone-fixed,
The expression of the virus antigen was observed by the fluorescent antibody method.

In addition, serum of AIDS patient,
FITC-labeled anti-human IgG was used as the secondary antibody.

Experimental Example 5. Human cervical cancer HeLa S ₃ , mouse leukemia L1210 and P388
The anticancer effect on cells was tested by the following method.

(Method 5) HeLa S ₃ cells were prepared at 7.5 × 10 ³ cells / ml and seeded at 0.2 ml / well on a 96-well flat bottom plate. After culturing for 24 hours at 37 ° C. in a 5% CO ₂ incubator, 10 μl of a drug was added and culturing was performed for 72 hours. After the culture, the culture solution in each well is withdrawn, fixed with methanol, and then 0.05% methylene blue / 10m
M-Tirs-HCl (pH 8.5) solution was added at 0.1 ml / well, and 30
Stain for minutes at room temperature. The staining solution in each well was extracted using an aspirator, and then washed three times with pure water. 3% HC
l at a rate of 0.2 ml / well, seal with a seal for about 24
The dye was extracted from the cells at room temperature for a period of time. 66 in each well
The absorbance at 0 nm was measured with a Dynatech microplate reader, and the growth inhibition rate (%) at each concentration was calculated by the formula shown below, and plotted on a log probability paper to show a 50% inhibitory concentration (IC ₅₀ value, μg / μg / ml).

Growth inhibition rate (%) = (1−A ₁ / A ₀ ) × 100 where A ₁ = absorbance of drug-treated group A ₀ = absorbance of control group (Method 6) P388 and L1210 cells were seeded on a 24-well plate, The drug was added, and the cells were cultured at 37 ° C. and 5% CO ₂ for 48 hours. The number of cells after completion of the culture was calculated using a Coulter counter. The growth inhibition rate of the treated group with respect to the control group was calculated from the following formula,
The 50% inhibitory concentration (IC ₅₀ value, μg / ml) was determined by the Litchfield method.

Growth inhibition rate (%) = _{[1- (N T -N 0) /} (N C -N 0) ] ×
100 Here, the results of the N _T = drug treated group cell number N ₀ = cultured start cell number N _C = less than the number of control group cells Experiment 1-5 in the following table.

Experimental Example 6. In Vitro Against Herpes Simplex Type 2 Virus (HSV-II)
The vo antiviral effect was tested in the following manner.

(Method 7) HSV-II (strain 186, strain 186, BALB / c mice (male, 6 weeks old))
(4.8 × 10 ⁵ PFU / 0.2 ml / mouse) was intraperitoneally transplanted, and after 6 hours, a drug dissolved in physiological saline was intraperitoneally or orally administered once a day for 10 days every day. Observation was performed for 20 days after infection, and the antiviral effect of the compound was determined from the number of surviving mice and the average number of surviving days.

The antiviral effect was compared using a commercially available antiviral drug acyclovir (ACV) as a control drug.

(Results) As shown in the following table, the compounds of the present invention showed very strong HSV
-Suppressed the mortality of mice infected with II. In the control group, the average survival time is 7.7 days, whereas in the compound-administered group of the present invention, a wide dose range (1.25-20 mg / kg / day)
A large number of mice survived the 20 days observed. Survival was observed in the acyclovir-administered group, but the effective range was narrow.

Effect Since the compound of the present invention has a strong antiviral effect, herpes simplex virus type 1, type 2 (HSV-I, II), varicella zostar virus (lipase, genital herpes, shingles, immunosuppression) VZV), cytomegalovirus (C
MV), Epstan-Barr virus (EBV) infection, viral hepatitis, viral respiratory disease, viral digestive disease, AIDS, ATL, and many other viral diseases. In addition, since it has an anticancer effect, it is also expected as an anticancer agent.

When the compound of the present invention thus obtained is used as an antiviral agent or an anticancer agent, it can be administered orally, intravenously, or transdermally. The dosage varies depending on the condition, age, and administration method of the patient to be administered.
-500 mg / Kg / day. The compound of the present invention is administered in the form of a preparation prepared by mixing with an appropriate preparation carrier. As the form of the preparation, tablets, granules, fine granules, powders, capsules, injections, creams, suppositories and the like are used.

