JPH09286786A - Pyrimidine derivative and its use as an antitumor agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pyrimidine derivative which manifests toxicity to immortalized cells and is useful for treatment of malignant tumors by coupling a pyrimidine base isolated from RNA of a yeast to a prolinol derivative. SOLUTION: This novel pyrimidine derivative is represented by formula I (R<1> is an amino group or hydroxyl group; R<2> and R<3> are a direct bond, R<1> and R<2> incorporate to form oxo, R<2> is H, N-arylsulfonyl-2-pyrrolidinylmethyl; R<4> is H, halogen, trans-2-halovinyl, 1-5C alkyl; ArS is an arylsulfonyl) or its salt. This pyrimidine reveals toxicity to immortablized cells in a reduced concentration and is very effective for treatment of malignant tumor. The objective compound is prepared by reducing L-proline with a reducing agent to a prolinol derivative, treating the prolinol derivative with an arylsulnonyl chloride to give an N-arylsulfonylated prolinol derivative followed by reaction the sulfonylated prolinol derivative with a pyrimidine base isolated from RNA of a yeast.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a skeleton in which a pyrimidine base released from RNA of yeast or the like and a prolinol derivative derived from the amino acid proline are coupled to each other and a strong electronegative group is present. The present invention relates to a novel antitumor substance having a sulfonyl group (electron-withdrawing group) in its molecule.

[0002]

2. Description of the Related Art In recent years, with the progress of research on various anticancer and antitumor substances, the development of preventive and therapeutic agents for malignant tumors has attracted attention. Conventionally, as examples of chemotherapy-based antitumor agents, nimustine hydrochloride, fluorouracil, 6-mercaptopurine, improsulfan, and busulfan are known (for example, edited by Haruaki Yajima, Masaaki Hirobe, Drug Development, Volume 4) , Synthetic Drugs III Chapter 12 pp. 877-905, 1989
(December 11, 2004, see Hirokawa Shoten), and various other anti-tumor active nucleosides or sulfonyl drugs are being developed.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have synthesized compounds having a basic skeleton of a structure consisting of a nucleic acid base and an amino acid derivative, and investigated their physiological activities. In the examination, (S) -2,6-diamino-9- (N-arylsulfonyl-2-pyrrolidinylmethyl) purine (hereinafter referred to as “DASP”) and its derivatives have excellent antiviral activity. Therefore, we have already applied for a patent (Japanese Patent Application No. 7-294911).

However, until now, of the DASP analogs, the pyrimidine derivative of the present invention (in which the purine base moiety of DASP is replaced with pyrimidine) has not been studied. In the study of DASP analogs, the inventors
As a result of further study on a pyrimidine derivative in which the purine base part of DASP was replaced with pyrimidine, it was found for the first time that strong cytotoxicity was expressed. Generally, DAS
Many of P and its derivatives have low cytotoxicity (MTT
Law (J. Immunol. Methods, 65, 55 (1983)) when using, CC ₅₀ is 100 to 200 [mu] g / ml or more with respect to MT-4 cells), as CC ₅₀ is in the pyrimidine derivative 2
Some of them had an activity of about 3 μg / ml, which was about 100 times higher than that of DASP.

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

[0006]

The present invention includes the following inventions.

(1) The following equation (I):

[0008]

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(Wherein R ¹ represents an amino group or a hydroxyl group, R ² and R ³ together represent another direct bond, or R ¹ and R ² together represent an oxo group. , R ³ is a hydrogen atom or N-arylsulfonyl-2-
Represents a pyrrolidinylmethyl group; R ⁴ represents a hydrogen atom, a halogen atom, a trans-2-halovinyl group, or a carbon number of 1 to 5
Represents an alkyl group, and ArS represents an arylsulfonyl group. ) The pyrimidine derivative or its salt shown by these.

(2) The pyrimidine derivative represented by the above formula (I) has the following formula (Ia):

[0011]

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(In the formula, R ¹ represents an amino group or a hydroxyl group, R ² and R ^{3 ′} jointly represent another direct bond, or R ¹ and R ² jointly represent an oxo group. R ^{3 ′} represents a hydrogen atom; R ⁴ represents a hydrogen atom, a halogen atom, a trans-2-halovinyl group or an alkyl group having 1 to 5 carbon atoms, and ArS represents an arylsulfonyl group.). The compound according to (1) above, which is a compound.

