NL8921278A - NEW CYCLOBUTANE DERIVATIVE AND METHOD FOR PREPARING IT. - Google Patents

Description

New cyclobutane derivative and process for its preparation.

BACKGROUND OF THE INVENTION

1. Field of the invention.

The invention relates to cyclobutane derivatives which are expected to be useful as medicaments such as antiviral, carcinogenic and the like, as well as the useful preparation of their intermediates and a process for their preparation.

2. Description of the known technique.

Many of the nucleic acid-related substances are known to have antiviral or carcinostatic activity, and some of them are used clinically as useful drugs. For example, Vidarabine (M. Privat de Garilhe and J. de Rubber, CR Acad. Soc. D (Paris) 259, 2725 (1964)), Aciclovir (GB Elion et al., Proc. Natl. Acad. Sci. USA, 74, 5716 (1977) and Azidothymidine (H. Mitsuya et al., Proc Natl. Acad. Sci. USA, 82, 7096 (1985) are known as antivirals, and 5-fluorouracil and cytosine arabinoside are known as carcinostatic agents.

However, the aforementioned antivirals are not widely applicable and limited in the method of administration because of their solubility, oral absorbency and influence on metabolism. Furthermore, they have many problems such as the difficulty of long-term administration due to side reactions such as bone marrow suppression. Furthermore, due to the increasing tendency of malignant virus diseases such as acquired immunodeficiency syndrome (AIDS); T cell leukemia in adults (ATL), etc., requires the development of new excellent antiviral drugs.

On the other hand, the above mentioned carcinostatic agents also have many unsolved problems in terms of applicability and side reactions, etc.

SUMMARY OF THE INVENTION

The invention relates to cyclobutane derivatives represented by the following general formula (IV): (IV) wherein B represents a nucleic acid base and a hydrogen atom or a protecting group.

DETAILED DESCRIPTION OF THE INVENTION

As the nucleic acid base B in the general formula (IV), reference can be made to pyrimidine base and purine base. Examples of the pyrimidine base included the compounds represented by the following formulas:

, and examples of the purine base comprising compounds represented by the following formulas:

In these formulas, Y - * - represents hydrogen atom or C 1-4 lower alkyl group; Y ^ hydrogen atom, halogen atom or amino group, Y ^ represents hydrogen atom or amino group; and Y ^ represents hydrogen atom or amino group.

Among the compounds represented by the general formula (IV), those whose substituents are sterically constructed so that substituent B and its adjacent hydroxymethyl group are in transrelation and the hydromethyl group adjacent to B and the other hydroxymethyl group are in transrelation, preferred, and those having a steric configuration of (IR, 2R, 3S) are even more preferred.

Concrete examples of the compound represented by the general formula (IV) are shown below. In this description, the relative steric configuration of compounds is expressed in the following manner. For example, when the cyclobutane ring is considered a flat plane, a substituent located below the plane (one side) is denoted by the sign oL, and a substituent located above the plane (the other side) is denoted by the sign β .

1. (±) -9 - [(1α, 2α, 3 | 3) -2,3-Bis (hydrorymethyl) cyclobutan-1-yl] -adenine 2. 9 - [(1S, 2R, 3S) - 2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -adenine 3. 9 - [(1R, 2R / 3R) -2,3-Bis (hydroxymethyl) cyclobutane -1-yl] -adenine 4. (±) -9 - [(1a, 2a, 3 (3) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -guanine 5. 9 - [(IS, 2R, 3S) -2, 3-Bis (hydroxymethyl) cyclobut to -1-yl] -guanine 6. 9 - [(1R, 2S, 3R) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -guanine 7. (±) - 9 - [(1β, 2α, 3β) -2,3-Bis (hydroxymethyl) cyclo-buta.an-1-yl] - adenine 8.9- [(IR, 2R, 3S) -2,3-Bis ( hydroxymethyl) cyclobutane -1-yl] -adenine 9.- [(IS # 2S, 3R) -2,3-Bis (hydroxymethyl) cylobutane.-1-yl] _ adenine 10 (±) -9- [( 1β / 2α, 3β) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -guanine 11.9 - [(1R, 2R, 3S) -2,3-Bis (hydroxymethyl) cyclobutane -1- yl] -guanine 12.9- [(IS / 2S / 3R) -2 / 3-Bis (hydroxymethyl) cyclobut-1-yl] -guanine 13. (+) - 2-Amino-2 - [(10 , 2α, 3β) -2,3-bis (hydroxymethyl) cyclobutane; -1-yl] -purine 14.2-Amino-9- [(IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclo -butan-1-yl] -purin 15. 2-Amino-9- [(1S, 2S, 3R) -2,3-bis (hydroxymethyl) cyclo-butan-1-yl] -purin 16. (+) - 2-Amino-9- [(1β, 2α, 3β) -2,3-bis (hydroxymethyl) -cyclobutan-1-yl] -6-chloropurine 17. 2-Amino-9- [(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclo-butan-1-yl] -6-chloropurine 18. 2-Amino-9 - [(IS, 2S, 3R ) -2,3-bis (hydroxymethyl) eye lo-butan-1-yl] -6-chloropurine 19 (±) -2,6-Diamino-9- [(1β, 2α, 3β) -2,3- bis (hydroxy methyl) cyclobutane -1-v1] purine 20. 2,6-Diamino-9 - [(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] purine 21 2,6-Diamino-9 - [(IS, 2S, 3R) -2,3-bis (hydroxymethyl) -cyclobutan-1-yl] -purine 22. (+) -9 - [(1β, 2α, 3β 2,3-Bis (hydroxymethyl) eyelo-butan-1-yl] -hydroxanthine 23. 9 - [(IR, 2R, 3S) -2,3-Bis (hydroxymethyl) cyclobutane -1-yl] hypoxanthine 24. 9 - [(1S / 2S / 3R) -2 / 3-Bis (hydroxymethyl) cyclobutane- 1-yl] hypoxanthine 25. (±) -1 ~ C (1β / 2α / 3β) -2 / 3-Βίε (hydroxymethy1) cyclobutan-1-yl 3 -2,4 (1H, 3H) -pyrimidindione 26. 1 - [(1R, 2R, 3S) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -2,4 (1H, 3H) -pyrimidindione 27.1 - [(1S, 2S, 3R) -2 1,3-Bis (hydroxymethyl) cyclobutan-1-yl] ^, 4 (1H, 3H) -pyrimidindione 28. (±) -1- [(1β, 2a, 3β) -2,3-Bis (hydroxymethyl) cyclo- but on-1-yl] -5-methyl-2,4 (1H, 3H) -pyrimidindione 29.1 - [(IR, 2R, 3S) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] - 5-methyl-2,4 (1H, 3H) -pyrimidindione 30. 1 - [(IS, 2S, 3R) -2,3-Bis (hydroxymethyl) cyclobutan-1-yl] -5-methyl-2,4 ( 1H, 3H) pyrimidindione 31. (+) - 4-amino-1 - [(1β, 2α, 3β) -2,3-bis (hydroxymethyl) -cyclobutan-1-yl] -2 (1H) pyrimidinone 32.4 -Amino-1- [(IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclo-buta an-1-yl] -2 (1H) -pyrimidinone 33,4-Amino-1 - [(IS, 2S, 3R) -2,3-bis (hydroxymethyl) cyclo-buta an-1-yl] -2 (1H) -pyrimidinone34. (+) - 2-Amino-9 - [(13,2a, 3B) -2i3-bi s (acetoxy-methyl) cyclobutan-1-yl] -purin> 35. 2-Amino-9 - [(IR, 2R, 3S) -2,3-bis (acetoxymethyl) cyclobutan-1-yl] -pyrin · 36 2-Amino-9 - [(1S, 2S, 3R) -2,3-bis (acetoxymethyl) cyclo-buta an-i-yi)] - purin

Among the compounds of this invention, the compounds represented by the general formula (IV) may be prepared by reacting a compound represented by the following general formula (V) ï

(V) (R4 represents hydrogen atom or a protecting group and X represents a disappearing group) with a nucleic acid base to obtain a compound represented by the following general formula (VI):

(VI) (R4 represents hydrogen atom or a protecting group and B4 represents a nucleic acid base) and, when the last compound has a protecting group, optionally eliminate the protecting group with an appropriate reagent to remove the protecting group.

As protecting group R4 in the general formulas (V) and (VI), any group can be used without limitation as far as it is known to be used as protecting group. Examples of the protecting group R4 include ester type protecting groups such as acyl groups (e.g. acetyl, benzoyl and the like) and carbamoyl groups (e.g. dimethylcarbamoyl, diphenylcarbamoyl and the like), ether type protecting groups such as silyl groups (e.g. t-butyldimethylsily, t-butyldiphenylsilyl and the like), (alkoxy) C 1 -C 2 alkyl groups (e.g., methoxymethyl and the like), benzyl groups, and the like. Examples of the disappearing group X in the general formula (V) included sulfonyloxy groups such as a methanesulfonyloxy, p-toluene sulfonyloxy, trifluoromethane sulfonyloxy and the like, and halogen atoms such as chlorine, bromine, iodine and the like.

Examples of the nucleic acid base include pyrimidine bases such as uracil, thymine, cytosine, 5-fluorouracil and the like, and purine bases such as adenine, hypoxanthine, guanine, 2-amino-6-chloropurine, 2-aminopurine, 2,6-diamino-purine and of such. These compounds can have a protecting group. For example, reference can be made to the compounds indicated by the following general formulas (XII) to (XVII):

(defined in these formulas as above; r5 represents C19-C8 lower alkyl group such as benzyl, butyl and the like, (C1-C5 alkoxy) - (0 ^ -05 alkyl) group such as methoxyethyl and the like, or R ^; R ® represents hydrogen atom, halogen atom or NHR ^; R ^ represents hydrogen atom or NHR ^; and represents hydrogen atom, halogen atom or C1-C5 lower alkyl group).

In the reaction between a compound represented by the general formula (V) and a nucleic acid base (e.g. a compound of the general formulas (XII) - (XVII)), the ratio of the compound of general formula (V) to the compound of general formulas (XII) - (XVII) recommended at 0.5 to about 10 equivalents and more preferably about 1 to about 5 equivalents of the last compound per 1 equivalent of the first compound. This reaction is carried out either in the presence of a basic catalyst or in the absence of a catalyst. As the basic catalyst, potassium carbonate, lithium hydride, sodium hydride and the like can be used. The reaction is performed in a solvent such as Ν, Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric acid triamide (HMPA) and the like, at a temperature ranging from 0 ° C to the boiling-back temperature of the solvent, preferably from ambient temperature to about 170 ° C. Based on the amount of the compound of general formula (XII) - (XVII), it is recommended to use the basic catalyst in an amount of 0 to 2 equivalents, preferably 0.5 to 1.5 equivalents and even more preferably about 0 , 8 to 1.2 equivalents.

