JPH04217982A - Cyclopentane derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new cyclopentane derivative exhibiting strong antiviral action against human herpes virus and having low toxicity and, accordingly, usable as an antiviral agent. CONSTITUTION:A compound of formula I [B is purine base residue having a bonding arm at 9-site; one of R<1> and R<2> is H and the other is univalent group bonded through S or N; R<3> is phosphoric acid ester or (protected) OH] or its salt, e.g. N<2>-(p-methoxytrityl)-9-[(1R,3R,4R)-4-(p- methoxytrityloxymethyl)-3-(methylthio)cyclopentan-1-yl] guanine. Among the above compounds, the compound of formula II [one of R<7> and R<8> is H and the other is univalent group, azide or amino bonded through S; R<3>' is (protected) OH] can be produced by reacting a compound of formula III (one of R<4> and R<5> is activated OH and the other is H; R<6> is protected OH) with a thiol salt or an azidation agent.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to optically active cyclopentane derivatives having various substituents at the 3-position and a method for producing the same.

0002

BACKGROUND OF THE INVENTION In the field of nucleosides, derivatives have been synthesized in which the hydroxyl group at the 2- or 3-position of the sugar moiety is converted into various substituents in order to improve their efficacy and stability as pharmaceuticals. For example, 2',3'-dideoxy-2'-fluoro-β-D-arabinofuranosyl-nucleoside derivatives (V. E. Marquez
et al., Biochem. Pharmacol. , Vol. 36, pp. 2719-2722 (1987)), 3
'-azido-3'-deoxythymidine (AZT) (H.
Mitsuya et al., Proc. Natl. Aca
d. Sci. U. S. A. , Volume 82, 7096
-7100 (1985)) is known to exhibit inhibitory activity against human immunodeficiency virus (HIV). Also, 3'-[(L-p-methoxyphenylalanyl)amino]-3'-deoxy-β-D-ribofuranosyl-nucleoside derivatives (D. Nathans, Pr.
oc. Natl. Sci. U. S. A. , 5th
1, pp. 585-592 (1964)) is known to exhibit antibacterial and antitumor activity.

On the other hand, some so-called carbocyclic nucleosides, in which the oxygen atom in the ring of the sugar moiety of the nucleoside is replaced with a carbon atom, are known to exhibit antiviral activity. Also in these carbocyclic nucleosides, derivatives have been synthesized in which various substituents have been introduced into the cyclopentyl moiety with the aim of enhancing antiviral effects. That is, as a derivative into which a fluorine atom is introduced, for example, 2-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivative (
J. Chem. Soc. , Chem. Commun
．． , pp. 251-254 (1987); J. Chem
．． Soc. , Chem. Commun. , 65
pp. 6-658 (1988); J. Chem. So
c. , Chem. Commun. , pp. 898-900 (1988); JP-A-62-84086), 5-fluoro-4-(hydroxymethyl)cyclopentyl derivatives (J. Med. Chem., Vol. 31, 1798-1)
804 (1988)), 5-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivatives (J. Chem. Soc., Chem. Comm.
un. , pp. 255-256 (1987)), and these fluorine-containing carbocyclic nucleosides are known to have an inhibitory effect on herpes simplex virus (HSV). In addition, 3-fluoro-2-hydroxy-4-(hydroxymethyl)cyclopentyl derivative (JP-A-1-151541), 4-fluoro-2-hydroxy-4-(hydroxymethyl)cyclopentyl derivative (JP-A-1-151541), A 3-fluoro-4-(hydroxymethyl)cyclopentyl derivative (JP-A-1-151542) has been synthesized.

Examples of derivatives having an azido group include 3-azido-4-(hydroxymethyl)cyclopentyl derivatives (M. Bodenteich et al., Tetr
ahedron Lett. , Volume 28, 5311-5
312 pages (1987); Y. F. Shealy et al.
J. Med. Chem. , Volume 29, 483-4
88 (1986)), 2-azido-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivative (T
-S. Lin et al., J. Med. Chem. ，
Vol. 31, pp. 484-486 (1988)), 3-
Azido-2-hydroxy-4-(hydroxymethyl)cyclopentyl derivative (R. Vince et al., Bio
chem. Biophys. Res. Commu
n. , Vol. 156, pp. 1046-1053 (1988)), among which 3-azido-4-
(Hydroxymethyl)cyclopentyl derivatives are HSV
It is known to have an inhibitory effect on

Examples of derivatives having an amino group include 3-amino-4-(hydroxymethyl)cyclopentyl derivatives (Y.F. Shealy et al., J.M.
ed. Chem. , Volume 29, pp. 483-488 (
(1986)), 2-amino-3-hydroxy-4-(
hydroxymethyl)cyclopentyl derivative (T-S.
Lin et al., J. Med. Chem. , 31st
Vol., pp. 484-486 (1988)), 3-amino-
2-Hydroxy-4-(hydroxymethyl)cyclopentyl derivative (R. Vince et al., Bioche
m. Biophys. Res. Commun. ，
Volume 156, pages 1046-1053 (1988);S
．． Daluge et al., J. Org. Chem.
, Vol. 43, pp. 2311-2320 (1978)
), 2-hydroxy-4-(hydroxymethyl)-3
-[L-p-methoxyphenylalanyl)amino]cyclopentyl derivative (R. Vince et al., J.M.
ed. Chem. , Volume 29, 2400-2403
(1986)), 2-hydroxy-3-methanesulfonylamino-4-(hydroxymethyl)cyclopentyl derivatives (S. Daluge et al., J. Org.
．． Chem. , Volume 43, pp. 2311-2320
(1978)), and among these, 3-
Amino-2-hydroxy-4-(hydroxymethyl)cyclopentyl derivatives are known to have an inhibitory effect on HSV.

[0006]

Problems to be Solved by the Invention Among the carbocyclic nucleosides having various substituents that have been obtained so far, 2-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivatives, 5-fluoro- 4
-(hydroxymethyl)cyclopentyl derivative, 5-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl derivative, 3-azido-2-hydroxy-4
-(hydroxymethyl)cyclopentyl derivative and 3
-amino-2-hydroxy-4-(hydroxymethyl)
Although cyclopentyl derivatives have an inhibitory effect on HSV, their activity is still unsatisfactory.

The reason why carbocyclic nucleoside derivatives exhibit antiviral activity is that the chemical structure of carbocyclic nucleosides is similar to nucleosides. In other words, carbocyclic nucleosides are mistaken for natural nucleosides and the viral DNA
Alternatively, it is thought to be taken up by RAN and as a result exhibit antiviral effects. However, carbocyclic nucleosides may also be incorporated into host cell DNA or RAN, and this is considered to be one of the manifestations of toxicity of carbocyclic nucleosides. Therefore, by introducing various substituents in place of the hydroxyl group at the 3-position of the cyclopentyl moiety of carbocyclic nucleosides, even if they are incorporated into the host cell's DNA or RAN,
Further elongation of the nucleic acid is not possible. That is, since polymeric RAN or DNA containing such 3-substituted carbocyclic nucleosides cannot be produced, a reduction in toxicity can be expected.

[0008] These substituents at the 3-position include a fluorine atom that exhibits electronic equivalence with a hydroxyl group, a monovalent group via sulfur that is deeply involved in redox reactions in vivo, and a monovalent group that is expected to exhibit anti-HIV activity. Of particular note are the azide groups that exist in living organisms, and the amino groups that interact strongly with carboxylic acids and phosphoric acids that exist in living organisms. Therefore, carbocyclic nucleosides in which a monovalent group via sulfur or nitrogen is introduced at the 3-position of the cyclopentyl moiety are expected to be excellent antiviral agents. However, in a carbocyclic nucleoside having a purine base residue, there is no known compound in which the 2-position of the cyclopentyl moiety is unsubstituted and the 3-position has the above-mentioned substituent. Therefore, there has been a strong demand for efficient synthesis of these compounds.

[0009]

[Means for Solving the Problems] Under the above circumstances, the present inventors used an optically active 3-hydroxy-4-(hydroxymethyl)cyclopentyl derivative as a starting material to carry out a substitution reaction accompanied by Walden inversion. The present invention was completed after various studies and, if necessary, oxidation reactions, reduction reactions, or deprotection reactions. That is, the present invention relates to (1) general formula

[In the formula, B is a purine base residue having a bond at the 9-position,
R1 and R2 are H and the other is a monovalent group connected to sulfur or nitrogen, and R3 is a hydroxyl group which may be phosphoric acid esterified or protected] or a salt thereof; 2) General formula

[In the formula, B is a purine base residue having a bond at the 9-position,
One of R4 and R5 is an activated hydroxyl group, the other is H, and R6 is a protected hydroxyl group] is reacted with a thiol salt or an azidating agent, and if necessary, oxidized. A general formula characterized by subjecting it to a reaction or reduction reaction and, if necessary, removing a protecting group.

[C6
] [In the formula, B is a purine base residue having a bond at the 9-position,
R7 and R8 are H and the other is a sulfur-mediated monovalent group, an azide group, or an amino group, and R3' is an optionally protected hydroxyl group. It is. In general formulas [1], [1'] and [2], the purine base residue represented by B is, for example,

[In the formula, Y is -OH, -NH2 or -SH, and Z is -
H, -NH2 or halogen]. The amino groups of these purine base residues may be protected, and the protecting groups include protecting groups used as protecting groups for the amino groups of purine bases in nucleic acid chemistry;
For example, alkyl type protecting groups, aralkyl type protecting groups, aryl type protecting groups, Schiff base type protecting groups and acyl type protecting groups are used.

Examples of alkyl-type protecting groups include lower alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and pentyl; trimethylsilyl;
Lower alkyl groups having 1 to 5 carbon atoms, such as tert-butyldimethylsilyl and tert-butyldiphenylsilyl,
Trisubstituted silyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups such as tetrahydropyranyl, 4-methoxytetrahydropyranyl, etc., in which a phenyl group or the like is a substituent, are used. Aralkyl-type protecting groups include, for example, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, triphenylmethyl (trityl), p-methoxyphenyldiphenylmethyl (p-methoxytrityl), etc. having 1 to 1 carbon atoms. A lower alkoxy group of 5, a nitro group, a benzyl group which may be substituted with halogen, a triphenylmethyl group, etc. are advantageously used. Examples of the aryl-type protecting group include lower alkoxy groups having 1 to 5 carbon atoms such as phenyl, p-methoxyphenyl, and p-chlorophenyl, and phenyl groups that may be substituted with halogen. Examples of Schiff base-type protecting groups include dimethylamino groups such as methylidene, N,N-dimethylaminomethylidene, benzylidene, ethylidene, propylidene, butylidene, pentylidene, etc., and carbon atoms 1 to 5 which may be substituted with a phenyl group. A lower alkylidene group is used. As the acyl-type protecting group, the acyl-type protecting group mentioned below in the hydroxyl group-protecting group can be used similarly.

Next, general formulas [1], [1'] and [2
] In the case where R3, R3' and R6 are protected hydroxyl groups, the protecting groups used include protecting groups used as hydroxyl group protecting groups in sugar chemistry, such as ether-type protecting groups and acyl-type protecting groups. It will be done. Examples of ether-type protecting groups include halogen, lower alkoxy groups having 1 to 5 carbon atoms, benzyloxy groups, and lower alkyl groups having 1 to 5 carbon atoms which may be substituted with phenyl groups;
Lower alkenyl group of 4; trisubstituted silyl group whose substituent is a lower alkyl group having 1 to 5 carbon atoms, phenyl group, benzyl group, etc.; even if substituted with a lower alkoxy group having 1 to 5 carbon atoms, a nitro group A good benzyl group; a lower alkoxy group having 1 to 5 carbon atoms, a tetrahydropyranyl group which may be substituted with halogen, etc. are used.