(3) The pyrimidine derivative represented by the above formula (I) has the following formula (Ib):

[0014]

[Chemical 6]

(In the formula, R ⁴ is a hydrogen atom, a halogen atom,
It represents a trans-2-halovinyl group or an alkyl group having 1 to 5 carbon atoms, and ArS represents an arylsulfonyl group. )
The compound according to (1) above, which is a compound represented by:

(4) An antitumor agent containing the compound according to any one of (1) to (3) as an active ingredient. In the present specification, as the arylsulfonyl group, an unsubstituted arylsulfonyl group such as a benzenesulfonyl group, a naphthalenesulfonyl group, and an indolylsulfonyl group, and these arylsulfonyl groups are an alkyl group having 1 to 5 carbon atoms and a carbon number. Examples thereof include a substituted arylsulfonyl group substituted with one or more substituents such as 1 to 5 alkoxy groups, amino groups, N-substituted amino groups, hydroxyl groups and halogen atoms.

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.

Examples of the trans-2-halovinyl group represented by R ⁴ in the above formulas (I), (Ia) and (Ib) include trans-2-bromovinyl group and trans-
Examples thereof include 2-chlorovinyl group and trans-2-iodovinyl group. In the above formula (I), R ¹ represents a hydroxyl group, R ² and R ³ jointly represent another direct bond, and R ¹ and R ² jointly represent an oxo group, and R ^2
The compound in which ³ represents a hydrogen atom is in a tautomeric relationship, and all are included in the compound of the present invention. In the following, the tautomers are represented by any structural formula for convenience.

The pyrimidine derivative of the present invention represented by the above formula (I) is a mono (N-arylsulfonyl-2-pyrrolidinylmethyl) derivative represented by the above formula (Ia),
It is roughly classified into a bis (N-arylsulfonyl-2-pyrrolidinylmethyl) derivative represented by the formula (Ib).
Examples of the mono (N-arylsulfonyl-2-pyrrolidinylmethyl) derivative represented by the formula (Ia) include the following compounds.

(S) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -1-
(Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -5-fluoro-1- (Np-
Toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -5-fluoro-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S)
-5-Bromo-1- (Np-toluenesulfonyl-2
-Pyrrolidinylmethyl) cytosine, (R) -5-bromo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -5-iodo-1- (N-
p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -5-iodo-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine,
(S) -5-methyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -5
Methyl-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -1- (Np-toluenesulfonyl-2-
Pyrrolidinylmethyl) uracil, (S) -5-methyl-
1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5-methyl-1- (Np
-Toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5-ethyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R)
-5-ethyl-1- (N-p-toluenesulfonyl-2
-Pyrrolidinylmethyl) uracil, (S) -5- (trans-2-bromovinyl) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R)
-5- (trans-2-bromovinyl) -1- (N-p
-Toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5-fluoro-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil,
(R) -5-Fluoro-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5
-Bromo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5-bromo-1
-(Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5-iodo-1- (Np-
Toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5-iodo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil.

Examples of the bis (N-arylsulfonyl-2-pyrrolidinylmethyl) derivative represented by the above formula (Ib) include the following compounds.

1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-methyl-
1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-ethyl-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5- Fluoro-1,3-bis (Np-
Toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-bromo-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-iodo-1,3-bis (N- p-toluenesulfonyl-2-
Pyrrolidinylmethyl) uracil, 5- (trans-2-
Bromovinyl) -1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil.

Examples of the salt of the pyrimidine derivative represented by the above formula (I) include pharmaceuticals such as hydrochloride, sulfate, nitrate, carbonate, sodium salt, potassium salt, calcium salt, barium salt and hydrates thereof. Included are pharmaceutically acceptable salts. The pyrimidine derivative represented by the above formula (I) and a salt thereof are MTs that have acquired infinite proliferation like cancer cells.
Since it can suppress the proliferation of -4 cells, it has high antitumor activity and is useful as an antitumor agent. The antitumor activity is amplified by using S-form proline (L-proline) as one of the raw materials rather than R-form proline (D-proline).

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The pyrimidine derivative of the present invention can be produced, for example, by the following four reaction steps. The first step is proline which is a raw material compound (hereinafter, L-proline or D- which is an optically active substance).
The case of using proline will be described. ) (Formula (1)) is reduced to 2-hydroxymethylpyrrolidine represented by Formula (2) with a reducing agent.

[0025]

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[0026]

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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 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
Can be used in the reaction as a raw material for the next step without particular purification.

In the second step, the imino group and the primary alcoholic hydroxyl group of 2-hydroxymethylpyrrolidine (2) are protected by an arylsulfonyl group (hereinafter, p-toluenesulfonyl group will be described) to give a compound of formula This is a step of obtaining the compound represented by (3).