Elimination of the protecting group (including alkyl group) of the compound of general formula (VI) can be achieved by appropriate protecting group eliminating reagents and protecting group eliminating methods according to the type of protecting group. As the protecting group eliminating reagent, there may be mentioned, for example, alkaline such as sodium hydroxide, sodium methylate, ammonia and the like, acids such as hydrochloric acid, sulfuric acid and the like, fluorinated reagents such as tetrabutyl ammonium fluoride and the like. As a protecting group eliminating method, reference can be made, for example, to hydrogenolysis and the like.

Among the compounds of this invention, represented by the general formula (IV), those whose B is 2,6-diaminopurine, 2-aminopurine or 2-amino-6-halopurine can be prepared with a compound represented by the following general formula (IVa), according to:

Reaction Scheme (1) (defined in this scheme as above; X represents a disappearing group; and represents hydrogen atom, halogen atom or amino group).

For example, as shown in reaction scheme (1), a hydroxyl group of a guanine derivative, represented by the general formula (IVa), is protected for preparing a compound represented by the general formula (XX), after which it is reacted with a halogenating agent such as phosphorus oxychloride and the like or a sulfonylating agent such as 1,3,5-trimethylbenzenesulfonyl chloride and the like to synthesize a compound represented by the general formula (XXI). The compound (XXI) thus obtained is heated in an ampoule together with ammonia-methanol to give a compound of the general formula (IVb), wherein Y2 represents amino group. When this compound is catalytically reduced using a palladium carbon catalyst and then its protective group is removed, a compound of the general formula (IVb), wherein Y2 is hydrogen, is obtained. On the other hand, by eliminating the protecting group of a compound of general formula (XXI), wherein X is halogen atom, a compound of general formula (IVb), wherein Y2 is halogen atom is obtained.

The compounds of the invention represented by the general formula (IV) wherein B is hypoxanthine may be prepared from a compound represented by the following general formula (IVc) according to:

Reaction schedule (2)

As shown in reaction scheme (2), an adenine derivative of general formula (IVc) is diazotized by, for example, treatment with nitrous acid, and then hydrolyzed or treated with a hydrolysing enzyme such as Adenosine deaminase or the like, to give a compound represented by the general formula ( IVd) can be obtained.

Furthermore, the compounds of general formula (IV) can be synthesized in the following manner. For example, as shown in the following reaction scheme (3):

(in this reaction scheme hydrogen represents or a protecting group, X represents a disappearing group, B represents a nucleic acid base, and represents a substituent, which can be converted to B in one step or a number of steps) a compound of the general formula (V ) treated with an azide ion compound such as sodium azide or the like and then reduced in the usual way to synthesize an amine derivative represented by the general formula (XXII), and the latter (XXII) is converted to the compound of the general formula (IV) via an intermediate represented by the general formula (XXIII) by the known method (R. Vince et al., J, Med. Chem., 21_, 1358 (1984); R. Vince et al., J. Med. Chem., 30, 2026 (1987); YF Shealy and CA O'Dell, J. Heterocyclic Chem., 13, 1015, (1976); YF Shealy et al., J. Heterocyclic Chem., 18, 383 ( 1981); etc.).

It has further been found that a compound represented by the general formula (III) is very useful for the preparation of a compound of the general formula (V) or a compound of this invention represented by the general formula (IV). Since the compounds of general formula (III) can be obtained in an optically active form, the compounds of general formula (IV) can also be obtained in an optically active form. Thus, as shown in the following reaction scheme (4);

Reaction theme (4) (in this reaction scheme, R - * - taken individually represents an alkyl group of 1 to 5 carbon atoms or an aralkyl group, or, taken in conjunction with two R * groups, represents a cyclic alkylene group of 2-3 carbon atoms; R2 represents hydrogen atom, alkyl group of 1-5 carbon atoms, protected hydroxyalkyl group or protected carbonyl group; R2 represents hydrogen atom, lower alkyl group of 1-5 carbon atoms, lower alkoxy group of 1-5 carbon atoms or aralkyloxy group; A represents an alkylene group of 2 -5 straight or branched chain carbon atoms; Y represents oxygen atom or sulfur atom; and Z represents substituted or unsubstituted methylene group, oxygen atom or sulfur atom), a compound of the general formula (I) and a compound of the general formula (II) to reacted in the presence of a condensation catalyst to give a cyclobutane compound represented by the general formula (III). Order in high yield, and this product is racically or optically active according to the type of catalyst. As the condensation catalyst useful in this reaction, there may be mentioned, for example, Lewis acids and combinations of a Lewis acid and an equivalent or excess amount of a ligand. Examples of said Lewis acid included titanium compounds such as titanium tetrachloride, dichloro diisopropoxy titanium and the like, tin compounds such as stannous chloride, stannic chloride, stannous trifluoromethanesulfonate or the like, and aluminum compounds such as dimethyl aluminum chloride, diethyl aluminum chloride and the like. As said ligand, sterically complicated diols are preferred. Examples of said ligand include the compounds having a ring no smaller than a 5-membered ring (e.g., a 5- to 8-membered ring) in the molecule and two hydroxy1-containing groups in both sides of the ring, such as (2S, 3S ) -2.3-0- (1-phenyl-ethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butane tetraol (Compound A), (2R, 3R) -2,3- 0- (1-phenylethylidene) -1,4,4-tetraphenyl-1,2,3,4-butane tetraol (compound B), (2S, 3S) - 2,3-0-benzylidene-1,1, 4,4-tetraphenyl-1,2,3,4-butane tetraol (compound C), (2R, 3R) -2,3-O-benzylidene-1,1,4,4-tetra-phenyl-1,2, 3,4-butane tetraol (compound D), (2S, 3S) -2,3-0- (1-phenylethylidene) -1,1,4,4-tetrakis (4-methoxyphenyl) -1,2,3,4 butane tetraol (compound E), (2R, 3R) -2,3-0- (1-phenylethylidene) -1,1,4,4-tetrakis (4-methoxyphenyl) -1,2,3,4-butane tetraol ( compound F), racemic forms of the above compounds, and the like. The compound of general formula (I) and the compound of general formula (II) are used in a ratio such that the amount of compound (II) is 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents, per an equivalent of compound (I). The condensation catalyst is used in an amount of 0.001 to 2 equivalents, preferably 0.01 to 1.2 equivalents, per one equivalent of the compound of the general formula (I). This reaction can sometimes be carried out even more efficiently by adding a dehydration agent such as molecular sieves 4A and the like in the reaction system. Examples of the solvent useful in this reaction include hydrocarbon solvents such as pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, trimethylbenzene, triisopropylbenzene and the like; halogenated hydrocarbon solvents such as Flon and the like; ethereal solvents such as ether, tetrahydrofuran and the like; acetonitrile; and mixtures of these solvents. The reaction temperature is recommended in the range from freezing point of the reaction solvent to its boiling point, and preferably in the range from -50 ° C to about 30 ° C. For example, by reacting one equivalent of a compound of general formula (I), wherein R 2 is methoxycarbonyl group, A CH 2 CH 2 / Y oxygen and Z oxygen, with 1.25 equivalent of a compound (II) in which R - * - methyl group and R2 is hydrogen in the presence of a condensation catalyst (combination of 0.05 equivalent dichloro diisopropoxy titanium and 0.055 equivalent (2S, 3S) - 2.3-0- (1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2 , 3,4-butane tetraol (compound A)) and molecular sieves 4A, in a solvent mixture consisting of hexane and toluene at a reaction temperature of 0 ° C, (2S, 3S) -3-methoxy-carbonyl-1,1 bis- (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane obtained in a high chemical yield and a high optical yield. If this reaction is carried out in the presence of a combined catalyst consisting of dichloro diisopropoxy titanium and (2R, 3R) - 2,3-0- (1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4- butane tetraol (compound B), (2R, 3R) -3-methoxycarbonyl> -1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclohexane. If further this reaction is carried out by racemic 2,3-0- (1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butane tetraol, (+) - (2 *., ) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane.

In the compound of the invention, the examples of the alkyl group having from 1 to 5 carbon atoms represented by R 1, R 2 and R 2 include alkyl groups such as methyl, ethyl, butyl and the like; examples of the arylkyl group include alkyl groups substituted by an aromatic ring such as benzyl group, 4-methoxybenzyl group and the like; examples of the protected hydroxyalkyl group include benzyloxymethyl group, acetyloxymethyl group, t-butyldiphenyl-silyloxymethyl group and the like; examples of the protected carbonyl group include alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and the like and aralkyloxycarbonyl groups such as benzyloxycarbonyl and the like; examples of the alkoxy group of 1-5 carbon atoms include methoxy group, allyloxy group and the like; and examples of the aralkyloxy group include benzyloxy group, 4-methoxybenzyloxy group, t-butyldiphenylsilyloxy group and the like.

In the invention, examples of the compound represented by the general formula (III) include the compounds of the general formula (III), wherein R 1, R 3, r 3, a, Y, and Z are as indicated in Table 1:

Table 1

provided that the two R 1 groups in the compound of general formula (III) may be identical or different from each other.

The compounds represented by the general formula (V) can be prepared, for example, from a compound represented by the general formula (III) (therein R 1 is a protected carboxyl group and R 1 hydrogen atom) according to a process represented by the following reaction scheme ( 5):

Response schedule (5) see page 16

Reaction scheme (5) (in this reaction scheme R- * is the same as in the general formula (III), R- ^ and R ^ each represent a hydrogen atom, an alkyl group with 1-5 carbon atoms or an aralkyl group, represents R ^ hydrogen atom or a protecting group, and X represents a disappearing group).

Thus, in the first step, a compound represented by the general formula (III) (herein R 1 is a protected carboxyl group and R 1 hydrogen atom) is reacted in an alcohol solvent such as methanol, ethanol or the like in the presence of a corresponding metal alkoxide such as magnesium methoxide, sodium ethoxide or the like at a temperature ranging from 78 ° C to the boiling point of the solvent (preferably at a temperature level no higher than room temperature), or solvolysis in an alcohol solvent such as methanol, ethanol or the like in the presence of an acid such as hydrochloric acid, p- toluene sulfonic acid and the like or a base such as triethylamine, sodium hydroxide and the like, whereby the corresponding ester represented by the general formula (VII), wherein R 1 and R 1 represent hydrogen, alkyl group of 1-5 carbon atoms or aralkyl group obtained. On the other hand, it is hydrolysed in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid and the like or a base such as sodium hydroxide, potassium carbonate and the like, whereby a carboxylic acid of the general formula (VII), wherein and R · * ·· * · hydrogen atoms, can be obtained.

By reducing the compound of general formula (VII) obtained here with a metal hydride such as lithium aluminum hydride, di (isobutyl) aluminum hydride, sodium borohydride, diborane and the like, an alcohol represented by the general formula (VIIII) is obtained . Then, the hydroxyl group of the compound of general formula (VIII) is protected to obtain a compound of general formula (IX), and the dithioketal portion thereof is hydrolyzed in an aqueous solvent with a halogenating agent such as iodine, N-bromo succinimide , N-chlorosuccinimide, sulfuryl chloride and the like or a heavy metal compound such as silver nitrate, silver oxide, silver perchlorate, mercury chloride, copper chloride, copper oxide and the like or a combination of these compounds to form a ketone compound represented by the general formula (X).

