JPH09316076A - 9-substituted purine derivative and its application as antiviral agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 9-substituted purine derivative, having antiviral activity and extremely useful for the treatment or prophylaxis of infectious diseases caused by viruses. SOLUTION: This compound is a purine derivative of formula I (A is methylene or S atom; R<1> is H or amino; R<2> is H or amino; R<3> is an arylsulfonyl; herein, in the case where A is methylene, R<3> is an arylsulfonyl other than p- toluenesulfonyl) or its salt, and e.g. (S)-2,6-diamino-9-(N-benzenesulfonyl-2- pyrrolidinylmethyl)purine is cited as an example of the compound. In order to obtain a compound of formula I in which A is methylene, e.g. the carboxyl group of a proline of formula II is reduced by a reducing agent into 2hydroxymethylpyrrolidine (prolinol) of formula III, the imino group and the primary alcoholic hydroxyl group of the reduced compound are protected with arylsulfonyl groups, and subsequently the resultant compound is coupled to a purine base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a skeleton in which a purine base of a nucleic acid is coupled with a prolinol derivative or a thioprolinol derivative derived from amino acids proline or thioproline, and has an arylsulfonyl group. The present invention relates to a 9-substituted purine derivative characterized by having it in its molecule and its use as an antiviral agent.

[0002]

2. Description of the Related Art Currently, anti-human immunodeficiency virus (HI
V) Azidothymidine, 2 ', 3'-dideoxycytidine, 2', 3 ', which is a nucleic acid compound, as a therapeutic or prophylactic agent for acquired immunodeficiency syndrome (AIDS) having an effect
-Dideoxyinosine is approved. It is considered that these nucleic acid derivatives act at a stage called reverse transcription in the life cycle of HIV and exert an anti-HIV effect. Although these drugs show strong antiviral activity, they have strong side effects and it is difficult for some patients to continue the drug administration. Further, resistant strains have been found in patients who have been administered for a long period of time, and it is becoming very difficult clinically to continue to administer the drug to patients while maintaining the effect of the drug. In addition, non-natural nucleic acid derivatives such as 3′-thio-2 ′, 3′-dideoxycytidine and some protease inhibitors are azidothymidine and 2 ′,
Since the effect can be expected by the combined use with 3′-dideoxyinosine and the like, its use is being approved under the condition of the combined use. However, it is still limited as a single use in terms of effect manifestation, etc., and there are still problems in the future. Among the problems in the development of anti-HIV agents described above, a more realistic and important problem is the easy and frequent acquisition of resistance of HIV. That is, AIDS over many years
From the research on viruses, no matter what kind of drug is given, a strain resistant to the drug will always emerge, and among the resistant strains, a strain still having infectivity and AIDS virulence. I've found out that there is.

[0003] Therefore, for the treatment of AIDS, it is required to maintain a system in which another drug is given as soon as resistance appears in a clinical trial, and therefore many new drug approvals and developments are awaited. Also, according to a recent study, in combination of multiple drugs, HI is used by HIV to acquire drug resistance.
There are also reports that mutations on the V gene can be blocked and the emergence of drug-resistant strains can be suppressed, and it is expected that the development of new drugs for multi-drug combination therapy will be increasingly expected in the future.

[0004] Conventionally, as a method for grasping the state of patients in the ARC stage and AIDS patients, immune system parameters such as the amount of viral protein p24 and the CD4 / CD8 ratio have been often used in addition to clinical findings such as weight loss. It was Therefore, although these parameters have been used at present when the drug is administered and the effect thereof is observed, there is a drawback that the reaction is slow to see the effect.

However, it has become possible to directly measure the amount of virus particles (and provirus) in real time by measuring the virus-DNA or RNA in the patient's body by the recently developed PCR method. Therefore,
It has become easier and more reliable to know the guideline for “when the first drug loses its effect, administer the second drug”, which has been thought to be difficult in the past. It is becoming more and more practical to give the next medicine. That is, the decrease in the effect of the drug was measured by the measure of increase in the virus in the body, and it became possible to administer a new drug at that time. For this reason, the demand for new drugs is increasing more than ever before. From the above background, development of a novel drug having high anti-HIV activity and low toxicity is very much desired. A new form of anti-HIV
It is important for the treatment and prevention of AIDS to synthesize and provide a drug or a substance that can be a lead compound of an anti-HIV drug.

[0006]

The present inventors have synthesized a compound having a basic skeleton of a structure composed of a nucleic acid base and an amino acid derivative, and have studied various physiological activities thereof. As a result, 2,6-diamino-9- (N-
An anti-HIV activity was found in a compound called p-toluenesulfonyl-2-pyrrolidinylmethyl) purine (DASP), and a patent application has already been filed (Japanese Patent Application No. 7-294911).
However, at that time it was unclear which skeleton or functional group of this DASP compound contributed to the activity. After that, the effects of the substituents on the purine base, the skeleton of the purine base, and the sulfonamide moiety were detailed. We have investigated and investigated the correlation between its structure and activity. In these studies, the present inventors have been excellent in a compound having a series of arylsulfonyl groups represented by a benzenesulfonyl group, in which a hydrogen atom or an amino group is bonded to the 2- and 6-positions of a purine base. The present invention has been achieved by finding that it has an antiviral effect.

That is, the first object of the present invention is to provide a novel purine derivative having an antiviral effect. A second object of the present invention is to provide an antiviral agent containing the purine derivative as an active ingredient.

[0008]

The present invention includes the following inventions. (1) The following formula (I):

[0009]

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(In the formula, A represents a methylene group or a sulfur atom, R ¹ represents a hydrogen atom or an amino group, R ² represents a hydrogen atom or an amino group, and R ³ represents an arylsulfonyl group. When A represents a methylene group, R ³ is p-
It represents an arylsulfonyl group other than a toluenesulfonyl group. ] The purine derivative shown by these, or its salt.

(2) The compound according to (1) above, wherein in the formula (I), A represents a methylene group. (3) The compound according to (1) above, wherein in the formula (I), A represents a sulfur atom. (4) An antiviral agent containing the compound according to any one of (1) to (3) as an active ingredient. (5) The antiviral agent according to (4) above, which is a drug for treating or preventing acquired immunodeficiency syndrome.

In the present specification, the arylsulfonyl group includes an unsubstituted arylsulfonyl group such as a benzenesulfonyl group, a naphthalenesulfonyl group and an indolylsulfonyl group, and these arylsulfonyl groups are alkyl groups having 1 to 5 carbon atoms. , An alkoxy group having 1 to 5 carbon atoms,
Examples thereof include a substituted arylsulfonyl group substituted with one or more substituents such as an amino group, an N-substituted amino group, a hydroxyl group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group and a halogen atom.

Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group,
Examples thereof include a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a pentyl group. As a halogen atom,
Examples thereof include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The purine derivative of the present invention represented by the above formula (I) includes an N-arylsulfonyl-2-pyrrolidinylmethyl derivative in which A is a methylene group in the above formula (I) and A in the above formula (I). N is a sulfur atom
-Arylsulfonyl-4-thia-2-pyrrolidinylmethyl derivative.

Examples of the N-arylsulfonyl-2-pyrrolidinylmethyl derivative include the following compounds. 2,6-Diamino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-ethylbenzenesulfonyl)
2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-isopropylbenzenesulfonyl)
-2-Pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-n-propylbenzenesulfonyl)
-2-Pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-tert-amylbenzenesulfonyl)
-2-Pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-methoxybenzenesulfonyl) -2
-Pyrrolidinylmethyl) purine, 2,6-diamino-9
-(N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9-
(N- (4-chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N-
(4-Bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (2,
5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-
Iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-tert
-Butylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino -9- (N- (4
-Trifluoromethoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9-
(N- (3-methylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N-
(2-Bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-
Nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine.

Specific preferred examples of the N-arylsulfonyl-2-pyrrolidinylmethyl derivative include the following compounds. (S) -2,6-Diamino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N-
(4-Ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N
-(4-Isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-
9- (N- (4-n-propylbenzenesulfonyl)-
2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4-tert-amylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S)-
2,6-diamino-9- (N- (4-methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine,
(S) -2,6-Diamino-9- (N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4- Chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4-bromobenzenesulfonyl) -2-pyrrolidinylmethyl)
Purine, (S) -2,6-diamino-9- (N- (2,
5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N
-(4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9-
(N- (4-tert-butylbenzenesulfonyl) -2-
Pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S)-
2,6-diamino-9- (N- (4-trifluoromethoxybenzenesulfonyl) -2-pyrrolidinylmethyl)
Purine, (S) -2,6-diamino-9- (N- (3-
Methylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N-
(2-Bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N
-(4-Nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine.

The above N-arylsulfonyl-4-thia-
Examples of the 2-pyrrolidinylmethyl derivative include the following compounds.

2,6-Diamino-9- (N-benzenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (Np-toluenesulfonyl-4-thia- 2-pyrrolidinylmethyl) purine,
2,6-Diamino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-tert.
-Butylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N-
(4-Methoxybenzenesulfonyl) -4-thia-2-
Pyrrolidinylmethyl) purine, 2-amino-9- (N-
p-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, 2-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 2- Amino-9- (N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 6-amino-9- (Np-toluenesulfonyl) -4-thia-2-pyrroli Dinylmethyl) purine, 6-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine.

The N-arylsulfonyl-4-thia-
Specific preferred examples of the 2-pyrrolidinylmethyl derivative include the following compounds. (S) -2,6
-Diamino-9- (N-benzenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6-
Diamino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6
-Diamino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4-tert.
-Butylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9
-(N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2-amino-9- (Np-toluenesulfonyl-4-thia-
2-pyrrolidinylmethyl) purine, (S) -2-amino-9- (N- (4-isopropylbenzenesulfonyl))
-4-Thia-2-pyrrolidinylmethyl) purine, (S)
-2-Amino-9- (N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -6-amino-9- (Np-toluenesulfonyl)- 4-thia-2-pyrrolidinylmethyl) purine, (S) -6-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine.

The salts of the purine derivative represented by the above formula (I) include, for example, hydrochlorides, sulfates, nitrates, carbonates, sodium salts, potassium salts, calcium salts, barium salts and hydrates thereof. Included are pharmaceutically acceptable salts. The purine derivatives represented by the above formula (I) and salts thereof exhibit antiviral activity at relatively low concentrations, and
It is extremely effective in treating or preventing various viral infections such as S. When the arylsulfonyl group represented by R ³ in the above formula (I) is a substituted or unsubstituted benzenesulfonyl group, those substituted at the 4-position are excellent in antiviral activity.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION Among the purine derivatives of the present invention, the N-arylsulfonyl-2-pyrrolidinylmethyl derivative in which A in the formula (I) is a methylene group can be prepared, for example, by the following three reaction steps. Can be manufactured by. The first step is proline as a raw material compound (hereinafter, the case of using an optically active substance L-proline or D-proline will be described) (formula (1)).
Is a step of reducing the carboxyl group of 2 to 2-hydroxymethylpyrrolidine (prolinol) represented by the formula (2).