[0029]

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(In the formula, * represents an asymmetric carbon.) The tosylation reaction performed here may be carried out according to a conventional method, for example,
Obtained by p-toluenesulfonylation (tosylation) of the imino group and primary alcoholic hydroxyl group of 2-hydroxymethylpyrrolidine (2) with p-toluenesulfonyl chloride or the like in a dehydrated pyridine solvent at 0 ° C. under a nitrogen atmosphere. By isolating the product by silica gel column chromatography or the like, N, O-ditosylprolinol represented by the formula (3) can be obtained. The amount of the tosylating agent such as p-toluenesulfonyl chloride used is preferably 3.0 to 4.0 mol per 1 mol of 2-hydroxymethylpyrrolidine (2).

In the third step, N, O-ditosylprolinol (3) is coupled with a pyrimidine base (hereinafter, the case of using 5-bromouracil will be described) to give a compound of formula (4). ) Is a step of obtaining a compound represented by

[0032]

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(In the formula, * represents an asymmetric carbon.) The coupling reaction performed here may be carried out according to a conventional method, for example, in a dehydrated N, N-dimethylformamide (hereinafter referred to as "DMF") solvent. Under a nitrogen atmosphere, pyrimidine base, about equimolar amount of crown ether such as 18-crown-6 and about 2 times amount of base such as potassium carbonate are added, and the mixture is stirred at room temperature for 30 to 60 minutes. Tosyl prolinol (3)
The dehydrated DMF solution of was added dropwise, and the resulting mixed solution was 70-80
The compound (4) can be obtained by stirring at 1 ° C for 1-2 hours.

The obtained compound (4) 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. . Also,
When the amount of N, O-ditosylprolinol (3) used in the coupling reaction is at least twice the molar amount of the pyrimidine base, the compound represented by the formula (5) can be obtained.

[0035]

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(In the formula, Ts represents a p-toluenesulfonyl group (tosyl group), and * represents an asymmetric carbon.) Further, the compounds represented by the formulas (4) and (5) can be reacted at a reaction temperature or a reaction temperature. Its generation can be controlled even in time. For example, when N, O-ditosylprolinol and 5-bromouracil are reacted in approximately equimolar amounts, the reaction temperature is 70-80.
If the reaction is carried out for 1 to 2 hours at ℃, the compound of formula (4) is produced as the main product, but the reaction temperature is 80
When the temperature is raised to ℃ or higher and the reaction is performed for 3 hours or overnight
The compound represented by is produced as a by-product. As mentioned earlier,
When the amount of N, O-ditosylprolinol is 2 times or more the molar amount of the pyrimidine base, the compound represented by the formula (5) can be easily obtained as the main product.

The pyrimidine derivative (I) of the present invention can be pharmaceutically prepared by conventional methods such as hydrochloride, sulfate, nitrate, carbonate, sodium salt, potassium salt, calcium salt, barium salt and hydrates thereof. It can be converted into an acceptable salt. The antitumor agent of the present invention can be formulated by combining the pyrimidine 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 an 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 are produced by a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, 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, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose 2208, hydroxypropyl methyl cellulose 2906, hydroxypropyl methyl cellulose 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 disintegrants 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 include hydrous silicon dioxide, light silicic anhydride, dried aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

The antitumor agent of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good. On the other hand, parenteral preparations are manufactured according to a conventional method, and are generally used as diluents such as distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil,
Soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used. Further, if necessary, a bactericide, a preservative and a stabilizer may be added.
In addition, from the viewpoint of stability, this parenteral preparation is frozen after filling in vials and the like, and water is removed by a normal freeze-drying technique.
It is also possible to reconstitute a solution from a lyophilized product just before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.

[0044]

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) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 1)

[0046]

[Chemical 12]

1-1) Synthesis of (S) -2-hydroxymethylpyrrolidine LiAlH ₄ (6.0 g, 156 mmol) was placed in a 500 ml three-necked round bottom flask and dehydrated tetrahydrofuran (water content max.
(05%) 250 ml was added and the mixture was heated under reflux in an oil bath for 15 minutes. L-proline (8.9 g, 100 mmol) was added in an amount of about 0.2 g each, and the mixture was further refluxed for 1 hour. After confirming the completion of the reaction by thin layer chromatography, the heating was stopped and a 2.8 g / 11 ml aqueous solution of potassium hydroxide 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 dried under vacuum.