A compound represented by the general formula (X) is reduced with a metal-hydrogen complex compound such as lithium aluminum hydride, lithium tri (t-butoxy) aluminum hydride, sodium borohydride, lithium tri (s-butyl) borohydride, lithium borohydride and the like or a metal hydride such as diisobutylaluminum hydride, diborane and the like as reducing agent, in a solvent such as a hydrocarbon type solvent (e.g. pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene and the like), a halogenated hydrocarbon type solvent (e.g. a methylene chloride, chloro form and the like), an ethereal solvent (e.g. ether, tetrahydrofuran and the like), an alcohol solvent (e.g. methanol, ethanol and the like), water, or mixtures thereof, at a reaction temperature of -100 ° C to 50 ° C and at preferably -80 ° C to 30 ° C, to yield a compound represented by the general formula (XI). In this reduction, one of the stereoisomers can preferably be obtained by choosing the type of reducing agent and the reaction conditions. For example, if 2,3-transcyclobutanone, represented by the general formula (Xa) shown in the following reaction scheme (6):

(represents hydrogen atom or a protecting group in this scheme) is reduced with a sterically relatively simple reducing agent, selectively forms a 1,2-trans alcohol represented by the general formula (Xlb). However, if the reduction is carried out with a strong sterically hindered reducing agent, a 1,2-cis alcohol represented by the general formula (Xla) is preferably formed. For example, if (2S, 3S) -2,3-bis (t-butyldi-phenylsilyloxymethyl) -1-cyclobutanone is reduced with lithium tri (t-butoxy) aluminum hydride or sodium borohydride (each of these reducing agents are not strongly sterically hindered ), (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -cyclobutanol is selectively formed (isolation yield 88% and 80%, respectively). If the same starting compound as above is reduced with lithium tri (s-butyl) borohydride or di (isobutyl) aluminum hydride (each of these reducing agents are strongly sterically hindered), preferably (IS, 2S, 3S) -2,3- bis (t-butyl-diphenylsilyloxymethyl) -cyclobutanol (isolation yield 75% and 82%, respectively). The results obtained are as shown in Table 2.

Table 2

R4 = t-BuPh2Si (in Xa, Xla and Xlb)

The stereoisomers obtained in this way, i.e. the compound of the general formula (Xla) and the compound of the general formula (Xlb), are both easily convertible from one to the other after isolation. For example, a compound represented by the general formula (Xla) or a compound represented by the general formula (Xlb) is again oxidized to a ketone represented by the general formula (Xa) using a conventional oxidant or oxidation method (e.g. a metal oxidizing agent such as chromic acid / acetic acid, chromic acid / pyridine and the like, or dimethyl sulfoxide (DMSO) oxidation method such as DMSO acetic anhydride / acetic acid, DMSO oxalyl chloride triethylamine / methylene chloride and the like), after which the oxidized product (Xa) is subject to a selective reduction. On the other hand, a steric configuration of a 1-carbon atom to which a hydroxyl group is attached is converted into a compound of the general formula (Xla) or a compound of the general formula (Xlb), for example, using the Mitsunobu reaction. The Mitsunobu reaction will be explained below with the latter method. Thus, a compound represented by the general formula (Xla) or (Xlb) is reacted with a trivalent phosphorus compound such as triphenylphosphine, trimethylphosphite, triethylphosphite or the like, a carboxylic acid such as acetic acid, benzoic acid or the like, and an azodicarboxylic acid ester such as diethylazodicarboxylate or the like, in a solvent such as a hydrocarbon type solvent (e.g. pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene and the like), a halogenated hydrocarbon solvent (e.g. methylene chloride, chloroform and the like), an ether-like solvent (e.g. ether, tetrahydrofuran and the like), or a mixture thereof, at a reaction temperature of -100 ° C to 50 ° C (preferably -50 ° C to 30 ° C), to form an ester. Then the ester is hydrolyzed with an alkali such as potassium carbonate, sodium hydroxide, sodium methylate, ammonia and the like or an acid such as hydrochloric acid, sulfuric acid and the like, or reduced with a metal-hydrogen complex compound such as lithium aluminum hydride, lithium tri (s-butyl) - borohydride, lithium borohydride and the like, or a metal hydride such as di-iso-butyl aluminum hydride, diborane and the like. In this treatment, a compound represented by the general formula (X1b) or a compound represented by the general formula (Xla) can be obtained. For example, if (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol is reacted with triphenylphosphine benzoic acid diethylazodicarboxylate in benzene to form (IS, 2S, 3S) -1-benzoyl-2 , 3-bis (t-butyldiphenylsilyl-oxymethyl) cyclobutane and the latter is then reduced with diisobutylaluminum hydride in toluene, the benzoyl group can be eliminated and (IS, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol. By converting the second hydroxyl group of the compound represented by the general formula (XI) thus obtained into a disappearing group, a compound represented by the general formula (V) can be generated.

The test examples given below will demonstrate that the compounds of the invention exhibit broad and strong antiviral and carcinostatic actions,

Trial example 1.

Antiviral actions against simple Herpes 1 type virus (HSV-I) and simple Herpes 2 type virus (HSV-II), both belonging to DNA virus, were examined using the following methods.

(Method 1).

One 6-well multiplate with a single layer of Vero cell (derived from the African Green monkey kidney cell) was contaminated with 100 to 150 PFU (plague forming units) virus, after being adsorbed at 37 ° C for one hour agar medium (Eagle MEM medium, containing 1.5% agar), containing a varied concentration of sample, was placed, and cultivation was performed at 37 ° C for 48 hours in 5% (v / v) carbon dioxide incubator. plaque was measured, from which the 50% inhibition value (IC 50) was determined.

Trial example 2.

Antiviral activity against human Cytomegalovirus (HCMV) belonging to DNA virus was investigated by the following method.

(Method 2).

The anti-HCMV activity was determined in the following manner. A 35 mm dish with a single layer of human embryonic fibroblast was infected with 100 PFU HCMV (A0169 strain). After adsorption for one hour, one layer of a medium (0.5% agarose, 2% fetal calf serum) containing a varied concentration of sample compound was placed thereon, and the cultivation was performed at 37 ° C for 10 days in 5% ( v / v) carbon dioxide incubator. Plaque formation was then measured, from which the 50% inhibition value (IC50) was determined.

Test example 3.

Antiviral activity against B hepatitis virus (HBV), belonging to DNA virus, was tested according to the following method.

(Method 3).

Following the procedure of Dulbecco (Proc. Natl. Acad. Sci. USA, j} 4, 444 (1987)), the cultured liver cell strain HB611, which produces and releases active hepatitis B virus, was grown in a modified Eagle medium (GIBCO ) at 37 ° C at a CO2 concentration of 5% in the presence of 10% fetal calf serum, 200 micrograms / ml G418, 100 / h / ml penicillin and 100 / h / ml streptomycin. The broth was inoculated on a 6-well plate at a rate of 5 x 10 4 cells / well (35 mm). One or two days later, 50% confluency was reached when a predetermined amount of sample compound was added, and cultivation was continued. Culturing was then continued for 15 days, while the medium was refreshed with a fresh medium containing the same concentrations of the chemicals at three day intervals. The medium was then removed and the cell bodies treated with 0.5 ml Lysis buffer (10 mM Tris HCl, pH 7.8 / 5 mM Na2EDTA, 1% SDS / 0.1 mg / ml Pronase K) at 37 ° C for one hour and dissolved therein. The DNA thus obtained was purified by RNase treatment, phenol chloroform treatment and ethanol precipitation.

Subsequently, 5 micrograms of DNA was subjected to Hind III treatment, and the DNA pattern was analyzed according to the Southern method using 32 P-labeled hepatitis B virus DNA as the investigative means.

Test example 4.

Antiviral activity against Human Immunodeficiency Virus (HIV), belonging to DNA virus, was tested according to the following method.

(Method 4).

MT-4 cell (about 50,000 cells / ml) was placed in a 24-well plate, to which was added 100 micrograms of a solution containing a predetermined amount of sample compound. Culturing was performed at 37 ° C for 2 hours in 5% (v / v) carbon dioxide incubator. Then, 10 · 10 to 10 ^ infection units of HIV were added and cultured for 4 days, after which part of the culture liquid was applied to a microscope slide and immobilized with acetone, and the development of virus antigen was examined using the fluorescent antibody method.

Serum from AIDS patients was used as the primary antibody of the fluorescent antibody method. As the second antibody, FITC-labeled human IgG was used.

Test example 5.

Carcinostatic actions on the HeLa S3 cell of human neck cancer, the L1210 cell of leukemia in mice and the P388 cell of leukemia in humans were investigated using the following methods.

(Method 5).

HeLa S3 cell was made up in a suspension (7.5 x 10 ^ cells / ml). The suspension was spread on a 96-well flat plate in the amount of 0.2 ml / well. After cultivation at 3-7 ° C for 24 hours in 5% carbon dioxide incubator, 10 µl of sample was added and cultivated for 72 hours. Then the broth was taken from each well and immobilized with methanol, then 0.1 ml / well of 0.05% methylene blue / 10 mM-Tris-HCl (pH 8.5) solution was added and the staining was performed at room temperature for 30 min. The colored liquid in each pit was removed using an aspirator and washed three times with pure water. Then, 3% HCl was added at 0.2 ml / well and the resulting mixture was sealed and left at room temperature for about 24 hours to extract pigment from the cells. Optical absorbance of each well at 660 nm was measured using Dynatic Microplate Reader, from which the growth inhibition rate (%) at different concentration was calculated according to the following equation. The results were plotted on logarithmic graph paper, from which 50% inhibition concentration (ICj-q, micrograms / ml) was determined.

Growth inhibition rate (%) = (1 - a ^ / Aq) x 100 where A ^ = Absorbance in the treated group,

Aq = Absorbance in the control group.

(Method 6).

Cells of P388 and L1210 were spread on a 24-well plate. After adding sample, it was grown at 37 ° C for 48 hours in 5% CO2 incubator.

After cultivation, the cell number was counted using a coal tar counter. The growth inhibition rate in the treated group, based on that in the control group, was calculated from the following equation, from which 50% inhibition concentration (CI, -q, micrograms / ml) was determined: The results obtained are as shown in Table 3. Growth inhibition rate

where Nqi = Number of cells in treated group

Nq = Number of cells at the start of culture Nc = Number of cells in control group

Table 3

Test example 6.

The efficacy of the sample (Compound No.