The above halogens include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
-5 alkyl groups include, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec
-butyl, tert-butyl, pentyl, isopentyl, neopentyl group, etc., and the alkoxy group having 1 to 5 carbon atoms is, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, vinyloxy, allyloxy, which may be substituted with halogen. Examples include groups. More specific examples of ether protecting groups include methyl, methoxymethyl, benzyloxymethyl, tert
-butoxymethyl, 2-methoxyethoxymethyl, 2,
2,2-trichloromethoxymethyl, ethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2,2
, 2-trichloroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, ethoxyethyl, triphenylmethyl, p-methoxyphenyldiphenylmethyl; allyl; trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl Silyl; benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl; tetrahydropyranyl, 4-methoxytetrahydropyranyl, tetrahydrofuranyl, etc.

Examples of the acyl protecting group include halogen, a lower alkoxy group having 1 to 5 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms which may be substituted with a phenoxy group which may have halogen, and a nitro group. group, phenyl group, benzoyl group optionally substituted with a lower alkyl group having 1 to 5 carbon atoms which may be substituted with halogen, 2 carbon atoms
Benzoyl group optionally substituted with ~6 lower alkyloxycarbonyl group, alkoxycarbonyl group having 2 to 6 carbon atoms optionally substituted with halogen, 3 to 6 carbon atoms
5 alkenyloxycarbonyl group, a lower alkoxy group having 1 to 5 carbon atoms, a benzyloxycarbonyl group which may be substituted with a nitro group, a phenoxycarbonyl group substituted with a nitro group, and the like. The above halogen, lower alkoxy group having 1 to 5 carbon atoms, and 2 carbon atoms
As the alkenyl group in ~4, those similar to those exemplified in the case of the ether type protecting group can be used.

More specifically, the acyl protecting group is as follows:
Formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl, propionyl, isopropionyl, 3-phenylpropionyl, isobutyryl, pivaloyl; benzoyl, p-nitrobenzoyl, p-phenylbenzoyl, o-(methoxycarbonyl)benzoyl, 2,4,6-trimethylbenzoyl; methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isobutyryloxycarbonyl;
Vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; p-nitrophenoxycarbonyl, and the like.

In general formulas [1] and [1'], R
Examples of sulfur-mediated monovalent groups represented by 1, R2, R7 or R8 include thiol groups, -S(O
) a group represented by n-Ra [wherein Ra represents an optionally substituted alkyl, alkenyl, aryl, aralkyl or heterocyclic group, and n represents 0, 1 or 2],
Examples include a sulfone group (SO3H), a group represented by the formula -SO2NRbRc [wherein Rb and Rc are the same or different and represent hydrogen, an alkyl group, an aryl group, or an aralkyl group]. Here, the alkyl group in the "optionally substituted alkyl group" represented by Ra is preferably a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n
-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. Among these, those having 1 to 3 carbon atoms are particularly preferred. . "Optionally substituted alkenyl group" represented by Ra
The alkenyl group in, for example, has 2 to 6 carbon atoms.
Preferably, vinyl,
Allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-methyl-3-butenyl, 1,3-butadienyl, 1,3-pentadienyl, 4-pentenyl, 1,3-
Examples include hexadienyl, and among these, those having 2 to 4 carbon atoms are particularly preferred. Examples of the aryl group in the "optionally substituted aryl group" represented by Ra include phenyl, naphthyl, biphenyl, anthryl, and indenyl. Indicated by Ra
Examples of the aralkyl group in "optionally substituted aralkyl group" include benzyl, phenethyl, and phenylpropyl. Examples of the heterocyclic group in the "optionally substituted heterocyclic group" represented by Ra include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom, or oxygen atom, and a 2- to 4-membered heterocyclic group containing 2 to 4 nitrogen atoms. 5-6 membered heterocyclic group containing 1-2 nitrogen atoms and 1 sulfur or oxygen atom
Examples include membered heterocyclic groups.

Specific examples of the above heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, benzothiazolyl, oxazolyl, isoxazolyl,
Benzopyranyl, quinolyl, thieno[2,3-b]pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, furyl, pyrrolidinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, benzothienyl, pyranyl, indolyl, isoindo Examples include lysinyl and chromanyl.

The above alkyl, alkenyl, aryl, aralkyl or heterocyclic group represented by Ra may be substituted with one or with 2 to 4 substituents that are the same or different, and such substituents include , such as halogen (e.g. Br, Cl, F, I), oxo, thioxo, nitro, amino (e.g. methyl, ethyl, etc.)
-4 alkyl; C2-4 alkenyl such as vinyl and allyl; C3-6 cycloalkyl such as cyclopropyl and cyclohexyl; C6-10 aryl such as phenyl and naphthyl; C2-4 acyl such as acetyl and propionyl; carbamoyl, N- may have one or two substituents such as sulfocarbamoyl), sulfo, cyano, hydroxy, carboxy (esterified with C1-4 alkyl such as methyl, ethyl, n-butyl, t-butyl) ), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl, etc.)
6cycloalkyl), cycloalkenyl (e.g. 1-
C3-6 cycloalkenyl such as cyclopropenyl, 1-cyclobutenyl, 1-cyclohexenyl), C1-4 alkoxy (amino; hydroxy; carboxy such as methoxy, ethoxy; halogen such as Cl, Br; C6- such as phenyl, naphthyl) 10 aryl; C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclohexyl; C6- such as phenyl, naphthyl, which may have 1 or 2 substituents such as C1-4 alkoxy such as methoxy and ethoxy) 10 aryl (e.g. halogen such as Br, Cl; C1-4 alkyl such as methyl, ethyl; C1-4 such as methoxy, ethoxy)
4 alkoxy; mono- or di-C1-4 alkylamino such as methylamino, dimethylamino, ethylamino;
Amino; Carbamoyl; Sulfo; C1-4 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl; Cyano; Hydroxy; Carboxy; Nitro; Acetoxy,
C2-4 acyloxy such as propionyloxy; C7-10 aralkyloxy such as benzyloxy and phenylethyloxy; may have one or two substituents such as sulfooxy), and the same substituents as the above aryl. C6-10 arylcarbonyl such as phenylcarbonyl and naphthylcarbonyl, which may have the same substituent as the above-mentioned aryl, C6-10 aryloxy such as phenyloxy and naphthyloxy, heterocyclic group (For example, a 5- to 7-membered heterocyclic group containing 1 sulfur, nitrogen, or oxygen atom, a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, 1 to 2 nitrogen atoms, and 1 A 5- to 6-membered heterocyclic group containing a sulfur atom or an oxygen atom, and these heterocyclic groups are a 6-membered ring group containing two or less nitrogen atoms, a benzene ring, or a 5-membered heterocyclic group containing one sulfur atom. may be condensed with a ring group). Specific examples of such heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrazolyl, thiadiazolyl, thienyl, thiazolyl, isothiazolyl, benzothiazolyl, and the like. These heterocyclic groups may be substituted with one substituent or two to four same or different substituents, such as halogen (for example, Br, Cl, F, I),
, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo, thioxo, etc. Also, R
The "alkyl group, aryl group or aralkyl group" represented by b and Rc has the same meaning as the alkyl group, aryl group or aralkyl group represented by Ra.

In general formula [1], R1 or R2
Examples of nitrogen-mediated monovalent groups represented by include, for example, azide, -NRdRe [wherein Rd and Re
are the same or different and represent hydrogen, optionally substituted alkylsulfonyl, arylsulfonyl, alkyl, alkenyl, aryl, aralkyl, heterocycle or acyl group. Above Rd
The alkyl, aryl, alkenyl, aralkyl, and heterocyclic group in "optionally substituted alkylsulfonyl, arylsulfonyl, alkyl, alkenyl, aryl, aralkyl, or heterocyclic group" represented by and Re are the same as in the above Ra. have significance. Further, the explanation of each substituent when each is substituted is the same as in the case of Ra described above. "Optionally substituted acyl group" represented by Rd and Re above
Examples of the optionally substituted acyl group include the above-mentioned optionally substituted alkyl, alkenyl, aryl, aralkyl, or a combination of a heterocyclic group and a carbonyl group.

Specific examples of the above-mentioned optionally substituted acyl group include formyl, acetyl, glycyl,
Chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl, propionyl, alanyl, β-alanyl, seryl, homoseryl, histidyl, butyryl, isobutyryl, methionyl,
Valeryl, isovaleryl, pivaloyl, prolyl, ornityl, valyl, tryptophyl, acryloyl, methacryloyl, benzoyl, naphthoyl, salicyloyl,
p-anisoyl, p-nitrobenzoyl, vanilloyl,
veratoyl, galloyl, phenylacetyl, thyronyl,
Examples include tyrosyl, 3-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl, and the like. Also, the above formula -N
In the group represented by RdRe, when Rd and Re are an alkyl, alkenyl, aryl, aralkyl, heterocyclic, or acyl group that may be substituted the same or differently, these groups mutually form a ring. Good too. Examples of such cases include phthalimide,
Succinimide, piperidin-1-yl, pyrrolidine-
Examples thereof include 1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, morpholino, 1,2,3,4-tetrahydroquinolin-1-yl, thiazolidin-3-yl, imidazolyl, and the like.

In the general formula [1], when R3 is a hydroxyl group which may be phosphoric esterified, the phosphoric ester residue is represented by the general formula

[Formula, m is an integer of 1 to 3, R9 is H or carbon number 1 to
14 hydrocarbon residues]. Examples of the hydrocarbon residue of R9 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
1 carbon number such as c-butyl, tert-butyl, pentyl, etc.
-5 lower alkyl groups; aralkyl groups such as benzyl, p-methoxybenzyl and p-methylbenzyl; phenyl groups and the like.

Compound [1'] has the formula R
Metal salts of thiols (e.g., sodium, potassium, cesium salts, etc.) and organic amine salts (e.g., aliphatic amine salts such as triethylamine, tributylamine, etc.) of thiols represented by aSH [wherein Ra has the same meaning as above];
After reacting (aromatic amine salts such as pyridine, N,N-dimethylaniline, etc.) or subjecting compound [2] to an azidation reaction accompanied by Walden inversion, subjecting it to an oxidation reaction or a reduction reaction as necessary, Accordingly, it can be produced by removing the protecting groups of the hydroxyl group and the amino group of the nucleobase moiety. In the reaction with the above-mentioned thiols, the amount of the reactant relative to the substrate is not particularly limited, but usually 1 to 5 equivalents are used, and it is particularly preferable to use 1 to 2 equivalents. As the reaction solvent, alcohols such as methanol and ethanol, N,N-dimethylformamide, dimethyl sulfoxide, etc. can be used, but are not limited to these. The reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from room temperature to 70°C.

Examples of the oxidizing agent used in the oxidation reaction include peroxides such as peracetic acid, perbenzoic acid, and metachloroperbenzoic acid, potassium permanganate, ozone, and potassium periodate. In this oxidation reaction, when producing the target product with n=1, 0.9 to 1.2 mol of such an oxidizing agent is reacted with 1 mole of the raw material, and when producing the target product with n=2, This is carried out by reacting 2 moles or more, preferably 2 to 6 moles, per mole of the raw material.