Light yellow oily substance, yield: 80% Rf value: 0.47 (n-butanol: acetic acid: water = 6: 2: 2) ¹ H-NMR (D ₂ 0) δ (ppm): 1.33- 1.42 (1H, m, Hc), 1.70-1.76
(2H, 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 (1
H, 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 (S) -N-p-toluenesulfonyl-2-p-toluenesulfonyloxymethylpyrrolidine (S) -2-hydroxymethylpyrrolidine (2.0 g, 20
mmol) was placed in a 100-ml three-necked round bottom 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 (11.7
g, 62 mmol) / 20 ml of dehydrated pyridine solution was added dropwise, then 30
Stir for 0 min at 0 ° C. After confirming the completion of the reaction by thin-layer chromatography, the mixture was added to ice water and extracted with ethyl acetate. Pyridine was extracted and removed with 1N-HCl, concentrated under reduced pressure at 30 ° C., and purified by preparative thin layer chromatography (ethyl acetate: n-hexane = 1: 3).

White crystal, yield: 45% Rf value: 0.31 (ethyl acetate: n-hexane = 1: 3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.50-1.63 (2H, m, Hc) , 1.73-
1.83 (2H, m, Hd), 2.40 (3H, s, Ph-C H ₃ ), 2.45 (3H, s, Ph-
H ₃ ), 3.01-3.07 (1H, m, He), 3.35-3.41 (1H, m, He), 3.69-
3.74 (1H, m, Hb), 3.96-4.00 (1H, m, Ha), 4.25-4.29 (1
H, m, Ha), 7.30-7.82 (8H, d, Ph- H ) ¹³ C-NMR (CDCl ₃ ) δ (ppm): 21.45 (Ph- C H ₃ ), 21.60 (Ph- C H ₃ ),
23.70 (Cc), 28.46 (Cd), 49.34 (Ce), 57.64 (Cb), 71.52 (C
a), 127.47,127.91,129.83,130.01,132.55,133.36,143.9
5,145.12 (Ph- C )

1-3) Synthesis of (S) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine Cytosine (107.9 mg, 0.97 mmol), potassium carbonate (255.9)
mg, 1.85 mmol), 18-crown-6 (240.5 mg, 0.91 mm
ol) in a 50 ml three-necked round bottom flask and dehydrated DMF
(Water content max. 0.005%) 10 ml was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. (S) -N-p-toluenesulfonyl-2-p-toluenesulfonyloxymethylpyrrolidine (377.7 mg, 0.93 mmol) / 2 ml dehydrated DMF 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, the solvent was distilled off using a glass tube distillation apparatus and purified by preparative thin-layer chromatography (CH ₂ Cl ₂ : CH ₃ OH = 9: 1). did.

Yield: 52% Rf value: 0.64 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5) MASS: 349.4 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.21 -1.30 (1H, m, Hd), 1.32-1.
41 (1H, m, Hd), 1.52-1.58 (1H, m, Hc), 1.62-1.74 (1H, m, H
c), 2.41 (3H, s, Ph-C H ₃ ), 3.09-3.15 (1H, m, He), 3.29-3.34
(1H, m, He), 3.68-4.81 (2H, m, Ha), 3.91-4.00 (1H, m, Hb), 5.
63-5.65 (1H, d, Pyrimidine- H ), 6.92,7.02 (2H, s, N H ₂ ), 7.4
1-7.45 (2H, d, Ph- H ), 7.50-7.52 (1H, d, Pyrimidine- H ), 7.
68-7.71 (2H, d, Ph- H )

Example 2 Production of (R) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 2)

[0054]

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In Example 1, all were synthesized by the same method except that D-proline was used instead of L-proline. Total yield from D-proline: 22% Rf value: 0.64 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5) MASS: 349.4 (M + 1) (Example 3) (S) -5-fluoro- Production of 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 3)

[0056]

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In Example 1, 5 instead of cytosine
-All were synthesized by the same method except using fluorocytosine. Total yield from L-proline: 26.2% Rf value: 0.72 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 367.4 (M + 1)

Example 4 Production of (R) -5-fluoro-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 4)

[0059]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using fluorocytosine. Total yield from D-proline: 27% Rf value: 0.72 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 367.4 (M + 1) (Example 5) (S) -5-bromo- Synthesis of 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 5)

[0061]

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In Example 1, 5 instead of cytosine
All were synthesized by the same method except using -bromocytosine. Total yield from L-proline: 25.4% Rf value: 0.80 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 428.3 (M + 1)

Example 6 Synthesis of (R) -5-bromo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 6)

[0064]