11) against herpes simplex virus type 2 (HSV-2) infection was tested in mice. Balb / c mice (6 weeks old, male) were inoculated intraperitoneally (l.p.) with HSV-2 strain 186 at 4.8 x 10 PFU / 0.2 ml per mouse. The sample was formulated in saline and administered either orally (p.o.) or i.p. with the indicated dose once a day for 10 days, starting 6 hours after virus infection.

Mortality was recorded for 20 days after inoculation. The yield of the sample was indicated as the extension of the survival time and the number of survivors. Aciclovir (ACV: commercialized antivirus agent) was used as the reference sample.

Results:

The results obtained are shown in Table 4.

Table 4

To test the potential of compound No. To evaluate in vivo, this was compared to AGV. Connection No.

11 was highly effective in reducing the mortality rate of mice infected with HSV-2 regardless of the routes of administration (Table 4). The mean survival time of mice in a control group was 7.7 days, while a number of survivors were observed over a 20-day observation period in a wide dosing range of compound Nr. 11 from 1.25 to 20 mg / kg per day. Survivors were also observed in the treatment of ACV. However, the number of survivors and the effective dose range were much greater with compound No. 11 then with ACV.

Since they have a strong antiviral activity, the compounds of the invention represented by the general formula (IV) are expected to be effective in controlling a number of viral diseases such as herpes labialis, genital herpes, herpes zoster, simple infection of herpes virus 1 and 2 (HSV-I, II), Varicel zoster virus (VZV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), viral hepatitis, viral respiratory diseases, viral diseases of the digestive organs, AIDS, ATL, etc. Since they have a carcino-static activity, they are further expected to be useful as a carcinostatic agent.

Using the compounds of the invention obtained in the above manner as an antiviral or carcinostatic drug, they can be administered orally, intravenously, or percutaneously to a warm-blooded animal. Although the dose may vary depending on symptoms and age of the warm-blooded animal and the method of administration, it usually consists of 0.1 to 500 mg / kg / day. The compounds of the invention are administered in the form of a composition prepared by mixing them with suitable excipients. As the form of composition, tablets, granules, powder, capsules, injection, cream, suppositories, and the like can be used.

Next, the preparation of the compounds of the invention will be concretely illustrated by the following examples.

Example 1: Preparation of (-) - (2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) carbonylcyclobutane.

Example 1-1.

In an argon gas atmosphere, 80 ml of 1,3,5-trimethylbenzene (TMB) was added to dichloroisopropoxy titanium (905 mg, 3.8 mmol) and (2S, 3S) -2.3-0- (1-phenyl-) ethylidene) -1 # 1,4,4-tetraphenyl-1,2,3,4-butane tetraol (compound A) 2.22 g, 4.2 mmol), and the mixture was stirred at room temperature for 30 min. molecular sieves 4A (3.2 g) in powder form added to the resulting solution and stirred for a while, then 3-Z ”(E) -3- (methoxycarbonyl) -propenoyl-7-oxazolidin-2-one (3.98 g, 20 mmol) was added, and the resulting suspension was cooled to -15 ° C. Then 1,1-bis (methylthio) -ethylene (3.61 g, 30 mmol) was dissolved in 20 ml TMB solution, added slowly and the temperature of the total mixture was raised from that temperature to 0 ° C over a period of Stir for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, the inorganic material was filtered with celite, and the organic material was extracted with ethyl acetate. The extract solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solution was 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- on-3-yl) -carbonylcyclobutane (3.94 g, 62%) was obtained. This compound had an optical purity of 86% (compare Example 8) NMR (500 MHzFT, CDCl3) 5: 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, Jd = 9.9Hz, Jt = 7r9Hz), 3.71 (3H, s), 4.02 (1H, ddd, J = 6.4, 8.9, 11.0Hz), 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 (net) cm @ -1: 1780, 1730, 1690.

Example 1-2.

»'..... mi

In a manner as in Example 1-1, 3 / (E) -3- (methoxycarbonyl) -propenoyl-7-oxazolidin-2 * -one (3.98 g, 20 mmol), 1,1-bis (methylthio) ethylene (3.61g, 30mmol), dichloro diisopropoxy titanium (474mg, 2.0mmol), (2S, 3S) -2.3-0- (1-phenylethylidene) -1,4,4-tetraphenyl- 1,2,3,4-butane tetraol (compound A) 1.16 g, 2.2 mmol) and molecular sieves 4A (4 g) in powder form react in a solvent mixture consisting of toluene (160 ml) and hexane (120 ml) at 0 ° C for 40 min to form (-) - (2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl ) -carbonylcyclobutane (6.13 g, 96%) (f ^ Jd - -10.4 ° (c 1.34, CH 2 Cl 2)). This was recrystallized from a methylene chloride isopropyl ether system to give a compound = 11.1 ° (c 1.15, CH 2 Cl 2)) in a yield of 5.30 g (83%). The optical purity of this compound was 98% ee or higher as determined by the method of Example 8.

Example 1-3.

In a manner similar to Example 1-1, 3- / 1E) -3- (methoxycarbonyl) -propenoyl-oxazolidin-2-one (19.9 g, 100 mmol), 1,1-bis (methylthio) ethylene (15.03 g, 125 mmol), dichloro diisopropoxy titanium (1.18 g, 5.0 mmol), (2S, 3S) -2.3-0- (1-phenylethylidene) -1,1,4,4-tetraphenyl -1,2,3,4-butane tetraol (compound A) (2.91 g, 5.5 iranol) and molecular sieves 4A (20 g) in powder form react at 0 ° C for 5 hours in a solvent mixture consisting of toluene ( 800 ml) and hexane (600 ml), to obtain (-) - (2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) carbonylcyclobutane (26.69 g, 84%) (ZV-7D = -10.5 ° (c 1.00, CH 2 Cl 2)).

Example 2: Preparation of (+) - (2R, 3R) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane.

In an atmosphere of argon gas, dichloroisopropoxy titanium (124 mg, 0.53 mmol), (2R, 3R) - (2,3-0- (1-phenylethylidene) -1,1,4,4-tetraphenyl-1, 2,3,4-butane-tetraol (compound B) (305 mg, 0.58 mmol) and toluene (5 ml) mixed together and stirred at room temperature for 1 hour A portion (0.5 ml, 00.053 mol) of the resulting solution was taken out and added to powdered molecular sieves 4A (100mg), and toluene (1.5ml was added thereto. To the resulting suspension was added 3-C (E) -3- (methoxycarbonyl) -propenoyl J7-oxazolidin 2-one (107 mg, 0.534 mmol) and petroleum ether (boiling point about 80 ° C) (PE) (2 ml), and the resulting mixture was cooled to 0 ° C. To this suspension a solution of 1.1 was slowly added bis (methylthio) ethylene (115mg, 0.956mmol) in PE (1.5ml), and the resulting mixture was stirred at 0 ° C for 3 hours. Then 0.2M phosphate buffer (pH 7) was added to the reaction mixture and the inorganic material was decanted filtered with Celite and the organic material was extracted with ethyl acetate. The extract solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by fractional silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1, v / v) to give (+) - (2R, 3R) -3-methoxycarbonyl-1,1-bis (methylthio) -2- ( oxazolidin-2-on-3-yl) -carbonylcyclobutane (162 mg, 95%). This product had an optical purity of 98% ee (compare Example 9).

NMR and IR of this product were identical to that of the compound of Example 1.

Example 3: Preparation of (+) - (2R, 3R) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane.

The following table illustrates the results of a study of the conditions in the preparation of this compound (including Example 2). The other conditions and methods of treatment were the same as in example 1 or 2.

a) Oxz is the oxazolidin-2-on-3-yl group.

b) A mixture (1.0: 1.1) of T1CI2 (i-PrO) 2 and compound B.

c) The optical purity was determined from the NMR of bis-MTPA ester of compound (VII).

d) TMB means 1,3,5-trimethylbenzene.

e) T-PE means toluene-petroleum ether.

Example 4: Preparation of (+) - 1,1-Bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane.

The reaction of Example 2 was repeated except that the 3-ΖΓ (E) -3- (methoxycarbonyl) -propenoyl-7-oxazolidin-2-one was replaced by 3-propenoyl-oxazoli-din-2-one, which (+ ) -1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane (82%). This product had an optical purity of 88% ee (compare Example 10).

NMR (500 MHzFT, CDCI3): 2.00 (3H, s), 2.12 (3H, s), 2.26-2.33 (1H, m), 2.34-2.38 (1H, m ), 2.39-2.48 (1H, m), 2.52-2.61 (1H, m), 4.00-4.13 (2H, m), 4.41 (2H, t, J = 8.0 Hz), 4.63 (1H, m).

Example 5; Preparation of (-) - (2S, 3S) -2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane. Example 5-1.

In an atmosphere of argon gas, 1M-dimethoxy-magnesium / methanol (25ml, 25mmol) was added to a methanol solution (25ml) of (-) - (25, 3S) -3-methoxy-carbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) carbonylcyclobutane (3.94 g, 12.3 mmol) obtained in Example 1-1 and stirred at room temperature for 1 hour.

The reaction mixture was concentrated under reduced pressure, saturated aqueous solution of ammonium chloride was added to the concentrate, extracted with ether. The ether extract was washed with saturated aqueous sodium chloride solution, then the solvent was 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-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane yield (2.17 g, 67%). This compound had an optical purity of 86% ee (compare Example 8).

NMR (500 MHzFT, CDCI3)%: 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 ( net) cm ”* *: 1730.

Example 5-2.

In an atmosphere of argon gas, (-) - (2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) carbonylcyclobutane (26.0 g, 81 .4 mmol) added to 1M-dimethoxymagnesium / methanol (400 ml, 400 mmol) at 0 ° C, the mixture was stirred at that temperature for 15 min. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and this was extracted with ether. After washing the extract solution with saturated aqueous sodium chloride solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9, v / v) to yield (-) - (2S, 3S) -2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane ( 20.73 g, 96%).

*

Example 6; Preparation of (+) - (2R, 3R) -2,3-bis (methoxy-carbonyl) -1,1-bis (methylthio) cyclobutane.

The procedure of Example 5-2 was repeated except that (+) - (2R, 3R) -3-methoxycarbonyl-1,1-bis- (methylthio) -2- (oxazolidin-2-on-3-yl) carbonyl cyclobutane prepared in Example 2 was used as the starting compound. Thus, (+) - (2R, 3R) -2,3-bis (methoxycarbonyl) -1,1-bis- (methylthio) cyclobutane in 95% yield. This compound had an optical purity of 98% ee (compare Example 9).

NMR and IR of this compound were identical to the compound of Example 5.

Example 7: Preparation of (+) - 2-methoxycarbonyl-1,1-bis (methylthio) cyclobutane.

The procedure of Example 6 was repeated, except that the (+ J 1,1-bis (methylthio) -2- (oxazolidin-2-on-3-yl) -carbonylcyclobutane produced in Example 4 was used as the starting compound. (+) - 2-methoxycarbonyl-1,1-bis (methylthio) cyclobutane was obtained in a yield of 83% This compound had an optical purity of 88% ee (compare Example 10).