[0023] This oxidation reaction can be carried out in a solvent. Any solvent may be used as such a solvent as long as it does not inhibit the reaction, and specific examples include water, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, diethyl ether, and tetrahydrofuran. ethers, ketones such as acetone, amides such as N,N-dimethylformamide, etc. are used. The reaction temperature is usually -20°C to 100°C.
°C, preferably from 0 °C to 30 °C. The reaction time is
Although not particularly limited as long as the purpose is achieved, the time is usually 10 minutes to 30 hours, preferably 30 minutes to 15 hours.

As the azidating agent, metal salts of hydrogen azide (such as the above-mentioned salts) and organic amine salts (such as the above-mentioned salts) are used, but particularly preferred azidating agents are sodium azide, sodium azide, etc. Tetrabutylammonium azide. The azidation reaction is usually carried out using N,N-dimethylformamide, dimethyl sulfoxide, methanol,
It is carried out in a polar solvent such as, but not limited to, ethanol. Although the amount of the azidating agent relative to the substrate is not particularly limited, it is usually used in an amount of 1 to 5 times, and preferably in an amount of 1 to 2 times. The reaction temperature ranges from room temperature to the reflux temperature of the solvent, preferably from 40°C to 80°C. As a reduction reaction, a catalytic reduction reaction using a palladium catalyst (Y. F. She
aly et al., J. Med. Chem. , 29th
Vol., pp. 483-488 (1986)) and reduction reactions using organic bases (e.g., aliphatic amines such as triethylamine and tributylamine, aromatic amines such as pyridine and N,N-dimethylaniline) and hydrogen sulfide (
T. Adachi et al., Synthesis, 45
-46 page (1977)) is preferred, but is not particularly limited.

[0025] Compound [1'] in which R7 or R8 is an amino group can be obtained by reacting compound [2] with a metal salt of phthalimide (eg, potassium, sodium, cesium salt, etc.), and then removing the phthaloyl group. It can also be manufactured by The amount of reactant to substrate is not particularly limited, but is usually 1 to 1.
5 times equivalent is used, and it is particularly preferable to use 1 to 2 times equivalent. In this case, a phase transfer catalyst (e.g. 18-
Crown-6, 15-Crown-5, etc.) from 0.1 to 1
It is preferable to coexist two equivalents. As a reaction solvent,
For example, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, etc. are used, but are not limited to these. The reaction temperature is 5
The reflux temperature of the solvent is adopted from 0°C to 70°C to 130°C.
°C is preferred. Removal of phthaloyl groups is carried out by reacting hydrazine, methylhydrazine, etc. in alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and dichloroethane, and solvents such as N,N-dimethylformamide and dimethyl sulfoxide. However, it is not limited to this.

The hydroxyl group-protecting group and the amino group-protecting group of the nucleobase moiety of compounds [1], [1'] and [2] are as follows:
As mentioned above, these include, for example, “Protec
tive Groups inOrganic Ch.
emistry”, J. F. W. McOmie
(Plenum Press, 1973)
or “Protective Groups in
Organic Chemistry”, Theodo
raW. Edited by John Wiley
and Sons, 1981). These protecting groups can be removed using conventional means. For example, acyl groups can be removed by hydrolysis under acidic or basic conditions, substituted trityl groups can be removed by hydrolysis under acidic conditions, and substituted benzyl groups can be removed by catalytic reduction. .

Compound [2] in which R5 is an activated hydroxyl group is, for example, the known 9-[(1R,
3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclopentan-1-yl]adenine (JP-A-61
-137887), or 9-[(1R,3S,4R)
-3-hydroxy-4-(hydroxymethyl)cyclopentan-1-yl]guanine (JP-A-62-17409
7) as a starting material, it is produced as follows. That is, the above-described protecting group is added to the compound in the presence of a base (for example, an aliphatic amine such as triethylamine or tributylamine, an aromatic amine such as pyridine or N,N-dimethylaniline, etc.), an acyl chloride, an acid, etc. Compounds introduced by reacting anhydrides, substituted trityl chloride, substituted benzyl chloride, etc.
It is synthesized by reacting an activated base.

[0028] Examples of the activating group here include:
Examples include sulfonyl groups such as methanesulfonyl group, trifluoromethanesulfonyl group, p-toluenesulfonyl group, and imidazolylsulfonyl group. Particularly preferred are methanesulfonyl group and trifluoromethanesulfonyl group. The reaction for introducing the activating group is performed by adding the corresponding sulfonyl chloride or sulfonic anhydride to a base (for example, an aliphatic amine such as triethylamine or tributylamine,
The reaction is carried out in the presence of aromatic amines such as pyridine, N,N-dimethylaniline, etc.). In this case, the reaction is usually carried out in an inert solvent. For example, halogenated hydrocarbon solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, pentane,
Aliphatic hydrocarbon solvents such as hexane and aromatic hydrocarbon solvents such as benzene and toluene are suitable.
It is not limited to these. Preferably, methylene chloride and dichloroethane are used. The amount of activated base relative to the substrate is not particularly limited, but it is usually used in an amount of 1 to 3 times, and preferably 1 to 1.5 times. The amount of base used is usually 1 to 10 times equivalent, and preferably 2 to 4 times equivalent. The reaction temperature ranges from -78°C to the reflux temperature of the solvent, preferably from -20°C to room temperature. general formula

[Formula 9] [wherein R6 and B have the same meanings as above, one of R4' and R5' is a hydroxyl group and the other is H] A compound in which R5' is a hydrogen atom is produced, for example, by subjecting a compound in which R5' in compound [2] is an activated hydroxyl group to an acyloxylation reaction accompanied by Walden inversion, followed by deacylation. The acyloxylation reaction accompanied by Walden inversion is a reaction between metal salts of carboxylic acids such as cesium acetate and cesium phenylacetate and 18-crown-6.
, 15-crown-5, and preferably cesium acetate and 18-crown-6. In this case, the reaction is usually carried out in an inert solvent. For example, aromatic hydrocarbon solvents such as benzene and toluene, and halogenated hydrocarbon solvents such as dichloroethane are suitable, but are not limited to these. The reaction temperature ranges from 50°C to the reflux temperature of the solvent, preferably from 70°C to 130°C.

[0029] Compound [5] in which R4' is a hydroxyl group and R5' is a hydrogen atom is the compound [5].
5], a compound in which R4' is a hydrogen atom and R5' is a hydroxyl group is subjected to a Mitsunobu reaction (O. Mitsunobu reaction).
, Synthesis, pp. 1-28 (1981))
Alternatively, a compound in which R4' is a hydrogen atom, R5' is a hydroxyl group, and R6 is a hydroxyl group protected by an acyl group in compound [5] is subjected to an acyl group rearrangement reaction (P.A.
．． M. Herdewijn, J. Org. Che
m. , Vol. 53, pp. 5050-5053 (1988)) and then deacylated. Deacylation is carried out by a hydrolysis reaction under acidic or basic conditions according to conventional means.

The compound [2] in which R4 is an activated hydroxyl group is synthesized by reacting the compound [5] in which R4' is a hydroxyl group with an activated base. Examples of the activating group include sulfonyl groups such as methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, and imidazolylsulfonyl. Particularly preferred are methanesulfonyl group and trifluoromethanesulfonyl group.
The reaction for introducing an activating group is performed by adding the corresponding sulfonyl chloride or sulfonic acid anhydride to a base (for example, fatty acid amines such as triethylamine and tributylamine, pyridine,
It is synthesized by reacting in the presence of aromatic amines such as N,N-dimethylaniline, etc.). In this case, the reaction is usually carried out in an inert solvent. For example, halogenated hydrocarbon solvents such as methylene chloride, dichloroethane, chloroform, and carbon tetrachloride, aliphatic hydrocarbon solvents such as pentane and hexane, and aromatic hydrocarbon solvents such as benzene and toluene are suitable, but they are not limited to these. It's not something you can do. Preferably, methylene chloride and dichloroethane are used. The amount of activator to substrate is not particularly limited, but is usually 1
-3 times equivalent is used, and it is particularly preferable to use 1-1.5 times equivalent. The amount of base used is usually 1 to 10 times equivalent, and preferably 2 to 4 times equivalent. The reaction temperature is in the range of -78°C to the reflux temperature of the solvent, but -
20°C to room temperature is preferred.

Compound [1] in which R3 is a phosphoric acid esterified hydroxyl group is produced as follows. For example, the monophosphoric acid ester compound [1
] can be obtained by reacting a compound in which R3 is a hydroxyl group with a phosphorylating agent and then hydrolyzing the compound. This can be preferably carried out by using the phosphorylating agent in an amount of about 2.5 to 10 times the theoretical amount in moles, allowing the reaction to take place for about 30 minutes to 10 hours, and then hydrolyzing the reaction under ice cooling.

Generally, the phosphorylating agents used in the phosphorylation reaction include those that directly introduce phosphoric acid residues, such as phosphorus oxychloride, pyrophosphoryl tetrachloride, phosphorus trichloride, polyphosphoric acid, and metaphosphoric acid. Phosphoric acid benzyl ester dichloride, morpholinophosphoric acid dichloride, phenylphosphoric acid dichloride, di-β-cyanoethyl phosphoric acid chloride, dibenzylphosphoric acid chloride, O-
After phosphorylation, the protecting group of phosphoric acid is removed, such as benzyl phosphorous acid, O, O-diphenyl pyrophosphoric acid, etc.
Examples include those that involve an oxidation process. In addition, the monophosphoric acid ester was prepared at -20°C to 10°C according to a method known per se.
By reacting with 1-fluoro-2,4-dinitrobenzene or carbonyldiimidazole, etc., an active phosphoric acid ester is obtained, and by reacting this with an organic amine salt of orthophosphoric acid or pyrophosphoric acid at 0 to 40°C, A diphosphate or triphosphate can be produced.

Each phosphoric acid derivative synthesized by the above reaction can be purified by desalting using charcoal powder or the like, and then by chromatography using anion exchange cellulose or anion exchange resin. After purification, it can be obtained in a free form, but if necessary, it can also be isolated as potassium, sodium, calcium, barium, ammonium, or organic amine salts. After completion of phosphorylation, a hydrocarbon residue designated by R9 is introduced. Although alkylating agents are generally used for this introduction, it is preferably achieved by reacting a diazoalkane (eg, diazomethane, diazobenzyl, etc.) in an organic solvent or a mixture of an organic solvent and water. In addition, after activating the phosphoric acid residue with an activating agent such as mesitylene sulfonyl chloride,
Substituted phenyl groups can be introduced by reacting phenols.

The present invention has made it possible to synthesize an optically active cyclopentane derivative [1]. Furthermore, the optically active cyclopentane derivative [1] of the present invention exhibits excellent activity against, for example, human herpesvirus type 1 (HSV-1), has low toxicity, and is useful as an antiviral agent. The compounds of the present invention are not racemic and are optically pure compounds that can be used as pharmaceuticals. The present compound can be used as an antiviral agent in the treatment of viral diseases in animals, especially mammals (for example, laboratory animals such as rabbits, rats, and mice; companion animals such as dogs and cats; and humans). In the medical field, it has potential as an antifungal, antibacterial, and antiprotozoal agent, and is also expected to have anticancer effects.