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In Example 2, 5 instead of cytosine
All were synthesized by the same method except using -bromocytosine. Overall yield from D- proline: 24.7% Rf _{value: 0.80 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 428.3 (M + 1) ( Example 7) (S) -5- iodo - Synthesis of 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 7)

[0066]

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In Example 1, 5 instead of cytosine
-All were synthesized by the same method except using iodocytosine. Total yield from L-proline: 33.0% Rf value: 0.66 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 475.3 (M + 1)

Example 8 Synthesis of (R) -5-iodo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 8)

[0069]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using iodocytosine. Overall yield from D- proline: 32.6% Rf _{value: 0.65 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 475.3 (M + 1) ( Example 9) (S) -5- methyl - Synthesis of 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 6)

[0071]

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In Example 1, 5 instead of cytosine
-All were synthesized by the same method except using methylcytosine. Total yield from L-proline: 28.1% Rf value: 0.52 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 363.5 (M + 1)

Example 10 (R) -5-methyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine (Compound No. 1)
Synthesis of 0)

[0074]

[Chemical 21]

In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using methylcytosine. Total yield from D-proline: 29.3% Rf value: 0.52 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1) MASS: 363.5 (M + 1) (Example 11) (S) -1- (N -P-Toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 11)

[0076]

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In Example 1, all were synthesized by the same method except that uracil was used instead of cytosine. Total yield from L-proline: 22.2% Rf value: 0.66 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5) MASS: 350.4 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 1.25-1.32 (1H, m, Hd), 1.37-1.
46 (1H, m, Hd), 1.50-1.59 (1H, m, Hc), 1.70-1.81 (1H, m, H
c), 2.40 (3H, s, Ph-C H ₃ ), 3.10-3.21 (1H, m, He), 3.31-3.39
(1H, m, He), 3.61-4.79 (2H, m, Ha), 3.92-4.01 (1H, m, Hb), 5.
49-5.54 (1H, d, Pyrimidine- H ), 7.40-7.48 (2H, d, Ph- H ),
7.56-7.59 (1H, d, Pyrimidine- H ), 7.62-7.69 (2H, d, Ph- H ),
11.20 (1H, s, N H )

Example 12 Production of (R) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 12)

[0079]

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In Example 2, all were synthesized by the same method except that uracil was used instead of cytosine. Overall yield from D- proline: 23.5% Rf _{value: 0.66 (CH 2 Cl 2:} CH 3 OH = 95: 5) MASS: 350.4 (M + 1) ( Example 13) (S) -5- methyl - 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 1
Synthesis of 3)

[0081]

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In Example 1, instead of cytosine, 5
-All were synthesized by the same method except using methyluracil. Total yield from L-proline: 35.7% Rf value: 0.87 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 364.4 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 1.31-1.38 (1H, m, Hd), 1.40-1.
49 (1H, m, Hd), 1.50-1.59 (1H, m, Hc), 1.71-1.81 (1H, m, H
c), 1.77 (3H, s, Pyrimidine-C H ₃ ), 2.40 (3H, s, Ph-C H ₃ ), 3.1
0-3.19 (1H, m, He), 3.30-3.39 (1H, m, He), 3.61-3.73 (2H,
m, Ha), 3.94-4.01 (1H, m, Hb), 7.41-7.49 (3H, m, Pyrimidine
-H , Ph- H ), 7.66-7.71 (2H, d, Ph- H ), 11.19 (1H, s, N H )

Example 14 (R) -5-Methyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 1)
4) Synthesis

[0084]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using methyluracil. Overall yield from D- proline: 32% Rf _{value: 0.87 (CH 2 Cl 2:} CH 3 OH = 95: 5) MASS: 364.4 (M + 1) ( Example 15) (S) -5- ethyl - 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 1
Synthesis of 5)

[0086]

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In Example 1, 5 instead of cytosine
-All were synthesized by the same method except using ethyluracil. Total yield from L-proline: 32% Rf value: 0.90 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 378.5 (M + 1)

Example 16 (R) -5-ethyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 1)
Synthesis of 6)

[0089]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using ethyluracil. From D- proline total yield: 33% Rf _{value: 0.90 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 378.5 (M + 1) ( Example 17) (S) -5- (trans -2-Bromovinyl) -1-
Synthesis of (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 17)

[0091]

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In Example 1, 5 instead of cytosine
All were synthesized by the same method except that-(trans-2-bromovinyl) uracil was used. Total yield from L-proline: 28.0% Rf value: 0.92 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 455.3 (M + 1)

(Example 18) (R) -5- (trans-2-bromovinyl) -1-
Synthesis of (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 18)

[0094]