[0021]

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[0022]

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(In the formula, * represents an asymmetric carbon.) The reducing agent in this step can be appropriately selected from known ones, but particularly lithium aluminum hydride (LiAlH ₄ ) is used. Is preferred. The amount of lithium aluminum hydride used is 1 mol of proline
It is preferably 1.5 to 2.0 mol. The reaction solvent is
The solvent is not particularly limited as long as it is a solvent suitable for the reduction reaction, but dehydrated tetrahydrofuran (hereinafter referred to as “THF”) is particularly preferably used. Further, the reduction reaction in this step is preferably carried out by heating under reflux in a nitrogen atmosphere for 1 hour, and 2-hydroxymethylpyrrolidine (2) obtained from the reduction reaction is used as a raw material for the next step without particular purification. It can be used in the reaction.

The second step is a step of protecting the imino group and primary alcoholic hydroxyl group of 2-hydroxymethylpyrrolidine (2) with an arylsulfonyl group to obtain a compound represented by the formula (3).

[0025]

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(In the formula, R ³ and * have the same meanings as described above.) The arylsulfonylation reaction carried out here may be carried out according to a conventional method, for example, in a dehydrated pyridine solvent at 0 ° C. under a nitrogen atmosphere, 2- The imino group and primary alcoholic hydroxyl group of hydroxymethylpyrrolidine (2) are arylsulfonylated with arylsulfonyl chloride or the like, and the resulting product is isolated by silica gel column chromatography or the like to give N represented by the formula (3). , O-bis (arylsulfonyl) prolinol can be obtained. The amount of the arylsulfonylating agent such as arylsulfonyl chloride used is preferably 3.0 to 4.0 mol per 1 mol of 2-hydroxymethylpyrrolidine (2). The third step is a step of coupling N, O-bis (arylsulfonyl) prolinol (3) with a purine base to obtain a compound represented by the formula (Ia).

[0027]

[Chemical 6]

(In the formula, R ¹ , R ² , R ³ and * have the same meanings as described above.) The coupling reaction carried out here may be carried out according to a conventional method. For example, dehydrated N, N-dimethylformamide (hereinafter "DMF") In a solvent, under nitrogen atmosphere, purine base and about equimolar amount of crown ether such as 18-crown-6 and about 2 times mole of base such as potassium carbonate are added, and the temperature is kept at room temperature for 30 minutes to 2 hours. After stirring at 70 ° C., a dehydrated DMF solution of N, O-bis (arylsulfonyl) prolinol (3) was added dropwise, and the obtained mixed solution was stirred at 70 to 80 ° C. for 1 to 3 hours to obtain the compound (Ia). Can be obtained.

Among the purine derivatives of the present invention, the N-arylsulfonyl-4-thia-2-pyrrolidinylmethyl derivative in which A is a sulfur atom in the above formula (I) is
For example, it can be produced by the following five reaction steps. In the first step, thioproline which is a raw material compound (hereinafter, the case where L-thioproline or D-thioproline which is an optically active substance is used is described.) (Formula (4)) is methyl-esterified to form a carboxyl group. , A step of obtaining a compound represented by the formula (5).

[0030]

[Chemical 7]

[0031]

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(In the formula, * has the same meaning as above.) The methyl esterification method in this step is a method of methylating with methanol under an acidic catalyst such as sulfuric acid, or using a methyl ester such as dimethyl succinate. A method of transesterification, a method of using Magic Methyl, etc. can be considered, but diazomethane is preferable as a reagent that can be used under milder conditions.

When thioproline (4) was added as a powder to a diethyl ether solution containing an appropriate amount of diazomethane, the reaction gradually proceeded, and the methyl esterified compound (5) was eluted in ether. If stirring is continued for a while, thioproline (4) is completely consumed, the reaction solution becomes uniform, and the reaction is completed. At this time, the amount of diazomethane used for methyl esterification is preferably 2.0 to 3.0 mol per 1 mol of thioproline (4). The ether solution of thioproline methyl ester (5) thus obtained is evaporated at room temperature to obtain a yellow oily compound (5).

The second step is a step of protecting the imino group of thioproline methyl ester (5) with various arylsulfonyl groups. Arylsulfonylation of thioproline methyl ester (5) is carried out by dissolving thioproline methyl ester (5) in dehydrated pyridine at 0 ° C. with an arylsulfonylating agent (eg p-toluenesulfonyl chloride).
Of pyridine solution is slowly added dropwise. At this time, the amount of the arylsulfonylating agent is preferably 1.0 to 2.0 mol per 1 mol of thioproline methyl ester (5). After completion of the reaction, the mixture was blown into ice water, the target product was extracted with an organic solvent such as chloroform and ethyl acetate, and pyridine was extracted and removed with 1N-HCl.
The solvent can be distilled off to obtain the arylsulfoamide represented by the formula (6).

[0035]

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(In the formula, R ³ and * have the same meanings as described above.) The third step is a step of obtaining the N-arylsulfonylimino alcohol represented by the formula (7).

[0037]

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(In the formula, R ³ and * have the same meanings as described above.) The arylsulfoamide (6) is dissolved in a suitable anhydrous organic solvent (eg, THF or diethyl ether), and then methoxy is added with a suitable reducing agent. The carbonyl group is reduced to give alcohol (7). At this time, the reducing agent is selected from known ones, and for example, sodium borohydride (NaBH ₄ ), lithium aluminum hydride (LiAlH ₄ ) and alkyl modified products thereof (for example, diisobutylaluminum hydride etc.) can be used.

The reduction reaction of this third step is the most important of all steps and must be carried out carefully. The temperature of the reaction solution should be kept low during the reduction reaction. It is usually room temperature or lower, but it is preferable to keep it at 0 ° C. or lower in preparation for sudden heat generation. The temperature range for favorably proceeding the reaction is -2
It is preferable to keep the temperature between 0 ° C. and 0 ° C., but if necessary, the temperature is set to a temperature lower than that so that the inside of the flask does not freeze. If the inside of the flask rises abnormally, not only the methoxycarbonyl group but also the sulfide portion may be damaged, and the target product may not be obtained.

As the reducing agent in this step, it is particularly preferable to use lithium aluminum hydride. The amount of lithium aluminum hydride used is preferably 1.0 to 1.5 mol per 1 mol of the compound (6). The reaction solvent is not particularly limited as long as it is a solvent suitable for the reduction reaction, but dehydrated THF is particularly preferably used. Further, the reduction reaction in this step is performed in a nitrogen atmosphere. Further, the reaction is runaway due to the sudden heat generation in the flask due to the heat of reaction, and the reaction is appropriately cooled to prevent the occurrence of side reactions. Preferably, the reaction is performed by cooling to 0 ° C or lower. The product (7) obtained from the reduction reaction can be used in the reaction as a raw material for the next step without particular purification. The fourth step is a step of protecting the primary alcoholic hydroxyl group of compound (7) with an arylsulfonyl group to obtain a compound represented by formula (8).

[0041]

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[0042] (wherein, R 3 ^'represents an arylsulfonyl group, R ³ and * are as defined above.) Arylsulfonyl reaction carried out here may according to a conventional method, for example, dehydrated pyridine solvent At 0 ° C. under a nitrogen atmosphere, the primary alcoholic hydroxyl group of compound (7) is arylsulfonylated with arylsulfonyl chloride or the like, and the obtained product is isolated by silica gel column chromatography, preparative thin layer chromatography or the like. Thus, the compound represented by the formula (8) can be obtained. The amount of the arylsulfonylating agent such as arylsulfonyl chloride used is preferably 1.1 to 4.0 mol per 1 mol of the compound (7). The fifth step is a step of coupling the compound (8) with a purine base to obtain a compound represented by the formula (Ib).

[0043]

[Chemical 12]

(In the formula, R ¹ , R ² , R ³ and * have the same meanings as described above.) The coupling reaction performed here may be carried out according to a conventional method, for example, in a dehydrated DMF solvent under a nitrogen atmosphere. , Purine base and about equimolar 18-crown-6 and about twice as much base as potassium carbonate were added, and the mixture was stirred at room temperature for 30 minutes to 2 hours.
A dehydrated DMF solution of the compound (8) was added dropwise, and the obtained mixed solution was stirred at 70 to 80 ° C. for 1 to 2 hours to obtain the compound (I).
b) can be obtained.

Compound (Ia) obtained as described above
The compounds (Ib) and (Ib) can be separated and purified by appropriately combining the usual methods used for the isolation and purification of nucleosides. The method of separation and purification performed here is to obtain the free form (form not containing salt) by distilling off the solvent, followed by crystallization from a suitable solvent such as ethanol, or lyophilization. Can be obtained in the form of an acceptable salt, or can be purified by ion exchange column chromatography using an ion exchange resin or the like, adsorption column chromatography using activated carbon or the like, preparative thin layer chromatography or the like. .

The purine derivative (I) of the present invention can be prepared by a conventional method from hydrochloride, sulfate, nitrate, carbonate, sodium salt,
It can be converted into pharmaceutically acceptable salts such as potassium salt, calcium salt, barium salt and hydrates thereof.

The antiviral agent of the present invention can be formulated by combining the purine derivative (I) of the present invention or a pharmaceutically acceptable salt thereof with a known pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral agents such as tablets, capsules, granules, fine granules and powders, parenteral agents such as injections and suppositories. To be

The dose of the compound represented by the above formula (I) or a salt thereof, which is the active ingredient, depends on the patient's age, body weight,
Depending on the severity of the disease, oral administration usually 1 daily
-30 mg / kg body weight, and usually 0.2-10 mg / kg body weight daily by intravenous, intramuscular or subcutaneous administration. The number of administrations is usually 1 to 3 times a day for oral administration and 1 to 2 times a day for injections.

Oral preparations include, for example, starch, lactose, sucrose,
Manufactured according to a conventional method using mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like. In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavor, and the like can be used as appropriate in addition to the excipients.

Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxy. Propyl methyl cellulose phthalate 200731, hydroxypropyl methyl cellulose phthalate 220820, hydroxypropyl methyl cellulose acetate succinate, carmellose sodium, ethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, wheat starch, rice starch, corn starch, potato starch, dexme Phosphorus, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, aminoalkylmethacrylate copolymer E, aminoalkylmethacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S , Methacrylic acid copolymer LD, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar,
Gelatin, white shellac, tragacanth, refined white sugar, Macrogol 200, Macrogol 300, Macrogol 6
000 is included.

Specific examples of the disintegrant include crystalline cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, Partially pregelatinized starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth are mentioned.

Specific examples of the surfactant include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 100, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, poly. Oxyethylene hydrogenated castor oil 6
0, polyoxyethylene [42] polyoxypropylene [67] glycol, polyoxyethylene [54] polyoxypropylene [39] glycol, polyoxyethylene [105] polyoxypropylene [5] glycol, polyoxyethylene [160] Polyoxypropylene [80] glycol, polyoxyethylene [196]
Polyoxypropylene [67] glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate,
Examples include sorbitan monolaurate, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, glyceryl monostearate, sodium lauryl sulfate, and lauromacrogol.

Specific examples of the lubricant include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, and dried aluminum hydroxide gel. , Talc, magnesium aluminometasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.

Specific examples of the fluidity promoter are hydrous silicon dioxide, light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate and magnesium silicate. The antiviral agent of the present invention can also be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain a flavoring agent and a coloring agent.