When the compound of the present invention is used for the above-mentioned therapeutic purposes, it can be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, and water. It can be administered orally or parenterally in the form of tablets, emulsifiers, ointments, injections, etc. Examples of the above-mentioned carriers include lactose, starch, mineral oil, petroleum jelly, polyethylene glycol, propylene glycol, and saline for injection, which can be used depending on the purpose. The dosage varies depending on the type of virus, symptoms, subject, administration method, etc., but for example, in the case of a herpes virus infection in adults, approximately 1.0 to 100 mg per day should be administered.
It is preferable to administer intravenously in ~3 doses, and for oral administration, it is desirable to administer 5 mg to 100 mg/time in 1 to 3 doses.

[0036]

[Operations and Examples] The present invention will be explained in detail in the following Reference Examples, Examples, and Test Examples, but these examples are merely illustrative and do not limit the present invention, and do not limit the scope of the present invention. may be changed within a range that does not deviate from the above. Reference example 1 N2-(p-methoxytrityl)-9-[(1R,3S
,4R)-3-hydroxy-4-(p-methoxytrityloxymethyl)cyclopentan-1-yl]guanine production: 9-[(1R,3S,4R)-3-hydroxy-4-(hydroxymethyl) cyclopentan-1-yl]guanine (1 g) was suspended in dry N,N-dimethylformamide (15 ml) and added to pyridine (1.19 g).
) and p-anisylchlordiphenylmethane (1.51g
) and stirred at room temperature for 45 minutes. After adding p-anisylchlordiphenylmethane (1.51 g) to the reaction solution and stirring at room temperature for 3 hours, ethyl acetate (70 ml) was added, washed with water (50 ml x 3), and dried (M
gSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, and the column was filled with a mixture of ethyl acetate, methylene chloride, and methanol (10:10:1).
After eluting with a mixture of ethyl acetate, methylene chloride, and methanol (4:4:1), fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (2.05 g).
was obtained as a powder. IR (KBr, cm-1): 3350, 1692,
1608, 1565, 1512, 1248. NMR (200MHz, CDCl3) δ: 1.38 (
1H, m), 1.92 (3H, m), 2.05 (1
H, m), 2.26 (1H, d, J=2.2Hz),
2.99 (1H, t, J=8.6Hz), 3.23
(1H, dd, J=5.6, 8.6Hz), 3.69
(3H,s), 3.78(3H,s), 3.97(
1H, m), 4.40 (1H, m), 6.71 (2
H, d, J = 8.8Hz), 6.86 (2H, d, J
=8.8Hz), 7.04~7.50 (25H, m)
, 10.73 (1H, br.s).

Reference Example 2 N2-(p-methoxytrityl)-9-[(1R,3S
,4R)-4-(p-methoxytrityloxymethyl)
-3-(methanesulfonyloxy)cyclopentane-1
-yl]guanine production: Compound obtained in Reference Example 1 (
2.4 g) was dissolved in methylene chloride (70 ml), to which triethylamine (0.902 g) and methanesulfonyl chloride (0.476 g) were added under ice-cooling, and the solution was dissolved at the same temperature for 40 min.
Stir for a minute. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution, then with a saturated saline solution, and then dried (MgSO4
)did. The solvent was distilled off under reduced pressure to obtain the title compound (2.62
g) was obtained as a powder. This product is not purified and is used in reference example 3 below.
Alternatively, it was used in the following examples.

Reference Example 3 9-[(1R,3R,4R)-3-acetoxy-4-(
p-methoxytrityloxymethyl)cyclopentane-
1-yl]-N2-(p-methoxytrityl)guanine: The compound obtained in Reference Example 2 was mixed with toluene (200
ml) and add 18-crown-6 (0.78
5 g) and cesium acetate (2.85 g) were added, and the mixture was stirred under heating under reflux for 14 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was passed through a column of silica gel, the column was washed with ethyl acetate, and then a mixture of ethyl acetate, methylene chloride and methanol (10:10:
After elution with step 1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (1.88 g) as a powder. IR
(KBr, cm-1): 3355, 1736, 1
688, 1604, 1562, 1510, 12
45. NMR (200MHz, DMSO-d6) δ:
1.23 (1H, m), 1.68 (1H, m), 1
．． 76 (3H, s), 2.23 (3H, m), 2.9
3 (2H, m), 3.67 (3H, s), 3.75
(3H,s), 4.05(1H,s), 5.25(
1H, m), 6.84 (2H, d, J=8.8Hz),
6.92 (2H, d, J=8.8Hz), 7.05
~7.50 (25H, m), 7.56 (1H, s),
10.52 (1H, s).

Reference Example 4 9-[(1R,3R,4R)-3-hydroxy-4-(
p-methoxytrityloxymethyl)cyclopentane-
1-yl]-N2-(p-methoxytrityl)guanine: The compound obtained in Reference Example 3 (0.054 g) was dissolved in methanol (5 ml), and a 1N sodium methoxide-methanol solution (0. 05ml) and
Stir at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, and the column was filled with a mixture of ethyl acetate, methylene chloride, and methanol (10:1).
After eluting with a mixture of ethyl acetate, methylene chloride, and methanol (4:4:1), fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.0
45 g) was obtained as a powder. IR (KBr, cm-1): 3360, 1683,
1603, 1560, 1510, 1246. NMR (200MHz, DMSO-d6) δ: 1.2
8 (1H, m), 1.54 (1H, m), 1.88
(2H, m), 2.07 (1H, m), 2.92 (1
H, m), 3.20 (1H, m), 3.67 (3H
,s), 3.75(3H,s), 4.04(2H,
m), 4.70 (1H, d, J=3.8Hz), 6.
87 (2H, d, J = 9.0Hz), 6.91 (2H
, d, J=9.0Hz), 7.08~7.46 (24
H, m), 7.56 (1H, s), 7.61 (1H
, s), 10.51 (1H, s).

Reference Example 5 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
-3-(methanesulfonyloxy)cyclopentane-1
-yl]guanine production: Compound obtained in Reference Example 4 (
1.2 g) was dissolved in methylene chloride (35 ml), to which were added triethylamine (0.451 g) and methanesulfonyl chloride (0.238 g) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution, then with a saturated saline solution, and then dried (MgSO4).
did. The solvent was distilled off under reduced pressure to obtain the title compound (1.31 g
) was obtained as a powder. This product was used in the following examples without being purified.

Reference Example 6 9-[(1R,3S,4R)-3-hydroxy-4-(
p-methoxytrityloxymethyl)cyclopentane-
Production of 1-yl]adenine: 9-[(1R,3S,4R
)-3-hydroxy-4-(hydroxymethyl)cyclopentan-1-yl]adenine (4 g) was dried with N,N-
Dimethylformamide (60ml) and pyridine (10ml)
1), p-anisylchlorodiphenylmethane (5.94 g) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. After adding p-anisylchlorodiphenylmethane (0.75 g) to the reaction solution and stirring at room temperature for 2 hours, ethyl acetate (200 ml) was added, washed with water (100 ml x 3), and dried (MgSO4). The solvent was distilled off under reduced pressure, the resulting residue was passed through a silica gel column, and a mixture of methylene chloride and methanol (10
:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (5.74 g) as a powder. IR (KBr, cm-1): 3390, 3325,
3190, 1641, 1598, 1250. NMR (200MHz, DMSO-d6) δ: 1.8
7 (1H, dt, J=11.6, 10.2, 10.2H
z), 2.03 (1H, m), 2.10 to 2.50
(3H, m), 3.03 (1H, dd, J=6.6,
9.0Hz), 3.20 (1H, dd, J=5.4,
9.0Hz), 3.74(3H,s), 4.15(
1H, m), 4.88 (1H, d, J=4.8Hz)
, 5.02 (1H, m), 6.90 (2H, d, J
=9.0Hz), 7.13~7.47 (13H, m)
, 8.10 (1H, s), 8.16 (1H, s).

Reference Example 7 9-[(1R,3S,4R)-3-hydroxy-4-(
p-methoxytrityloxymethyl)cyclopentane-
1-yl]-N6-(p-methoxytrityl)adenine: The compound (3 g) obtained in Reference Example 6 was mixed with N,N-
It was dissolved in dimethylformamide (50 ml), triethylamine (1.75 g) and tert-butyldimethylchlorosilane (1.3 g) were added thereto, and the mixture was stirred at room temperature for 3 hours. Pyridine (15 ml) and p-anisylchlorodiphenylmethane (2.66 g) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. p-anisylchlorodiphenylmethane (1.33 g) was added to the reaction solution, and after stirring for another 5 hours, ethyl acetate (200 ml) was added.
It was washed with water (100 ml x 3) and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was diluted with N,N-
Dissolved in dimethylformamide (30 ml), and added tetrabutylammonium fluoride trihydrate (3.63 g) to this solution.
) and stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was added to the reaction solution, washed with water (50 ml x 3), and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and methylene chloride (1:1). Fractions containing the target product were collected and concentrated under reduced pressure. and the title compound (4.5 g
) was obtained as a powder. IR (KBr, cm-1): 3425, 1605,
1512, 1466, 1443, 1250. NMR (200MHz, DMSO-d6) δ: 1.7
7-2.45 (5H, m), 3.01 (1H, t, J
=8.8Hz), 3.18(1H, dd, J=5.4
,8.8Hz), 3.71(3H,s), 3.72
(3H, s), 4.13 (1H, m), 4.88 (
1H, d, J=4.8Hz), 5.01 (1H, m)
, 6.84 (2H, d, J=8.8Hz), 6.8
9 (2H, d, J=8.8Hz), 7.15-7.4
2 (25H, m), 7.87 (1H, s), 8.2
6 (1H, s).

Reference Example 8 N6-(p-methoxytrityl)-9-[(1R,3S
,4R)-3-(methanesulfonyloxy)-4-(p
-methoxytrityloxymethyl)cyclopentane-1
-yl] adenine production: Compound obtained in Reference Example 7 (
0.5 g) was dissolved in methylene chloride (10 ml), to which were added triethylamine (0.191 g) and methanesulfonyl chloride (0.087 g) under ice-cooling, and at the same temperature
Stir for 5 minutes. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution, then with a saturated saline solution, and then dried (MgSO
4) I did. The solvent was distilled off under reduced pressure to obtain the title compound (0.5
4 g) was obtained as a powder. This product was used in the following examples without purification.

Reference Example 9 9-[(1R,2R,4S)-2-hydroxy-4-(
Production of hydroxymethyl)cyclopentan-1-yl]guanine: 9-[(1R,2S,3R,4R)-2,3
-Dihydroxy-4-(hydroxymethyl)cyclopentan-1-yl]guanine (140 mg) was suspended in acetonitrile (4 ml), methanol (30 mg) was added, and acetyl bromide (0.5 ml) was added. The mixture was heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in hydrobromic acid (40%, 4 ml) and stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and ethanol-ethyl ether (1:5, 6 ml) was added to the residue to obtain a colorless powder. This powder (200mg) was mixed with methanol-water (4:1,5).
ml), added sodium acetate (400 mg), then added 5% palladium-carbon (200 mg),
Catalytic reduction was performed at room temperature and normal pressure for 3 hours. The catalyst was filtered and washed with ethanol-water-pyridine (1:1:1). The filtrate and washing solution were combined, concentrated under reduced pressure, and the residue was subjected to Amberlite XAD-II (25 ml) column chromatography.
Elution was performed with water and 3% methanol/water. The eluted fractions were concentrated under reduced pressure to obtain the title compound (45 mg) as white crystals. NMR (200MHz, DMSO-d6) δ: 1.6
25 (2H, m), 1.83 (1H, q, J=6.6
Hz), 2.177 (2H, m), 3.378 (2
H, dd, J=3.6, 19.6Hz), 4.33(
2H, m), 4.60 (1H, t, J=5.4Hz)
, 5.126 (1H, d, J=4.4Hz), 6.3
66 (2H, broad s), 7.759 (1H, s)
, 10.504 (1H, Broads).