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In Example 2, 5 instead of cytosine
All were synthesized by the same method except that-(trans-2-bromovinyl) uracil was used. From D- proline total yield: 25.4% Rf _{value: 0.92 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 455.3 (M + 1) ( Example 19) (S) -5- fluoro - Synthesis of 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 19)

[0096]

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In Example 1, 5 instead of cytosine
-All were synthesized by the same method except using fluorouracil. Total yield from L-proline: 22.3% Rf value: 0.88 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 368.4 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 1.23-1.34 (1H, m, Hd), 1.39-1.
47 (1H, m, Hd), 1.51-1.59 (1H, m, Hc), 1.69-1.81 (1H, m, Hc),
2.39 (3H, s, Ph-C H ₃ ), 3.10-3.18 (1H, m, He), 3.29-3.38 (1H,
m, He), 3.56-3.72 (2H, m, Ha), 3.93-3.99 (1H, m, Hb), 7.40-
7.45 (3H, m, Pyrimidine- H , Ph- H ), 7.64-7.69 (2H, d, Ph- H ),
7.85-7.90 (1H, d, N H )

Example 20 Synthesis of (R) -5-fluoro-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 20)

[0099]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using fluorouracil. Total yield from D-proline: 25.7% Rf value: 0.88 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 368.4 (M + 1) (Example 21) (S) -5-bromo- 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 2
Synthesis of 1)

[0101]

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In Example 1, 5 instead of cytosine
All were synthesized by the same method except using -bromouracil. Overall yield from L- proline: 23.9% Rf _{value: 0.69 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 429.3 (M + 1)

Example 22 (R) -5-Bromo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 2)
2) Synthesis

[0104]

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In Example 2, 5 instead of cytosine
All were synthesized by the same method except using -bromouracil. Overall yield from D- proline: 23.1% Rf _{value: 0.69 (CH 2 Cl 2:} CH 3 OH = 98: 2) MASS: 429.3 (M + 1) ( Example 23) (S) -5- iodo - 1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 2
Synthesis of 3)

[0106]

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In Example 1, instead of cytosine, 5
-All were synthesized by the same method except using iodouracil. Total yield from L-proline: 28.6% Rf value: 0.79 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 475.3 (M + 1)

Example 24 (R) -5-iodo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 2)
4) Synthesis

[0109]

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In Example 2, 5 instead of cytosine
-All were synthesized by the same method except using iodouracil. Total yield from D-proline: 32.6% Rf value: 0.79 (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 475.3 (M + 1)

Example 25 (S, S) -1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 2)
5-S) and (R, R) -1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 25-R)

[0112]

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25-1) Synthesis of (S) -2-hydroxymethylpyrrolidine Synthesis was carried out in the same manner as in Example 1. Light yellow oily substance, yield: 82% Rf value: 0.47 (n-butanol: acetic acid: water = 6: 2: 2) 25-2) (S) -Np-toluenesulfonyl-2-
Synthesis of p-toluenesulfonyloxymethylpyrrolidine Synthesized in the same manner as in Example 1. White crystal, yield: 45% Rf value: 0.31 (ethyl acetate: n-hexane = 1: 3)

25-3) (S, S) -1,3-bis (N)
-P-toluenesulfonyl-2-pyrrolidinylmethyl)
Synthesis of uracil (Compound No. 25-S) Uracil (110.1 mg, 0.97 mmol), potassium carbonate (255.9 m
g, 1.85 mmol), 18-crown-6 (480.5 mg, 1.81 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 1 hour. (S) -N-p-toluenesulfonyl-2-p-toluenesulfonyloxymethylpyrrolidine
(789.2 mg, 1.92 mmol) / 3 ml dehydrated DMF solution was added dropwise at room temperature and then stirred at 80 ° C. for 4 hours. After confirming the completion of the reaction by thin layer chromatography, the solvent was distilled off by a glass tube distillation apparatus, and preparative thin layer chromatography (CH ₂
It was purified by Cl ₂ : CH ₃ OH = 9: 1). Yield: 77% Rf value: 0.69 (CH ₂ Cl ₂ : CH ₃ OH = 95: 5) MASS: 644.7 (M + 1)

25-4) (R, R) -1,3-bis (N)
-P-toluenesulfonyl-2-pyrrolidinylmethyl)
Synthesis of Uracil (Compound No. 25-R) In all of 25-1) to 25-3) of this example, except that D-proline was used instead of L-proline, synthesis was performed in the same manner (R, R) -1,3-bis (Np
-Toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 25-R) was obtained. Total yield from D-proline: 24%