NMR (500 MHzFT, CDCl3) 8: 1.97 (3H, s), 2.07 (3H, s), 2.18-2.30 (3H, m), 2.49 (1H, m), 3 .37 (1H, m), 3.67 (3H, s).

Example 8: Preparation of (-) - (2S, 3S) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane.

In an atmosphere of argon gas, 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 Example 5-1, slowly added to an ether suspension of lithium aluminum hydride (562 mg, 14.8 mmol) at 0 ° C, and the resulting mixture was stirred at 0 ° C for 2 hours. After adding a saturated aqueous solution of sodium sulfate to the reaction mixture to decompose excess reducing agent, anhydrous sodium sulfate was added and stirred for a while. The inorganic material was then filtered off and washed with hot isopropyl alcohol. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 15: 20: 1, v / v / v) to give (-) - (2S, 3S) -2,3-bis (hydroxymethyl) -1, 1-bis (methylthio) cyclobutane was obtained (1.48 g, 96%).

NMR (270 MHzFT, CDCI3) S: 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 (net) cirr 1 -: - 3350.

Part of this compound was taken out and converted to bis (R) -TMPA ester in the usual manner using (R) -ct-methoxy-1-trifluoromethyl-phenyl-acetyl chloride ((R) -MTPACl), dimethylaminopyridine (DMAP pyridine (pyr).

At 500 MHz NMR, four signals of methyl groups from the racemic mixture were observed at 1.852, 1.856, 1.912 and 1.970 ppm. Below, the methyl group signals at 1,852 and 1,912 ppm were greater than the others, from which an optical purity of 86% ee was determined.

The title compound (-) - (2S, 3S) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane can be converted into a crystal with 100% optical purity by recrystallization from an ethyl acetate-hexane system (ZocJ / D = -32.0 ° (c 1.03, CH 2 Cl 2)).

Example 9; Preparation of (+) - (2R, 3R) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane.

The procedure of Example 8 was repeated, except that (+) - (2R, 3R) -2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane prepared in Example 6 was used. Thus, (+) - (2R, 3R) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane in 70% yield.

NMR and IR of this compound were identical to that of the compound of Example 8.

Part of this compound was taken out and converted to (R) -TMPA ester by the usual method ((R) -MTPAC1, DMAP / pyr).

The NMR of the product was studied in the manner of Example 8. It was thus found that the signals of 1,856 and 1,970 ppm were greater than the others, and the optical purity was 98% ee.

Apart from the above, part of the title compound was recrystallized from an ethyl acetate-hexane system to give a colorless crystal. On X-ray analysis of this single crystal, its absolute steric configuration was determined as (2R, 3R), as indicated in the title.

Example 10: Preparation of (+) - 2-hydroxymethyl-1,1-bis-methylthio) cyclobutane.

The procedure of Example 8 was repeated except that (+) -2-methoxycarbonyl-1,1-bis (methylthio) cyclobutane obtained in Example 7 was used. Thus, (+) - 2-hydroxymethyl-1,1-bis (methylthio) cyclobutane was obtained in 54% yield.

NMR (500 MHzFT, CDCl3) &: 1.92 (1H, m), 2.05 (3H, s), 2.07 (3H, m), 2.12-2.32 (4H, m), 2 .68 (1H, m), 3.73 (1H, dd, J = 4.8, 11.8 Hz), 3.84 (1H, dd, J = 7.5, 11.8 Hz).

Part of this compound was taken out and converted to (R) -MTPA ester by the usual method {(R) -MTPAC1, DMAP / pyr).

At 500 MHz NMR, four methyl group signals of this compound from the racemic mixture were found at 1,696, 1,927, 1,930, and 1,955 ppm. Among these, the signals at 1,927 and 1,955 ppm were greater than the others, from which the optical purity was determined to be 88% ee.

Example 11: Preparation of (+) - (2S, 3S) -2,3-bis (t-butyl-diphenylsilyloxymethyl) -1,1-bis (methylthio) -cyclobutane.

Dissolved (-) - (2S, 3S) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane (1.37 g, 6.58 mmol), triethylamine in methylene chloride (25 ml) (2.8 ml, 20 mmol), 4-dimethylaminomethylpyridine catalytic amount) and DMF (1 ml). Then t-butyldiphenylsilyl chloride (4.52g, 25mmol) was added to the solution and stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the concentrate was dissolved in ether, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent from the ether solution, the residue was purified by silica gel column chromatography (ether: hexane = 1:20, v / v) to give (+) - (2S, 3S) -2,3-bis (t-butyldiphenyl-silyloxymethyl) -1,1-bis (methylthio) cyclobutane (4.50 g, 100%).

NMR (200 MHzFT, CDCI3) £: 0.99 (9H, s), 1.02 (9H, s), 2.06 (6H, s), 2.09-2.25 (2Ή, m), 2 .85 (1H, m), 3.52-3.73 (3H, m), 3.90 (1H, dd, J = 9.0, 10.8 Hz), 7.26-7.47 (12H , m), 7.55-7.74 (8H, m).

Example 12: Preparation of (-) - (2R, 3R) -2,3-bis (t-butyl-diphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane.

t-Butyldiphenylsilyl chloride (292 mg, 1.06 moles) was added to a solution of (+) - (2R, 3R) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane (82 mg, 0.39mmol), imidazole (106mg, 1.55mmol) and 4-dimethylaminomethylpyridine (catalytic amount) in DMF (4ml), and the resulting mixture was stirred at room temperature overnight. After adding 2M phosphate buffer (pH 7.0) to the reaction mixture, it was extracted with ethyl acetate. The extract solution was washed with water then with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel TLC (ethyl acetate: hexane = 1:10, v / v) to give (-) - (2R, 3R) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane (266 mg, 100%).

NMR and IR of this compound were identical to that of the compound of Example 11.

Example 13: Preparation of (+) - (2S, 3S) -2,3-bis (t-butyl-di-phenylsilyloxymethyl) -1-cyclobutanone.

N-Chlorosuccinimide (1.60 g, 12 mmol) and silver nitrate (2.29 g, 13.5 mmol) were dissolved in an 80% aqueous solution of acetonitrile (45 ml), added quickly at 25 ° C a solution of (+) - (2S, 3S) - 2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane (2.06 g, 3 mmol) in a mixture consisting of acetonitrile ( 6 ml) and methylene chloride (1 ml). The resulting mixture was stirred for 10 min. After adding 3 ml of saturated aqueous solution of sodium sulfite to the reaction mixture and stirring for 1 min, a saturated aqueous solution of sodium hydrocarbonate (3 ml) was added and stirred for 1 min. the saturated aqueous solution of sodium chloride (3 ml) was added and stirred for 1 min. Then, 60 ml of a mixture of methylene chloride and hexane (1 µl, v / v) was added to this solution and the insoluble matter was filtered off using from Hyflc ^ (manufactured by Johns-Manville Co.). After drying the filtrate 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) to give (+) - (2S, 3S) -2 1,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.49 g, 82%).

NMR (270 MHzFT, CDCl3) S: 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, 10.3 Hz), 3.88 (1H, dd, J = 4 , 8, 10.3 Hz), 3.97 (1H, dd, J = 4.0, 10.6 Hz), 7.32-7.44 (12H, m), 7.62-7.68 ( 8H, m), IR (net) cm -1; 1785.

Example 14; Preparation of (-) - (2R, 3R) -2,3-bis (t-butyl-di-phenylsilyloxymethyl) -1-cyclobutanone.

The procedure of Example 13 was repeated except that (-) - (2R, 3R) -2,3-bis (t-butyldiphenylsilyloxyraethyl) -1,1-bis (methylthio) cyclobutane was used. Thus, (-) - (2R, 3R) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone was obtained in 99% yield.

NMR and IR of this compound were identical to that of the compound of Example 13.

Example 15: Preparation of 2,3-bis (t-butyldiphenylsilyloxy-methyl) cyclobutanol.

Example 15-1.

In an atmosphere of argon gas, lithium tri (t-butoxy) aluminum hydride (1.27 g, 5.0 mmol) was added to tetrahydrofuran (THF) (10 ml) and cooled to -78 ° C. To this suspension was added a solution of (+) - (2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.21 g, 2.0 mmol) in THF, and the temperature of the mixture was slowly raised to room temperature with stirring over several hours.

After adding 0.2 M phosphate buffer to the reaction mixture to decompose excess reductant, methylene chloride was added and the inorganic material filtered off. The filtrate was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 4, v / v) to give (+) - (1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (0.104 g, 9%): NMR (200 MHzFT, CDCl 3) S: 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), 4η46 (1H, m), 7.26-7.48 (12H , m), 7.54-7.72 (8H, m), and (+) - (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (1.068 g, 88%): NMR (200MHZFT, CDC13) &: 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, ra), 7, 27-7.46 (12H, m), 7.56-7.69 (8H, m).

Example 15-2.

In an atmosphere of argon gas, 1M-diisobutylaluminum hydride / toluene (8.2ml, 8.2mmol) was slowly added at -78 ° C and a solution of (+) - (2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (4.12 g, 6.8 mmol) in toluene (70 ml) and the mixture was stirred at that temperature for 10 min. After adding 0.2 M phosphate buffer (pH 7) to the reaction mixture and stirring for a while, an excess amount of methylene chloride was added and the inorganic matter filtered off. The filtrate was extracted with methylene chloride and dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 4, v / v) to yield (+) - (1S, 2S, 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%).

Example 15-3: Transformation of (+) - (1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -cyclobutanol to (+) - (1S, 2S, 3S) -2,3-bis ( t-butyldiphenylsilyloxymethyl) cyclobutanol.

Step 1.

In an atmosphere of argon gas, diethylazodi-carboxylate (217 microliters, 1.38 mmol) was added to a solution of (+) - (1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (700 mg, 1.15mmol), benzoic acid (167mg, 1.37mmol) and triphenylphosphine (362mg, 1.38mmol) in benzene (10ml), and the resulting mixture was stirred at room temperature overnight. After distillation of volatiles from the reaction mixture, the residue was purified by 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%).

NMR (200 MHzFT, CDCl3> S: 0.97 (9H, s) / 1.06 (9H, S) / 2.23-2.40 (2H, m), 2r45 (1H, ra), 2.85 (1H, m), 3.71 (2H, d, J = 5.4Hz), 3.83 (1H, dd, J = 6.1, 10.5Hz), 3.99 (1H, aa, J = 7.3, 10.5Hz), 5.48 (1H, apparent q, J = 6.5Hz), 7.21-7.45 (14H, m), 7.49-7.72 (9H, m) , 7.98 (2H, a, J = 7.1Hz).

Step 2.