Reference Example 10 9-[(1R,2S,4S)-2-hydroxy-4-(
Production of 9-[(1R,2R,4S)-2-hydroxy-4-(hydroxymethyl)cyclopentan-1-yl]guanine (315 mg) with N,N -Dissolved in dimethylformamide (5 ml) and concentrated under reduced pressure. The residue was dissolved in pyridine (5 ml), p-anisylchlorodiphenylmethane (770 mg) was added, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in silica gel (20 g
) and eluted with chloroform-methanol (24:1). The eluted fraction was concentrated to dryness under reduced pressure.
Di(p-methoxytrityl) form as colorless powder (550 mg
) was obtained. A solution of the obtained powder (550 mg) in dichloromethane (4 ml) was added to chromium trioxide (273 mg).
- Pyridine (0.476 ml) in dichloromethane (4 m
l) Add dropwise to the solution and stir at room temperature for 10 minutes, then add acetic anhydride (
0.27 ml) and stirred at room temperature for 20 minutes. The reaction solution was added to a column of silica gel (10 g), and the column was eluted with chloroform-methanol (24:1). The eluate was concentrated to dryness under reduced pressure, and the obtained solid (200 mg) was dissolved in tetrahydrofuran (2 ml). A 1M solution (1 ml) of L-selectride was added to this, and the mixture was stirred at room temperature for 2 hours. A 10% methanol solution of hydrochloric acid (2
ml) was added thereto, and after stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. After washing the residue with ethyl ether, Amberlite XAD
-II (55 ml) column chromatography. The column was eluted with 5% ethanol water, and the eluted fraction was concentrated under reduced pressure. The residue was dissolved in water (2 ml) with heating, and the mixture was allowed to stand overnight in a refrigerator to obtain crystals of the title compound (40 mg). NMR
(200MHz, DMSO-d6) δ: 1.3-2.4
5 (5H, m), 3.427 (2H, m), 4.4
07 (1H, t, J = 4.7Hz), 4.699 (1
H, m), 4.922 (1H, d, J=6.4Hz)
, 6.414 (2H, broad s), 7.681 (1
H, s), 10.55 (1H, broad s).

004
6] Example 1 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylthio)cyclopentan-1-yl]guanine: Compound obtained in Reference Example 2 (1.09g)
was dissolved in dry N,N-dimethylformamide (20 ml), and a solution of water (2.88 ml) containing the sodium salt of methyl mercaptan (0.43 g) in a nitrogen stream was added thereto, and the mixture was heated at 40 to 50°C for 1 hour. Stir, another 70
Stir at ~75°C for 3 hours. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed with water (40 ml).
ml x 3) and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column.
A mixture of ethyl acetate, methylene chloride and methanol (1
After elution (0:10:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (0.995 g) as a powder. IR (KBr, cm-1): 3360, 1
690, 1607, 1565, 1512, 12
52. NMR (200MHz, CDCl3) δ: 1.
56 (1H, m), 1.93 (3H, s), 2.0
4 (1H, m), 2.28 (3H, m), 3.11
(1H, dd, J=6.6, 11.8Hz), 3.1
6 (1H, t, J=9.1Hz), 3.33 (1H,
dd, J=6.3, 9.1Hz), 3.66 (3H,
s), 3.78 (3H, s), 4.09 (1H, m
), 6.70 (2H, d, J=8.8Hz), 6.
84 (2H, d, J=8.8Hz), 7.00~7.
50 (25H, m), 11.39 (1H, br.s)
．．

Example 2 Production of 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylthio)cyclopentan-1-yl]guanine: The compound obtained in Example 1 (0 .4g)
was dissolved in 80% aqueous acetic acid (15 ml) and stirred at 45-50°C for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (8:1). Fractions containing the target product were collected and concentrated under reduced pressure. , the title compound (0.081g)
was obtained as a powder. SIMS m/z: 296(M+1)IR(KBr
, cm-1): 3428, 3330, 3153,
1692, 1635, 1600, 1367. NMR (200MHz, DMSO-d6) δ: 1.8
4 (1H, m), 1.98 (1H, m), 2.10
(3H, s), 2.33 (2H, m), 2.58 (1
H, m), 3.27 (1H, dd, J = 7.0, 14
．． 2Hz), 3.52 (1H, m), 3.68 (1
H, m), 4.60 (1H, t, J=5.0Hz),
4.66 (1H, hex, J=8.4Hz), 6.
40 (2H, s), 7.82 (1H, s).

Example 3 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
-3-(Methylsulfonyl)cyclopentan-1-yl]guanine: Compound obtained in Example 1 (0.2
g) was dissolved in methylene chloride (5 ml), m-chloroperbenzoic acid (0.124 g) was added thereto under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with a 5% aqueous sodium bisulfite solution, then with a saturated aqueous sodium bicarbonate solution, and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and mixed with a mixture of ethyl acetate, methylene chloride, and methanol (10:1).
After elution with 0:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (0.157 g) as a powder. IR (KBr, cm-1): 3340, 16
90, 1608, 1572, 1512, 129
8, 1252, 1179. NMR (200MHz,
CDCl3) δ: 1.87 (1H, m), 2.02
(2H, m), 2.26 (1H, m), 2.46 (
1H, m), 2.70 (3H, s), 3.36 (1
H, dd, J=8.0, 14.8Hz), 3.50(
1H, dd, J=8.0, 9.6Hz), 3.63
(1H, m), 3.68 (3H, s), 3.79 (
3H,s), 4.00(1H,m), 6.71(2
H, d, J = 9.0Hz), 6.85 (2H, d, J =
9.0Hz), 6.94-7.57 (25H, m),
7.81 (1H, s), 11.52 (1H, br.
s).

Example 4 Production of 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylsulfonyl)cyclopentan-1-yl]guanine: The compound obtained in Example 3 ( 0.
237g) in 80% acetic acid water (10ml),
Stir at 45-50°C for 3 hours. The solvent was distilled off under reduced pressure, and ethanol (10 ml) was added to the resulting residue.
After evaporation under reduced pressure again, ethyl ether (15 ml) was added and the resulting powder was collected by filtration. The obtained powder was soaked in hot water (1
5 ml), filtered off insoluble matter, cooled, and collected the resulting powder by filtration to obtain the title compound (0.056 g). SIMS m/z: 328(M+1)IR(KBr
, cm-1): 3335, 1725, 1690,
1624, 1285, 1150. NMR (200MHz, DMSO-d6) δ: 2.0
1 (1H, dt, J = 12.4, 10.0, 10.0H
z), 2.36 (2H, m), 2.62 (2H, m
), 3.04 (3H, s), 3.69 (1H, m)
, 3.82 (1H, dd, J=10, 18.6Hz)
, 3.93 (1H, m), 4.63 (1H, m),
4.77 (1H, t, J = 4.9Hz), 6.40 (
2H,s), 7.81(1H,s), 10.57(
1H,s).

Example 5 N2-(p-methoxytrityl)-9-[(1R,3S
,4R)-4-(p-methoxytrityloxymethyl)
-3-(Methylthio)cyclopentan-1-yl]guanine production: Compound obtained in Reference Example 5 (1.75g)
was dissolved in dry N,N-dimethylformamide (15 ml), and a solution of sodium salt of methyl mercaptan (0.69 4 g) in water (4.7 ml) was added thereto in a nitrogen stream. Stir the time, 7 more
Stir at 0-75°C for 3 hours. Ethyl acetate (80 ml) was added to the reaction solution, and washed with water (30 ml).
1×3) and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column.
A mixture of ethyl acetate, methylene chloride and methanol (10
:10:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (1.42 g) as a powder. IR (KBr, cm-1): 3300, 1690,
1608, 1570, 1510, 1256. NMR (200MHz, CDCl3) δ: 1.56 (
1H, m), 1.86 (3H, s), 1.96 (1
H, m), 2.05 (2H, m), 2.34 (1H
, m), 2.74 (1H, m), 3.04 (1H,
m), 3.17 (1H, m), 3.62 (3H, s
), 3.77 (3H, s), 4.23 (1H, m)
, 6.69 (2H, d, J=8.8Hz), 6.8
4 (2H, d, J=8.8Hz), 6.90-7.6
0 (25H, m), 11.28 (1H, br.s).

Example 6 Production of 9-[(1R,3S,4R)-4-(hydroxymethyl)-3-(methylthio)cyclopentan-1-yl]guanine: The compound obtained in Example 5 (0 .35g
) in 80% acetic acid water (10 ml) and heated at 45-50°C.
I stirred it for 3 hours. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The obtained residue was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (8:1). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.066 g). Obtained as a powder. SIMS m/z: 296(M+1)IR(KBr
, cm-1): 3325, 3210, 1685,
1635, 1603. NMR (200MHz, DM
SO-d6) δ: 1.79 (1H, dt, J=11.
8, 9.4, 9.4Hz), 1.97 (1H, m),
2.07 (3H, s), 2.17 (1H, m),
2.34 (2H, m), 3.16 (1H, m), 3
．． 56 (2H, m), 4.77 (1H, t, J=5.
3Hz), 4.78 (1H, m), 6.43 (2H
,s), 7.84(1H,s), 10.54(1H
, s).

Example 7 N2-(p-methoxytrityl)-9-[(1R,3S
,4R)-4-(p-methoxytrityloxymethyl)
-3-(Methylsulfonyl)cyclopentan-1-yl]guanine: The compound obtained in Example 5 (0.4
7 g) was dissolved in methylene chloride (5 ml), m-chloroperbenzoic acid (0.29 g) was added thereto under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with a 5% aqueous sodium bisulfite solution, then with a saturated aqueous sodium bicarbonate solution, and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the resulting residue was passed through a silica gel column and mixed with a mixture of ethyl acetate, methylene chloride, and methanol (10:1).
0:1), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (0.361 g) as a powder. IR (KBr, cm-1): 3350, 1697,
1611, 1570, 1513, 1257. NMR (200MHz, CDCl3) δ: 1.98 (
3H, m), 2.23 (2H, m), 2.70 (3
H, s), 2.91 (1H, m), 3.13 (2H
, m), 3.65 (3H, s), 3.76 (3H,
s), 4.27 (1H, m), 6.64 (2H, d
, J=8.8Hz), 6.83 (2H, d, J=8.
8Hz), 6.96-7.50 (26H, m), 1
1.35 (1H, br.s).