On the other hand, parenteral preparations are manufactured according to a conventional method,
Generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. Further, if necessary, a bactericide, a preservative and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and a liquid preparation can be prepared from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.

[0056]

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited thereto. Example 1 Production of (S) -2,6-diamino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 1)

[0057]

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1-1) Reduction of L-proline LiAlH ₄ (6.0 g, 156 mmol) was placed in a 500 ml three-necked round bottom flask under a nitrogen atmosphere, and dehydrated THF (water content max.
(0.005%) 250 ml was added and the mixture was heated under reflux in an oil bath for 15 minutes. About L-proline (8.9 g, 100 mmol, Wako Pure Chemical)
After adding 0.2 g each, the mixture was refluxed for 1 hour. After confirming the completion of the reaction by thin layer chromatography (hereinafter referred to as "TLC"), heating was stopped and 2.8 g / 11
A ml of aqueous potassium hydroxide solution was slowly added dropwise. After the dropwise addition was completed, the mixture was refluxed for 25 minutes, and immediately suction-filtered. The obtained filtrate was concentrated under reduced pressure at 30 ° C. and then dried under vacuum.

Yield: 80% ¹ H-NMR (D ₂ 0) δ (ppm): 1.33-1.42 (1H, m, Hc), 1.70-1.76 (2
H, m, Hd), 1.82-1.90 (1H, m, Hc), 2.76-2.88 (2H, m, He), 3.
12-3.19 (1H, m, Hb), 3.47-3.54 (2H, m, Ha), 4.85 (1H, s, Hf) ¹³ C-NMR (D ₂ O) δ (ppm): 25.27 (Cd), 28.19 (Cc), 46.13 (C
e), 59.70 (Cb), 65.28 (Ca)

1-2) Synthesis of N, O-bis (benzenesulfonyl) -L-prolinol L-prolinol (2.3 g, 23 mmol) was added under nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. Benzenesulfonyl chloride (14.0 g, 79 mmol) /
After adding 15 ml dehydrated pyridine solution dropwise, 30 minutes at 0 ℃
Stir underneath. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. Pyridine was removed by extraction with 1N-HCl, concentrated under reduced pressure at 30 ° C,
Silica gel column chromatography (ethyl acetate: n-
It was purified by hexane = 1: 2).

Yield: 58% Rf value: 0.37 (ethyl acetate: n-hexane = 1: 2) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.53-1.67 (2H, m, Hc), 1.78-
1.90 (2H, m, Hd), 3.04-3.09 (1H, m, He), 3.38-3.43 (1H, m, H
e), 3.73-3.79 (1H, m, Hb), 3.99-4.03 (1H, m, Ha), 4.27-
4.30 (1H, m, Ha), 7.51-7.63 (5H, m, Ph- H ), 7.68-7.79 (3H, m,
Ph- H ), 7.94-7.96 (2H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 21.05 (Cc), 28.57 (Cd), 49.38 (C
e), 57.75 (Cb), 71.63 (Ca), 127.52,127.60,128.00,129.2
4,129.42,132.99,133.06,134.01,135.66,136.56 (Ph- C ).

1-3) (S) -2,6-diamino-9-
(N-benzenesulfonyl-2-pyrrolidinylmethyl)
Synthesis of purines 2,6-diaminopurine (129.6 mg, 0.86 mmol), potassium carbonate (204.4 mg, 1.48 mmol), 18-crown-6
(183 mg, 0.69 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. N, O-bis (benzenesulfonyl) -L-prolinol (265.5 m
g, 0.70 mmol) / 2 ml dehydrated DMF solution was added dropwise at room temperature, and then the mixture was stirred at 80 ° C. for 3 hours. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 43% Rf value: 0.70 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -104.2 (C = 0.31, DMSO) ¹ H-NMR (DMSO-d ₆ ). δ (ppm): 1.30-1.37 (2H, m, Hc, d), 1.43-
1.46 (1H, m, Hd), 1.61-1.64 (1H, m, Hc), 3.10-3.14 (1H, m, H
e), 3.26-3.32 (1H, m, He), 3.98-4.00 (1H, m, Hb), 4.01-4.10
(1H, m, Ha), 4.21-4.26 (1H, m, Ha), 5.84 (2H, s, N H ₂ ), 6.72 (2
H, s, N H ₂ ), 7.62-7.74 (4H, m, Ph- H , Purine- H ,), 7.90-7.9
2 (2H, t, Ph- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 23.06 (Cd), 28.22 (Cc), 46.25
(Ca), 49.10 (Ce), 58.58 (Cb), 127.39,129.37,133.14,136.
15 (Ph- C ), 112.84,137.58,151.97,156.02,160.26 (Purine
-C)

Example 2 Preparation of (±) -2,6-diamino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 2)

[0065]

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The same procedure as in Example 1 was repeated except that (±) -proline was used instead of L-proline as a raw material, and (±) -2,6-diamino-9- (N-
Benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 2) was obtained.

Total yield from (±) -proline: 20%

Example 3 Preparation of (S) -2,6-diamino-9- (N- (4-ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 3)

[0069]

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3-1) Synthesis of N, O-bis (4-ethylbenzenesulfonyl) -L-prolinol L-prolinol (2.2 g, 22 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-Ethylbenzenesulfonyl chloride (16.
(6 g, 81 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hr. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. Pyridine 1N-H
After extraction and removal with Cl, the mixture was concentrated under reduced pressure at 30 ° C, and n-hexane was added to the obtained oily substance for crystallization in a freezer. The obtained crude crystal was recrystallized from methanol.

Yield: 27% Rf value: 0.41 (ethyl acetate: n-hexane = 1: 3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.25-1.31 (6H, m, Hg, i), 1.54-
1.67 (2H, m, Hc), 1.80-1.91 (2H, m, Hd), 2.70-2.79 (4H, m, H
f, g), 3.03-3.07 (1H, m, He), 3.37-3.42 (1H, m, He), 3.74-
3.78 (1H, m, Hb), 3.94-3.99 (1H, m, Ha), 4.24-4.28 (1H, m, H
a), 7.33-7.35 (2H, d, Ph- H ), 7.40-7.42 (2H, d, Ph- H ), 7.68-
7.70 (2H, d, Ph- H ), 7.84-7.86 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 25.00 (Cg, i), 23.75 (Cd), 28.52,
28.76,28.90 (Cc, f, h), 49.31 (Ce), 57.67 (Cb), 71.46 (Ca),
127.66,128.10,128.61,128.81,132.76,133.71,149.93,1
51.09 (Ph- C )

3-2) (S) -2,6-diamino-9-
Synthesis of (N- (4-ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (114.7 mg, 0.76 mmol), potassium carbonate (194.8 mg, 1.41 mmol), 18-crown-6
(188.3 mg, 0.71 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. N, O-bis (4-ethylbenzenesulfonyl) -L-prolinol
(311.6 mg, 0.71 mmol) / 2 ml dehydrated DMF solution was added dropwise at room temperature, and then the mixture was stirred at 80 ° C. for 1 hour. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 96% Rf value: 0.71 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁷ = -55.0 (C = 0.20, MeOH) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 1.25-1.29 (4H, m, Hd, g), 1.31-1.4
3 (1H, m, Hd), 1.52-1.62 (1H, m, Hc), 1.79-1.86 (1H, m, Hc),
2.71-2.76 (2H, q, Hf), 3.04-3.09 (1H, m, He), 3.31-3.35 (1
H, m, He), 3.86-3.91 (1H, m, Hb), 4.29-4.42 (2H, m, Ha), 4.88
(2H, s, N H ₂ ), 5.82 (2H, s, N H ₂ ), 7.36-7.38 (2H, d, Ph- H ), 7.7
6-7.80 (3H, m, Ph- H , Purine- H ,) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 14.97 (Cg), 23.75 (Cd), 28.74 (C
f), 29.03 (Cc), 47.14 (Ca), 49.51 (Ce), 59.52 (Cb), 127.7
1,128.65,133.64,149.99 (Ph- C ), 113.83,139.07,152.37,
155.91,159.94 (Purine- C )

Example 4 Preparation of (±) -2,6-diamino-9- (N- (4-ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 4)

[0075]

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Example 3 was repeated except that (±) -proline was used instead of L-proline as a raw material, and (±) -2,6-diamino-9- (N
-(4-Ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 4) was obtained. (±) -Total yield from proline: 21%

(Example 5) (S) -2,6-diamino-9- (N- (4-isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 5)

[0078]

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5-1) Synthesis of N, O-bis (4-isopropylbenzenesulfonyl) -L-prolinol L-prolinol (2.2 g, 22 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-Isopropylbenzenesulfonyl chloride (17.6 g, 80 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hr. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. Pyridine
After extraction and removal with 1N-HCl, the mixture was concentrated under reduced pressure at 30 ° C, and n-hexane was added to the obtained oily substance for crystallization in a freezer. The crude crystal was recrystallized from methanol.

Yield: 51% Rf value: 0.51 (ethyl acetate: n-hexane = 1: 3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.26-1.30 (12H, m, Hg, h, j , k),
1.53-1.68 (2H, m, Hc), 1.78-1.93 (2H, m, Hd), 2.96-3.08
(3H, m, He, f, i), 3.39-3.41 (1H, m, He), 3.75-3.79 (1H, m,
Hb), 3.95-4.00 (1H, m, Ha), 4.25-4.28 (1H, m, Ha), 7.35-7.3
7 (2H, d, Ph- H ), 7.42-7.44 (2H, d, Ph- H ), 7.69-7.71 (2H, d, P
h- H ), 7.84-7.86 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 25.00 (Cg, i), 23.56 (Cg, h, j, k),
23.75 (Cd), 28.52 (Cc), 34.12,34.28 (Cf, i), 49.31 (Ce), 5
7.67 (Cb), 71.46 (Ca), 127.26,127.46,127.71,128.13,13
2.83,133.82,154.49,155.64 (Ph- C )

5-2) (S) -2,6-diamino-9-
(N- (4-isopropylbenzenesulfonyl) -2-
Synthesis of pyrrolidinylmethyl) purine 2,6-diaminopurine (118.4 mg, 0.79 mmol), potassium carbonate (195.8 mg, 1.42 mmol), 18-crown-6
(183.9 mg, 0.70 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours.