Experimental Example Next, the production of the compound of the present invention will be specifically described with reference to examples.

Experimental Example 1. (-)-(2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-
Production of 3-yl) carbonylcyclobutane Example 1-1. Dichlorodiisopropoxytitanium (905 mg, 3.8 mmol) and (2S, 3S) -2,3-O- (1-phenylethylidene) -1 in an argon atmosphere. , 1,4,4-tetraphenyl-1,2,
3,4-butanetetraol (Compound A) (2.22 g, 4.2 mmo
To l), 1,3,5-trimethylbenzene (TMB) (80 ml) is added and stirred at room temperature for 30 minutes. To this solution, add powdered molecular sieves 4A (3.2 g) and stir for a while.
Add 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidin-2-one (3.98 g, 20 mmol) and cool to -15 ° C. After slowly adding a TMB solution (20 ml) of 1,1-bis (methylthio) ethylene (3.61 g, 30 mmol) to the suspension, the temperature is raised to 0 ° C. over 3 hours from the same temperature with stirring. A saturated aqueous solution of sodium hydrogen carbonate is added to the reaction solution, the inorganic substance is removed by filtration using celite, and the organic substance is extracted with ethyl acetate. The extract is washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2, v / v) to give (-)-(2S,
3S) -3-Methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane (3.94 g, 62%) is obtained. The optical purity of this compound is 86% ee (see Example 3).

NMR (500 MHz FT, CDCl ₃ ) δ: 2.01 (3H, s), 2.10 (3H, s), 2.54 (1H, dd, J = 9.9,12.3Hz), 2.70 (1H, dd, J = 7.9,12.3Hz) , 3.86 (1H, dt, J _d = 9.9 Hz, J _t = 7.9 Hz), 3.71 (3H, s), 4.02 (1H, ddd, J = 6.4,8.9,11.0 Hz), 4.12 (1H, ddd, J = 7.6,9.3,11.0Hz), 4.39−4.47 (2H, m), 5.01 (1H, d, J = 7.9Hz). IR (neat) cm ^-1 : 1780, 1730, 1690. Example 1-2. Almost in the same manner as in Example 1-1, 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidin-
2-one (3.98 g, 20 mmol), 1,1-bis (methylthio)
Ethylene (3.61 g, 30 mmol), dichlorodiisopropoxytitanium (474 mg, 2.0 mmol), (2S, 3S) -2,3-O- (1
-Phenylethylidene) -1,1,4,4-tetraphenyl-
1,2,3,4-butanetetraol (Compound A) (1.16 g, 2.2
mmol) and powdered molecular sieves 4A (4 g) in a mixed solvent of toluene (160 ml) and hexane (120 ml) at 0 ° C.
(-)-(2S, 3S)-
3-methoxycarbonyl-1,1-bis (methylthio)-
2- (Oxazolidin-2-one-3-yl) carbonylcyclobutane (6.13 g, 96%) ([α] _D = -10.4 ゜ (c1.34, CH ₂ Cl ₂ )) is obtained. This was recrystallized from methylene chloride-isopropyl ether to give 5.30 g (83
%) ([Α] _D = -11.1 ゜ (c1.15, CH ₂ Cl ₂ )). The optical purity of this compound is 98% ee or more (determined by the method described in Example 3).

Example 1-3. Almost in the same manner as in Example 1-1, 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidine-
2-one (19.9 g, 100 mmol), 1,1-bis (methylthio)
Ethylene (15.03 g, 125 mmol), dichlorodiisopropoxytitanium (1.18 g, 5.0 mmol), (2S, 3S) -2,3-O-
(1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A) (2.91
g, 5.5 mmol) and powdered molecular sieves 4A (20 g) in a mixed solvent of toluene (800 ml) and hexane (600 ml) at 0 ° C. for 5 hours to obtain (−) − (2S, 3).
S) -3-Methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane (26.69 g, 84%) ([α] _D = −1
0.5 ゜ (c1.00, CH ₂ Cl ₂ )).