Example 8 Production of 9-[(1R,3S,4R)-4-(hydroxymethyl)-3-(methylsulfonyl)cyclopentan-1-yl]guanine: The compound obtained in Example 7 ( 0.
348g) in 80% acetic acid water (8ml),
Stir at 50°C for 3 hours. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The resulting residue was passed through a silica gel column and treated with a mixture of methylene chloride and methanol (4:1).
After elution with , fractions containing the target compound were collected and concentrated under reduced pressure, then dissolved in hot water (15 ml), the insoluble matter was filtered off, and then cooled. The resulting powder was collected by filtration to obtain the title compound. (0
．． 072g) was obtained. SIMS m/z: 328(M+1)IR(KBr
, cm-1): 3400, 3315, 3140,
1695, 1632, 1599, 1576,
1290, 1121. NMR (200MHz, DMS
O-d6) δ: 1.92 (1H, q, J=11.4H
z), 2.25-2.65 (4H, m), 3.03
(3H, s), 3.58 (3H, m), 4.73 (
1H, m), 4.94 (1H, t, J=5.1Hz)
, 6.47 (2H, s), 7.87 (1H, s),
10.55 (1H, s).

Example 9 N6-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylthio)cyclopentan-1-yl]adenine: Compound obtained in Reference Example 8 (0.55g)
was dissolved in dry N,N-dimethylformamide (10 ml), to which was added a solution of sodium salt of methyl mercaptan (0.22 g) in water (1.5 ml) in a nitrogen stream, and the solution was heated at 40 to 50°C for 1 hour. Stir the time, another 70
Stir for 1 hour at ~75°C. Ethyl acetate (5
0 ml), washed with water (20 ml x 3) and dried (MgS
O4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the target product were collected and concentrated under reduced pressure. The title compound (0.467 g) was obtained as a powder. IR (KBr, cm-1): 3415, 1600,
1510, 1463, 1440, 1246. NMR (200MHz, CDCl3) δ: 1.93 (
1H, m), 2.02 (3H, s), 2.05 (1
H, m), 2.54 (2H, m), 2.78 (1H
, ddd, J=6.9, 9.3, 14.5Hz), 3
．． 32 (2H, m), 3.39 (1H, m), 3.
77 (3H, s), 3.79 (3H, s), 5.0
5 (1H, m), 6.78 (2H, d, J = 9.2H
z), 6.83 (2H, d, J=9.0Hz), 6
．． 90 (1H, s), 7.15-7.48 (24H,
m), 7.99 (1H, s), 8.04 (1H, s
).

Example 10 Production of 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylthio)cyclopentan-1-yl]adenine: The compound obtained in Example 9 (0 .415
Dissolve g) in 80% acetic acid water (20 ml) and add 45 to 50
Stir at ℃ for 1 hour. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The obtained residue was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (5:1). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.132 g). Obtained as a powder. SIMS m/z: 280(M+1)IR(KBr
, cm-1): 3270, 3095, 1678,
1602, 1299. NMR (200MHz, DM
SO-d6) δ: 1.98 (1H, m), 2.11
(3H, s), 2.17 (1H, m), 2.39 (2
H, m), 2.62 (1H, dt, J=14.2,7
．． 1,7.1Hz), 3.62 (1H, dd, J=7
．． 8,13.6Hz), 3.55(1H, ddd, J
=5.0,7.0,10.8Hz), 3.71(1H
, dt, J=14.6, 5.0, 5.0Hz), 4.
62 (1H, t, J=5.0Hz), 4.90 (1H
, hex, J=8.2Hz), 7.20(2H,s)
, 8.13 (1H, s), 8.24 (1H, s).

Example 11 N6-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylsulfonyl)cyclopentan-1-yl]adenine: Compound obtained in Example 9 (0.4
6g) in methylene chloride (5ml), m-chloroperbenzoic acid (0.193g) was added to this under ice cooling, and after stirring at the same temperature for 30 minutes, m-chloroperbenzoic acid was dissolved.
(0.193g) was added and stirred for an additional 30 minutes. The reaction solution was washed with a 5% aqueous sodium bisulfite solution, then with a saturated aqueous sodium bicarbonate solution, and then dried (M
gSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and methylene chloride (1:1). Fractions containing the target product were collected and concentrated under reduced pressure. The title compound (0.432 g) was obtained as a powder. IR (KBr, cm-1): 3415, 1600,
1508, 1290, 1248. NMR (200
MHz, CDCl3) δ: 2.20 to 2.99 (5H
, m), 2.83 (3H, s), 3.64 (3H,
m), 3.78 (3H, s), 3.80 (3H, s
), 5.09 (1H, m), 6.79 (2H, d,
J=9.0Hz), 6.84(2H,d,J=9.0
Hz), 6.95 (1H, s), 7.14~7.4
8 (24H, m), 7.99 (1H, s), 8.0
4 (1H, s).

Example 12 Production of 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylsulfonyl)cyclopentan-1-yl]adenine: The compound obtained in Example 11 ( 0
．． 42g) in 80% acetic acid water (8ml),
Stir at 50°C for 3 hours. The solvent was distilled off under reduced pressure, and ethanol (
10 ml) was added thereto and concentrated under reduced pressure again. The obtained powder was washed with a mixture of ethyl ether and methanol (5:1), filtered, and dried to give the title compound (0.13 g).
) was obtained. SIMS m/z: 312(M+1)IR(KBr
, cm-1): 3415, 3320, 3155,
1666, 1597, 1303, 1290,
1270, 1124. NMR (200MHz, DMS
O-d6) δ: 2.15 (1H, dt, J=12.0
, 10.0, 10.0Hz), 2.43 (2H, m)
, 2.66 (2H, m), 3.05 (3H, s),
3.72 (1H, m), 3.87 (1H, dd, J
=8.4, 16.8Hz), 3.96 (1H, m),
4.77 (1H, t, J = 5.2Hz), 4.92 (
1H, m), 7.23 (2H, s), 8.14 (1
H,s), 8.23(1H,s).

Example 13 N2-(p-methoxytrityl)-9-[(1R,3R
,4S)-3-azido-4-(p-methoxytrityloxymethyl)cyclopentan-1-yl]guanine: The compound (0.54 g) obtained in Reference Example 2 was dried with N
, N-dimethylformamide (8 ml) and added sodium azide (0.079 g) to give 75-8
Stir at 0°C for 3 hours. Add ethyl acetate (50m
l), washed with water (20ml x 3) and dried (MgSO4
)did. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, eluted with a mixture of ethyl acetate, methylene chloride, and methanol (15:15:1), and fractions containing the target product were collected and evaporated under reduced pressure. The title compound (0
．． 383 g) was obtained as a powder. IR (KBr, cm
-1): 3340, 2097, 1683, 16
00,1562, 1508, 1243. NMR(2
00MHz, DMSO-d6) δ: 1.67 (2H,
m), 2.22 (3H, m), 3.05 (2H, m)
, 3.67 (3H, s), 3.75 (3H, s),
4.24 (2H, m), 6.83 (2H, d, J=8
．． 8Hz), 6.93 (2H, d, J=8.8Hz)
, 7.09-7.65 (24H, m), 10.52
(1H, s).

Example 14 Production of 9-[(1R,3R,4S)-3-azido-4-(hydroxymethyl)cyclopentan-1-yl]guanine: The compound obtained in Example 13 (0.343 g ) in 80% acetic acid water (8 ml) and incubate at 45-50℃ for 3
I stirred the time. The solvent was distilled off under reduced pressure, and ethanol (
After concentrating again under reduced pressure, ethyl ether (15 ml) was added and the resulting powder was collected by filtration. The obtained powder was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (3:1). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.10
6 g) was obtained as a powder. SIMS m/z: 291(M+1)IR(KBr
, cm-1): 3320, 3115, 2100,
1686. NMR (200MHz, DMSO-d6)
δ: 1.69 (1H, m), 1.95 (1H, dd
d, J=3.6, 6.2, 14.2Hz), 2.27
(2H, m), 2.58 (1H, m), 3.53 (
2H, m), 4.27 (1H, m), 4.72 (1
H, m), 6.39 (2H, s), 7.77 (1H
, s), 10.55 (1H, s).

Example 15 9-[(1R,3S,4S)-3-azido-4-(p-
methoxytrityloxymethyl)cyclopentane-1-
[yl]-N2-(p-methoxytrityl)guanine: The compound obtained in Reference Example 5 (0.44 g) was dried with N2-(p-methoxytrityl)guanine.
, N-dimethylformamide (8 ml), and added sodium azide (0.097 g) to 75-8 ml.
Stir at 0°C for 5 hours. Add ethyl acetate (50m
l), washed with water (20ml x 3) and dried (MgSO4
)did. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, eluted with a mixture of ethyl acetate, methylene chloride, and methanol (10:10:1), and fractions containing the target product were collected and evaporated under reduced pressure. The title compound (0
．． 412 g) was obtained as a powder. IR (KBr, cm-1): 3330, 2098,
1680, 1607, 1573, 1512,
1244. NMR (200MHz, CDCl3) δ: 1.33 (
1H, m), 1.64 (1H, m), 1.87 (2
H, m), 2.03 (1H, m), 2.89 (2H
, m), 3.28 (1H, m), 3.66 (3H,
s), 3.72 (3H, s), 4.33 (1H, m
), 6.70 (2H, d, J=9.0Hz), 6.
94 (2H, d, J=9.0Hz), 7.00-7.
63 (25H, m), 10.52 (1H, s).

Example 16 Production of 9-[(1R,3S,4S)-3-azido-4-(hydroxymethyl)cyclopentan-1-yl]guanine: The compound obtained in Example 15 (0.412 g ) was dissolved in 80% acetic acid water (10 ml) and incubated at 45-50°C for 30 minutes.
I stirred the time. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, the mixture was concentrated again under reduced pressure, ethyl ether (15 ml) was added, and the resulting powder was collected by filtration. The obtained powder was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (6:1). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.095 g) as a powder. obtained as. SIMS m/z: 291(M+1)IR(KBr
, cm-1): 3335, 3220, 2093,
1730, 1628, 1390. NMR (200MHz, DMSO-d6) δ: 1.7
0 (1H, dt, J=12.4, 9.5, 9.5Hz)
, 2.12 (2H, m), 2.32 (3H, m),
4.50 (2H, m), 4.15 (1H, m),
4.73 (1H, m), 4.91 (1H, d, J=5
．． 1Hz), 6.43(2H,s), 7.82(1
H,s), 10.55(1H,s).

Example 17 9-[(1R,3R,4S)-3-azido-4-(p-
methoxytrityloxymethyl)cyclopentane-1-
Production of N6-(p-methoxytrityl)adenine: The compound (0.55 g) obtained in Reference Example 8 was dried with N
, N-dimethylformamide (8 ml) and added sodium azide (0.082 g) to give 75-8
Stir at 0°C for 4 hours. Add ethyl acetate (50m
l), washed with water (20ml x 3) and dried (MgSO4
)did. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of ethyl acetate and hexane (3:2). Fractions containing the target product were collected and concentrated under reduced pressure. , the title compound (0.419 g) was obtained as a powder. IR (KBr, cm-1): 3420, 21
00, 1601, 1510, 1463, 144
2, 1245. NMR (200MHz, CDCl3)
δ: 1.69 (1H, m), 2.05 (1H, dd
, J=4.0, 14.2Hz), 2.37(2H, m
), 2.68 (1H, ddd, J=5.6, 10.2
, 15.6Hz), 3.31 (2H, m), 3.7
7 (3H, s), 3.81 (3H, s), 4.34 (
1H, m), 5.13 (1H, m), 6.79 (2
H, d, J = 9.0Hz), 6.85 (2H, d, J
=8.8Hz), 6.91(1H,s), 7.15
~7.50 (24H, m), 7.96 (1H, s),
8.04 (1H, s).