N, O-bis (4-isopropylbenzenesulfonyl) -L-prolinol (320.6 mg, 0.69 mmo
l) / 2 ml of dehydrated DMF solution was added dropwise at room temperature and then stirred at 80 ° C. for 1 hour. After confirming that the reaction was completed by TLC, the solvent was distilled off by a glass tube distillation apparatus,
Purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 70% Rf value: 0.68 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁷ = -64.3 (C = 0.14, MeOH) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 1.27-1.28 (7H, m, Hd, g, h), 1.33
-1.44 (1H, m, Hd), 1.53-1.62 (1H, m, Hc), 1.80-1.87 (1H, m, H
c), 2.97-3.09 (1H, m, He, f), 3.3 1-3.37 (1H, m, He), 3.87
-3.91 (1H, m, Hb), 4.30-4.42 (2H, m, Ha), 4.93 (2H, s, N H ₂ ),
5.90 (2H, s, N H ₂ ), 7.38-7.40 (2H, d, Ph- H ), 7.76-7.80 (3H,
m, Purine- H , Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.56 (Cg, h), 23.75 (Cd), 29.05
(Cc), 34.10 (Cf), 47.14 (Ca), 49.51 (Ce), 59.50 (Cb), 127.2
9,127.75,133.75,154.54 (Ph- C ), 113.81,139.07,152.37,
155.95,159.97 (Purine- C )

Example 6 (±) -2,6-diamino-9- (N- (4-isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 6)

[0085]

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Example 5 was repeated except that (±) -proline was used in place of L-proline as a raw material, and (±) -2,6-diamino-9- (N
-(4-Isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 6) was obtained. (±) -Total yield from proline: 29%

Example 7 (S) -2,6-diamino-9- (N- (4-n-propylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 7)

[0088]

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7-1) Synthesis of N, O-bis (4-n-propylbenzenesulfonyl) -L-prolinol L-prolinol (2.2 g, 22 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-n-Propylbenzenesulfonyl chloride (17.5 g, 80 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hr. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. Pyridine
After extraction and removal with 1N-HCl, the mixture was concentrated under reduced pressure at 30 ° C, and n-hexane was added to the obtained oily substance for crystallization in a freezer. The obtained crude crystal was recrystallized from methanol.

Yield: 48% Rf value: 0.49 (ethyl acetate: n-hexane = 1: 3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.92-0.98 (6H, m, Hh, k), 1.54-
1.73 (6H, m, Hc, g, j), 1.77-1.90 (2H, m, Hd), 2.64-2.71 (4
H, m, Hf, i), 3.02-3.08 (1H, m, He), 3.37-3.42 (1H, m, He),
3.74-3.79 (1H, m, Hb), 3.95-3.99 (1H, m, Ha), 4.25-4.28
(1H, m, Ha), 7.30-7.32 (2H, d, Ph- H ), 7.37-7.39 (2H, d, Ph-
H ), 7.67-7.69 (2H, d, Ph- H ), 7.83-7.85 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 13.67 (Ch, k), 23.75 ( Cd), 24.08
(Cg, j), 28.52 (Cc), 37.81,37.92 (Cf, i), 49.31 (Ce), 57.67
(Cb), 71.46 (Ca), 127.57,127.99,129.18,129.38,132.78,
133.73,148.47,149.64 (Ph- C )

7-2) (S) -2,6-diamino-9-
(N- (4-n-propylbenzenesulfonyl) -2-
Synthesis of pyrrolidinylmethyl) purine 2,6-diaminopurine (109.8 mg, 0.73 mmol), potassium carbonate (191.3 mg, 1.39 mmol), 18-crown-6
(184.2 mg, 0.70 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. N, O-bis (4-n-propylbenzenesulfonyl) -L-prolinol (314.2 mg, 0.68 mmol) / 2 ml dehydrated DMF solution was added dropwise at room temperature and then stirred at 80 ° C. for 1 hour. After confirming that the reaction was completed by TLC, the solvent was distilled off by a glass tube distillation apparatus, and preparative TLC (CH ₂ Cl ₂ : CH ₃ OH =
Purified by 9: 1).

Yield: 85% Rf value: 0.64 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁷ = -50.0 (C = 0.16, MeOH) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 0.93-0.96 (3H, t, Hh), 1.23-1.2
8 (1H, m, Hd), 1.34-1.40 (1H, m, Hd), 1.52-1.72 (3H, m, Hc,
g), 1.79-1.85 (1H, m, Hc), 2.65-2.68 (2H, t, Hf), 3.03-3.09
(1H, m, He), 3.31-3.36 (1H, m, He), 3.86-3.91 (1H, m, Hb), 4.
29-4.42 (2H, m, Ha), 4.89 (2H, s, N H ₂ ), 5.83 (2H, s, N H ₂ ), 7.3
4-7.36 (2H, d, Ph- H ), 7.76-7.80 (3H, m, Ph- H , Purine- H ,) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 13.67 (Cg), 23.75 ( Cd), 24.06 (C
g), 29.03 (Cc), 37.79 (Cf), 47.14 (Ca), 49.51 (Ce), 59.54
(Cb), 127.62,129.21,133.66,148.54 (Ph- C ), 113.83,139.
07,152.38,155.91,159.94 (Purine- C )

(Example 8) (±) -2,6-diamino-9- (N- (4-n-propylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 8)

[0094]

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Example 7 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- (N-
(4-n-Propylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 8) was obtained. (±) -Total yield from proline: 33%

Example 9 (S) -2,6-diamino-9- (N- (4-tert-amylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 9)

[0097]

[Chemical 21]

9-1) Synthesis of N, O-bis (4-tert-amylbenzenesulfonyl) -L-prolinol L-prolinol (1.3 g, 13 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 100 ml three-necked round bottom flask, 15 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-tert-amylbenzenesulfonyl chloride (10.0 g, 41 mmol) 10 ml dehydrated pyridine solution was added dropwise, and the mixture was stirred at 0 ° C for 2 hr. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, 30 ℃
The solution was concentrated under reduced pressure under reduced pressure, and the obtained crude crystals were recrystallized from methanol-ethyl acetate.

Yield: 48% Rf value: 0.65 (ethyl acetate: n-hexane = 1: 3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.63-0.70 (6H, m, Hi, m), 1.31-
1.33 (12H, d, Hf, g, j, k), 1.51-1.72 (6H, m, Hc, h, l), 1.75
-1.92 (2H, m, Hd), 3.02-3.10 (1H, m, He), 3.38-3.43 (1H, m, H
e), 3.76-3.82 (1H, m, Hb), 3.96-4.00 (1H, m, Ha), 4.26-4.
30 (1H, m, Ha), 7.46-7.48 (2H, d, Ph- H ), 7.52-7.55 (2H, d, Ph
-H ), 7.70-7.72 (2H, d, Ph- H ), 7.85-7.87 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 8.99 (Ci, m), 23.75 (Cd), 28.15 (C
f, g, j, k), 28.52 (Cc), 36.66,36.73 (Ch, l), 38.43,38.60 (C
n, o), 49.31 (Ce), 57.69 (Cb), 71.46 (Ca), 126.80,127.00,1
27.33,127.73,132.41,133.36,155.35,156.55 (Ph- C ).

9-2) (S) -2,6-diamino-9-
(N- (4-tert-amylbenzenesulfonyl) -2-
Synthesis of pyrrolidinylmethyl) purine 2,6-diaminopurine (105.6 mg, 0.70 mmol), potassium carbonate (193.8 mg, 1.40 mmol), 18-crown-6 (19
2.5 mg, 0.73 mmol) was placed in a 50 ml three-necked round bottom flask, and 10 ml of dehydrated DMF (water content max. 0.005%) was added,
The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. N, O-bis (4
-Tert-Amylbenzenesulfonyl) -L-prolinol (353.2 mg, 0.68 mmol) / 2 ml A dehydrated DMF solution was added dropwise at room temperature, and then the mixture was stirred at 80 ° C for 1 hr. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).
And purified.

Yield: 92% Rf value: 0.66 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁷ = -60.0 (C = 0.20, MeOH) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 0.63-0.67 (3H, t, Hj), 1.25-1.4
1 (2H, m, Hd), 1.31 (6H, s, Hf, g), 1.54-1.70 (3H, m, Hc, h),
1.79-1.86 (1H, m, Hc), 3.04-3.10 (1H, m, He), 3.31-3.36 (1
H, m, He), 3.87-3.92 (1H, m, Hb), 4.30-4.42 (2H, m, Ha), 4.91
(2H, s, N H ₂ ), 5.85 (2H, s, N H ₂ ), 7.48-7.51 (2H, d, Ph- H ), 7.7
6-7.81 (3H, m, Purine- H , Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 9.28 (Cj), 24.06 (Cd), 28.41 (Cf,
g), 29.36 (Cc), 37.00 (Ch), 38.74 (Ck), 47.45 (Ca), 49.82 (C
e), 59.85 (Cb), 127.15,127.68,133.62,155.75 (Ph- C) , 11
4.13,139.38,152.68,156.22,160.27 (Purine- C )

(Example 10) (±) -2,6-diamino-9- (N- (4-tert-amylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 10)

[0103]

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Example 9 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- (N
-(4-tert-Amylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 10) was obtained. (±) -Total yield from proline: 35%

Example 11 Production of (S) -2,6-diamino-9- (N- (4-methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 11)

[0106]

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11-1) Synthesis of N, O-bis (4-methoxybenzenesulfonyl) -L-prolinol L-prolinol (2.5 g, 25 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-methoxybenzenesulfonyl chloride (1
6.9 g, 82 mmol) / 15 ml dehydrated pyridine solution was added dropwise, and the mixture was stirred at 0 ° C. for 1.5 hr. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl,
After concentration under reduced pressure at ℃, the obtained oily substance was crystallized with methanol. The crude crystal was recrystallized from methanol-ethyl acetate.

Yield: 57% Rf value: 0.54 (ethyl acetate: n-hexane = 1: 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.57-1.65 (2H, m, Hc), 1.75-
1.90 (2H, m, Hd), 3.01-3.06 (1H, m, He), 3.36-3.41 (1H, m, H
e), 3.71-3.74 (1H, m, Hb), 3.87 (3H, s, OC H ₃ ), 3.90 (3H,
s, OC H ₃ ), 3.91-3.96 (1H, m, Ha), 4.22-4.25 (1H, m, Ha), 6.9
7-7.06 (4H, m, Ph- H ), 7.69-7.73 (2H, m, Ph- H ), 7.85-7.89 (2
H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.81 (Cc), 28.60 (Cd), 49.38 (C
e), 55.63 (O C H ₃ ), 55.70 (O C H ₃ ), 57.68 (Cb), 71.38 (Ca), 11
4.36,114.59,127.01,128.25,129.68,130.25,163.20,16
3.95 (Ph- C )

11-2) (S) -2,6-diamino-9
Synthesis of-(N- (4-methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (120.8 mg, 0.81 mmol), potassium carbonate (207.4 mg, 1.50 mmol), 18-crown- 6
(198 mg, 0.75 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. N, O-bis (4-methoxybenzenesulfonyl) -L-prolinol (265.5 mg, 0.70 mmol) / 2 ml dehydrated DMF solution was added dropwise at room temperature and then stirred at 80 ° C for 1 hour. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).
And purified.

Yield: 35% Rf value: 0.69 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -102.9 (C = 0.35, MeOH) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 1.26-1.28 (1H, m, Hd), 1.36-1.3
9 (1H, m, Hd), 1.55-1.60 (1H, m, Hc), 1.81-1.83 (1H, m, Hc),
3.01-3.08 (1H, m, He), 3.30-3.35 (1H, m, He), 3.88 (4H, s, OC
H ₃ , Hb), 4.28-4.40 (2H, m, Ha), 4.95 (2H, s, N H ₂ ), 5.92 (2H,
s, N H ₂ ), 6.99-7.02 (2H, m, Ph- H ), 7.75-7.82 (3H, m, Purine-
H , Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.87 (Cd), 29.13 (Cc), 47.22 (C
a), 49.56 (Ce), 55.65 (O C H ₃ ), 59.58 (Cb), 114.41, 128.27,
129.75,163.24 (Ph- C ), 113.97,139.15,152.47,156.03,16
0.04 (Purine- C )

Example 12 Production of (±) -2,6-diamino-9- (N- (4-methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 12)

[0112]

Embedded image

Example 11 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9-
(N- (4-methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 12) was obtained. (±) -Total yield from proline: 16%

Example 13 Production of (S) -2,6-diamino-9- (N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 13)

[0115]

Embedded image

13-1) Synthesis of N, O-bis (4-fluorobenzenesulfonyl) -L-prolinol L-prolinol (2.1 g, 20 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-Fluorobenzenesulfonyl chloride (1
5.8 g, 81 mmol) / 15 ml of dehydrated pyridine solution was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes. After confirming that the reaction was completed by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, 30 ℃
The solution was concentrated under reduced pressure under reduced pressure, and the obtained crude crystals were recrystallized from methanol-ethyl acetate.