Example 2 (-)-(2S, 3S) -2,3-bis (methoxycarbonyl)
Production of -1,1-bis (methylthio) cyclobutane Example 2-1. (-)-Produced in Example 1-1 in an argon atmosphere.
1M was added to a methanol solution (25 ml) of (2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane (3.94 g, 12.3 mmol). Add dimethoxymagnesium / methanol (25 ml, 25 mmol) and stir at room temperature for 1 hour. After the reaction solution is concentrated under reduced pressure, a saturated aqueous ammonium chloride solution is added, and the mixture is extracted with ether. After the ether extract is washed with a saturated saline solution, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:
Hexane = 1: 9, v / v) to purify (-)-(2S, 3S) -2,3
-Bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (2.17 g, 67%) is obtained. The optical purity of this compound is 86% ee (see Example 3).

NMR (500 MHz FT, CDCl ₃ ) δ: 2.01 (3H, s), 2.12 (3H, s), 2.47 (1H, dd, J = 9.0,12.2 Hz), 2.50 (1H, dd, J = 9.4,12.2 Hz) , 3.63-3.75 (2H, m), 3.69 (3H, s), 3.72 (3H, s), IR (neat) cm ^-1 : 1730. Example 2-2. 1M-dimethoxymagnesium / methanol in an argon atmosphere (400 ml, 400 mmol) at 0 ° C. with (−) − (2S, 3
S) -3-Methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane (26.0 g, 81.4 mmol) is added, and the mixture is stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ether. After the ether extract is washed with a saturated saline solution, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9, v / v) to give (-)-(2S, 3S) -2,3-
This gives bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (20.73 g, 96%).

Example 3 (-)-(2S, 3S) -2,3-bis (hydroxymethyl)-
Production of 1,1-bis (methylthio) cyclobutane Lithium aluminum hydride (56
2 mg, 14.8 mmol) in ether suspension at 0 ° C.
An ether solution (10 ml) of (-)-(2S, 3S) -2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (1.96 g, 7.4 mmol) prepared in 1 was gradually added. Stir at 0 ° C. for 2 hours. After adding a saturated aqueous solution of sodium sulfate to the reaction solution to decompose excess reducing agent, anhydrous sodium sulfate is added and the mixture is stirred for a while. After the inorganic substance is removed by filtration and further washed with hot isopropyl alcohol, the filtrate and the washing solution are combined and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 15: 2: 1, v / v / v) (-)-(2S, 3S)
This gives -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane (1.48 g, 96%).

NMR (270 MHz FT, CDCl ₃ ) δ: 2.02 (1H, dd, J = 9.1,12.1 Hz), 2.05 (3H, s), 2.06 (3H, s), 2.28 (1H, dd, J = 8.1,12.1 Hz) , 2.47-2.68 (2H, m), 3.26 (2H, brs), 3.54 (1H, dd, J = 8.8, 10.3 Hz), 3.67-3.77 (2H, m), 3.83 (1H, dd, J = 5.0, 10.4 Hz), IR (neat) cm ^-1 : 3350. A part of this compound was taken and subjected to a conventional method ((R) -α-methoxy-
α-trifluoromethyl-phenylacetyl chloride ((R) -MTPAC1), dimethylaminopyridine (DMAP)
/ Pyridine (pyr)) to give the bis (R) -MTPA ester.

In 500 MHz NMR, the signal of the methyl group of this compound derived from the racemate was 1.852, 1.856, 1.912, and 1.970 ppm in total of 4
Although this is observed, the signal of the methyl group of this substance is 1.852
And the signal at 1.912 ppm was greater than the others, and the optical purity was determined to be 86% ee.

The title compound (-)-(2S, 3S) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane was recrystallized from ethyl acetate-hexane to give an optical purity of 100%. Can be obtained.
([Α] _D = −32.0 ゜ (c1.03, CH ₂ Cl ₂ )).