Example 18 9-[(1R,3R,4S)-3-azido-4-(hydroxymethyl)cyclopentan-1-yl]adenine.
Production of acetate: Compound obtained in Example 17 (0.39
9g) in 80% acetic acid water (10ml),
Stir at 0°C for 2 hours. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The obtained residue was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (3:1). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.118 g). Obtained as a powder. SIMS m/z: 275 (M+1) IR (KBr
, cm-1): 3440, 3360, 3140,
2100, 1679, 1601, 1333,
1260. NMR (200MHz, DMSO-d6) δ: 1.8
4 (1H, m), 2.09 (1H, ddd, J=3.
7, 6.7, 14.5Hz), 2.28 (2H, m)
, 2.50 (3H, s), 2.66 (1H, ddd
, J=6.2, 9.2, 15.4Hz), 3.59
(2H, m), 4.32 (1H, m), 4.73 (
1H, t, J=4.8Hz), 4.95 (1H, m),
7.21 (2H, s), 8.13 (1H, s)
, 8.20 (1H, s).

Example 19 Production of 9-[(1R,3S,4S)-3-amino-4-(hydroxymethyl)cyclopentan-1-yl]guanine: The compound obtained in Example 16 (0.0048 g )
was dissolved in methanol (2 ml), 10% palladium-carbon (0.0024 g) was added thereto, and the mixture was stirred at room temperature in a hydrogen stream for 3 hours. After removing the catalyst by filtration and concentrating the filtrate under reduced pressure, the obtained powder was washed with ethyl ether and dried to obtain the title compound (0.004 g) as a powder. SIMS m/z: 265 (M+1) IR (KBr, cm-1): 3325, 3110,
1688, 1598, 1368. NMR (200
MHz, DMSO-d6) δ: 1.76 (3H, m)
, 2.13 (2H, m), 4.81 (1H, m),
6.42 (2H, s), 7.79 (1H, s).

0
Example 20 9-[(1R,3R,4S)-3-phthalimide-4-
Production of (p-methoxytrityloxymethyl)cyclopentan-1-yl]-N2-(p-methoxytrityl)guanine: Potassium phthalimide (1.5g) and 18-crown-6 (0.5g) in toluene (50ml) ) was added thereto, and the mixture was heated under reflux for 1 hour. After cooling this, the compound obtained in Reference Example 2 (0.5g) was added to it, and 1
The mixture was heated to reflux for 6 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was passed through a silica gel column and mixed with a mixture of methylene chloride and methanol (100:1).
), fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound (0.163 g) as a powder. N
MR (200MHz, DMSO-d6) δ: 1.87
(1H, m), 1.96 (2H, m), 2.27 (
2H, m), 2.82 (1H, t, J=9.8Hz),
3.19 (1H, dd, J=4.0, 9.8Hz),
3.67 (3H, s), 3.74 (3H, s), 4
．． 14 (1H, m), 4.95 (1H, q, J=9.
2Hz), 6.50-7.50 (29H, m), 7
．． 66 (4H, s), 11.02 (1H, br.s)
．．

Example 21 9-[(1R,3R,4S)-3-phthalimide-4-
(Hydroxymethyl)cyclopentan-1-yl]guanine: Compound obtained in Example 20 (0.163
Dissolve g) in 80% acetic acid water (5 ml) and heat at 45-50°C.
I stirred it for 2 hours. The solvent was distilled off under reduced pressure, ethanol (10 ml) was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The resulting residue was passed through a silica gel column and eluted with a mixture of methylene chloride and methanol (10:1). Fractions containing the target product were collected and concentrated under reduced pressure.
The title compound (0.046 g) was obtained as a powder. NMR (200MHz, DMSO-d6) δ: 2.2
2 (1H, d, J = 3.6Hz), 2.25 (1H,
d, J=8.8Hz), 2.48 (1H, m), 2
．． 61 (1H, d, J = 8.8Hz), 2.66 (1
H, d, J = 8.6 Hz), 3.16 to 3.74 (2
H, m), 4.49 (1H, t, J=4.4Hz),
4.70 (1H, t, J=9.2Hz), 4.87
(1H, q, J = 8.8Hz), 6.44 (2H, s
), 7.86 (2H, s), 7.88 (2H, s)
, 7.90 (1H, s), 10.54 (1H, s)
．．

Example 22 Production of 9-[(1R,3R,4S)-3-amino-4-(hydroxymethyl)cyclopentan-1-yl]guanine: The compound obtained in Example 21 (0.04 g ) was dissolved in methanol (10 ml), hydrazine hydrate (0.15 g) was added thereto, and the mixture was heated under reflux for 2 hours. After the solvent was distilled off under reduced pressure, the obtained residue was passed through a column of Amberlite
21 g) was obtained as a powder. SIMS m/z: 265 (M+1) NMR (20
0MHz, DMSO-d6) δ: 1.17 (1H, m
), 1.68 (1H, m), 2.05 (2H, m)
, 2.50 (1H, m), 4.63 (1H, m),
6.67 (2H, s), 7.87 (1H, s).

0
Example 23 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylsulfinyl)cyclopentan-1-yl]guanine: Compound obtained in Example 1 (0.
7g) in methylene chloride (30ml), and add -
m-chloroperbenzoic acid (0.126 g
) and stirred at the same temperature for 30 minutes. 5% reaction solution
It was washed with an aqueous sodium bisulfite solution and then with a saturated aqueous sodium bicarbonate solution, and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, eluted with a mixture of ethyl acetate, methylene chloride, and methanol (10:10:1), and fractions containing the target product were collected and evaporated under reduced pressure. By concentrating, the powdered title compound is converted into a mixture of two stereoisomers derived from the chirality of sulfur (0.
532g). IR (KBr, cm-1): 3340, 1685,
1600, 1560, 1505, 1250,
1026. NMR (200MHz, CDCl3) δ: 1.13,
1.49 (total 1H, each m), 1.66-2.
70 (4H, m), 2.29 (3H, s), 2.9
6 (1H, m), 3.47 (2H, m), 3.68
(3H, s), 3.75, 3.79 (total 3H, each s), 3.87, 4.07 (total 1H, each
m), 6.70, 6.73 (total 2H, each d,
J=8.8Hz), 6.82, 6.86 (total 2H,
d, J=8.8Hz), 6.90~7.60(
26H, m), 11.14, 11.38 (total 1H,
Each br. s).

Example 24 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylsulfinyl)cyclopentane-1-
Production of guanine: Compound obtained in Example 23 (
0.10g) in 80% acetic acid water (5ml),
Stir at ~50°C for 3 hours. The solvent was distilled off under reduced pressure,
Ethanol (10 ml) was added to the obtained residue, and the mixture was again distilled off under reduced pressure. The resulting residue was washed with a mixture of ethanol and ethyl ether (1:10) to obtain the powdered title compound as a mixture of two stereoisomers (0.031 g) derived from the chirality of sulfur. Ta. SIMS m/z: 312(M+1)IR(KBr
, cm-1): 3335, 3180, 1685,
1620, 1595. NMR (200MHz, DM
SO-d6) δ: 1.60-2.07 (2H, m),
2.10-2.70 (3H, m), 2.41, 2.5
7 (total 3H, each s), 3.11~3.53 (
Total 1H, each m), 3.71 (1H, m),
3.87 (1H, m), 4.66 (1H, m), 4
．． 79,4.81 (total 1H, each t, J=4.6
Hz), 6.40 (2H, s), 7.81, 7.8
5 (total 1H, each s), 10.55 (1H
, s).

Example 25 N2-(p-methoxytrityl)-9-[(1R,3S
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylsulfinyl)cyclopentan-1-yl]guanine: Compound obtained in Example 5 (0.
4g) was dissolved in methylene chloride (15ml), and -
m-chloroperbenzoic acid (0.066 g
) and stirred at the same temperature for 30 minutes. 5% reaction solution
It was washed with an aqueous sodium bisulfite solution and then with a saturated aqueous sodium bicarbonate solution, and then dried (MgSO4). The solvent was distilled off under reduced pressure, the resulting residue was passed through a silica gel column, the column was washed with a mixture of ethyl acetate, methylene chloride, and methanol (10:10:1), and then ethyl acetate, methylene chloride, and methanol was added. mixture (3:3:1
) was eluted. Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the powdered title compound as a mixture (0.206 g) of two stereoisomers derived from the chirality of sulfur. IR (KBr, cm-1): 3340, 1688,
1601, 1563, 1506, 1247,
1028. NMR (200MHz, CDCl3) δ: 1.94 (
4H, m), 2.28, 2.35 (total 3H, each s), 2.51 (1H, m), 2.92, 3.1
0 (total 1H, each t, J=8.4Hz), 3.
21 (1H, m), 3.62, 3.65 (total 3H
, each s), 3.75, 3.76 (total 3H, each s), 4.10 (1H, m), 6.59, 6.
65 (total 2H, each d, J = 8.8Hz), 6
．． 82, 6.84 (total 2H, each d, J = 8.8
Hz), 6.96-7.48 (25H, m), 7.7
0 (1H, br.s), 11.34, 11.49 (
Total 1H, each br. s).

Example 2
6 9-[(1R,3S,4R)-4-(hydroxymethyl)-3-(methylsulfinyl)cyclopentane-1-
Production of guanine: Compound obtained in Example 25 (
0.2g) in 80% acetic acid water (10ml),
Stir at ~50°C for 5 hours. The solvent was distilled off under reduced pressure,
The resulting residue was passed through a silica gel column and eluted with a mixture of chloroform, methanol, and water (65:25:4). Fractions containing the target compound were collected and concentrated under reduced pressure to extract the powdered title compound from sulfur. It was obtained as a mixture (0.059 g) of two stereoisomers derived from the chirality of . IR (KBr, cm-1): 3335, 3110,
1690, 1599, 1367, 1015. NMR (200MHz, DMSO-d6) δ: 1.9
0 (1H, m), 2.28 (3H, m), 2.50
(3H, s), 2.57 (1H, m), 3.12 (1
H, m), 3.54 (2H, m), 4.63 (1H
, m), 4.87 (1H, t, J=5.4Hz),
6.47 (2H, s), 7.85, 7.87 (total
1H, s), 10.54 (1H, s).