(Example 26) (S, S) -5-methyl-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 26-S) and (R, R) -5-methyl-
Production of 1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 26-R)

[0117]

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Synthesis was carried out by the same method as in Example 25 except that 5-methyluracil was used instead of uracil. Total yield from D-proline and L-proline: 22.4, 2
3.5% Rf value: 0.90 = (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 601.8 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.17-1.61 (6H, m, Hc, d), 1.72-
1.89 (2H, m, Hd), 1.83 (3H, s, Pyrimidine-C H ₃ ), 2.40 (6H, s,
Ph-C H ₃ ), 3.12-3.19 (2H, m, He), 3.30-3.39 (2H, m, He), 3.72
-3.87 (2H, m, Ha), 4.03-4.07 (3H, m, Ha, b), 7.40-7.43 (4H,
m, Ph- H ), 7.55 (1H, s, Pyrimidine- H ), 7.63-7.68 (4H, m, Ph-
H ) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 12.69 (Pyrimidine- C H ₃ ), 20.
90 (Ph- C H ₃ ), 23 .19,23.26 (Cd), 27.91,27.94 (Cc), 48.76
(Ce), 43.12,52.18 (Ca), 56.27,57.11 (Cb), 127.10,127.1
9,129.70,129.75,133.83,134.09,143.20,143.41 (Ph- C ).
107.00,140.87,151.37,163.55 (Pyrimidine- C ) (Example 27) (S, S) -5-ethyl-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 27-S) and (R, R) -5-ethyl-
Production of 1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 27-R)

[0119]

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Synthesis was carried out by the same method as in Example 25 except that 5-ethyluracil was used instead of uracil. Total yield from D-proline and L-proline: 27.4, 2
5.5% Rf value: 0.92 = (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 615.8 (M + 1)

Example 28 (S, S) -5-Fluoro-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 28-S) and (R, R) -5-Fluoro-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 28-R)

[0122]

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Synthesis was carried out by the same method as in Example 25 except that 5-fluorouracil was used instead of uracil. Total yield from D-proline and L-proline: 22.8,2
4.5% Rf _{value: 0.89 = (CH 2 Cl 2} : CH 3 OH = 98: 2) MASS: 605.7 (M + 1) ( Example 29) (S, S) -5- bromo-1,3-bis ( N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 29-S) and (R, R) -5-bromo-
Production of 1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 29-R)

[0124]

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Synthesis was carried out by the same method as in Example 25 except that 5-bromouracil was used instead of uracil. Total yield from D-proline and L-proline: 26.8,2
8.5% Rf value: 0.71 = (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 666.6 (M + 1)

Example 30 (S, S) -5-iodo-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 30-S) and (R, R) -5-Iodo-
Production of 1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 30-R)

[0127]

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Synthesis was carried out by the same method as in Example 25 except that 5-iodouracil was used instead of uracil. Total yield from D-proline and L-proline: 32.5,3
3.5% Rf _{value: 0.80 = (CH 2 Cl 2} : CH 3 OH = 98: 2) MASS: 713.6 (M + 1) ( Example 31) (S, S) -5- ( trans-2-bromovinyl) -
1,3-Bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 31-S) and (R, R) -5- (trans-2-bromovinyl)-
Production of 1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil (Compound No. 31-R)

[0129]

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Synthesis was carried out in the same manner as in Example 25 except that 5- (trans-2-bromovinyl) uracil was used instead of uracil. Total yield from D-proline and L-proline: 35.1,3
6.4% Rf value: 0.93 = (CH ₂ Cl ₂ : CH ₃ OH = 98: 2) MASS: 692.7 (M + 1)

(Example 32) Antitumor test The antitumor activity of a test compound was measured by the following experiment using MT-4 cells. In this method, the suppressive effect of a drug is determined by using MT-4, which is one of the cells capable of undergoing infinite division in a flask due to virulence of normal cells caused by viruses such as HTLV1. It is an excellent method for predicting anticancer activity by measuring its cytotoxicity.

1 × 10 ⁴ MT-4 cells were added to each well of a 96-well microplate with various concentrations of test compound,
The cells were 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 2 hours. During this time, MTT taken up by living cells was reduced by an enzyme possessed by mitochondria in the cells to form a blue-violet insoluble pigment (formazan) in water. Then 5%
After adding a hydrochloric acid acidic 2-propyl alcohol solution containing Triton X-100 to solubilize the produced dye, 595 nm
The difference between the two was determined by measuring the specific absorbance at and the nonspecific absorbance at 655 nm using a microplate reader (BIO-RAD model 3550). The 50% cytotoxic concentration (CC ₅₀ value) was calculated from the obtained numerical values.
The results are shown in Tables 1 and 2.