Example 4 Production of (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane (-)-(2S, 3S) -2 , 3-Bis (hydroxymethyl)
-1,1-bis (methylthio) cyclobutane (1.37 g, 6.58 m
mol), triethylamine (2.8 ml, 20 mmol), 4-dimethylaminomethylpyridine (catalytic amount) and DMF (1 ml) dissolved in methylene chloride (25 ml) were added to t-butyldiphenylsilyl chloride (4.52 g, 25 mmol). And stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, dissolved in ether, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the ether solution is purified by silica gel column chromatography (ether: hexane = 1: 20, v / v) to give (+)-(2S, 3S) -2,3bis (t-butyl). Diphenylsilyloxymethyl) -1,1
To obtain bis (methylthio) cyclobutane (4.50 g, 100%).

NMR (200 MHz FT, CDCl ₃ ) δ: 0.99 (9H, s), 1.02 (9H, s), 2.06 (6H, s), 2.09-2.25 (2H, m), 2.85 (1H, m), 3.52-3.73 ( 3H, m), 3.90 (1H, dd, J = 9.0,10.8Hz), 7.26-7.47 (12H, m), 7.55-7.74 (8H, m), Example 5 (+)-(2S, 3S)- Production of 2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone N-chlorosuccinimide (1.60 g, 12 mmol) and silver nitrate (2.29 g, 13.5 mmol) were added to an 80% aqueous acetonitrile solution (45%).
(+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-
A solution of bis (methylthio) cyclobutane (2.06 g, 3 mmol) in acetonitrile (6 ml) and methylene chloride (1 ml) is quickly added and stirred for 10 minutes. A saturated aqueous solution of sodium sulfite (3 ml) is added to the reaction solution, and the mixture is stirred for 1 minute. A saturated aqueous solution of sodium hydrogen carbonate (3 ml) is added, and the mixture is stirred for 1 minute. Saturated saline (3 ml) is further added, and the mixture is stirred for 1 minute. A methylene chloride-hexane mixture (1: 1, v / v
v) (60 ml) is added, and the insoluble matter is filtered off using Hyflo. The filtrate was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ether: hexane = 1: 10, v / v) (+).
-(2S, 3S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.49 g, 82%) is obtained.

NMR (270 MHz FT, CDCl ₃ ) δ: 1.02 (9H, s), 1.04 (9H, s), 2.74-3.05 (2H, m), 3.29 (1H, m), 3.69 (1H, dd, J = 3.7,10.6) Hz), 3.82 (1H, dd, J = 4.8,10.3Hz), 3.88 (1H, dd, J = 4.8,10.3Hz), 3.97 (1H, dd, J = 4.0,10.6Hz), 7.32-7.44 (12H , m), 7.62-7.68 (8H, m), IR (neat) cm ^-1 : 1785. Example 6 Production of 2.3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol Example 6-1. Argon atmosphere Below, lithium tri (t-butoxy) aluminum hydride (1.27 g, 5.0 mmol) is added to tetrahydrofuran (THF) (10 ml) and cooled to -78 ° C. To this suspension, a THF solution of (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.21 g, 2.0 mmol) was added, and the mixture was stirred. Warm slowly to room temperature over time. After adding 0.2 M-phosphate buffer to the reaction solution to decompose excess reducing agent, methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-1: 4, v / v).
(+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (0.104 g, 9
_{%) NMRJ200MHzFT, CDCl 3) δ} : 1.00 (9H, s), 1.07 (9H, s), 1.97-2.25 (2H, m), 2.32 (1H, m), 2.48 (1H, m), 3.17 (1H, d, J = 7.3Hz), 3.56 (2H, d, J = 5.8Hz), 3.88 (1H, dd, J = 5.6,11.4Hz), 3.98 (1H, dd, J = 4.0,11.4Hz), 4.46 ( 1H, m), 7.26-7.48 (12H, m), 7.54-7.72 (8H, m), and (+)-(1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) Cyclobutanol (1.
068 g, 88%).