In an atmosphere of argon gas, slowly add 1M-diisobutylaluminum hydride / toluene (2.6ml, 2.6mmol) at -78 ° C to a solution of (+) - (1s, 2S, 3S) -1 benzoyl-2,3-bis (t-butyiphenylsilyloxymethyl) cyclobutane (790 mg, 1.1 inmol) in toluene (10 ml), and the mixture was stirred at a temperature for 30 min. 0.2 M phosphate buffer ( pH 7) added to the reaction mixture and stirred for a while, then an excess amount of methylene chloride was added and the inorganic material was filtered off. The filtrate was extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (ether: hexane = 1: 5, v / v) to yield (+} - {1S, 2S, 3S) - 2,3-bis (t-butyldiphenylisilyloxymethyl) cyclobutanol (644 mg , 95%).

Example 16: Preparation of (+) - (1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-methanesulfonyl-oxycyclobutane.

Methanesulfonyl chloride (0.17ml, 2.2mmol) was added at 0 ° C to a solution of (+) - (1R, 2S, 3S) - 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (911mg, 1 .5 mmol) and triethylamine (0.6 ml, 4.3 mmol) in methylene chloride, and the mixture was stirred at 0 ° C for 15 min. After adding 0.2 M phosphate buffer to the reaction mixture and extracting with ether, the extract solution was dried over anhydrous sodium sulfate and the solution was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6, v / v) to give (+) - (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyl-oxymethyl) -1-methanesulfonyloxycyclobutane yield (1.034 g, 100%).

NMR (200 MHzFT, CDClg) S: 1.04 (9H, m), 1.05 (9H, m), 2.07-2.23 (2H, m), 2.43 (1H, m), 2.64 (2H , m), 2.91 (3H, m), 3.52-3.65 (3H, m), 3.76 (1H, dd, J = 4.0, 11.0Hz), 4.97 (1H , m), 7.24-7.48 (12H, m), 7.56-7.70. (8H, m),

Example 17: Preparation of (-) - 9 - / * (1S, 2R, 3S) - 2,3 - bis (hydroxymethyl) cyclobutan-1-yl7adenine (compound 2).

Step 1: Preparation of (+) -9- / ~ (1S, 2R, 3S) -2,3-bis- (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl-7-adenine.

60% sodium hydroxide (52 mg, 1.3 mmol) was added to a suspension of adenine (177 mg, 1.3 mmol) in DMF (6.5 ml). After stirring the mixture for one hour, a solution of (+) - (1R, 2S, 3S) -2,3-bis (t-butyldi-phenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (450 mg, 0.65 mmol) in DMF (1.5 ml) added to the reaction mixture and stirred at 145 ° C for 6 hours. After cooling, 0.2 M phosphate buffer was added and the mixture was extracted with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate, then the solvent was dried over anhydrous sodium sulfate and then the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1 to 30: 1, v / v) which was unreacted (+) - (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) - 1-methanesulfonyloxycyclobutane (100 mg, 22% recovery) and (+) - 9- / 718,2R, 3S) -2,3-bis (t-butyldiphenylsilyloxy-methyl) cyclobutan-1-yl-adenine (203 mg, 43%).

NMR (400 MHzFT, CD30D) S: 0.75 (9H, s), 1.03 (9H, s), 2.42-2.54 (2H, m), 2.92-3.08 (2H, m), 3.53 (1H, dd, J = 4.0, 11.0Hz), 3.68 (1H, dd, J = 8.8, 11.0Hz), 3.73-3.85 (2H , m), 5.23 (1H, m), 7.20-7.46 (16H, m), 7.60-7.72 (4H, m), 8.18 (1H, s),

Step 2: Preparation of (-) - 9- / ~ (1S, 2R, 3S) -2,3-bis (hydroxy methyl) cyclobutan-1-ylj-adenine (compound 2)

To a methanolic solution (1 ml) of (+} - 9- / 1S, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -cyclo-butan-1-yl / -adenine (203 mg, 0, 28 mmol) obtained in step 1 was added 4N-hydrochloric acid / dioxai (0.15 ml, 0.6 mm). After stirring the mixture at room temperature overnight, the solvent was distilled off from the reaction mixture under reduced pressure, and water was added. After removal of the ether solubles, it was neutralized with 0.1 N sodium hydroxide solution and the solvent was distilled off. The crude product thus obtained was purified by Sephadex LH-20 column chromatography (methanol: water = 1: 1, v / v) and then washed with acetone to give (-) - 9 / 1IS, 2S, 3S) - 2,3-bis (hydroxymethyl) cyclobutan-ly 1] -adenine gave (compound 2) (26 mg, 37%).

NMR (400 MHzFT, CDgOD) δ: 2.43-2.57 (2H, m), 2.78 (1H, m), 3.03 (1H, m), 3.41 (1H, dd, J = 6.2, 11.4Hz), 3.46 (1H, dd, J = 7.3, 11.4Hz), 3.74 (2H, d, J = 6.2Hz), 5.25 (1H, apparent q, J = 8.1 Hz), 8.20 (1H, s), 8.37 (1H, s).

UV Xmax (H 2 O) nm: pH 1.258; pH 7.260; pH 13.260.

Example 18: Preparation of (-) - 9- / ~ (1S ', 2R, 3S) -2,3-bis- (hydroxymethyl) cyclobutan-1-yl / -guanine (compound 5).

Step 1: Preparation of (-) - 2-amino-9- / T (1.S, 2R, 2S) - 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclo-butan-1-ylJ-6- (2- methoxyethoxy) purine.

Lithium hydride (10 mg, 1.3 mmol) was added to a suspension of 2-amino-6- (2-methoxyethoxy) purine (274 mg, 1.3 mmol) in DMF (6.5 ml), and the mixture was stirred for one hour. Then a solution of (+) - (IR, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxy-methyl) -1-methanesulfonyloxycyclobutane (450 mg, 0.65 mmol) in DMF (1.5 ml) added to the reaction mixture, and stirred at 145 ° C for 6 hours. After cooling, 0.2 M phosphate buffer and ethyl acetate were added, the insoluble matter was filtered off, and then the filtrate was extracted with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1 to 3: 1, v / v) »yielding unreacted (+) - (1R, 2S, 3S) -2,3-bis ( t-butyldiphenylsilyloxymethyl) -1-methane-sulfonyloxycyclobutane (157 mg, 35% recovered) and (-) - 2-amino-9- / T (1S, 2R, 2S) -2,3-bis (t-butyldiphenylsilyl-oxymethyl) ) cyclobutan-1-yl J-6- (2-methoxyethoxy) purine (160 mg, 31%).

NMR (400 MHzFT, CDgOD) S: 0.79 (9H, s), 1.03 (9H, s), 2.38-2.40 (2H, m), 2.92 (1H, m), 2 .98 (1H, m), 3.54 (1H, dd, J = 4 f 0.11.0 Hz), 3.68 (1H, dd, J = 8.8, 11.0 Hz), 3.72- 3.85 (4H, m), 4.56-4.67 (2H, m), 5.18 (1H, apparent5, J = 8.0Hz), 7.23-7.47 (16H, m), 7.50-7.60 (4H, m), 8.07 (1H, s).

Step 2: Preparation of (-) - 2-amino-9- / T (1S, 2R, 2S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl_7-guanine (compound 5) 2 N hydrochloric acid (1 ml ) was added to (-) - 2-amino-9 - / "(IS, 2R, 2S) -2,3-bis (t-butyldiphenylsilyl-oxymethyl) cyclobutan-1-yl J-6- (2-methoxyethoxy) purine (140mg, 0.17mmol) obtained in step 1, and the mixture was heated under reflux for one hour.

After distilling off the solvent of the reaction mixture under reduced pressure, water was added and the ether solubles were removed. Then it was neutralized with 0.1 N sodium hydroxide solution and the solvent was distilled off. The residue was purified by HP-20 column chromatography (water: methanol = 1: 0 to 1: 3, v / v) and then washed with acetone to give (-) - 9-C (IS, 2R, 3S) -2, 3-bis (hydroxymethyl) cyclobutan-1-yl J-guanine (compound 5) yielded (15 mg, 32%).

NMR (400 MHzFT, CD3OD) δ: 2.36-2.55 (2H, m), 2.72 (1H, m), 2.90 (1H, m), 3.45 (2H, d, J = 7, 0Hz), 3.70 (2H, d, J = 6.2Hz), 5.05 (1H, apparent q, J = 8.lHz),.

7.94 (1H, s), UV kmax (H30) nm: pH 1,253,279 (sh); pH 7,252,272 (sh); pH 13.257 (sh), 267.

Example 19: Preparation of (+) - (1S, 2S, 3S) -2,3-bis (t-butyl-diphenylsilyloxymethyl) -1-methanesulfonyl-oxycyclobutane.

The treatment of Example 16 was repeated, except that (+) - (IS, 2S, 3S) -2,3-bis (t-butyldiphenyl-silyloxymethyl) cyclobutanol was used. Thus, (+) - (IS, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -methanesulfonyloxycyclobutane was obtained in a quantitative yield.

NMR (200 MHzFT, CDCl3) Si 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, Ö, J = 4.0Hz), 3.85 (1H, öd, 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).

• By recrystallizing this compound from an ether hexane system, a crystalline product = + 12.0 ° (c 1.01, CH 2 Cl 2)) (optical purity 100%) was obtained.

Example 20; Preparation of (-) - 9- (IR, 2R, 3S) -2,3-bis- (hydroxymethyl) cyclobutan-1-yl-adenine (compound 8).

Step 1: Preparation of (+) - 9- / Γ (1R, 2R, 3S) -2,3-bis- (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl7 "a <2enin.

60% sodium hydride (30mg, 0.75mmol) was added to a solution of adenine (100mg, 0.74mmol) in DMF (4ml). After stirring the mixture for one hour, a solution of (+) - (1S, 2S, 3S) -2,3-bis (t-butyldi-phenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (254 mg, 0.37 mmol) in DMF (1.5 ml) added to the reaction mixture and stirred at 145 ° C for 6 hours. After cooling, 0.2 M phosphate buffer was added and the mixture was extracted with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1, v / v) to give (+) - 9-ZT (1R, 2R, 3S) -2,3-bis (t-butyl-diphenylsilyloxymethyl) cyclobutane -1-yl7-adenine (125 mg, 47%).

NMR (200 MHzFT, CDCl3) 5 0.98 (9H, s), 1.06 (9H, s), 2.30-2.65 (3H, m), 3.07 (1H, m), 3.62-3, 84 (4H, m), 4.81 (1H, m), 5.61 (2H, brs), 7.20-7.52 (12H, m), 7.52-7.75 (8H, m) , 7.85 (1H / s), 8.33 (1H7 S).