Yield: 41% Rf value: 0.58 (ethyl acetate: n-hexane = 1: 2) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.59-1.71 (2H, m, Hc), 1.83-
1.92 (2H, m, Hd), 3.02-3.07 (1H, m, He), 3.38-3.43 (1H, m, H
e), 3.73-3.77 (1H, m, Hb), 4.01-4.05 (1H, m, Ha), 4.25-
4.28 (1H, m, Ha), 7.20-7.30 (4H, m, Ph- H ), 7.79-7.83 (2
H, m, Ph- H ), 7.95-7.99 (2H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.85 (Cc), 28.62 (Cd), 49.41
(Ce), 57.81 (Cb), 71.65 (Ca), 116.42,116.66,116.70,116.
92,130.17,130.27,130.47,130.85,130.94,131.63,132.7
2,164.12,164.67,166,66,167.23 (Ph- C )

13-2) (S) -2,6-diamino-9
Synthesis of-(N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (114 mg, 0.76 mmol), potassium carbonate (201.7 mg, 1.46 mmol), 18-crown- 6 (185
mg, 0.70 mmol) into a 50 ml three-necked round bottom flask, and add 10 ml of dehydrated DMF (water content max. 0.005%),
The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. N, O-bis (4
-Fluorobenzenesulfonyl) -L-prolinol
(298.1 mg, 0.71 mmol) / 5 ml dehydrated DMF solution was added dropwise at room temperature and then stirred at 80 ° C. for 3 hours. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 66% Rf value: 0.68 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -75.0 (c = 0.53, MeOH) ¹ H-NMR (DMSO-d ₆ ). δ (ppm): 1.35-1.45 (2H, m, Hc, d), 1.48
-1.59 (1H, m, Hd), 1.61-1.65 (1H, m, Hc), 3.09-3.15 (1H, m, H
e), 3.28-3.35 (1H, m, He), 3.94-3.99 (1H, m, Hb), 4.04-4.10
(1H, m, Ha), 4.21-4.26 (1H, m, Ha), 5.83 (2H, s, N H ₂ ), 6.71 (2
H, s, N H ₂ ), 7.41-7.50 (2H, m, Ph- H ), 7.68 (1H, s, Purine-
H ), 7.94-8.01 (2H, m, Ph- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 23.08 (Cd), 28.27 (Cc), 46.23
(Ca), 49.17 (Ce), 58.56 (Cb), 116.42,130.50,132.57,163.
31,165.82 (Ph- C ), 112.87,137.60,151.96,156.03,160.26
(Purine- C )

Example 14 Production of (±) -2,6-diamino-9- (N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 14)

[0121]

[Chemical formula 26]

Example 13 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- (N
-(4-Fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 14) was obtained. (±) -Total yield from proline: 22%

Example 15 Preparation of (S) -2,6-diamino-9- (N- (4-chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 15)

[0124]

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15-1) Synthesis of N, O-bis (4-chlorobenzenesulfonyl) -L-prolinol L-prolinol (2.1 g, 20 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-chlorobenzenesulfonyl chloride (16.
8 g, 80 mmol) / 15 ml dehydrated pyridine solution was added dropwise,
Stir for 30 minutes at 0 ° C. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, the mixture was concentrated under reduced pressure at 30 ° C, and the obtained crude crystals were recrystallized from methanol-ethyl acetate.

Yield: 34% Rf value: 0.67 (ethyl acetate: n-hexane = 1: 2) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.60-1.71 (2H, m, Hc), 1.83-
1.92 (2H, m, Hd), 3.02-3.07 (1H, m, He), 3.38-3.43 (1H, m, H
e), 3.72-3.75 (1H, m, Hb), 4.01-4.05 (1H, m, Ha), 4.25-
4.27 (1H, m, Ha), 7.50-7.59 (4H, m, Ph- H ), 7.71-7.73 (2H,
m, Ph- H ), 7.87-7.89 (2H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.85 (Cc), 28.64 (Cd), 49.4
1 (Ce), 57.81 (Cb), 71.71 (Ca), 128.93,129.46,129.59,12
9.79,134.12,135.11,139.74,140.82 (Ph- C )

15-2) (S) -2,6-diamino-9
-(N- (4-chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (119 mg, 0.79 mmol), potassium carbonate (204.5 mg, 1.48 mmol), 18-crown-6 (185 m
g, 0.70 mmol) into a 50 ml 3-neck round bottom flask,
10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. N, O-bis (4-chlorobenzenesulfonyl) -L-prolinol (314.4m
g, 0.70 mmol) / 5 ml dehydrated DMF solution was added dropwise at room temperature, and then the mixture was stirred at 80 ° C. for 3 hours. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 69% Rf value: 0.70 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -95.2 (c = 0.48, MeOH) ¹ H-NMR (DMSO-d ₆ ). δ (ppm) 1.35-1.55 (3H, m, Hc, d), 1.59-
1.65 (1H, m, Hc), 3.11-3.15 (1H, m, He), 3.29-3.34 (1H, m, H
e), 3.96-3.99 (1H, m, Hb), 4.05-4.10 (1H, m, Ha), 4.22-4.27
(1H, m, Ha), 5.85 (2H, s, N H ₂ ), 6.72 (2H, s, N H ₂ ), 7.68-7.72
(3H, m, Ph- H , Purine- H ), 7.93-7.95 (2H, m, Ph- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 23.04 (Cd), 28.27 (Cc) , 46.23
(Ca), 49.21 (Ce), 58.54 (Cb), 129.41,129.48,134.97,138.
09 (Ph- C ), 112.86,137.56,151.94,156.02,160.24 (Purine
-C )

Example 16 Preparation of (±) -2,6-diamino-9- (N- (4-chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 16)

[0130]

Embedded image

Example 15 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- (N
-(4-Chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 16) was obtained. (±) -Total yield from proline: 19%

Example 17 Preparation of (S) -2,6-diamino-9- (N- (4-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 17)

[0133]

[Chemical 29]

17-1) Synthesis of N, O-bis (4-bromobenzenesulfonyl) -L-prolinol L-prolinol (2.6 g, 26 mmol) was added under a nitrogen atmosphere.
The mixture was placed in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. 4-Bromobenzenesulfonyl chloride (20.
9 g, 82 mmol) / 15 ml dehydrated pyridine solution was added dropwise,
Stir for 30 minutes at 0 ° C. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, the mixture was concentrated under reduced pressure at 30 ° C, and the obtained crude crystals were recrystallized from methanol-ethyl acetate.

Yield: 49% Rf value: 0.62 (ethyl acetate: n-hexane = 1: 2) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.59-1.73 (2H, m, Hc), 1.81-
1.93 (2H, m, Hd), 3.00-3.03 (1H, m, He), 3.04-3.07 (1H, m, H
e), 3.71-3.75 (1H, m, Hb), 4.00-4.05 (1H, m, Ha), 4.25-
4.29 (1H, m, Ha), 7.63-7.82 (8H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 23.85 (Cc), 28.64 (Cd), 49.41
(Ce), 57.83 (Cb), 71.71 (Ca), 128.24,129.00,129.37,1
29.48,132.59,132.79,132.92,134.66,135.64 (Ph- C )

17-2) (S) -2,6-diamino-9
Synthesis of-(N- (4-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (117 mg, 0.78 mmol), potassium carbonate (213.3 mg, 1.55 mmol), 18-crown- 6 (198
mg, 0.75 mmol) into a 50 ml three-necked round bottom flask, and add 10 ml of dehydrated DMF (water content max. 0.005%),
The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. N, O-bis (4
-Bromobenzenesulfonyl) -L-prolinol (37
1.8 mg, 0.69 mmol) / 5 ml dehydrated DMF solution was added dropwise at room temperature, and the mixture was stirred at 80 ° C. for 1 hr. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 87.7% Rf value: 0.71 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -61.8 (c = 0.66, MeOH) ¹ H-NMR (DMSO-d ₆ ). δ (ppm) 1.38-1.49 (3H, m, Hc, d), 1.61-
1.69 (1H, m, Hc), 3.10-3.14 (1H, m, He), 3.31-3.32 (1H, m, H
e), 3.84-3.96 (1H, m, Hb), 4.04-4.09 (1H, m, Ha), 4.21-4.26
(1H, m, Ha), 5.82 (2H, s, N H ₂ ), 6.70 (2H, s, N H ₂ ), 7.66 (1H, s,
Purine- H ), 7.85 (4H, s, Ph- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 23.96 (Cd), 29.20 (Cc), 47.14
(Ca), 50.14 (Ce), 59.43 (Cb), 122.40,130.37,133.34,136.
30 (Ph- C ), 113.79,138.49,152.85,156.93,161.15 (Purine
-C )

Example 18 Production of (±) -2,6-diamino-9- (N- (4-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 18)

[0139]

Embedded image

Example 17 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-Bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 18) was obtained. Total yield from (±) -proline: 34% (Example 19) (S) -2,6-diamino-9- (N- (2,5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 19)

[0141]

[Chemical 31]

19-1) Synthesis of N, O-bis (2,5-dichlorobenzenesulfonyl) -L-prolinol L-prolinol (2.6 g, 26 mmol) was added under a nitrogen atmosphere.
It was put in a 200 ml three-necked round bottom flask, 30 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. After 2,5-dichlorobenzenesulfonyl chloride (19.8 g, 81 mmol) / 15 ml dehydrated pyridine solution was added dropwise, the mixture was stirred for 2 hours at 0 ° C. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl,
The mixture was concentrated under reduced pressure at ℃ and the obtained crude crystals were recrystallized from methanol-ethyl acetate.

Yield: 54% Rf value: 0.62 (ethyl acetate: n-hexane = 1: 2) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.83-1.86 (1H, m, Hd), 2.02-
2.07 (3H, m, Hc, d), 3.31-3.35 (1H, m, He), 3.44-3.48 (1H,
m, He), 4.11-4.15 (1H, m, Ha), 4.21-4.26 (2H, m, Ha, b), 7.
45-7.46 (2H, m, Ph- H ), 7.54-7.58 (2H, m, Ph- H ), 8.02-8.05
(2H, m, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 24.20 (Cd), 28.75 (Cc), 49.05
(Ce), 58.06 (Cb), 71.98 (Ca), 130.23,131.20,131.75,132.
04,133.28,133.32,133.37,133.45,133.50,133.76,134.8
7,137.82 (Ph- C )

19-2) 2,6-Diamino-9- (N-
Synthesis of (2,5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine 2,6-diaminopurine (117 mg, 0.78 mmol), potassium carbonate (222.8 mg, 1.61 mmol), 18-crown-6 ( 198
mg, 0.75 mmol) into a 50 ml three-necked round bottom flask, and add 10 ml of dehydrated DMF (water content max. 0.005%),
The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. N, O-bis (2,5-dichlorobenzenesulfonyl) -L-prolinol (377.7 mg, 0.73 mol) / 5 ml dehydrated DMF solution was added dropwise at room temperature, and then the mixture was stirred at 80 ° C for 50 minutes. After confirming that the reaction was completed by TLC, the solvent was distilled off by a glass tube distillation apparatus, and preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9:
Purified by 1).