0
Example 27 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-4-(p-methoxytrityloxymethyl)
Production of -3-(methylsulfinyl)cyclopentan-1-yl]adenine: Compound obtained in Example 9 (0.
472 g) was dissolved in methylene chloride (10 ml), and m-chloroperbenzoic acid (0.10
9 g) was added and stirred at the same temperature for 30 minutes. The reaction solution was washed with a 5% aqueous sodium bisulfite solution, then with a saturated aqueous sodium bicarbonate solution, and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column, eluted with a mixture of ethyl acetate, methylene chloride, and methanol (10:10:1), and fractions containing the target product were collected and evaporated under reduced pressure. By concentrating, one of the two stereoisomers of the title compound derived from the chirality of sulfur (isomer A) (0.326 g) was obtained as a powder. IR (KBr, cm-1): 3405, 1597,
1245, 1027. NMR (200MHz, DM
SO-d6) δ: 1.93 (1H, dt, J=11.
2, 12.8, 12.8 Hz), 2.29 (1H, d
t, J=12.6, 6.4, 6.4Hz), 2.35
(3H, s), 2.73 (3H, m), 3.16 (
1H, dd, J=7.9, 15.3Hz), 3.58
(2H, m), 3.78 (3H, s), 3.81 (
3H, s), 5.10 (1H, m), 6.79 (2
H, d, J = 9.0Hz), 6.85 (2H, d, J
=9.0Hz), 6.93(1H,s), 7.16
~7.59 (24H, m), 8.05 (1H, s),
8.19 (1H, s). Furthermore, after elution with a mixture of ethyl acetate, methylene chloride, and methanol (4:4:1),
Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the other stereoisomer (isomer B) (0.136 g) of the title compound.
was obtained as a powder. IR (KBr, cm-1): 3422, 1603,
1255, 1036. NMR (200MHz, CD
Cl3) δ: 1.92 (1H, dt, J=13.6,
9.8, 9.8Hz), 2.18 (1H, q, J=1
1.2Hz), 2.51(3H,s), 2.57(
2H, m), 3.26 (1H, dd, J=9.0,1
6.4Hz), 3.71 (1H, dd, J=6.2,
16.4Hz), 3.78 (6H, s), 4.87
(1H, m), 6.79 (2H, d, J=9.0Hz
), 6.84 (2H, d, J=8.8Hz), 6.
92 (1H, s), 7.16-7.52 (24H, m
), 7.70 (1H, s), 8.02 (1H, s)
．．

Example 28 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylsulfinyl)cyclopentane-1-
Production of adenine: Isomer A (0.316 g) of the compound obtained in Example 27 was added to 80% acetic acid water (10 ml).
and stirred at 50-55°C for 2 hours. The solvent was distilled off under reduced pressure, and ethanol (10 ml) was added to the resulting residue.
) and concentrated again under reduced pressure. The obtained residue was passed through a silica gel column and eluted with a mixture of methylene chloride, methanol and water (100:50:4). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.088 g).
) was obtained as a powder. IR (KBr, cm-1): 3320, 3125,
1672, 1596, 1300, 1007. NMR (200MHz, DMSO-d6) δ: 1.8
4 (1H, dt, J=11.2, 11.7, 11.7H
z), 2.30 (1H, dt, J=12.2, 7.0
,7.0Hz), 2.43(3H,s), 2.61
(3H, s), 3.26 (1H, dd, J=7.9,
15.3Hz), 3.71 (1H, m), 3.87
(1H, m), 4.83 (1H, t, J=4.7Hz
), 4.98 (1H, m), 7.22 (2H, s)
, 8.15 (1H, s), 8.29 (1H, s).

Example 29 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(methylsulfinyl)cyclopentane-1-
Production of yl]adenine: Isomer B (0.133 g) of the compound obtained in Example 27 was dissolved in 80% aqueous acetic acid (6 ml) and stirred at 50-55°C for 2 hours. The solvent was distilled off under reduced pressure, and ethanol (10 ml) was added to the resulting residue.
was added and concentrated again under reduced pressure. The resulting residue was passed through a silica gel column and eluted with a mixture of methylene chloride, methanol, and water (100:50:4). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.038 g). )
was obtained as a powder. IR (KBr, cm-1): 3330, 3195,
1663, 1596, 1257, 1037. NMR (200MHz, DMSO-d6) δ: 2.0
0(1H, dt, J=11.4, 11.0, 11.0H
z), 2.14 (1H, dt, J=11.6, 10.
6, 10.6Hz), 2.41 (2H, m), 2.
57 (3H, s), 2.63 (1H, m), 3.4
5 (1H, dd, J=9.2, 16.8Hz), 3.
72 (1H, m), 3.92 (1H, m), 4.8
5 (2H, m), 7.21 (2H, s), 8.13
(1H, s), 8.23 (1H, s).

[0075]
Example 30 N2-(p-methoxytrityl)-9-[(1R,3R
,4R)-3-(benzylthio)-4-(p-methoxytrityloxymethyl)cyclopentan-1-yl]guanine: Compound obtained in Reference Example 2 (0.443
g) in dry N,N-dimethylformamide (10 ml)
benzyl mercaptan (0
．． 496g) and 5N sodium hydroxide solution (1ml), stirred at 40-50℃ for 1 hour, and then stirred for 7 hours.
The mixture was stirred at 5 to 80°C for 3 hours. Add ethyl acetate (
100 ml) was added, and the ethyl acetate solution was washed with water (40 ml).
x3) and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain the title compound as a powder. This was used in Example 31 without purification.

Example 31 9-[(1R,3R,4R)-3-(benzylthio)-
4-(hydroxymethyl)cyclopentan-1-yl]
Production of guanine: Dissolve the entire amount of the compound obtained in Example 30 in 80% acetic acid water (10 ml), and
Stir for 0 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column and eluted with a mixture of chloroform and methanol (10:1). Fractions containing the target product were collected and concentrated under reduced pressure to obtain the title compound. (0.154 g) was obtained as a powder. NMR (200MHz, DMSO-d6) δ: 1.7
5-1.90 (1H, m), 2.03 (1H, m),
2.30 (2H, m), 3.24 (1H, m),
3.56 (1H, m), 3.64 (1H, m), 3
．． 81 (2H, d, J = 3.2Hz), 4.63 (1
H, t, J=5.0Hz), 4.63 (1H, m),
6.39 (2H, s), 7.24~7.34 (5H
, m), 7.80 (1H, s), 10.54 (
1H,s).

Example 32 Production of 9-[(1R,3R,4R)-4-(hydroxymethyl)-3-(mercapto)cyclopentan-1-yl]guanine: The compound obtained in Example 31 (0 .12
4g) in liquid ammonia (10ml), -70
Metallic sodium (0.05 g) was added at °C and stirred until the blue color faded. Ammonium chloride (0.
After adding 2 g) and stirring for 15 minutes, the cooling bath was removed and the ammonia was distilled off while being left at room temperature. The obtained residue was passed through a column of Amberlite XAD-2 and eluted with 10% ethanol. Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the title compound (0.044 g) as a powder. NMR (200MHz, DMSO-d6) δ: 1.9
1 (2H, m), 2.21 (2H, m), 2.65
(1H, d, J=7.2Hz), 2.68 (1H, m
), 3.55 (3H, m), 4.62 (1H, t,
J=5.0Hz), 4.65 (1H, m), 6.3
9 (2H, s), 7.80 (1H, s), 10.5
4 (1H, s).

Example 33 [(1R,2R,4R)-2-(hydroxymethyl)-
Production of ammonium salt of 4-(guanine-9-yl)cyclopentan-1-yl]sulfonic acid: The compound obtained in Example 32 (0.026 g) was suspended in water (1 ml), and the mixture was cooled with ice. 1N sodium hydroxide solution (0.2ml)
and 30% (w/w) hydrogen peroxide (0.2 ml) were added, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. Acetic acid was added to the reaction solution to adjust the pH to 5.0, and then it was added to a column of activated carbon (1 g). After washing the column with water, mix water, ethanol, and concentrated ammonia water (48:50:2).
The fractions containing the target product were collected and concentrated under reduced pressure. The obtained residue was passed through a column of Amberlite XAD-2, eluted with water, and fractions containing the target product were collected and concentrated under reduced pressure.
The title compound (0.016 g) was obtained as a powder. SIMS m/z: 369 (M+NH4+)NMR
(200MHz, D2O) δ: 1.90 to 2.73 (
4H, m), 2.88 (1H, m), 3.89 (1
H, dd, J=7.8, 11.0Hz), 4.13
(1H, m), 8.02 (1H, s).

0079
] Example 34 9-[(1R,3S,4R)-3-(benzylthio)-
4-(hydroxymethyl)cyclopentan-1-yl]
Production of guanine: Compound obtained in Reference Example 5 (610m
g) was dissolved in N,N-dimethylformamide (20 ml), and benzyl mercaptan (992 mg), sodium hydroxide (400 mg) and water (2 ml) were added.
Stirred at 0°C for 2 hours. The reaction solution was neutralized with acetic acid and then concentrated under reduced pressure. The residue was mixed with chloroform (15 ml) and water (15 ml).
ml), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml).
), added 4N hydrochloric acid (5 ml), stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in silica gel (15 g).
column chromatography using chloroform-methanol (
9:1). The eluted fractions were concentrated to dryness under reduced pressure to obtain the title compound (70 mg) as a colorless powder. NMR (200MHz, DMSO-d6) δ: 1.72
6 (1H, m), 1.973 (1H, m), 2.1
32 (1H, m), 2.298 (2H, m), 3.
443 (3H, m), 3.802 (2H, s), 4
．． 772 (2H, m), 6.492 (2H, broad s), 7.303 (5H, m), 7.800 (1H
, s), 10.596 (1H, Broad s).

00
80 Example 35 Production of 9-[(1R,3S,4R)-4-(hydroxymethyl)-3-(mercapto)cyclopentan-1-yl]guanine: 9-[(1R,3S,4R)- 3-(Benzylthio)-4-(hydroxymethyl)cyclopentan-1-yl]guanine (70 mg) was dissolved in liquid ammonia (3 ml), sodium metal (40 mg) was added, and the mixture was stirred for 1 hour under cooling at -65°C. After that, ammonium chloride (250 mg) was added. The cooling bath was removed, and the reaction solution was allowed to stand at room temperature to distill off ammonia. The residue was subjected to column chromatography using Amberlite XAD-II (25 ml) and eluted with 10% ethanol water. The eluted fractions were concentrated to dryness under reduced pressure to obtain the title compound (15 mg) as a colorless powder. NMR (200MHz, DMSO-d6) δ: 1.93
7 (1H, m), 2.089 (1H, m), 2.3
71 (2H, m), 2.735 (1H, d, J=6.
6Hz), 3.524 (3H, m), 4.745 (
1H, t, J=5.4Hz), 4.846(1H, t
, J=8.2Hz), 6.410(2H, broad s
), 7.811 (1H, s), 10.543 (1H
, Broad s).

Test Example Vero cells were incubated at 100 T.
The cells were infected with virus at CID50 (the amount of virus that infects 50% of tissue culture cells) and cultured in the presence of various concentrations of antiviral agents. Antiviral activity (ID50: 50% inhibitory dose) was assessed 3 days after infection. Control cells to which no antiviral agent was administered at this time had 100% tissue infection. Cytotoxicity was determined simultaneously using control cells that were not infected with the virus. When the antiviral effect against human herpes simplex virus (HSV-1) was investigated using the compound of Example 4 by the above method, the ID50 was 12.5.
The cytotoxicity was 400 μg/ml or more. Furthermore, when the antiviral effect of the compound of Example 8 against HSV-1 was investigated, the ID50 was 50 μg/m
1, and the cytotoxicity was 100 μg/ml or more.

[0082]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits a strong antiviral effect against human herpesvirus (HSV) and has low toxicity, so it can be used as an antiviral agent.

Claims (2)

[Claims] Claim 1: General formula [Formula 1] [wherein B is a purine base residue having a bond at the 9-position,
A compound or a salt thereof, wherein one of R1 and R2 is H and the other is a monovalent group via sulfur or nitrogen, and R3 is a hydroxyl group which may be phosphoric acid esterified or protected. [Claim 2] General formula [Formula 2] [wherein B is a purine base residue having a bond at the 9-position,
One of R4 and R5 is an activated hydroxyl group, the other is H, and R6 is a protected hydroxyl group] is reacted with a thiol salt or an azidating agent, and if necessary, [In the formula, B represents a purine base residue having a bond at the 9-position,
A method for producing a compound represented by the following formula: R7 and R8 are either H and the other is a monovalent group via sulfur, an azide group or an amino group, and R3' is an optionally protected hydroxyl group.