Step 2: Preparation of (-) - 9 - / * (1R, 2R, 3S) -2,3-bis (hydroxy methyl) cyclobutan-1-yl7-adenine (compound 8). To a methanol solution (2 ml) of (+) -9 - / "(1R, 2R, 3 S) - 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-y 1,7-adenine (118 mg, 0 , 16 mmol) obtained in step 1, 4 N-hydrochloric acid / dioxane (0.17 ml, 0.65 mmol) was added, and the mixture was stirred overnight at room temperature After distilling off the solvent from the reaction mixture under reduced pressure, water was added and the ether solubles were removed, then neutralized with 0.1 N aqueous solution of sodium hydroxide and the solvent was distilled off. The crude product, thus obtained, was purified by Sephadex ΗΡ-2Ό column chromatography (water: methanol = 1: 0 to 1: 1, v / v), then by silica gel column chromatography (methylene chloride: ethanol = 5: 1, v / v) and then further by Sephadex IH-20 column chromatography (methanol), which (-) - 9-C (IS, 2R, 3S) -2., 3-bis- (hydroxymethyl) cyclobutan-1-yl J-adenine (compound 8) gave (37 mg, 91%).

NMR (200 MHzFT, CD3OD) S: 2.24 (1H, m), 2j37 (1H / apparently 9 / J = 9.5Hz), 2.62 (1H, m), 2) 88 (1H, m), 3) 65-3.74 (4H, m), 4.71 (1H, disc ± 9 / J = 8.5Hz), 8.20 (1H, s), 8.26 (1H, S), UV λmax (H 2 O) nm: pH 1.259; pH 7/259; pH 13.259.

HRMS (FAB)

Calculated:'

250, 1304

Found: 250, 1305.

By crystallizing this compound from an ether methanol system, a crystalline product (Γ ° ί-7ο = 44.7 ° (c 0/98, pyridine) (optical purity: 98% or higher) was obtained.

By repeating the procedure of this example with the corresponding bases, the compounds No. 26 / no. 29, no. 32 and No. 35 also obtained. The physiochemical properties of No. 26 and No. 32 are indicated as follows:

No. 26 NMR (200 ΜΗεFT, CD3OD) 5: 2.30-2.46 (2H, m), 2.38 (1H, m), 2.57 (1H, m), 3.51-3.71 (4H , m), 4.54 (1H, m), 5.69 (1H, d, J = 8.0Hz), 7.80 (1H, d, J = 8.0Hz), UV Xmax (^ 0) nm : pH1, 268; pH7.268; pH1.267.

No. 32 NMR (200 MHzFT, CD3OD) S: 1.78-2.14 (2K, m), 2.20-2.54 (2H, m), 3.50-3.76 (4H, m), 4 .50 (1H, m), 5.91 (1H, a, J = 7.4Hz), 7.78 (1H, a, J = 7.4Hz), UV Xmax (H 2 O) nm: pH1, 284; pH7.273; pH13 / 274.

Example 21; Preparation of (+) - 9-ΖΓ (1R, 2R, 3S) -bis (hydroxymethyl) eyelobutane-1-yl-7-guanide (compound 11).

Step 1: Preparation of (+) - 2-amino-9Z7 (1R, 2R, 3S) - 2,3-bis- (t-butyldiphenylsilyloxymethyl) -cyclobutan-1-yl7-6- (2-methoxyethoxy) -purin.

Lithium hydride (6 mg, 0.75 mmol) was added to a suspension of 2-amino-6- (2-methoxyethoxy) purine (155 mg, 0.74 mmol) in DMF (4 ml), and the mixture was stirred for Stirred for one hour. Then 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 mixture and stirred at 145 ° C for 6 hours. After cooling, 0.2 M phosphate buffer and ethyl acetate were added and the insoluble matter filtered off and the filtrate extracted with ethyl acetate. After drying the extract solution over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1, v / v) to give (+) - 2-amino-9-ZT (IR, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl7-6- (2-methoxyethoxy) purine (88 mg, 30%).

NMR (200 MHzFT, CDCL1) S

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 were used as the solvent of this reaction, the reaction proceeded at resp. 75 ° C and 100 ° C to give results corresponding to the results in the case of DMF.

Step 2: Preparation of (+) - 9-Z ~ (IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yU-guanine (Compound 11).

To a methanol solution (2 ml) of (+) - amino-9- (IR, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -cyclobutane-7-6- (2-methoxyethoxy) - purine (79 mg, 0.10 mmol), obtained in step 1, was added 4N-hydrochloric acid / dioxane (0/1 ml, 0.4 mmol). After stirring the mixture overnight at room temperature, the solvent was distilled off from the reaction mixture under reduced pressure. Water was then added, the ether solubles were removed, the solvent was distilled off, 2N-hydrochloric acid (2 ml) was added, and the mixture was refluxed for 1 hour. After neutralizing the reaction mixture with 1M aqueous sodium hydroxide solution, it was purified by Sephadex HP-20 column chromatography (water: methanol = 1: 0 to 1: 4, v / v) to give (+) - 9-ΖΓ (IR, 2R) (3S) - 2,3-bis (hydroxymethyl) cyclobutan-1-yl7-guanine (compound 11) (23 mg, 88%).

NMR (200 MHzFT, CD30D) S: 2.18 (1H, m), 2.32 (1H, apparent- <3 / J = 10.0Hz), 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 Xmax (H20) nm: pH 1,253 / 277 (sh); pH 7,253,268 (sh); pH 13.256 (sh), 267.

HRMS (FAB)

Calculated for

266, 1253

Found: 266, 1251.

By crystallizing this compound from water, a crystalline product could be obtained (,

= + 26.5 ° (c 0.99, 0.1N-NaOH) (optical purity: 98% or higher).

By repeating the procedure of this example with the corresponding bases, the compounds No.

14, no. 17, no. 20 and No. 23 are obtained in a corresponding manner.

Example 22: Preparation of (1R, 2R, 3S) -1-amino-2,3-bis- (t-butyldiphenylsilyloxymethyl) cyclobutane. Step 1: Preparation of (1R, 2R, 3S) -1-azido-2,3-bis- (t-butyldiphenylsilyloxymethyl) cyclobutane.

In an atmosphere of argon gas, sodium azide (975mg, 15mmol) was added to a solution of (+) - (1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-methane-sulfonyloxycyclobutane ( 1.03 g, 1.5 mm) in DMF (6 ml), and the mixture was stirred at 120 ° C for 2 hours. After cooling, the reaction mixture was diluted with water, extracted with ether and the ether extract solution was washed twice with water and then with a saturated aqueous sodium chloride solution. After drying the ether solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride; hexane = 1: 4, v / v) to give (1R, 2R, 3S) -1-azido. 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (992 mg, quantitative yield).

IR (net) cm 2100.

NMR (200 MHzFT, CDC ^) S: 1.03 (9H, s), 1.05 (9H, s), 1.91 (1H, m), 2.02-2.29 (2H, m), 2, 44 (1H, m), 3.51-3.65 (4H, m), 3.71 (1H, dd, J = 4.0Hz, 10.8Hz), 7.31-7.44 (12H, m 7.57-7.67 (8H, m).

Step 2: Preparation of (1R, 2R, 3S) -1-amino-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane.

The (IR, 2R, 3S) -1-azido-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (992 mg), prepared in step 1, was dissolved in ethyl acetate (2 ml). After adding 10% palladium carbon (100 mg), the solution was stirred in an atmosphere of hydrogen at room temperature overnight. After filtering off the catalyst, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate; triethylamine = 20: 10: 1, v / v / v) to give (IR, 2R, 2S) -1. amino-2,3-bis (t-butyldiphenylsilyloxy-methyl) cyclobutane (642 mg, 67%).

NMR (200 MHzFT, CDClg) δ: 1.03 (9H, s), 1.05 (9H, s), 1.42 (1H, m), 1.54 (2H, brs, invariable with D20), 1 , 86-2.05 (2H, m), 2.24 (1H, m), 3.13 (1H, m), 3.54-3.65 (3H, m), 3.75 (IH, dd H = 4.1, 10.6 Hz), 7.27-7.46 (12H, m), 7.58-7.69 (8H, m).

Example 23: Preparation of 1- / Γ (IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yU-5-methyl-2,4 (1H, 3H) -pyrimidinedione (compound 29).

Step 1: Preparation of N- / TZr (1R, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutyljamino-carbonyl7-3-methoxy-2-methylacrylamide.

In an atmosphere of argon gas, a suspension of 3-methoxy-2-methyl acrylate chloride (674 mg, 5 mmol) and silver cyanate (1.50 g, 10 mmol) in anhydrous benzene (10 ml) was refluxed for one hour, then it was left to stand at room temperature.

The supernatant (2.6 ml) of this mixture was removed and added at 0 ° C to a solution of (1R, 2R, 3S) -1-amino-2,3-bis (t-butyldiphenylsilyloxymethyl) -cyclobutane (603 mg, 0.99 mmol) in anhydrous benzene (4 ml), and the resulting mixture was stirred overnight as it was. Then the solvent was distilled off from the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ether = 1: 1, v / v) to give crude N-Sr.T (1R, 2R, 3S) -2 3-bis (t-butyldiphenylsilylmethyl) cyclobuty17aminocarbonyU-3-methoxy-2-methyl acrylamide (592 mg).

Step 2: Preparation of 1-ZT (1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-5-methyl-2,4 (1H, 3H) -pyrimidinedione (Compound 29). 1M tetrabutyl ammonium fluoride / THF (2.4ml, 2.4mmol) was added to a solution of the N-ZTZ7 (1R, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobuty 17-aminocarbonyl7-3 methoxy-2-methyl acrylamide (590 mg), obtained in step 1, in methanol (8 ml), and the mixture was stirred at room temperature overnight. After distilling off the solvent from the reaction mixture, water and ether were added and it was extracted six times with water. The water extracts were concentrated under reduced pressure, 1M sulfuric acid (10 ml) was added thereto, and the mixture was refluxed for 30 min. The reaction mixture was neutralized with sodium hydroxide solution and pure with Sephadex HP-20 (water-30% aqueous) methanol) and then with Dowes 50W-X8 (H-form, water). After neutralization of the eluate with sodium hydroxide solution, it was purified again with Sephadex HP-20 (water-30% aqueous methanol) to give 1- / 7 (IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutane-1 -yl7-5-methyl-2,4- (1H, 3H) -pyrimidinedione (compound 29) yielded (127 mg, 67%).

NMR (200 MHzFt, CDgOD) S: 1.90 (3H, d, J = 1.1Hz), 1.97-2.18 (2H, m), 2.36 (1H, m), 2.58 ( 1H / m), 3.57-3.70 (4H, m), 4.55 (1H, m), 7.63 <1H, d, J = 1.1Hz), UV Xraax (H20) nm: pH 1,273; pH 7.273; pH 13.271.

Example 24: Preparation of 2-amino-9 - / (1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-6-chloro-purine (Compound 17).

Step 1: Preparation of 2-amino-9 - / '(1R, 2R, 3S) -2,3-bis- (acetoxymethyl) cyclobutan-1-yl7-6-chloropurine.

