JPH09169758A - New purine nucleoside derivative, its production and antivirus using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new purine nucleoside derivative excellent in antiviral activity such as anti-human immune deficiency virus activity, low in toxicity, effective for treating and preventing a virus disease such as acquired immune deficiency syndrome. SOLUTION: A compound is shown by formula I (R1 is H, amino, a halogen, OH or methoxy; R2 is H, amino or a halogen; R3 is H or amino; * is an asymmetric carbon) or its salt such as (±)-2,6-diamino-9-(N-p-toluenesulfonyl- pyrrolidinyl-2-methyl)-purine. The compound of formula I is obtained by reducing a proline to give 2-hydroxymethylpyrrolidine, tosylating the compound to give a compound of formula II (Ts is p-toluenesulfonyl) and coupling the compound of formula II with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound effective as an antiviral agent including anti-human immunodeficiency virus, and particularly to a novel purine nucleoside derivative or a salt thereof, a process for producing them, and an active ingredient thereof. Anti-viral agent.

[0002]

2. Description of the Related Art The number of patients with acquired immunodeficiency syndrome (hereinafter abbreviated as AIDS) is increasing worldwide. Particularly in Asia, mainly in Southeast Asia, human immunodeficiency virus (hereinafter abbreviated as HIV), which is the cause of AIDS, is in an explosive state of infection, and it is considered that AIDS patients will rapidly increase mainly in these areas.

On the other hand, in Japan, as an AIDS therapeutic agent or an AIDS preventive agent having an anti-HIV effect,
A nucleic acid compound, azidothymidine (hereinafter abbreviated as AZT),
2 ′, 3′-dideoxycytidine (hereinafter abbreviated as ddC), and 2 ′, 3′-dideoxyinosine (hereinafter d)
Only three types (abbreviated as dI) have been approved.
It is considered that these nucleic acid drugs exert anti-HIV activity by acting on the reverse transcription process in the life cycle of HIV.

However, although these certified drugs have strong antiviral activity, they have a problem that continuous administration for a long period of time becomes impossible due to strong side effects and the like.
In addition, since drug-resistant strains were detected in patients who had been administered for a long period of time, it has become clinically extremely difficult to continue administration to patients while maintaining the effect of antiviral agents. .

[0005] Further, although it is considered to use a vaccine for the purpose of prevention of onset, it is difficult to develop an effective vaccine because the antigenic protein on the HIV envelope is changed by mutation. There is a situation. Therefore, it is necessary to search for and provide a novel antiviral agent having excellent antiviral activity including anti-HIV and low toxicity, or a lead compound that can be such an antiviral agent.
It has become an urgent and important task to make the treatment or prevention of viral diseases including DS more effective.

[0006]

Therefore, as a result of intensive studies to solve the above problems, the present inventors have found that a coupling between an amino acid derivative and a purine derivative having a sulfonyl group, which is a strong electronegative group. It was found that a novel purine nucleoside derivative having a reaction structure as a basic skeleton has excellent antiviral activity under physiological environment,
The present invention has been reached.

Therefore, the first object of the present invention is to provide a novel purine nucleoside derivative having an antiviral effect. The second object of the present invention is to provide a novel method for producing a purine nucleoside derivative having an antiviral effect. A third object of the present invention is to provide an antiviral agent containing a novel purine nucleoside derivative as an active ingredient.

[0008]

Means for Solving the Problems The above-mentioned objects of the present invention are as follows: Purine nucleoside derivatives represented by the following chemical formula 3, or salts thereof, a method for producing the same, and antiviral agents containing the same. Achieved by

Embedded image However, in the formula, R ₁ represents a hydrogen atom, an amino group, a hydroxyl group, a halogen atom, or a methoxy group, R ₂ represents a hydrogen atom, an amino group, a halogen atom, and R ₃ represents a hydrogen atom or an amino group. Further, * in the formula represents an asymmetric carbon.

The novel purine nucleoside derivatives of the present invention show different antiviral effects depending on the substituents R ₁ , R ₂ and R ₃ . The types of purine derivatives are not particularly limited as long as R ₁ , R ₂ and R ₃ satisfy the above conditions,
An anti-HIV effect was confirmed in each case. The main specific examples of the derivative of the present invention are listed below.

[0010] 1. (±) -2,6-diamino-9 represented by Chemical Formula 4
-(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (DASP).

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However, * in the formula represents an asymmetric carbon. 2. (±) -2-Amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine represented by Chemical formula 5.

Embedded image However, * in the formula represents an asymmetric carbon.

3. (S) -2,6-diamino-9- represented by Chemical formula 6
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

[Chemical 6]

4. (R) -2,6-diamino-9- represented by Chemical formula 7
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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5. (S) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl)-
Pudding (MASP).

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6. (R) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl)-represented by Chemical formula 9
Pudding (MASP).

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[7] (S) -9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -adenine represented by Chemical formula 10.

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8. (R) -9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -adenine represented by Chemical formula 11.

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9. (S) -6-chloro-9- (N-
Paratoluenesulfonyl-pyrrolidinyl-2-methyl)
-Pudding.

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10. (S) -2-amino-6- represented by Chemical formula 13
Chloro-9- (N-paratoluenesulfonyl-pyrrolidinyl-
2-Methyl) -purine.

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11. (S) -2-amino-6- represented by Chemical formula 14
Methoxy-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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[12] (R) -6-chloro-9- represented by Chemical formula 15
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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13. (R) -2-amino-6- represented by Chemical formula 16
Chloro-9- (N-paratoluenesulfonyl-pyrrolidinyl-
2-Methyl) -purine.

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14. (R) -2-amino-6- represented by Chemical formula 17
Methoxy-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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15. Embedded image (S) -9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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16. (R) -9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine represented by Chemical formula 19.