Yield: 56% Rf value: 0.70 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) [α] ²⁶ = -27.3 (c = 0.44, DMSO) ¹ H-NMR (DMSO-d ₆ ). δ (ppm) 1.59-1.70 (2H, m, Hd), 1.71-1.
87 (2H, m, Hc), 3.32-3.42 (2H, m, He), 3.99-4.04 (1H, q, H
a), 4.11-4.16 (1H, q, Ha), 4.36-4.39 (1H, m, Hb), 5.77 (2H,
s, N H ₂ ), 6.68 (2H, s, N H ₂ ), 7.61 (1H, s, Purine- H ), 7.68-7.7
4 (2H, m, Ph- H ), 7.92 (1H, s, Ph- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 23.33 (Cd), 28.44 (Cc), 45.68
(Ca), 48.28 (Ce), 59.34 (Cb), 129.46,130.89,132.24,133.
89,134.20,137.30 (Ph- C ), 112.89,137.41,151.88,156.0
3,160.26 (Purine- C )

(Example 20) (±) -2,6-diamino-9- (N- (2,5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 20)

[0147]

Embedded image

Example 19 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (2,5-dichlorobenzenesulfonyl) -2-
Pyrrolidinylmethyl) purine (Compound No. 20) was obtained. (±) -Total yield from proline: 24%

Example 21 Production of (S) -2,6-diamino-9- (N- (4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 21)

[0150]

[Chemical 33]

Synthesis was carried out in the same manner as in Example 1 except that 4-iodobenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 18% ¹ H-NMR (DMSO-d ₆ ) δ (ppm) 1.41-1.50 (3H, m, Hc, d), 1.62-
1.70 (1H, m, Hc), 3.14-3.18 (1H, m, He), 3.35-3.37 (1H, m, H
e), 3.92-3.97 (1H, m, Hb), 4.14-4.19 (1H, m, Ha), 4.25-4.27
(1H, m, Ha), 5.82 (2H, s, N H ₂ ), 6.72 (2H, s, N H ₂ ), 7.67 (1H, s,
Purine- H ), 7.82-7.90 (4H, s, Ph- H ) FAB-MASS: 500 (M + 1)

Example 22 Production of (±) -2,6-diamino-9- (N- (4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 22)

[0153]

Embedded image

Example 21 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 22) was obtained. (±) -Total yield from proline: 22%

Example 23 (S) -2,6-diamino-9- (N- (4-tert-butylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 23)

[0156]

Embedded image

Synthesis was carried out in the same manner as in Example 1 except that 4-tert-butylbenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 25% ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.26-1.42 (2H, m, Hd), 1.32 (9H,
s, Hf, g, h), 1.54-1.69 (1H, m, Hc), 1.79-1.86 (1H, m, Hc),
3.04-3.11 (1H, m, He), 3.30-3.35 (1H, m, He), 3.88-3.91 (1
H, m, Hb), 4.30-4.40 (2H, m, Ha), 4.90 (2H, s, N H ₂ ), 5.85 (2H,
s, N H ₂ ), 7.44-7.50 (2H, d, Ph- H ), 7.77-7.82 (3H, m, Purine-
H , Ph- H ) FAB-MASS: 430 (M + 1)

(Example 24) (±) -2,6-diamino-9- (N- (4-tert-butylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Production of purines (Compound No. 24)

[0159]

Embedded image

Example 23 was repeated except that (±) -proline was used in place of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-tert-butylbenzenesulfonyl) -2-
Pyrrolidinylmethyl) purine (Compound No. 24) was obtained. (±) -Total yield from proline: 23%

Example 25 Production of (S) -2,6-diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 25)

[0162]

Embedded image

Synthesis was carried out in the same manner as in Example 1 except that 4-trifluoromethylbenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 19% ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.22-1.25 (1H, m, Hd), 1.29-1.3
3 (1H, m, Hd), 1.50-1.53 (1H, m, Hc), 1.77-1.81 (1H, m, Hc),
3.00-3.06 (1H, m, He), 3.25-3.33 (1H, m, He), 3.88-3.90 (1
H, m, Hb), 4.25-4.40 (2H, m, Ha), 5.30 (2H, s, N H ₂ ), 6.45 (2H,
s, N H ₂ ), 7.31-7.33 (2H, t, Ph- H ), 7.73-7.76 (3H, m, Purine-
H , Ph- H ) FAB-MASS: 442 (M + 1)

Example 26 Production of (±) -2,6-diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 26)

[0165]

Embedded image

Example 25 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-trifluoromethylbenzenesulfonyl)
-2-Pyrrolidinylmethyl) purine (Compound No. 26)
I got (±) -Total yield from proline: 22%

Example 27 Preparation of (S) -2,6-diamino-9- (N- (4-trifluoromethoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 27)

[0168]

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Synthesis was carried out in the same manner as in Example 1 except that 4-trifluoromethoxybenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 23% ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.24-1.27 (1H, m, Hd), 1.35-1.
40 (1H, m, Hd), 1.55-1.62 (1H, m, Hc), 1.80-1.83 (1H, m, Hc),
3.03-3.09 (1H, m, He), 3.30-3.36 (1H, m, He), 3.88 (1H, s, H
b), 4.28-4.40 (2H, m, Ha), 4.96 (2H, s, N H ₂ ), 5.90 (2H, s, N
H ₂ ), 6.98-7.03 (2H, m, Ph- H ), 7.76-7.81 (3H, m, Purine- H , P
h- H ) FAB-MASS: 458 (M + 1)

Example 28 Preparation of (±) -2,6-diamino-9- (N- (4-trifluoromethoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 28)

[0171]

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Example 27 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-trifluoromethoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 2
8) was obtained. (±) -Total yield from proline: 20%

Example 29 Production of (S) -2,6-diamino-9- (N- (3-methylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 29)

[0174]

Embedded image

Synthesis was carried out in the same manner as in Example 1 except that 3-methylbenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 21% ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.22-1.25 (1H, m, Hd), 1.30-1.3
5 (1H, m, Hd), 1.54-1.56 (1H, m, Hc), 1.77-1.80 (1H, m, H
c), 2.62 (3H, s, Ph-C H ₃ ), 3.01-3.04 (1H, m, He), 3.27-3.33
(1H, m, He), 3.85-3.90 (1H, m, Hb), 4.25-4.40 (2H, m, Ha), 5.
32 (2H, s, N H ₂ ), 6.46 (2H, s, N H ₂ ), 7.35-7.70 (4H, m, Ph- H ),
7.74-7.77 (3H, m, Purine- H , Ph- H ) FAB-MASS: 388 (M + 1)

Example 30 Production of (±) -2,6-diamino-9- (N- (3-methylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 30)

[0177]

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Example 29 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (3-methylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 30) was obtained. (±) -Total yield from proline: 23%

(Example 31) Production of (S) -2,6-diamino-9- (N- (2-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 31)

[0180]

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Synthesis was carried out in the same manner as in Example 1 except that 2-bromobenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 28% ¹ H-NMR (DMSO-d ₆ ) δ (ppm) 1.39-1.50 (3H, m, Hc, d), 1.60-
1.70 (1H, m, Hc), 3.11-3.15 (1H, m, He), 3.31-3.33 (1H, m, H
e), 3.84-3.97 (1H, m, Hb), 4.05-4.09 (1H, m, Ha), 4.22-4.26
(1H, m, Ha), 5.82 (2H, s, N H ₂ ), 6.72 (2H, s, N H ₂ ), 7.69 (1H, s,
Purine- H ), 7.75-7.90 (4H, m, Ph- H ) FAB-MASS: 453 (M + 1)

Example 32 Production of (±) -2,6-diamino-9- (N- (2-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 32)

[0183]

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Example 31 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (2-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 32) was obtained. (±) -Total yield from proline: 24%

Example 33 Production of (S) -2,6-diamino-9- (N- (4-nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 33)

[0186]

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Synthesis was carried out in the same manner as in Example 1 except that 4-nitrobenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. Total yield from L-proline: 18% ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.30-1.35 (2H, m, Hc, d), 1.41
-1.45 (1H, m, Hd), 1.60-1.62 (1H, m, Hc), 3.07-3.11 (1H, m,
He), 3.22-3.30 (1H, m, He), 3.95-4.00 (1H, m, Hb), 4.00-4.0
7 (1H, m, Ha), 4.20-4.24 (1H, m, Ha), 5.80 (2H, s, N H ₂ ), 6.72
(2H, s, N H ₂ ), 7.65 (1H, s, Purine- H ,), 7.85-7.90 (4H, m, Ph-
H ) FAB-MASS: 419 (M + 1)

Example 34 Production of (±) -2,6-diamino-9- (N- (4-nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 34)

[0189]

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Example 33 was repeated except that (±) -proline was used instead of L-proline as a starting material, and (±) -2,6-diamino-9- was used.
(N- (4-nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 34) was obtained. (±) -Total yield from proline: 24%

Example 35 (S) -2-Amino-9- (N-benzenesulfonyl-
Preparation of 2-pyrrolidinylmethyl) purine (Compound No. 35)

[0192]

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In Experimental item 1-3) of Example 1,
The same procedure was followed except that 2-aminopurine was used instead of 6-diaminopurine, and (S) -2-amino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 35 ) Got. Total yield from L-proline: 21% FAB-MASS: 359 (M + 1)

Example 36 (S) -6-amino-9- (N-benzenesulfonyl-
Preparation of 2-pyrrolidinylmethyl) purine (Compound No. 36)

[0195]

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In Experimental item 1-3) of Example 1,
The same procedure was followed except that 6-aminopurine was used instead of 6-diaminopurine, and (S) -6-amino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 36 ) Got. Total yield from L-proline: 25% FAB-MASS: 359 (M + 1)

Example 37 Preparation of (S) -9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 37)

[0198]

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In Experimental item 1-3) of Example 1,
The same procedure was repeated except that purine was used instead of 6-diaminopurine to obtain (S) -9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine (Compound No. 37). Total yield from L-proline: 24% FAB-MASS: 344 (M + 1)

Example 38 Preparation of (S) -2-amino-9- (N- (4-isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine (Compound No. 38)

[0201]

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In Experimental item 5-2) of Example 5,
The same procedure as in (S) -2-amino-9- (N- (4-isopropylbenzenesulfonyl)) was conducted except that 2-aminopurine was used instead of 6-diaminopurine.
-2-Pyrrolidinylmethyl) purine (Compound No. 38)
I got Total yield from L-proline: 21% FAB-MASS: 401 (M + 1)

Example 39 Preparation of (S) -2,6-diamino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine (Compound No. 39)

[0204]

[Chemical 51]

39-1) Methyl esterification of thioproline A suspension of L-thioproline (5.1 mg, 38 mmol, Tokyo Kasei) in methanol (50 ml) was placed in a 500 ml Erlenmeyer flask,
A CH ₂ N ₂ ether solution obtained from 13 g of N-methyl-N′-nitro-N-nitrosoguanidine (Tokyo Kasei) was added, and the mixture was stirred overnight at room temperature. After confirming that the reaction was completed by TLC, the reaction mixture was concentrated under reduced pressure. The obtained yellow oily substance was purified by WAKO C-200 silica gel column chromatography (ethyl acetate: n-hexane = 1: 2).