NMR (200 MHz FT, CDCl ₃ ) δ: 1.03 (9H, s), 1.04 (9H, s), 1.60-1.73 (2H, m), 1.92 (1H, m), 2.10-2.37 (2H, m), 3.52- 3.70 (3H, m), 3.77 (1H, dd, J = 4.5,10.4Hz), 4.03 (1H, m), 7.27-7.46 (12H, m), 7.56-7.69 (8H, m), Example 6 2. Under an argon atmosphere, a solution of (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (4.12 g, 6.8 mmol) in toluene (70 ml) was added with- 1M at 78 ° C-diisobutylaluminum hydride /
Toluene (8.2 ml, 8.2 mmol) is gradually added, and the mixture is stirred at the same temperature for 10 minutes. A 0.2 M phosphate buffer (pH 7) is added to the reaction solution, and after stirring for a while, an excess of methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-1: 4, v / v), and (+)-(1S, 2
(S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (3.38 g, 82%) and (+)
-(1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (0.69 g, 17%) is obtained.

Example 6-3. From (+)-(1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol to (+)-(1S, 2S, 3S) -2,3 Conversion step to -bis (t-butyldiphenylsilyloxymethyl) cyclobutanol 1. In an argon stream, (+)-(1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclo Butanol (700 mg, 1.15 mmol), benzoic acid (167 mg, 1.37 mm
ol) and triphenylphosphine (362 mg, 1.38 mmol)
To a benzene (10 ml) solution was added diethyl azodicarboxylate (217 μl, 1.38 mmol), and the mixture was stirred at room temperature overnight. After evaporating volatile substances under reduced pressure, the reaction mixture was subjected to silica gel column chromatography (ether: hexane =
1:10, v / v) to give (+)-(1S, 2S, 3S) -1-benzoyl-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (791 mg, 97%). obtain.

NMR (200 MHz FT, CDCl ₃ ) δ: 0.97 (9H, s), 1.06 (9H, s), 2.23-2.40 (2H, m), 2.45 (1H, m), 2.85 (1H, m), 3.71 (2H, d, J = 5.4Hz), 3.83 (1H, dd, J = 6.1,10.5Hz), 3.99 (1H, dd, J = 7.3,10.5Hz), 5.48 (1H, apperent q, J = 6.5Hz), 7.21 −7.45 (14H, m), 7.49−7.72 (9H, m), 7.98 (2H, d, J = 7.1Hz). Step 2. In an argon stream, the (+)-(1S, 2S,
3S) -1-benzoyl-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (790 mg, 1.1 mmol)
l) in toluene (10 ml) at −78 ° C. with 1M diisobutylaluminum hydride / toluene (2.6 ml, 2.6 mmol)
And slowly stirred at the same temperature for 30 minutes. 0.2M-
After adding a phosphate buffer (pH 7) and stirring for a while, an excess of methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ether: hexane = 1: 5, v / v), and (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) Cyclobutanol (64
4 mg, 95%).

Example 7 Production of (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (+)-(1S, 2S, 3S)- 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (911 mg,
To a methylene chloride solution of 1.5 mmol) and triethylamine (0.6 ml, 4.3 mmol) was added methanesulfonyl chloride (0.17 ml, 2.2 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 15 minutes. The reaction solution is added with a 0.2 M phosphate buffer and extracted with ether. After the ether extract is dried over anhydrous sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6, v / v) to give (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl)- 1-methanesulfonyloxycyclobutane (quantitative) is obtained.

NMR (200 MHz FT, CDCl ₃ ) δ: 1.04 (9H, s), 1.06 (9H, s), 2.25−2.53 (3H, m), 2.78 (1H, m), 2.87 (3H, s), 3.65 (2H, d, J = 4.0Hz), 3.85 (1H, dd, J = 6.3,10.5Hz), 3.93 (1H, dd, J = 6.5,10.5Hz), 5.25 (1H, m), 7.32-7.50 (12H, m ), 7.60-7.75 (8H, m). The compound was recrystallized from ether-hexane to give a crystal ([α] _D = + 12.0 ゜ (c1.01, CH ₂ Cl ₂ ))
(Optical purity 100%).