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17. (S) -2,6-dichloro represented by Chemical formula 20
-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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18. (S) -6-iodo-9- represented by Chemical formula 21
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine

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19. (S) -6-cyano-9- represented by Chemical formula 22
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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20. (S) -6-hydroxy represented by Chemical formula 23
-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

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21. (S) -2-amino-6- represented by Chemical formula 24
Hydroxy-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine

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Each of the novel purine nucleoside derivatives of the present invention is produced by using the purine derivative, which is a nucleobase, and proline, which is an amino acid, as the raw materials according to the three steps shown in the following Chemical formula 25.

Embedded image However, * in the formula represents an asymmetric carbon.

The first step in the production method of the present invention is a step of reducing the carboxyl group of proline which is a raw material compound to a compound represented by the following chemical formula 26 by a reducing agent. As the proline used here, either D-proline or L-proline is selected depending on the purine nucleoside derivative to be obtained.

Embedded image However, * in the formula represents an asymmetric carbon.

The reducing agent in this step can be appropriately selected from known ones, but it is particularly preferable to use lithium aluminum hydride (LiAlH ₄ ). The amount of the reducing agent used is 1.5 to 2.0 with respect to 1 mol of proline.
It is preferably molar.

The reaction solvent is not particularly limited as long as it is a solvent suitable for the reduction reaction, but in the present invention, dehydrated tetrahydrofuran is particularly preferably used. Also,
The reduction reaction is preferably performed by heating under reflux in a nitrogen atmosphere. The product represented by Chemical formula 26 obtained by the reduction reaction can be used as a raw material for the next step without any particular purification.

The second step in the production method of the present invention is a tosylation reaction, in which the amino group and the primary alcoholic hydroxyl group of the compound represented by the above chemical formula 26 are protected by a protecting group for the paratoluenesulfonyl group. 27 is a step of obtaining the compound represented by 27.

Embedded image However, Ts in the formula represents a paratoluenesulfonyl group,
* Represents an asymmetric carbon.

The tosylation reaction carried out here may be carried out according to a conventional method, for example, using dehydrated pyridine as a solvent at 0 ° C. in a nitrogen atmosphere to remove the amino group and primary alcoholic hydroxyl group of the compound represented by the above chemical formula 26. The compound represented by Chemical formula 27 can be obtained by p-toluenesulfonylation and isolating the obtained product by silica gel column chromatography or the like. The amount of p-toluenesulfonyl chloride used is preferably 2.2 to 4.0 mol with respect to 1 mol of the compound represented by Chemical formula 26.

The third step in the production method of the present invention is a step of obtaining the purine nucleoside derivative of the present invention by coupling the obtained compound represented by Chemical formula 27 with a purine derivative. The coupling reaction referred to herein may be carried out according to a conventional method, for example, in a dehydrated dimethylformamide (DMF) solvent under a nitrogen atmosphere, 18-crown-6 in an equimolar amount to the above purine derivative, and 2 times in molar amount of K. ₂ CO ₃ was added and after stirring at room temperature for 30-60 minutes,
A dehydrated DMF solution of the compound represented by the chemical formula 27 is added dropwise, and the obtained mixed solution is stirred at 80 ° C. overnight.

The obtained compound can be separated and purified by appropriately combining the usual methods used for the isolation and purification of nucleosides. For example, as a separation and purification method,
After distilling off the solvent, a method of crystallization from a suitable solvent such as ethanol or freeze-drying can be mentioned. Further, in these methods, the product can be obtained by combining ion exchange column chromatography such as ion exchange resin and adsorption column chromatography such as activated carbon as necessary.

Next, the method for producing the purine nucleoside derivative of the present invention is described by using (±) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine,
(±) -2-Amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine, (S) -2,6-diamino-9-
To illustrate a method for producing (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine and (S) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. Will be described in more detail.

First, the carboxyl groups of D- and L-proline used as a raw material are reduced to a compound represented by the above chemical formula 26 with a reducing agent, and then the amino group and alcoholic hydroxyl group of the obtained compound after reduction are reduced. Is protected with a protecting group, a paratoluenesulfonyl group. Finally, the protected compound is coupled with 2,6-diaminopurine to give (±) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. can get.

In the final coupling reaction,
Replacing 2,6-diaminopurine with 2-aminopurine gives (±) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. In addition,
As a raw material, if a mixture of D- and L-proline is L-proline only and the above steps are performed, (S)-
2,6-Diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine and (S) -2-amino-9-
(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine can be obtained.

In general, the toxicity of antiviral agents is CC ₅₀ value (50% cytotoxic concentration; the higher the value, the lower the toxicity), and its activity is EC ₅₀ value (suppresses 50% of virus). Effective concentration of the drug; the smaller the value, the higher the activity). Furthermore, an SI value represented by the following formula can be given as an index in consideration of both antiviral activity and toxicity. SI = CC ₅₀ value / EC ₅₀ value The above SI is called a therapeutic index, and a larger value means a better antiviral agent.

The purine nucleoside derivative of the present invention is a generally known nucleic acid antiviral agent such as HI.
The ddI to V, dideoxyadenosine (dd
Like A) or acyclovir against herpes virus, it has a common feature of having a purine base as a partial structure. However, the purine nucleoside derivative of the present invention has an intracellular structure such as dideoxyribose as a nucleic acid moiety found in ddI and ddA, and 2-hydroxyethoxymethyl group which is a pseudo sugar found in acyclovir and the like. Does not have a hydroxyl group that is phosphorylated.

Therefore, all of the purine nucleoside derivatives of the present invention have low cytotoxicity (the highest CC ₅₀ value is only 20 μg / ml), and have antiviral activity and cell death inhibitory effect. Among them, the following four types of purine nucleoside derivatives have particularly excellent effects. Their EC ₅₀ values are 13.5μ each
g / ml, 6.1 μg / ml, 12.
The values are as low as 8 μg / ml and 5.9 μg / ml.