Yield: 96% Rf value: 0.76 (n-butanol: acetic acid: water = 3: 1: 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.87-2.91 (1H, q, Hc) , 3.24-
3.26 (1H, q, Hc), 3.79 (3H, s, OC H ₃ ), 3.85-3.89 (1H, t, Hb),
4.12-4.14 (1H, d, Hd) , 4.37-4.39 (1H, d, Hd) 13 C-NMR (CDCl 3) δ (ppm): 36.98 (Cc), 52.54 (O C H 3), 54.41
(Cd), 65.22 (Cb), 171.83 ( C = O)

39-2) N-Tosylation of thioproline methyl ester Under a nitrogen atmosphere, L-thioproline methyl ester (1.0
g, 6.79 mmol) was placed in a 50 ml eggplant type flask, 10 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C. for a while. P-toluenesulfonyl chloride (2.2
8 g, 12 mmol) / 10 ml of dehydrated pyridine solution was added dropwise,
Stir for 2 hours at 0 ° C. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, it was concentrated under reduced pressure at 30 ° C. and preparative TLC (ethyl ether: n-hexane =
Purified by 1: 1).

Yield: 88% Rf value: 0.57 (ethyl ether: n-hexane = 1: 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.45 (3H, s, Ph-C H ₃ ), 2.91-2.96
(1H, q, Hc), 3.16-3.20 (1H, q, Hc), 3.75 (3H, s, OC H ₃ ), 4.42-
4.44 (1H, d, Hd), 4.70-4.73 (1H, d, Hd), 4.87-4.90 (1H, q, H
b), 7.32-7.34 (2H, d, Ph- H ), 7.75-7.77 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 21.61 (Ph- C H ₃ ), 34.51 (Cc), 50.
49 (Cd), 52.94 (Ca), 63.57 (Cb), 127.60,129.92,135.26,14
4.40, (Ph- C ), 169.99 ( C = O)

39-3) Reduction of N-tosyl-L-thioproline methyl ester Under a nitrogen atmosphere, 50 ml of a solution of N-tosyl-L-thioproline methyl ester (0.84 g, 2.92 mmol) in THF (15 ml) was added.
The mixture was placed in a round-bottomed flask and stirred at -20 ° C for a while. A THF (2.8 ml) solution of LiAlH ₄ (0.111 g, 2.92 mmol) was slowly added dropwise, and the mixture was reacted for 30 minutes. After confirming the completion of the reaction by TLC, ethyl acetate 10 m
l It was left to stand until it reached room temperature. Adjust pH to 3-4 with 1N-HCI
And extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure and then dried under vacuum.

Yield: 97% Rf value: 0.18 (ethyl ether: n-hexane = 1: 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.45 (3H, s, Ph-CH ₃ ), 2.65-2.69
(1H, q, Hc), 2.82-2.86 (1H, q, Hc), 3.70-3.71 (2H, d, Ha), 4.
15-4.19 (1H, m, Hb), 4.35-4.38 (1H, d, Hd), 4.68-4.71 (1H,
d, Hd), 7.33-7.35 (2H, d, Ph- H ), 7.74-7.76 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 21.64 (Ph- C H ₃ ), 33.30 (Cc), 51.
57 (Cd), 63.57 (Ca), 64.39 (Cb), 127.82,129.97,134.34,14
4.49, (Ph- C )

39-4) O-Tosylation of N-tosyl-L-thioprolinol Under a nitrogen atmosphere, N-tosyl-L-thioprolinol (44
7.3 mg, 1.73 mmol) was placed in a 50 ml eggplant type flask, 10 ml of dehydrated pyridine (water content max. 0.005%) was added, and the mixture was stirred at 0 ° C for a while. After p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) / 10 ml dehydrated pyridine solution was added dropwise, the mixture was stirred for 3 hours at 0 ° C. After confirming the completion of the reaction by TLC, the mixture was added to ice water and extracted with ethyl acetate. After removing pyridine by extraction with 1N-HCl, 30
The mixture was concentrated under reduced pressure at ℃ and purified by preparative TLC (ethyl ether: n-hexane = 1: 1).

Yield: 68% Rf value: 0.56 (ethyl ether: n-hexane = 1: 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.44 (3H, s, Ph-C H ₃ ), 2.47 (3H,
_{s, Ph- H 3), 2.64-2.69} (1H, m, Hc), 2.88-2.91 (1H, q, Hc),
4.03-4.08 (1H, m, Ha), 4.17-4.23 (2H, m, Ha, Hb), 4.25-4.28
(1H, d, Hd), 4.37-4.39 (1H, d, Hd), 7.32-7.34 (2H, d, Ph-
H ), 7.38-7.40 (2H, d, Ph- H ), 7.67-7.69 (2H, d, Ph- H ), 7.81-
7.83 (2H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 21.62 (Ph- C H ₃ ), 21.71 (Ph- C H ₃ ),
33.56 (Cc), 51.44 (Cd), 60.57 (Cb), 69.29 (Ca), 127.67,12
8.09,129.96,130.04,132.33,133.80,144.62,145.32 (Ph-
C )

39-5) Coupling of N, O-ditosyl-L-thioprolinol and 2,6-diaminopurine 2,6-diaminopurine (82.7 mg, 0.55 mmol), potassium carbonate (144.1 mg, 1.04) mmol), 18-crown-6 (12
6.9 mg, 0.48 mmol) was placed in a 50 ml three-necked round bottom flask, 10 ml of dehydrated DMF (water content max. 0.005%) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. N, O-ditosyl-L-thioprolinol (206.6 mg, 0.48 mmol) / 5
After adding ml of dehydrated DMF solution at room temperature, the mixture was stirred at 80 ° C. for 1 hour. After confirming the completion of the reaction by TLC, the solvent was distilled off by a glass tube distillation apparatus and purified by preparative TLC (CH ₂ Cl ₂ : CH ₃ OH = 9: 1).

Yield: 54% [α] ²⁶ = -48.3 (c = 0.50, MeOH) Rf value: 0.94 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) ¹ H-NMR (DMSO-d ₆ ). δ (ppm): 2.37 (3H, s, Ph-C H ₃ ), 2.50-2.5
4 (1H, m, Hc), 2.85-2.89 (1H, q, Hc), 4.05-4.07 (2H, d, Ha),
4.56-4.58 (1H, d, Hd), 4.65-4.67 (1H, m, Hb), 4.82-4.85 (1
H, d, Hd), 5.79 (2H, s, N H ₂ ), 6.69 (2H, s, N H ₂ ), 7.30-7.32 (2
H, d, Ph- H ), 7.58-7.60 (2H, d, Ph- H ), 7.67 (1H, s, Purine- H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 20.96 (Ph -C H ₃ ), 32.70 (Cc), 4
3.56 (Cd), 48.87 (Ca), 61.80 (Cb), 127.23,129.64,134.16,
143.93 (Ph- C ), 113.83,137.41,151.72,155.92,160.13 (Pu
rine- C )

Example 40 Production of (S) -2,6-diamino-9- (N-benzenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine (Compound No. 40)

[0216]

Embedded image

In Experimental section 39-2) of Example 39,
All were synthesized by the same method except that benzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride. Total yield from L-thioproline: 35% Rf value: 0.93 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 393 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 2.48-2.52 (1H, m, Hc), 2.82-2.
88 (1H, q, Hc), 4.03-4.07 (2H, d, Ha), 4.53-4.56 (1H, d, Hd),
4.64-4.66 (1H, m, Hb), 4.78-4.82 (1H, d, Hd), 5.75 (2H, s, N H
₂ ), 7.00 (2H, s, N H ₂ ), 7.33-7.58 (5H, d, Ph- H ), 7.67 (1H, s, P
urine- H )

Example 41 Production of (S) -2,6-diamino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine (Compound No. 41)

[0219]

Embedded image

In Experimental section 39-2) of Example 39,
All were synthesized by the same method except that 4-isopropylbenzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride. Total yield from L-thioproline: 32% Rf value: 0.94 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 435 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 1.27-1.29 (6H, dd, Hf, g), 2.49
-2.53 (1H, m, Hc), 2.84-2.88 (1H, q, Hc), 3.01-3.07 (1H, m,
He), 4.04-4.06 (2H, d, Ha), 4.52-4.56 (1H, d, Hd), 4.61-4.6
3 (1H, m, Hb), 4.80-4.83 (1H, d, Hd), 5.76 (2H, s, N H ₂ ), 7.01
(2H, s, N H ₂ ), 7.28-7.32 (2H, d, Ph- H ), 7.56-7.62 (2H, d, P
h- H ), 7.64 (1H, s, Purine- H )

Example 42 (S) -2,6-Diamino-9- (N- (4-tert-butylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine (Compound No. 42) Manufacturing of

[0222]

Embedded image

In Experimental section 39-2) of Example 39,
All were synthesized by the same method except that 4-tert-butylbenzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride. Total yield from L-thioproline: 37% Rf value: 0.94 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 449 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 1.33 (9H, s, He, f, g), 2.48-2.5
2 (1H, m, Hc), 2.83-2.86 (1H, q, Hc), 4.05-4.08 (2H, d, Ha),
4.56-4.58 (1H, d, Hd), 4.65-4.67 (1H, m, Hb), 4.82-4.85 (1
H, d, Hd), 5.79 (2H, s, N H ₂ ), 7.00 (2H, s, N H ₂ ), 7.30-7.32
(2H, d, Ph- H ), 7.58-7.60 (2H, d, Ph- H ), 7.67 (1H, s, Purine-
H )

Example 43 Synthesis of (S) -2,6-diamino-9- (N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine (Compound No. 43)

[0225]

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In Experimental section 39-2) of Example 39,
All were synthesized by the same method except that 4-methoxybenzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride. Total yield from L-thioproline: 38% Rf value: 0.91 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 423 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 2.49-2.55 (1H, m, Hc), 2.84-2.8
9 (1H, q, Hc), 3.88 (3H, s, OC H ₃ ), 4.05-4.07 (2H, d, Ha), 4.56
-4.58 (1H, d, Hd), 4.65-4.67 (1H, m, Hb), 4.82-4.85 (1H, d, H
d), 5.79 (2H, s, N H ₂ ), 6.69 (2H, s, N H ₂ ), 6.98-7.03 (2H, d, Ph
-H ), 7.73-7.80 (2H, d, Ph- H ), 7.66 (1H, s, Purine- H )

Example 44 Preparation of (S) -2-amino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine (Compound No. 44)