[0133]

[Table 1]

[0134]

[Table 2]

As shown in Tables 1 and 2, the compounds of the present invention show strong cytotoxicity against MT-4 cells,
This toxicity is effective for development as an anticancer agent. Particularly, in Table 2, it is represented by compound number 28-S (S, S)-
5-Fluoro-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil has the highest activity (CC ₅₀ = 2.4 μg / m 2) among the compounds shown in Tables 1 and 2.
l) is shown. A compound for which the present inventors have applied for a patent as Japanese Patent Application No. 7-294911, for example, (S) 2,6-diamino-9- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) purine is , It does not have such cytotoxicity (CC ₅₀ ≧ 300 μg / ml). It was also found that the S-form tends to have higher cytotoxicity than the R-form.

[0136]

INDUSTRIAL APPLICABILITY The pyrimidine derivative of the present invention is extremely effective in the treatment of malignant tumors, etc., since it shows toxicity to infinitely dividing cells at low concentrations.

 ─────────────────────────────────────────────────── ─── 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 (6)

[Claims] (1) The following formula (I): (In the formula, R ¹ represents an amino group or a hydroxyl group, and R ² and R
³ jointly represent another direct bond, or
R ¹ and R ² together represent an oxo group, R ³ represents a hydrogen atom or an N-arylsulfonyl-2-pyrrolidinylmethyl group; R ⁴ represents a hydrogen atom, a halogen atom, a trans-2-halovinyl group. Alternatively, it represents an alkyl group having 1 to 5 carbon atoms, and ArS represents an arylsulfonyl group. ) The pyrimidine derivative or its salt shown by these. 2. The pyrimidine derivative represented by the formula (I) is represented by the following formula (Ia): (In the formula, R ¹ represents an amino group or a hydroxyl group, and R ² and R
^{3 'represents} another direct bond jointly, or,
R ¹ and R ² together represent an oxo group, R ^{3 ′} represents a hydrogen atom; R ⁴ represents a hydrogen atom, a halogen atom, trans-
It represents a 2-halovinyl group or an alkyl group having 1 to 5 carbon atoms, and ArS represents an arylsulfonyl group. The compound of Claim 1 which is a compound shown by these. 3. The pyrimidine derivative represented by the formula (Ia) is (S) -1- (Np-toluenesulfonyl-2).
-Pyrrolidinylmethyl) cytosine, (R) -1- (N-
p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -5-fluoro-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine,
(R) -5-Fluoro-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -5
-Bromo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -5-bromo-1
-(Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -5-iodo-1- (Np-
Toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (R) -5-iodo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S)-
5-methyl-1- (Np-toluenesulfonyl-2-
Pyrrolidinylmethyl) cytosine, (R) -5-methyl-
1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) cytosine, (S) -1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R)
-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5-methyl-1- (N-
p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5-methyl-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil,
(S) -5-Ethyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5
Ethyl-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5- (trans-
2-Bromovinyl) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5
(Trans-2-bromovinyl) -1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil,
(S) -5-Fluoro-1- (N-p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5
-Fluoro-1- (Np-toluenesulfonyl-2-
Pyrrolidinylmethyl) uracil, (S) -5-bromo-
1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (R) -5-bromo-1- (Np
-Toluenesulfonyl-2-pyrrolidinylmethyl) uracil, (S) -5-iodo-1- (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, and (R) -5-iodo-1. The compound according to claim 2, which is a compound selected from the group consisting of-(Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil. 4. The pyrimidine derivative represented by the formula (I) has the following formula (Ib): (In the formula, R ⁴ is a hydrogen atom, a halogen atom, or trans-2.
-Represents a halovinyl group or an alkyl group having 1 to 5 carbon atoms,
ArS represents an arylsulfonyl group. The compound of Claim 1 which is a compound shown by these. 5. The pyrimidine derivative represented by the formula (Ib) is 1,3-bis (Np-toluenesulfonyl-2).
-Pyrrolidinylmethyl) uracil, 5-methyl-1,3
-Bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-ethyl-1,3-bis (N-
p-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-fluoro-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5
-Bromo-1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, 5-iodo-
1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil, and 5- (trans-2-
The compound according to claim 4, which is a compound selected from the group consisting of bromovinyl) -1,3-bis (Np-toluenesulfonyl-2-pyrrolidinylmethyl) uracil. 6. An antitumor agent containing the compound according to any one of claims 1 to 5 as an active ingredient.