1. (±) -2,6-Diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. 2. (S) -2,6-Diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. 3. (±) -2-Amino-9- (N-paratoluenesulfonyl-
Pyrrolidinyl-2-methyl) -purine. 4. (S) -2-Amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine.

Furthermore, since the mechanism of action of the purine nucleoside derivative of the present invention is different from that of conventional anti-virus agents, conventionally known nucleic acid antiviral agents, protease inhibitors and the like are referred to as purine nucleoside derivatives of the present invention. When used in combination, it can exert a higher effect, especially for the treatment of anti-HIV and AIDS-related syndrome (ARC).

In order to sufficiently bring out such an effect clinically, any one of the purine nucleoside derivatives of the present invention, including the above-mentioned four types of purine nucleoside derivatives having particularly antiviral activity, can be conveniently used for medical purposes. The nucleoside derivative may be used by synthesizing it into a physiologically acceptable salt. The salt here may be a salt derived from a suitable base, and examples thereof include alkali metal (sodium etc.) salts, alkaline earth metal (magnesium etc.) salts, ammonium salts, and NX ⁴⁺ (X is And a quaternary ammonium salt represented by (C _1-4 alkyl). Incidentally, a salt having a physiologically unacceptable anion can also be used as an intermediate useful in a method for producing a physiologically acceptable salt or as a non-therapeutic agent in studies outside the cell system,
Included in the salts of the purine nucleoside derivatives of the present invention.

The purine nucleoside derivative of the present invention has 1
One or two or more species may be used alone for the treatment or prevention of viral infections, but provided as a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers and / or other therapeutic ingredients. You can also The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient.

When the purine nucleoside derivative of the present invention is provided together with other therapeutic ingredients, for example, 3'-deoxy-3'-azidothymidine (zidovudine) used for the treatment of human immunodeficiency virus (HIV) infection or 2 ', 3'-
Such as dideoxyinosine, 2 ', 3'-dideoxyadenosine
Administration of the purine nucleoside derivatives of the present invention with 2 ', 3'-dideoxynucleosides, HIV prodease inhibitors, interferons, soluble proteins such as CD4, or other agents such as analgesics or antipyretics. This is the case.

The antiviral agent of the present invention is prepared by a well-known method well known in the field of pharmacy and provided as a unit dosage form. The above methods of preparation include the step of bringing into association the active ingredient with the carrier which constitutes at least one accessory ingredient. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquids and / or finely divided solids and then, if necessary, shaping the product.

The antiviral agents of the invention suitable for oral administration may be in the form of individual units, eg capsule tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as an aqueous or non-aqueous liquid or suspension. Alternatively, it is provided as an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may be presented as a pill or paste, and tablets which may be included within the ribosome may be prepared by compression or molding, optionally with one or more accessory ingredients.

The antiviral agent of the present invention can be applied to mammals including humans (hereinafter referred to as “administered person”) by mouth including oral, sublingual, rectal, nasal, vaginal, subcutaneous, intramuscular, Administered by any parenteral route such as intravenous. The administration route is appropriately selected depending on, for example, the age, weight, sex of the recipient, the nature of the condition to be treated, and the lightness or weight thereof.

The amount of the purine nucleoside derivative of the present invention required for the treatment or prevention of viral infections depends on several factors such as the severity of the condition to be treated and the age of the recipient. However, in general, a suitable effective dose for each condition is within the range of 1 to 200 mg / kg body weight per day, particularly preferably 10 to 100 mg / kg body weight per day.

This effective dose may be divided into two, three, four or more subdivided small doses to be administered at appropriate intervals throughout the day. These doses range from 100 to 60
Although it may be administered as a unit dosage form containing 0 mg of the antiviral agent of the present invention, it is also possible to administer an effective amount as a continuous infusion.

[0055]

BEST MODE FOR CARRYING OUT THE INVENTION The purine nucleoside derivative of the present invention is a compound obtained by protecting the amino group and primary alcohol group of reduced proline with a paratoluenesulfonyl group, etc. Therefore, it is synthesized and is effective as an antiviral agent.

[0056]

The purine nucleoside derivative of the present invention is
Since it has a sulfonyl group, which is a strong electronegative group, in its molecule, it has sugar moieties such as ribose, deoxyribose, dideoxyribose, which are found in general nucleic acid antiviral agents, while having a nucleobase as a partial structure. It is a substance that does not have a completely new structure. Therefore, HIV has a different mechanism of action from that of conventional antiviral agents.
Can be used to treat or prevent the onset of the virus.

[0057]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.
Unless otherwise specified, “%” described below means “% by weight”.

Example 1. ((S) -2,6-diamino-9- (N-paratoluenesulfonyl-pi-
Roridinyl-2-methyl) -purine] : 1. Synthesis of (S) -2-hydroxypyrrolidine (first production step): 6.0 g (156 mmol) of LiAlH ₄ (lithium aluminum hydride) was placed in a 500 ml three-necked round bottom flask and dehydrated tetrahydrofuran (maximum water content) Is 0.005
%), And the mixture was heated under reflux in an oil bath for 15 minutes, and then about 0.2 g of 8.9 g (100 mmol) of L-proline was added.
Each was added slowly. After the addition was completed, the mixture was refluxed for another hour.

After confirming the completion of the reaction by thin layer chromatography (TLC), the heating was stopped,
A 2.8 g / 11 ml aqueous potassium hydroxide solution was slowly added dropwise over 20 minutes, and the mixture was further refluxed for 25 minutes and immediately suction filtered. The obtained filtrate was concentrated under reduced pressure at 30 ° C. and then vacuum dried to obtain a light yellow oily substance. The yield was 90%, and the transfer rate (R _f value) was 0.4.
7 (n-butanol: acetic acid: water = 6: 2: 2). In addition, the structural formula was confirmed by the NMR measurement results of the compound shown in Table 1.