Pyridine (0.5ml) and acetic anhydride (1ml) were added to a suspension of 9-Z ~ (IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-guanine (Compound 11) ( 265 mg, 1.0 mmol) in anhydrous dimethylformamide (1.5 ml), and the mixture was stirred at 75 ° C for 30 min. After distilling off the solvent under reduced pressure, the residual solvent was eliminated by several times azotropic distillation together with toluene, after which the residue is dried. There was thus obtained crude O-Z'dR, 2R, 3S) -2,3-bis (acetoxymethyl) cyclobutan-1-yl '/ guanine (350 mg).

The crude 9 - / '(1R, 2R, 3S) -2,3-bis (acetoxymethyl) -cyclobutan-1-ylT-guanine (350 mg) thus obtained was dissolved in anhydrous acetonitrile (2 ml) together with tetra- ethyl ammonium chloride (331 mg, 2.0 mmol), to which was added N, N-dimethylaniline (130 microliters, 1.0 mmol) and phosphorus oxychloride (0.57 ml, 6.0 mmol). The mixture was refluxed at 100 ° C for 10 min.

After distillation of volatiles from the reaction mixture under reduced pressure, crushed ice and methylene chloride were added to the residue and stirred at 0 ° C for a while, then neutralized with saturated aqueous sodium hydrogen carbonate solution. After stirring the mixture at 0 ° C for a while, it was extracted with methylene chloride. The methylene chloride extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 1: 1, v / v) to give 2-amino-9 - / (1R, 2R, 3S) -2,3- (acetoxymethyl) -cyclobutane-1 -yl7-6-chloropurine (335 mg, 91%).

NMR (200 MHzFT, CDCl3) S: 2.02 (3H, s), 2.11 (3H, s), 2.18-2.73 (3H, ra), 3.09 (1H, m), 4 .25 (4H, d, J = 5.9Hz), 4.59 (1H, apparent q, J = 8T4Hz), 4.65 (2H, br), 7.88 (1H / s).

Step 2: Preparation of 2-amino-9 - <f (1R, 2R, 3S) -2,3-bis- (hydroxymethyl) cyclobutan-1-yl7-6-chloropurine (Compound 17).

2-Amino-9-Z "(1R, 2R, 3S) -2,3-bis (acetoxymethyl) -cyclobutan-1-ylJ-6-chloropurine (98 mg, 0.27 mmol) was dissolved in methanol (2ml) , mixed with potassium carbonate (90 mg, 0.65 mmol) and stirred at 0 ° C for 30 min.

The reaction mixture was neutralized with 1N-hydrochloric acid and then purified with Sephadex HP-20 (water-60% aqueous methanol) to give 2-amino-9-ZT (1R, 2R, 3S) -2,3-bis- ( hydroxymethyl) cyclobutan-1-yl7-6-chloropurine (compound 17) (65 mg, 86%).

NMR (200 MHzFT, CD3OD) S: 2.20 (1H, m), 2.37 (1H, m), 2.57 (1H, m), 2.89 (1H, m), 3.69 (4H , d, J = 5.5Hz), 4.64 (1H, apparent q, J = 8.8Hz), 8.19 (1H, s).

UV Xmax (10 O) nm: pH 1.244 (sh), 313; pH 7.248 (sh), 3.6; pH 13.248 (sh), 305.

Example 25; Preparation of 2-amino-9 - / (1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-ylj-purine (compound 14).

Step 1: Preparation of 2-amino-9- (1R, 2R, 3S) -2,3-bis (acetoxymethyl) cyclobutan-1-yl-purine. 2-Amino-9-AlR./2R/ 3S) -2,3-bis (acetoxymethyl) -cyclobutan-1-yl7-6-chloropurine (87 mg, 0.24 mmol) was dissolved in methanol (2 ml). After adding 10% palladium carbon (13 mg), it was stirred at room temperature in an atmosphere of hydrogen gas overnight. After adding a small amount of saturated aqueous solution of potassium hydrocarbonate to the reaction mixture and filtering off the catalyst, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1, v / v) to give 2 amino-9-> f (1R, 2R, 3S) -2,3-bis (acetoxymethyl) cyclobutan-1-yl7-purine (56 mg, 71%).

NMR (200 MHzFT, CDCI3) Si 2.01 (3H, s) / 2.12 (3H, s), 2.28-2.71 (3H, m), 3.11 (1H, m) / 4.17- 4.34 (4H / m), 4.60 (1H, apparently q. J = 8.6Hz), 5.11 (2H / brs), 7.80 (1H, s) / 8.70 (1H, s).

Step 2: Preparation of 2-amino-9 - ((1R, 2R, 3S) -2,3-bis- (hydroxymethyl) cyclobutan-1-yl-purine (compound 14).

2-Amino-9-Z '(1Rf 2R, 3S) -2,3-bis (acetoxymethyl) -cyclobutan-1-yl7-chloropurine (40 mg, 0.12 mmol) was dissolved in methanol (2 ml), mixed with potassium carbonate (40 mg, 0.29 mmol) and stirred at 0 ° C for 30 min.

After neutralizing the reaction mixture with 0.1 N hydrochloric acid, it was purified with Sephadex HP-20 (water-50% aqueous methanol) to give 2-amino-9-Z '(1Rr2R, 3S) - 2,3-bis (hydroxymethyl) cyclobutan-1-yl7-purine (compound 14) (27 mg, 90%).

NMR (200 MHzFT, CD3OD) è>: 2.10-2.66 (3H, m), 2.90 (1H, m), 3.70 (4H, d, J = 5.6Hz), 4.65 (1H, apparently 3 / J = 8.7Hz), 8.20 (1H, s), 8.54 (1H, s).

UV Xmax (H 2 O) nrn: pH 1.252 (sh), 312; pH 7.244 (sh), 304; pH 13.244 (sh), 304.

Example 26; Preparation of 2,6-diamino-9- / '(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl purine (compound 20).

2-Amino-9 Γ (IR / 2R, 3S) -2,3-bis (acetoxymethyl) -cyclobutan-1-yl7-chloropurine (87 mg, 0.24 mmol) was dissolved in methanol (2 ml) and cooled to -78 ° C. The solution thus obtained was saturated with liquid ammonia, sealed in an ampoule and heated at 100 ° C for 12 hours. After distillation of volatiles from the reaction mixture under reduced pressure, it was dissolved in water, neutralized with 0.1 N sodium hydroxide solution and purified with Sephadex HP-20 (water-40% aqueous methanol) to give 2,6-diamino -9 - / "(IR, 2R, 3S) gave -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-purine (compound 20) (41 mg, 82%).

NMR (200 MHzFT, CD3OD) S: 2.19 (IE, m), 2.31 (1H, m), 2.54 (1H, m), 2.75 (1H, m), 3.61-3 74 (4H, m), 4.49 (1H, apparently 9 / J = 8.6Hz), 7.90 (1H, s).

UV kmax (H 2 Q) nm: pH 1,253,291; pH 7,255,280; pH 13,255,280.

Example 27: Preparation of 9-f {IR, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-hypoxanthine (compound 23).

9- / "(IR, 2R, 3S) -2,3-Bis (hydroxymethyl) -cyclobutan-1-ylJ-adenine (compound 8) (25 mg, 0.10 mmol) was dissolved in water (2.5 ml), mixed with sodium nitrate (138 mg, 2.0 mmol) and cooled to 0 ° C. After addition of acetic acid (0.13 ml), the mixture was stirred at room temperature for one day. The reaction mixture was neutralized with 1N sodium hydroxide. solution and then purified with Sephadex HP-20 (water-40% aqueous methanol) to give 9- / T (1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-y17-hypoxanthine (compound 23) (23 mg, 90%).

NMR (200 MHzFT, CD ^ OD) 8: 2.25 (1H, m), 2.38 (1H / m), 2.58 (1H, m), 2.90 (1H, rn), 3.66 -3.74 (4H, m), 4.76 (1H, apparent q, Je8r5Hz), 8.04 (1H, s), 8.20 (1H, S).

UV kmax (H 2 O) nm: pH 1/250; pH 7.250; pH 13.254. INDUSTRIAL APPLICABILITY:

Cyclobutane derivatives of this invention are useful as drugs as an antiviral agent, carcinostatic agent, and the like.

Claims (15)

1. Cyclobutane derivative represented by the following general formula (IV):

(IV) wherein B is a nucleic acid base and R4 is a hydrogen atom or a protecting group. Cyclobutane derivative according to claim 1, characterized in that said nucleic acid base is a pyrimidine base or a purine base. Cyclobutane derivative according to claim 2, characterized in that said pyrimidine base

or is and

said purine base or, wherein Y * represents a hydrogen atom or a lower alkyl group, a hydrogen atom, halogen atom or amino group, Y 1 represents a hydrogen atom or amino group, and Y 1 represents a hydrogen atom or amino group. Cyclobutane derivative according to claim 1, characterized in that the substituents in formula (IV) are sterically configured such that substituent B and the adjacent hydroxymethyl group are in a transrelation and the hydroxymethyl group adjacent to B and the other hydroxymethyl group in a transrelation. Cyclobutane derivative according to claim 1, characterized in that the steric configuration of the substituents in formula (IV) is (1R, 2R, 3S). Cyclobutane derivative according to claims 1 to 3, characterized in that B is adenine or guanine. Cyclobutane derivative according to claim 1, characterized in that the protecting group of R 1 is an ester type protecting group or an ether type protecting group. Cyclobutane derivative according to claim 5, characterized in that the protecting group of R 1 is an acetyl group. 9. Cyclobutane derivative represented by the following general formula (III):

(III) (wherein R 1 - taken individually represents an alkyl group of 1 to 5 carbon atoms or an aralkyl group or, taken in conjunction of two R 1 * groups, represents a cyclic alkylene group of 2 - 3 carbon atoms; R 1 a hydrogen atom, alkyl group of 1-5 carbon atoms, a protected hydroxyalkyl group or protected carboxyl group; R ^ represents a hydrogen, alkyl group of 1-5 carbon atoms, alkoxy group of 1-5 carbon atoms, or aralkyloxy group; A represents an alkylene group of 2-5 carbon atoms in straight or branched chain Y represents an oxygen atom or sulfur atom and Z represents a substituted or unsubstituted methylene group, oxygen atom or sulfur atom. Antiviral, which contains as an active ingredient a cyclobutane derivative represented by the general formula (IV):

(IV) wherein B represents a nucleic acid base, and R4 hydrogen atom or a protecting group. Antiviral according to claim 10, characterized in that the virus is Herpes Simplex Virus, Cytomegalovirus, Hepatitis B Virus or Immunodeficiency Virus. Pharmaceutical use of a cyclobutane derivative represented by the following general formula (IV):

(IV) wherein B represents a nucleic acid base and R4 represents a hydrogen atom or a protecting group. 13. Use of 9 - / '(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl7-guanine for treatment of diseases caused by DNA virus. Use according to claim 13, characterized in that the DNA virus is Herpes Simplex virus, Cytomegalovirus or Hepatitis B Virus. 15. Use of 9-T (1R / 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-ylj-adenine for treatment of diseases caused by virus.