[0228]

Embedded image

In Experimental section 1-5) of Example 39,
All were synthesized by the same method except that 2-aminopurine was used instead of 2,6-diaminopurine. Total yield from L-thioproline: 32% Rf value: 0.91 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 392 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 2.36 (3H, s,
_{Ph-C H 3), 2.51-2.55} (1H, m, H
c), 2.83-2.90 (1H, q, Hc), 4.0.
3-4.06 (2H, d, Ha), 4.55-4.57
(1H, d, Hd), 4.64-4.66 (1H, m,
Hb), 4.81-4.86 (1H, d, Hd),
_{6.56 (2H, s, N H} 2), 7.29-7.33
(2H, d, Ph- H ), 7.58-7.63 (2H,
d, Ph- H ), 7.79, 8.50 (1H, s, Pu)
line- H )

Example 45 Preparation of (S) -2-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine (Compound No. 45)

[0231]

Embedded image

In Experimental section 39-2) of Example 39,
4-isopropylbenzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride, and 2-aminopurine was used instead of 2,6-diaminopurine in Experimental Example 1-5) of Example 39. Synthesized. Total yield from L-thioproline: 30% Rf value: 0.92 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 420 (M + 1)

Example 46 (S) -2-Amino-9- (N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl)
Production of purines (Compound No. 46)

[0234]

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In Experimental section 39-2) of Example 39,
4-methoxybenzenesulfonyl chloride instead of p-toluenesulfonyl chloride, and in the same manner as in Experimental Example 1-5) of Example 39, except that 2-aminopurine was used instead of 2,6-diaminopurine. Synthesized. Total yield from L-thioproline: 26.8% Rf value: 0.94 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 408 (M + 1)

Example 47 Preparation of (S) -6-amino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine (Compound No. 47)

[0237]

Embedded image

In Experimental item 1-5) of Example 39,
All were synthesized by the same method except that 6-aminopurine was used instead of 2,6-diaminopurine. Total yield from L-thioproline: 34% Rf value: 0.91 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 392 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 2.37 (3H, s, Ph-C H ₃ ), 2.51-2.5
4 (1H, m, Hc), 2.85-2.90 (1H, q, Hc), 4.05-4.09 (2H, d, Ha),
4.55-4.59 (1H, d, Hd), 4.64-4.67 (1H, m, Hb), 4.80-4.86 (1
H, d, Hd), 6.07 (2H, s, N H ₂ ), 7.28-7.33 (2H, d, Ph- H ), 7.52-
7.58 (2H, d, Ph- H ), 8.12,8.30 (1H, s, Purine- H )

Example 48 Production of (S) -6-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine (Compound No. 48)

[0240]

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In Experimental section 39-2) of Example 39,
4-isopropylbenzenesulfonyl chloride was used instead of p-toluenesulfonyl chloride, and 6-aminopurine was used instead of 2,6-diaminopurine in Experimental Example 1-5) of Example 39. Synthesized. Total yield from L-thioproline: 37% Rf value: 0.92 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 420 (M + 1)

(Example 49) Anti-HIV test The anti-HIV-1 activity of a test compound was measured by the following experiment using MT-4 cells. This method is for judging the infection death of CD-4-positive cells caused by HIV infection and the inhibitory effect by a drug, and is an excellent method capable of simultaneously and simply measuring anti-HIV activity and cytotoxicity. Is.

1 × 10 ⁴ HIV-1 (HTLV-III
MT-4 cells infected with B) and non-infected MT-4 cells were added to each well of a 96-well microplate together with various concentrations of a test compound, and cultured in a CO ₂ incubator at 37 ° C for 5 days. Next, 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (hereinafter referred to as "MTT") was added, and the culture was continued for another 2 hours. MTT taken up by living cells during this period
Is reduced by an enzyme possessed by mitochondria in the cell,
An insoluble dye (formazan) was formed in blue-violet water.
Then, acid 2-propyl alcohol solution containing 5% Triton X-100 was added to solubilize the produced dye, and then the specific absorbance at 595 nm and the nonspecific absorbance at 655 nm were measured using a microplate reader. (BIO-RAD model 3550) was used to determine the difference between the two. 30% cell death inhibitory concentration (EC
₃₀ values), 50% cell death inhibitory concentration (EC ₅₀ value), and 50% cytotoxic concentration (CC ₅₀ value) were calculated. EC ₃₀ and EC indicating drug efficacy
_The smaller the ₅₀ value, the more desirable, and the larger the CC ₅₀ value, which is a guideline for toxicity to normal cells, the better. The value showing the antiviral effect is
The EC ₅₀ was used as a standard, but due to the toxicity of the drug, the EC ₅₀
EC ₃₀ was used for samples for which no value was obtained. The results are shown in Tables 1 and 2.

[0244]

[Table 1]

[0245]

[Table 2]

Example 50 Anti-HIV Test The anti-HIV-1 activity of the test compound was measured by the following experiment using MT-4 cells. This method is for judging the infection death of CD-4-positive cells caused by HIV infection and the inhibitory effect by a drug, and is an excellent method capable of simultaneously and simply measuring anti-HIV activity and cytotoxicity. Is.

1 × 10 ⁴ HIV-1 (HTLV-III
MT-4 cells infected with B) and non-infected MT-4 cells were added to each well of a 96-well microplate together with various concentrations of a test compound, and cultured in a CO ₂ incubator at 37 ° C for 5 days. Next, 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (hereinafter referred to as "MTT") was added, and the culture was continued for another 2 hours. MTT taken up by living cells during this period
Is reduced by an enzyme possessed by mitochondria in the cell,
An insoluble dye (formazan) was formed in blue-violet water.
Then, acid 2-propyl alcohol solution containing 5% Triton X-100 was added to solubilize the produced dye, and then the specific absorbance at 595 nm and the nonspecific absorbance at 655 nm were measured using a microplate reader. (BIO-RAD model 3550) was used to determine the difference between the two. 30% cell death inhibitory concentration (EC
₃₀ values) and 50% cytotoxic concentration (CC ₅₀ value) are calculated. The smaller the EC ₃₀ value showing the drug effect is, the better, and the higher the CC ₅₀ value, which is a guideline for toxicity to normal cells, is the better. The results are shown in Table 3.

[0248]

[Table 3]

[0249]

INDUSTRIAL APPLICABILITY The purine derivative of the present invention exhibits antiviral activity and is extremely effective in treating or preventing infectious diseases caused by viruses.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kunimitsu Murakami 2-8-1, Iidamachi, Iwakuni-shi, Yamaguchi Prefecture Iwakuni Technical Research Institute, Nippon Paper Industries Co., Ltd.

Claims (9)

[Claims] (1) The following formula (I): (In the formula, A represents a methylene group or a sulfur atom, R ¹ represents a hydrogen atom or an amino group, R ² represents a hydrogen atom or an amino group, and R ³ represents an arylsulfonyl group. Group represents a group, R ³ represents an arylsulfonyl group other than p-toluenesulfonyl group) or a salt thereof. 2. The compound according to claim 1, wherein in the formula (I), A represents a methylene group. 3. The purine derivative represented by the formula (I) is 2,6-diamino-9- (N-benzenesulfonyl-2).
-Pyrrolidinylmethyl) purine, 2,6-diamino-9
-(N- (4-ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N
-(4-Isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N
-(4-n-Propylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N
-(4-tert-amylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N
-(4-Methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N-
(4-Fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4
-Chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (2,5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine,
2,6-diamino-9- (N- (4-tert-butylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine,
2,6-Diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-trifluoromethoxybenzenesulfonyl) 2-Pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (3-methylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Purine, 2,6-diamino-9- (N- (2-bromobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, and 2,6-diamino-9- (N- (4-nitrobenzenesulfonyl) -2. The compound according to claim 2, which is a compound selected from the group consisting of -pyrrolidinylmethyl) purine. 4. The purine derivative represented by the formula (I) is (S) -2,6-diamino-9- (N-benzenesulfonyl-2-pyrrolidinylmethyl) purine, (S) -2,
6-diamino-9- (N- (4-ethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S)-
2,6-diamino-9- (N- (4-isopropylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine,
(S) -2,6-Diamino-9- (N- (4-n-propylbenzenesulfonyl) -2-pyrrolidinylmethyl)
Purine, (S) -2,6-diamino-9- (N- (4-
tert-amylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N
-(4-Methoxybenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9-
(N- (4-fluorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-
9- (N- (4-chlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4-bromobenzenesulfonyl) -2-
Pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (2,5-dichlorobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,
6-diamino-9- (N- (4-iodobenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S)-
2,6-diamino-9- (N- (4-tert-butylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine,
(S) -2,6-Diamino-9- (N- (4-trifluoromethylbenzenesulfonyl) -2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N-
(4-trifluoromethoxybenzenesulfonyl) -2
-Pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (3-methylbenzenesulfonyl)-
2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (2-bromobenzenesulfonyl)
-2-pyrrolidinylmethyl) purine, and (S) -2,
The compound according to claim 3, which is a compound selected from the group consisting of 6-diamino-9- (N- (4-nitrobenzenesulfonyl) -2-pyrrolidinylmethyl) purine. 5. The compound according to claim 1, wherein in the formula (I), A represents a sulfur atom. 6. The purine derivative represented by the formula (I) is 2,6-diamino-9- (N-benzenesulfonyl-4).
-Thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- ( N- (4-isopropylbenzenesulfonyl)
-4-Thia-2-pyrrolidinylmethyl) purine, 2,6
-Diamino-9- (N- (4-tert-butylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 2,6-diamino-9- (N- (4-methoxybenzenesulfonyl)- 4-thia-2-pyrrolidinylmethyl) purine, 2-amino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine,
2-Amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, 2-amino-9- (N- (4-methoxybenzenesulfonyl) -4-thia -2-Pyrrolidinylmethyl) purine, 6-amino-9- (Np-toluenesulfonyl)
-4-thia-2-pyrrolidinylmethyl) purine, and 6
The compound according to claim 5, which is a compound selected from the group consisting of -amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine. 7. The purine derivative represented by the formula (I) is (S) -2,6-diamino-9- (N-benzenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine,
(S) -2,6-Diamino-9- (Np-toluenesulfonyl-4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9- (N- (4 -Isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2,6-diamino-9
-(N- (4-tert-butylbenzenesulfonyl) -4
-Thia-2-pyrrolidinylmethyl) purine, (S)-
2,6-Diamino-9- (N- (4-methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2-amino-9- (Np-toluenesulfonyl- 4-thia-2-pyrrolidinylmethyl) purine, (S) -2-amino-9- (N- (4-isopropylbenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -2-amino-9- (N- (4
-Methoxybenzenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, (S) -6-amino-9-
(Np-toluenesulfonyl) -4-thia-2-pyrrolidinylmethyl) purine, and (S) -6-amino-9.
-(N- (4-isopropylbenzenesulfonyl) -4
The compound according to claim 6, which is a compound selected from the group consisting of -thia-2-pyrrolidinylmethyl) purine. 8. An antiviral agent containing the compound according to any one of claims 1 to 7 as an active ingredient. 9. The antiviral agent according to claim 8, which is a drug for treating or preventing acquired immunodeficiency syndrome.