[0060]

[Table 1] ──────────────────────── ¹ H-NMR (D ₂ O) δ (ppm) ¹³ C-NMR (D ₂ O) δ (ppm) ──────────────────────── 1.33-1.42 (1H, m, Hc) 25.27 (Cd) 1.70-1.76 (2H, m, Hd) 28.19 (Cc) 1.82-1.90 (1H, m, Hc) 46.13 (Ce) 2.76-2.88 (2H, m, He) 59.70 (Cb) 3.12-3.19 (1H, m, Hb) 65.28 (Ca) 3.47- 3.54 (2H, m, Ha) 4.85 (1H, s, Hf) ─────────────────────────

2. Synthesis of (S) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxy-methylpyrrolidine (second production step): 2.0 g (20 mmol) of (S) -2-hydroxypyrrolidine in 100 ml three-necked The mixture was placed in a round bottom flask, 10 ml of dehydrated pyridine (maximum water content was 0.005%) was added, and the mixture was stirred at 0 ° C for a while. Next, p-toluenesulfonyl chloride 11.7 g (62 mmol) / 20 ml dehydrated pyridine solution was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes.

After confirming the completion of the reaction by thin layer chromatography (TLC), the reaction solution was added to ice water and extracted with ethyl acetate. Pyridine 1N-H
After removing by extraction with Cl and concentrating under reduced pressure at 30 ° C, preparative TL
Purification by C (ethyl acetate: n-hexane = 1: 3) gave white crystals. The yield is 85%
The transfer rate (R _f value) was 0.31 (acetic acid: n-hexane = 1: 3). The structural formula was confirmed by the NMR measurement results of the compound shown in Table 2.

[0063]

[Table 2]

3. Synthesis of (S) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (third production step): 80.3 mg (0.54 mmol) of 2,6-diaminopurine, 145.7 mg (1.06 mmol) K ₂ CO ₃ , and
131 mg (0.50 mmol) of 18-crown-6 was placed in a 50 ml three-necked round bottom flask and dehydrated N, N-dimethylformamide (hereinafter abbreviated as DMF) (maximum water content was 0.005%).
10 ml, and stirred for 1 hour at room temperature under a nitrogen atmosphere, and then (S)-
N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine 205.5mg (0.50mmol) / 5mlD
The MF solution was added dropwise at room temperature and then stirred at 80 ° C. for 2 hours.

After confirming the completion of the reaction by thin layer chromatography (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. The yield is 61.2%, and the transfer rate (R
_{The f} value) was 0.69 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). Also,
The structural formula was confirmed by the NMR measurement results of the compound shown in Table 3. The optical rotation of the compound [α] ²⁵
Is -91.0 ° (C = 1.0, MeOH) and FAB-MASS value is 38 each.
It was 8 (M + 1) and 386 (M-1).

[0066]

[Table 3]

Example 2. ((R) -2,6-diamino-9- (N-paratoluenesulfonyl-pi
Roridinyl-2-methyl) -purine] : 1. Synthesis of (R) -2-hydroxypyrrolidine (first production step): Light yellow and oily in the same manner as in the first step of Example 1 except that L-proline as a raw material was replaced with D-proline. Of (R) -2-hydroxypyrrolidine was synthesized. still,
The yield was 90%, and the transfer rate (R _f value) was 0.47 (n
-Butanol: acetic acid: water = 6: 2: 2). or,
¹ H-N measured to confirm the structural formula of the purified product
MR (δ (ppm) / D ₂ O) and ¹³ C-NMR (δ
The result of (ppm) / D ₂ O) was exactly the same as the result of (S) -2-hydroxypyrrolidine obtained in the first step of Example 1.

2. Synthesis of (R) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine (second production step): (R) -2-hydroxypyrrolidine in place of (S) -2-hydroxypyrrolidine as a raw material Example 1
White crystals of (R) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine were synthesized in exactly the same manner as in the second production step. The yield is 77.
At 3%, the transfer rate (R _f value) was 0.31 (acetic acid: n-hexane = 1: 3). In addition, ¹ H-NMR (δ (ppm) / measured to confirm the structural formula of the purified product was obtained.
CDCl ₃ ) and ¹³ C-NMR (δ (ppm) / CDC
l ₃ ) results were obtained in the second manufacturing step of Example 1.
The results were exactly the same as for (S) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine.

3. Synthesis of (R) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (3rd production step): (S) -N-paratoluenesulfonyl-2- starting material (R) -2, except that the paratoluenesulfonyloxymethylpyrrolidine was replaced with (R) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine (R) -2, 6-diamino-9
-(N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine was purified. The yield is 57.2%,
The transfer rate (R _f value) is 0.69 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1), the optical rotation [α] ²⁵ of the compound is + 91.7 ° (C = 1.0, MeOH), and FA
The B-MASS values were 388 (M + 1) and 386 (M-1), respectively.

Embodiment 3 FIG. [(±) -2,6-diamino-9- (N-paratoluenesulfonyl
-Pyrrolidinyl-2-methyl) -purine] : Synthesis of (±) -2-hydroxypyrrolidine (first production step): exactly the same as the first production step of Example 1 except that (±) -D, L-proline was used as the raw material L-proline. As a result, pale yellow, oily (±) -2-hydroxypyrrolidine was synthesized. The yield is 87%, and the transfer rate (R
_f value) is 0.47 (n-butanol: acetic acid: water = 6:
2: 2).

2. (±) -N-paratoluenesulfonyl-2
-Synthesis of paratoluenesulfonyloxymethylpyrrolidine (second production step): The second production step of Example 1 except that (S) -2-hydroxypyrrolidine as a raw material was replaced with (±) -2-hydroxypyrrolidine White crystals of (±) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine were synthesized in exactly the same manner. The yield was 70.0%, and the transfer rate (R _f value) was 0.31 (acetic acid: n-hexane = 1: 3).

3. Synthesis of (±) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (3rd production step): (S) -N-paratoluenesulfonyl-2- starting material (±) Except for replacing paratoluenesulfonyloxymethylpyrrolidine with (±) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine, exactly the same as in the third production step of Example 1, (±)
-2,6-Diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine was purified. The yield was 52.0% and the transfer rate (R _f value) was 0.69 (CH ₂ Cl ₂ :).
At CH ₃ OH = 9: 1), the FAB-MASS value was 388 (M + 1).

Embodiment 4 FIG. [(±) -2-Amino-9- (N-paratoluenesulfonylpyrroyl
Production of lysinylmethyl) -purine] : 1. Synthesis of (±) -2-hydroxypyrrolidine (first production step): exactly the same as the first production step of Example 1 except that (±) -D, L-proline was used as the raw material L-proline. As a result, pale yellow, oily (±) -2-hydroxypyrrolidine was synthesized. The yield was 92%, and the transfer rate (R
_f value) is 0.47 (n-butanol: acetic acid: water = 6:
2: 2).

2. (±) -N-paratoluenesulfonyl-2
-Synthesis of paratoluenesulfonyloxymethylpyrrolidine (second production step): The second production step of Example 1 except that (S) -2-hydroxypyrrolidine as a raw material was replaced with (±) -2-hydroxypyrrolidine White crystals of (±) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine were synthesized in exactly the same manner. The yield was 80.0% and the transfer rate (R _f value) was 0.31 (acetic acid: n-hexane = 1: 3).

3. Synthesis of (±) -2-amino-9- (N-paratoluenesulfonylpyrrolidinylmethyl) -purine (3rd
(Production process): 80.3 mg (0.54 mmol) of 2,6-diaminopurine as a raw material was replaced with 72.5 mg (0.54 mmol) of 2-aminopurine, and (±) -N-paratoluene obtained in the second production process was used. (±) -2-Amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2 was prepared in the same manner as in the third production step of Example 1 except that sulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine was used. -Methyl) -purine was purified. The yield was 55.0%, the transfer rate (R _f value) was 0.78 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1), and the FAB-MASS value was 374 (M +
It was 1).

Embodiment 5 FIG. [(S) -2-amino-9- (N-paratoluenesulfonyl-pyrroli
Dinylmethyl) -purine] Synthesis of (S) -2-hydroxypyrrolidine (first production step): In the same manner as in the first production step of Example 1, pale yellow, oily (S) -2-hydroxypyrrolidine was synthesized. The yield was 90%, and the transfer rate (R _f value) was 0.
It was 47 (n-butanol: acetic acid: water = 6: 2: 2). In addition, ¹ H-NMR (δ (ppm) / D ₂ O) and ¹³ C-N measured to confirm the structural formula of the purified product were obtained.
The result of MR (δ (ppm) / D ₂ O) was exactly the same as the result of (S) -2-hydroxypyrrolidine obtained in the first production process of Example 1.

2. Synthesis of (S) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine (second production step): White crystals of (S) -N- were obtained in exactly the same manner as in the second production step of Example 1. Paratoluenesulfonyl-2-
Paratoluenesulfonyloxymethylpyrrolidine was synthesized. The yield was 85.0%, and the transfer rate (R _f value)
Was 0.31 (acetic acid: n-hexane = 1: 3).
In addition, it was measured to confirm the structural formula of the purified product ¹
1 H-NMR (δ (ppm) / CDCl ₃ ) and ¹³ C-N
The results of MR (δ (ppm) / CDCl ₃ ) are shown in Example 1.
Was the same as the result of (S) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxymethylpyrrolidine obtained in the second production step.

3. Synthesis of (S) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (3rd production step): 80.3 mg (0.54 mmol) of the starting material 2,
(S)-was carried out in exactly the same manner as in Example 1 except that 72.5 mg (0.54 mmol) of 2-aminopurine was used instead of 6-diaminopurine.
2-Amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine was purified. The yield is 5
7.9%, transfer rate (R _f value) is 0.78 (CH ₂ Cl ₂ : CH ₃ OH =
At 9: 1), the FAB-MASS value was 374 (M + 1). Table 4
The structural formula was confirmed by the NMR measurement result of the compound shown in FIG.

[0079]

[Table 4]

Embodiment 6 FIG. [(R) -2-amino-9- (N-paratoluenesulfonyl-pyrroli
Dinylmethyl) -purine] Synthesis of (R) -2-hydroxypyrrolidine (first production step): (R) -2-hydroxypyrrolidine in the form of a pale yellow oil was synthesized in the same manner as in the first production step of Example 2. The yield was 90%, and the transfer rate (R _f value) was 0.
It was 47 (n-butanol: acetic acid: water = 6: 2: 2). In addition, ¹ H-NMR (δ (ppm) / D ₂ O) and ¹³ C-N measured to confirm the structural formula of the purified product were obtained.
The results of MR (δ (ppm) / D ₂ O) are as shown in Table 5.

[0081]

[Table 5] ──────────────────────── ¹ H-NMR (D ₂ O) δ (ppm) ¹³ C-NMR (D ₂ O) δ (ppm) ──────────────────────── 1.33-1.41 (1H, m, Hc) 25.36 (Cd) 1.69-1.76 (2H, m, Hd) 28.28 (Cc) 1.82-1.88 (1H, m, Hc) 46.19 (Ce) 2.76-2.88 (2H, m, He) 59.77 (Cb) 3.11-3.18 (1H, m, Hb) 65.37 (Ca) 3.50- 3.52 (2H, m, Ha) 4.83 (1H, s, Hf) ────────────────────────

2. Synthesis of (R) -N-paratoluenesulfonyl-2-paratoluenesulfonyloxy-methylpyrrolidine (second production step): White crystals of (R) -N were obtained in exactly the same manner as in the second production step of Example 2. -Paratoluenesulfonyl-2-
Paratoluenesulfonyloxymethylpyrrolidine was synthesized. The yield was 77.3%, and the transfer rate (R _f value)
Was 0.31 (acetic acid: n-hexane = 1: 3).
In addition, it was measured to confirm the structural formula of the purified product ¹
1 H-NMR (CDCl ₃ ) δ (ppm) and ¹³ C-NM
The results of R (CDCl ₃ ) δ (ppm) are as shown in Table 6.

[0083]

[Table 6]

3. Synthesis of (R) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine (third production step): 80.3 mg (0.54 mmol) of the starting material 2,
(S) -2-Amino-9- (N-para) was prepared in exactly the same manner as in the third production step of Example 2, except that 72.5 mg (0.54 mmol) of 2-aminopurine was used instead of 6-diaminopurine. Toluenesulfonyl-pyrrolidinyl-2-methyl) -purine was purified.
The yield was 61.0% and the transfer rate (R _f value) was 0.7.
At 8 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1), the FAB-MASS value was 373 (M + 1). Further, the structural formula was confirmed by the NMR measurement result of the compound shown in Table 7.

[0085]

[Table 7]

Example 7. (S) -9- (N-paratoluenesulfonylpyrrolidinyl methyl ester
Synthesis of ( l) -adenine : (S) -9- (N) in exactly the same manner as in Example 1 except that 2-aminopurine as a raw material was replaced with adenine.
-Paratoluenesulfonylpyrrolidinylmethyl) -adenine was purified. The yield is 56% and the transfer rate (R _f
The value) was 0.61 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). The structural formula was confirmed by the NMR measurement results of the compound shown in Table 8. The optical rotation [α] ²⁷ of the compound is
At -105.6 ° (DMSO), the FAB-MASS value was 373 (M + 1).

[0087]

[Table 8]

Embodiment 8 FIG. (R) -9- (N-paratoluenesulfonylpyrrolidinyl methyl ester
Synthesis of ( l) -adenine : (R) -9- (N) in the same manner as in Example 2 except that 2-aminopurine as a raw material was replaced with adenine.
-Paratoluenesulfonylpyrrolidinylmethyl) -adenine was purified. The yield was 45.3% and the transfer rate (R _f value) was 0.61 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). Further, the structural formula was confirmed by the NMR measurement result of the compound shown in Table 9. The optical rotation [α] ²⁷ of the compound was -104.3 ° (DMSO), and the FAB-MASS value was 373 (M + 1).
Met.

[0089]

[Table 9]

Example 9. (S) -6-Chloro-9- (N-paratoluenesulfonylpyrrolidini
Rumethyl) -purine synthesis
(S) -6-chloro-9- (N-paratoluenesulfonylpyrrolidinylmethyl) -purine was purified in exactly the same manner as in Example 1 except that chloropurine was used instead. The yield is 1
3.3%, transfer rate (R _f value) 0.59 (CH ₂ Cl ₂ : CH ₃ OH =
99.5: 0.5). The structural formula was confirmed by the NMR measurement results of the compound shown in Table 10.
The FAB-MASS value was 393 (M + 1).

[0091]

[Table 10]

Example 10. (S) -2-Amino-6-chloro-9- (N-paratoluenesulfonyl
Synthesis of Pyrrolidinylmethyl) -purine : (S) -2-Amino-6-in the same manner as in Example 1 except that 2-aminopurine as a starting material was replaced with 2-amino-6-chloropurine. Chloro-9- (N-
Paratoluenesulfonylpyrrolidinylmethyl) -purine was purified. The yield is 50.7% and the transfer rate (R _f
The value) was 0.51 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). Further, the structural formula was confirmed by the NMR measurement results of the compound shown in Table 11. The FAB-MASS value was 408 (M + 1).

[0093]

[Table 11]

Example 11. (S) -2-Amino6-methoxy-9- (N-paratoluenesulfonyl
Synthesis of pyrrolidinylmethyl) -purine : (S) -2-amino6-methoxy in the same manner as in Example 1 except that 2-aminopurine as a starting material was replaced with 2-amino-6-methoxypurine. -9-
(N-paratoluenesulfonylpyrrolidinylmethyl) -purine was purified. The yield was 46.5%, and the transfer rate (R _f value) was 0.53 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). The structural formula was confirmed by the NMR measurement results of the compound shown in Table 12. The FAB-MASS value is 404.
It was (M + 1).

[0095]

[Table 12]

Example 12.(R) -6-Chloro-9- (N-paratoluenesulfonylpyrrolidini
Lumethyl) -purine synthesis : 6-amino acid 2-aminopurine
Except for replacing with chloropurine, the same procedure as in Example 1 was carried out.
(R) -6-chloro-9- (N-paratoluenesulfonylpyrroli
Dinylmethyl) -purine was purified. The yield is 2
6.8%, migration rate (R_fValue) is 0.59 (CH_TwoCl _Two: CH_ThreeOH =
99.5: 0.5). Also, the compounds shown in Table 13
The structural formula was confirmed by the NMR measurement result of.
The FAB-MASS value was 393 (M + 1).

[0097]

[Table 13]

Example 13 (R) -2-Amino6-chloro-9- (N-paratoluenesulfonylpyrrole
Synthesis of loridinylmethyl) -purine : (R) -2-amino6-chloro-9-in the same manner as in Example 2 except that 2- aminopurine as a starting material was replaced with 2-amino-6-chloropurine. (N-paratoluenesulfonylpyrrolidinylmethyl) -purine was purified. The yield was 47.3% and the transfer rate (R _f value)
Was 0.51 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). In addition, Table 14
The structural formula was confirmed by the NMR measurement result of the compound shown in FIG. The FAB-MASS value was 408 (M + 1).

[0099]

[Table 14]

Example 14. (R) -2-Amino6-methoxy-9- (N-paratoluenesulfonyl
Synthesis of pyrrolidinylmethyl) -purine : (R) -2-amino6-methoxy in the same manner as in Example 2 except that 2-aminopurine as a starting material was replaced with 2-amino-6-methoxypurine. -9-
(N-paratoluenesulfonylpyrrolidinylmethyl) -purine was purified. The yield was 50.2% and the transfer rate (R _f value) was 0.53 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). Further, the structural formula was confirmed by the NMR measurement result of the compound shown in Table 15. The FAB-MASS value is 404.
It was (M + 1).

[0101]

[Table 15]

Example 15. (S) -9- (N-paratoluenesulfonyl-pyrrolidinyl methyl
Synthesis of ( l) -purine : (S) -9- (N- in the same manner as in Example 1 except that the starting 2-aminopurine was replaced with purine.
Paratoluenesulfonyl-pyrrolidinylmethyl) -purine was purified. The yield is 50.3% and the transfer rate (R
_{The f} value) was 0.55 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5), and the FAB-MASS value was 358 (M + 1). The structural formula was confirmed by the NMR measurement results of the compound shown in Table 16.

[0103]

[Table 16]

Example 16. (R) -9- (N-paratoluenesulfonyl-pyrrolidinyl methyl
Synthesis of ( l) -purine : (R) -9- (N- in the same manner as in Example 2 except that the starting 2-aminopurine was replaced with purine.
Paratoluenesulfonyl-pyrrolidinylmethyl) -purine was purified. The yield is 50.3% and the transfer rate (R
_{The f} value) was 0.55 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5), and the FAB-MASS value was 358 (M + 1). In addition, the structural formula was confirmed by the NMR measurement results of the compound shown in Table 17.

[0105]

[Table 17]

Example 17 (S) -2,6-Dichloro-9- (N-paratoluenesulfonyl-pyro
Synthesis of lysinylmethyl) -purine : (S) -2,6-dichloro-9- (N- in the same manner as in Example 1 except that the starting 2- aminopurine was replaced with 2,6-dichloropurine. Paratoluenesulfonyl-pyrrolidinylmethyl) -purine was purified.
The yield was 23.0% and the transfer rate (R _f value) was 0.6.
3 (CH ₂ Cl ₂ : CH ₃ OH = 99.5: 0.5), FAB-MASS value is 484 (M +
It was 1).

Example 18. (S) -6-Iodo-9- (N-paratoluenesulfonyl-pyrrolidi
Synthesis of (nylmethyl) -purine : (S) -6-iodo-9- (N-paratoluenesulfonyl-) was prepared in exactly the same manner as in Example 1 except that 2- aminopurine as a raw material was replaced with 6- iodopurine. Pyrrolidinylmethyl) -purine was purified. The yield was 23.0% and the transfer rate (R _f value) was 0.63 (CH ₂ Cl ₂ : CH
₃ OH = 99.5: 0.5), and FAB-MASS value was 484 (M + 1).

Example 19 (S) -6-Cyano-9- (N-paratoluenesulfonyl-pyrrolidi
Synthesis of (nylmethyl) -purine : (S) -6-cyano-9- (N-paratoluenesulfonyl-sulfonyl) in the same manner as in Example 1 except that 2- aminopurine as a raw material was replaced with 6- cyanopurine. Pyrrolidinylmethyl) -purine was purified. The yield was 25.0% and the transfer rate (R _f value) was 0.62 (CH ₂ Cl ₂ : CH
_{At 3} OH = 9: 1), the FAB-MASS value was 383 (M + 1).

Example 20. (S) -6-Hydroxy-9- (N-paratoluenesulfonyl-pyro
Lysinylmethyl) -purine synthesis : 40 mg (0.1 mmol)
(S) -6-Chloro-9- (N-paratoluenesulfonyl-pyrrolidinylmethyl) -purine was added to 1N hydrochloric acid and refluxed for 3 hours. After completion of the reaction, the reaction mixture was neutralized with 40% KOH aqueous solution and then concentrated by a rotary evaporator.
Then, it was purified by HPLC using a mixed solvent of acetonitrile and water (1: 1) to synthesize (S) -6-hydroxy-9- (N-paratoluenesulfonyl-pyrrolidinylmethyl) -purine. The yield was 58%.

Example 21. (S) -2-Amino-6-hydroxy-9- (N-paratoluenesulfo
Synthesis of Nyl-pyrrolidinylmethyl) -purine :
(S) -6-chloro-9- (N-paratoluenesulfonyl-pyrrolidinylmethyl) -purine to (S) -6-hydroxy-9- (N-paratoluenesulfonyl-pyrrolidinylmethyl) -purine Except for the fact that it is the same as in Example 20, (S) -2-amino
-6-Hydroxy-9- (N-paratoluenesulfonyl-pyrrolidinylmethyl) -purine was purified. The yield is 6
5%.

Example 22. Anti-HIV test : HIV-1 (human AIDS virus strain (I
IIB)) infected with 1 × 10 ⁴ proliferating cells of leukocytes (MT-4 cells) and uninfected MT-4 cells together with various concentrations of samples 1, 2 and 3 in 96-wells, respectively. In addition to each well of the microplate, it was cultured for 5 days in a CO ₂ incubator at 37 ° C. From the contents contained in each hole, the holes on the microplate can be classified into the following four types. A: Only MT-4 cells infected with HIV B: Only MT-4 cells not infected with HIV C: MT-4 cells infected with HIV and anti-HIV of the present invention
Agent D: MT-4 cells not infected with HIV and anti-HIV agent of the present invention

These cultured cells were treated with 3- (4,5-dimethyl-2).
-Thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (hereinafter abbreviated as "MTT") was added, and further 2
The culture was continued for an hour. During this period, M taken up by living cells
TT was reduced by an enzyme possessed by mitochondria in cells to form a blue-violet, water-insoluble dye (formazan).

Then, 5% polyethylene glycol alkyl phenyl ether (Triton X-100:
A solution of acidic 2-propyl alcohol containing hydrochloric acid (trade name, manufactured by Sigma) is added to solubilize the produced dye, and the specific absorbance at 595 nm and the specific absorbance at 655 nm are measured by a microplate reader (BI).
O-RAD model 3550), and
Absorbance difference between a pair of cultured cells A to D (ODa, OD
b, ODc and ODd) were determined.

From the values obtained, the anti-HIV assay of Samples 1, 2 and 3 is represented using the formula shown below,
50% cell death inhibitory concentration (EC ₅₀ value) and 50% cytotoxic concentration (CC ₅₀ value) and therapeutic index SI value (SI value = CC
_The results of calculating ( ₅₀ value / EC ₅₀ value) are as shown in Table 18. _{EC 50 = (ODb-ODc)} / (ODb-ODa) CC 50 = (ODb-ODd) / (ODb-ODa)

[0115]

[Table 18]

As is apparent from Table 18, Example 1,
At 3, 4 and 5, EC ₅₀ values (MTT assay) were 6.1 μg / ml, 13.5 μg / ml, 12.8 μg / ml and 5.9 μg / ml, respectively.
Since it showed an anti-HIV effect at a low concentration of milliliter, it was found to be effective as a therapeutic drug for AIDS and ARC. Further, Example 2 had weak activity and did not show an EC ₅₀ value, but EC around 50 μg / mL was obtained.
_It had a mild effect showing ₃₀ (the effect of recovering HIV-infected cells by 30% as compared with the non-medicated one).

Example 23. Preparation of tablets: Tablets A and B having the ingredients shown in Table 19 below were prepared by wet granulating the active ingredient with a solution of povidone and then adding magnesium stearate and compressing.

[Table 19] *: Product name of Japanese Pharmacopoeia Co., Ltd.

Embodiment 24 FIG. Production of Capsule Formulation: Capsule formulations C and D were prepared by mixing the ingredients shown in Table 20 and packing in a two-part hard gelatin capsule.

[Table 20]

Example 25. Preparation of injectable preparation: 0.2 g of the active ingredient is dissolved in a pyrogen-free phosphate buffer solution (pH 7.0) at a temperature of 35 to 40 ° C., and the above buffer solution is further added until the total amount becomes 10 ml. After replenishing, filter through a sterile micropore filter into a sterile 10 ml tan glass bottle (type 1), seal with a sterile lid and overseal, and inject formulation E.
Was prepared.

Example 26. Preparation of syrup preparation: Sodium benzoate 10 mg was dissolved in pure water 2 ml, and then sorbitol solution 1500
mg and 220 mg active ingredient were added. Separately from this, a solution in which 70 mg of cyclodextrin was dispersed in 2000 mg of glycerin was prepared. After mixing these two solutions and supplementing with pure water until the total volume becomes 5.0 ml,
The preparation F for syrup was prepared by aseptic storage.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Kunimitsu Murakami 2-8-1 Iida-cho, Iwakuni-shi, Yamaguchi Nippon Paper Industries Co., Ltd.

Claims (13)

[Claims] 1. A purine nucleoside derivative represented by the following chemical formula 1, or a salt thereof. Embedded image However, in the formula, R ₁ represents a hydrogen atom, an amino group, a hydroxyl group, a halogen atom, or a methoxy group, R ₂ represents a hydrogen atom, an amino group, a halogen atom, and R ₃ represents a hydrogen atom or an amino group. Further, * in the formula represents an asymmetric carbon. 2. The purine nucleoside derivative is (±) -2,6-
The purine nucleoside derivative according to claim 1, which is diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine, or a salt thereof. 3. The purine nucleoside derivative is (S) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-
The purine nucleoside derivative according to claim 2, which is 2-methyl) -purine, or a salt thereof. 4. The purine nucleoside derivative is (±) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2.
The purine nucleoside derivative according to claim 1, which is -methyl) -purine, or a salt thereof. 5. The purine nucleoside derivative is (S) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-
The purine nucleoside derivative according to claim 4, which is methyl) -purine, or a salt thereof. 6. At least one selected from the purine nucleoside derivatives according to claim 1 and salts thereof.
An antiviral agent comprising a seed and at least one pharmaceutically acceptable carrier. 7. At least one selected from the purine nucleoside derivatives according to claim 1 and salts thereof.
An antiretroviral agent comprising a seed and at least one pharmaceutically acceptable carrier. 8. At least one selected from the purine nucleoside derivatives according to claim 1 and salts thereof.
An anti-HIV agent comprising a seed and at least one pharmaceutically acceptable carrier. 9. Proline, a purine derivative, and paratoluenesulfonyl chloride are used as raw materials, and
The method for producing a purine nucleoside derivative according to claim 1, wherein the purine nucleoside derivative is synthesized by a step represented by. Embedded image However, in the formula, R ₁ represents a hydrogen atom, an amino group, a hydroxyl group, a halogen atom, or a methoxy group, R ₂ represents a hydrogen atom, an amino group, a halogen atom, and R ₃ represents a hydrogen atom or an amino group. Further, * in the formula represents an asymmetric carbon. 10. The (±) -2,6-diamino-9-, according to claim 9, wherein the purine derivative is 2,6-diaminopurine.
A method for producing (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine. 11. Production of (S) -2,6-diamino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine according to claim 10, wherein proline is L-proline. Method. 12. The preparation of (±) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine according to claim 9, wherein the purine derivative is 2-aminopurine. Method. 13. The method for producing (S) -2-amino-9- (N-paratoluenesulfonyl-pyrrolidinyl-2-methyl) -purine according to claim 12, wherein proline is L-proline.