Example 9 Production of (+)-9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine (compound of the present invention) Step 1. (+)-2 Preparation of -amino-9-[(1R, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6- (2-methoxyethoxy) -purine 2-amino Lithium hydride (6 mg, 0.75 mmol) is added to a suspension of -6- (2-methoxyethoxy) purine (155 mg, 0.74 mmol) in DMF (4 ml), and the mixture is stirred for 1 hour. A solution of (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (450 mg, 0.65 mmol) in DMF (1.5 ml) was added to the reaction solution. Stir at 145 ° C. for 6 hours. After cooling, a 0.2 M phosphate buffer and ethyl acetate were added, and the insoluble material was removed by filtration, followed by extraction with ethyl acetate. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10:
1, v / v) and purified by (+)-2-amino-9-[(1R, 2
(R, 3R) -2,3-Bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6- (2-methoxyethoxy) -purine (88 mg, 30%) is obtained.

NMR (200 MHz FT, CDCl ₃ ) δ: 1.01 (9H, s), 1.05 (9H, s), 2.25-2.60 (3H, m), 2.92 (1H, m), 3.44 (3H, s), 3.60-3.94 ( 6H, m), 4.50-4.90 (5H, m), 7.15-7.55 (12H, m), 7.55-7.80 (8H, m), 7.67 (1H, s). When DMSO and HMPA are used as the solvent for this reaction, the reaction proceeds at 75 ° C. and 100 ° C., respectively, and the same results as when DMF is used are obtained.

Step 2. Production of (+)-9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine (compound of the present invention) (+) produced in Step 1 -2-amino-9-[(1R, 2
R, 3S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6- (2-methoxyethoxy) -purine (79 mg, 0.10 mmol) in methanol solution (2 ml) is 4N. -Hydrochloric acid / dioxane (0.1 ml, 0.4 mmo
l) and stir at room temperature overnight. After evaporating the solvent under reduced pressure, water was added to remove the ether-soluble portion, the solvent was distilled off, a 2N aqueous hydrochloric acid solution (2 ml) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was neutralized with a 1 M sodium hydroxide solution, and then purified by Sephadex HP-20 column chromatography (water: methanol = 1: 0-1: 4, v / v) to obtain (+)-
9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl)
Cyclobutan-1-yl] -guanine (the compound of the present invention)
(23 mg, 88%).

NMR (200 MHz FT, CD ₃ OD) δ: 2.18 (1H, m), 2.32 (1H, apparent q, J = 10.0 Hz), 2.50 (1H, m), 2.79 (1H, m), 3.62-3.74 (4H, m), 4.54 (1H, apparent q, J = 8.8Hz), 7.89 (1H, s), UV λmax (H 2 O) nm: pH1,253,277 (sh); pH7,253,268 (sh): pH13,256 ( s
h), 267. NRMS (FAB) Calcd for [C ₁₁ H ₁₅ N ₅ O ₃ + H] ⁺ ; 266.1253 Found; 266.1251. This compound was recrystallized from water to give a crystal ([α] _D = + 26. 5% (c 0.99, 0.1 N-NaOH)) (optical purity> 98%).

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yukihiro Nishiyama 2-8-25 Shiratori, Togo-cho, Aichi-gun, Aichi (72) Inventor Kenichi Matsubara 3-18-1-804, Yamadahigashi, Suita-shi, Osaka (72) Invention Person Takemitsu Nagahata 2-6-25 Kamishida, Toyonaka-shi, Osaka 208 Senri-zaka Nogi Heights 208 (72) Inventor Hiroo Hoshino 1-14-5 Heiwacho, Maebashi-shi, Gunma Prefecture (72) Inventor Junichi Seki Gunma Prefecture 239 Iwahanacho, Takasaki-shi (72) Inventor Koichi Narasaka 1-3-17-310, Etchujima, Koto-ku, Tokyo (72) Inventor Yujiro Hayashi 2-6-2, Minamiyukiya, Ota-ku, Tokyo (56) References JP2 −6478 (JP, A)

Claims (1)

(57) [Claims] (1) 9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine