JPH0196191A - 2'-deoxyuridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (one of R1 and R2 is halogen- substituted benzyl and the other is lower alkyl, lower alkenyl, thienylmethyl, pyridylmethyl, carbamoylmethyl, lower alkylsulfonyl, phenylsulfonyl or thienylmethylcarbonyl). EXAMPLE:O<3>'-p-Chlorobenzyl-2'-deoxy-5-fluorouridine. USE:An antitumor agent. PREPARATION:A 2'-deoxyuridine derivative shown by formula II (one of R5 and R6 is H and the other is halogen-substituted benzyl, lower alkyl, lower alkenyl or thienylmethyl) is reacted with a halide shown by formula R7X (R7 is lower alkyl when one or R5 and R6 is halogen-substituted benzyl and R7 is halogen-substituted benzyl when one of R5 and R6 is lower alkyl; X is halogen) in a solvent in the presence of a basic compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel 2'-deoxyuridine derivatives. The 2'-deoxyuridine derivative of the present invention exhibits excellent anticancer activity and is useful as an antitumor agent.

BACKGROUND TECHNOLOGY AND PROBLEMS Conventionally, the general formula (wherein A and B are a benzyl group or a substituted benzyl group, and the other is a protecting group for the sugar hydroxyl group of 2'-deoxyuridine) has been used. The 2'-deoxyuridine derivatives represented are JP-A-58-99499, JP-A-59-7069, No. 9, JP-A-59-93096, JP-A-60-61519, JP-A-61=106593. These compounds have improved to some extent the drawbacks of the antitumor agent 2'-deoxy-5-fluorouridine (hereinafter abbreviated as FudR), which is highly toxic and has a narrow safety margin. , still not enough.

Means to Solve the Problems The present inventors have developed a 2'-
As a result of intensive research in order to develop deoxyuridine derivatives, the present compound was found that achieved this objective, and the present invention was completed.

The compound of the present invention is represented by the following general formula.

(In the formula, one of R1 and R2 is a /XX rosin-converted benzyl group, and the other is a lower alkyl group, a lower alkenyl group,
thienylmethyl group, pyridylmethyl group, carbamoylmethyl group, lower alkylsulfonyl group, phenylsulfonyl group, thienylmethylcarbonyl group, lower alkyl-substituted thienylcarbonyl group, thiazolidinylcarbonyl group,
It represents a lylunyl group, an N, N-di-lower alkylcarbamoyl group, or an R3-P=0 group. Here, R3 and R4 are the same as or different from R4 and represent a hydrogen atom, a lower alkyl group, or an alkali metal. ) A 2'-deoxyuridine derivative represented by:

In the above general formula (I), the lower alkyl groups represented by R and R2 include straight carbon atoms having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, 5ec-butyl, tert-butyl, pentyl, and hexyl. Chain or branched alkyl groups, lower alkenyl groups include vinyl,
Straight chain or branched alkenyl groups having 1 to 6 carbon atoms such as allyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, etc., sodium, potassium, etc. as alkali metals, fluorine, chlorine, iodine as halogens. can be mentioned respectively. In addition, the lower alkylsulfonyl group is a sulfonyl group substituted with the above lower alkyl group, the lower alkyl-substituted thienylcarbonyl group is a thienylcarbonyl group substituted with the above lower alkyl group, and the N,N-di-lower alkylcarbamoyl group is As for 2
Examples include carbamoyl groups substituted with the above-mentioned lower alkyl groups.

The compound of the present invention has an excellent anticancer effect that improves the conventional drawbacks of FucjR, such as high toxicity and narrow safety margin, and is produced by the following production steps 1 to 3.

Production Step 1> General Formula (wherein R6 and R6 represent a hydrogen atom, and the other represents a halogen-substituted benzyl group, a lower alkyl group, a lower alkenyl group, a thienylmethyl group, a pyridylmethyl group, or a carbamoylmethyl group. ) to the 2'-deoxyuridine derivative represented by the general formula % formula % () (wherein, R7 is a lower alkyl group when either of the above R5 and R6 is a halogen-substituted benzyl group,
Represents a lower alkenyl group, thienylmethyl group, pyridylmethyl group or carbamoylmethyl group, and the above R5 and R6
Either one of them is a lower alkyl group, a lower alkenyl group,
When it is a thienylmethyl group, a pyridylmethyl group or a carbamoylmethyl group, it represents a halogen-substituted benzyl group. X represents a halogen atom. The compound of the present invention having the following structure can be produced by reacting a halide represented by ) in a solvent in the presence of a basic compound.

(In the formula, one of R8 and R9 is) a \logen-substituted benzyl group, and the other is a lower alkyl group, a lower alkenyl group, a thienylmethyl group, a pyridylmethyl group, or a carbamoylmethyl group. 2'-deoxyuridine derivative represented by ).

As the solvent, water, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, etc. are used. Basic compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metals such as sodium and potassium. The halogen atom of X is chlorine, bromine, or iodine. The reaction ratio of the halide and the basic compound is usually equivalent to 5 times the mole of the raw material compound, and the reaction ratio is from room temperature to 60°C,
The reaction is completed in 3 to 12 hours.

2'-
Deoxyuridine derivatives include compounds represented by the general formula % formula % (1) (wherein RI2 represents a lower alkylsulfonyl group or phenylsulfonyl group. X is the same as above), or the general formula % formula % ( 2) (wherein R42' is a thienylmethyl group, a lower alkyl-substituted thienyl group, a thiazolidinylmethylcarbonyl group,
It represents a lylunyl group, an N,N-dilower alkylcarbamoyl group, or an OR3' -p=o group. Here R3' and R4'OR4
' represents a lower alkyl group. ) or its reactive derivative,
By reacting in the presence of a basic compound in a solvent or non-solvent, the compound of the present invention having the following structure can be produced.

(In the formula, one of RI3 and R44 is) a \logen-substituted benzyl group, and the other is a lower alkylsulfonyl group, a phenylsulfonyl group, a thienylmethylcarbonyl group, a lower alkyl-substituted thienylcarbonyl group, a thiazolylmethylcarbonyl group, It represents a lylunyl group, an N,N-dilower alkylcarbamoyl group, or an OR3' -P=0 group. Here, R3' and R4'OR4' are the same as above. ) A 2'-deoxyuridine derivative represented by:

As a solvent, water, diethyl ether, methylene chloride,
Chloroform, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, etc. are used. As the basic compound, amines such as triethylamine, pyridine, dimethylaminopyridine, and dicyclohexylcarbodiimide (DCC) can be used. When no solvent is used, a large excess of the basic compound is used. The reaction ratio of the compounds represented by general formulas (V-1) and (V-2) and the basic compound in the solvent is usually equivalent to -5 times the mole of the raw material compound, and the reaction ratio is from room temperature to 60% by mole. The reaction is completed in 3 to 12 hours at ℃. General formula (
Examples of the reactive derivative of carboxylic acid represented by V-2) include acid anhydrides and acid halides.

Production step 3> The compound represented by the general formula (rV) is reacted with 2-cyanoethyl phosphate in a solvent in the presence of DCC, followed by alkaline hydrolysis, and if necessary, an alkali metal atom is removed using an ion exchange resin. The compound of the present invention having the following structure can be produced by elimination and further subjecting to a salt formation reaction.

(In the formula, one of RI5 and R16 is a halogen-substituted benzyl group, and the other is an OR3'-P=0 group. Here, R37 and R4'0R4' represent a hydrogen atom or an alkali metal.) 2
'-Deoxyuridine derivative.

As the solvent, pyridine, triethylamine, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, etc. are used. The usage ratio of 2-cyanoethyl phosphate and DCC is determined by the general formula (
10 to 20 times the mole of the compound rV), respectively.
The amount is 5 to 10 times the molar amount, and the reaction time is about 2 to 5 days.

Alkaline hydrolysis is carried out for the purpose of removing the cyanoethyl group, which is a protective group, from the reaction product of the compound represented by the general formula (IV) and 2-cyanoethyl phosphate. As the alkali used for alkaline hydrolysis, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate are usually used at a concentration of 0.5 to 3N.
Heat to reflux for ~1 hour. After the alkaline hydrolysis is completed, the solvent is distilled off to obtain a dialkali phosphate in which R3' and R4'' are alkali metals. By passing this through a cation exchange resin, a dialkali phosphate in which R3' and R4' are hydrogen atoms is obtained. Furthermore, in order to obtain a monoalkali phosphate in which one of R3' and R4'' is an alkali metal and the other is a hydrogen atom, and a dialkali phosphate in which both are an alkali metal, R3'' and R4'' are hydrogen atoms. It can be produced by dissolving a certain compound in water, adding an alkali metal hydroxide, carbonate, hydrogen carbonate, etc., and adjusting the pH to 5.3 and 7.5, respectively.

The compound of the present invention produced in each of the above production steps can be isolated and purified by conventional separation and purification means, such as recrystallization and column chromatography.

The 2'-deoxyuridine derivative represented by general formula (I) of the present invention is useful as an antitumor agent and an antiviral agent. When the derivative of the present invention is used as the above-mentioned medicament, it is usually combined with a suitable pharmacologically acceptable carrier to prepare a formulation suitable for its administration route. As carriers used, known and commonly used excipients,
Binders, lubricants, coloring agents: disintegrants, etc. may be used, and the formulations are suitable for oral administration, such as tablets, capsules, granules, powders, liquids, etc., and parenteral formulations such as intravenous injection. Examples of dosage forms suitable for administration include injections, and semi-open forms suitable for intrarectal administration. The content of the active ingredient (the compound of the present invention) per unit form of each preparation may be appropriately determined depending on the form, and is not particularly different from that in ordinary pharmaceuticals. The preferred active ingredient content is generally about 25 to 500 mg per unit. Each of the above formulations may be prepared according to a conventional method.

The dosage of each preparation obtained in this way will of course vary depending on the symptoms, weight, age, etc. of the patient to whom it is administered, and although it cannot be generally limited, it is usually an adult dose of about 100 to 2000 mg of the active ingredient per day. It is sufficient that the amount is
This can be administered in 1 to 4 divided doses on day -.

Examples Hereinafter, production examples of the compounds of the present invention having the chemical structures shown in Table 1 below will be given as examples, and examples of formulations of the compounds of the present invention will also be given.

Example 1 9.26g of ()3',-chlorobenzyl-FudR was dissolved in 70rPf2 of tetrahydrofuran, and 60%
2.5 g of sodium hydride was added.

After stirring at 50°C for 30 minutes, allyl bromide 3. 02g was added thereto, and the mixture was stirred at 50°C for 3 hours. Next, the mixture was neutralized with an IN-HCΩ aqueous solution and concentrated, and the residue was extracted with methylene chloride, dried over Glauber's salt, and concentrated. The resulting residue was recrystallized from methylene chloride-petroleum ether to obtain Compound 1.

Yield 8. 54g (yield 83.2%) mp, 92-9
3°C nuclear magnetic resonance spectrum (measured during DMS Ods)
δppm (TMS internal standard, same below): 11.8
5 (IH, bs, NH), 8.00 (IH, d, J=7Hz.

H6), 7, 40 (4H,s, aromatic), 6.13 (IH, t, J=7Hz.

H+’), 3.8-4.3 (2H, m, H3'.

H4'), 3.62 (2H, m, H5'), 2, C1-2.
35 (2H, m, H''') Elemental analysis HCN Measured value (%) 5.07 55.50 6.82
Calculated value (%) 4.91 55.55 6.72
Example 2 Compounds 2.3.4.5.6.
7 was synthesized.

O compound 2 Yield 73% mp, 117-118°C Nuclear magnetic resonance spectrum (measured in DMSO-d6) δpp
m: 11.85 (IH, bs, NH), 7.9
7 (IH, d, J=7Hz.

Hs), 7, 39 ('4H,s, aromatic), 6.11 (IH, t, J=7Hz.

Hl'), 4, 52 (2H, s, -CH2-C)), 4
．． 0-4.3 (2H, m, H3'.

H4'), 3.52 (2H, m, H5'), 3.32 (3
H, s, 0CH3), 2.0~2.40 (2
H, m, H2') Elemental analysis HCN Measured value (%') 4.94 53.02 7.2
6 Calculated value (%) 4.72 53.06 7.2
80 Compound 3 Yield 85% mp, 79-80°C Nuclear magnetic resonance spectrum (measured in DMSO-d6) δpp
m: 11.85 (IH, bs, N)T), 8.1
0 (IH, d, J=7Hz.

Hs), 7, 40 (4H,s, aromatic), 6.14 (IH, t, J=7Hz.

H+’), 4.16 (2H, bs, H3'.

H4′), 3.61 (2H, bs, H”), 3.50 (2H, q, J=7Hz.

CH3CH20-), 2.1-2.4 (2H, m, H2'), 1.15
(3H, t, J=7Hz.

C and 3 CH20-) Elemental analysis HCN Measured value (%) 5.24 53.99 6.90
Calculated value (%) 5.05 54.21 7.020 Compound 4 Yield 81% Oil nuclear magnetic resonance spectrum (DMSOds measurement δppm
: 11.80 (IH, bs, NH), 7.90
(IH, d, J=7Hz.

Hs), 7.49 (IH, dd, J=4Hz.

7, 32 (4H,s, aromatic), 7.01 (IH, dd, J=5Hz.

6.10 (IH, t, J=7Hz.

Hl ′), 4.09-4.25 (2H, bs.

H3t, H4t), 3.5-3-78 (2H, m, H5'), 2.09
~2.35 (2H, m.

H2') O compound 5 Yield 68% Amorphous nuclear magnetic resonance spectrum (DMSO-ds medium measurement δI)
pm: 11.84 (IH, bs, NH), 8.5
5 (IH, m, aromatic), 8.04 (IH, d, J-7Hz.

7, 39 (4H, s, aromatic), 7, 0-7.8 (3H, m, aromatic), 6, 15
(IH, t, J=7Hz.

4, 54 (2H, s, -CH2ri), 4, 0
~4. 30 (2H, bs.

H3t, H4t), 3, 5-3.8 (2H, m, H5'), 2,
1-2.40 (2H, m, H2')0 Compound 6 Yield 87.4% Amorphous nuclear magnetic resonance spectrum (DMSO-dSS measurement δpp
m two 1 1. 86 (IH, b, NH)
, 8, 09 (IH, d, J-7Hz.

7, 40 (4H,s, aromatic), 6.14 (IH, t, J=7Hz.

Hl ′), 4.0-4.40 (2H, m, H3'.

H4′), 3.91 (2H, s.

NH2CCH201), 3.83 (2H, bs, H5'), 2.2-2.
4 (2H, m, H2')0 Compound 7 Yield 88.6% Amorphous nuclear magnetic resonance spectrum (measured in DMSO-d6) δpp
m: 11.86 (IH, b, NH), 8.05
(IH, d, J=7Hz.

H6), 7.1-7.5 (4H, m, aromatic), 6.13
(IH, t, I=7Hz.

Hl'), 4, 53 (2H,s, CH2a), 4.05~4
．． 22 (2H, m.

H3/ , ) (4・ ), 3.63 (2H, bs, H5' ), 3.50
(2H, Q, J=7Hz.

OC Danyu CH3), 2.0-2.5 (2H, m, H"'), 1.
15 (3H, t, J=7Hz.

OCH2CHa) Example 3 03'-p-thalolbenzyl-FudR3,70g and 5
- Dissolve 1.71 g of methyl-2-thiophenecarboxylic acid in 100 mf2 of pyridine, add 4.13 g of DCC, - concentrate after stirring overnight, add 100 methylene chloride to the residue, filter insoluble matter, and remove synovial fluid. The residue was concentrated and purified by column chromatography to obtain Compound 8.

Yield 1.88g (yield 38%) Oil nuclear magnetic resonance spectrum (measured in CDCΩ3) 699m
near, 65 (IH, d, J=7Hz.

H6), 7-26 (4H, s + aromatic), 6.25 (IH, t, J=7Hz.

H1’), 4.30-4.50 (2H, m.

H3/ , H4/ ), 4.20 (2H, m, H5'), 2.50 (2H, m, H2' ), Example 4 Compound 9.10.11 was synthesized in the same manner as Example 3 did.

0 Compound 9 Yield 11% Oil nuclear magnetic resonance spectrum (measured in CDCΩ3) 699m
: 9.93 (IH, b, NH), 7.65 (IH
, d, J=7Hz.

H6), 7, 28 (4H,s, aromatic), 6, 21 (IH, t, J = 7Hz.

H1′), 5.11-5.45 (2H, m.

H3t, H4/), 4.30 (IH, bs, H5'), 1.08-2.82 (30H, m.

H2') O compound 10 Yield 25% mp, 235-238°C Nuclear magnetic resonance spectrum (measured in DMSOd6) 699m
: 11.80 (LH, bs, NH), 7.85
(IH, d, J=7Hz.

H6), 7.40 (6H, m, aromatic), 6.09 (LH, t, J=7Hz.

H1/), 4, 50 (2H, s, -CH2-), 4.0
2'~4.40 (4H, m.

) (3/, H4/, H5t), 2.15~2
．． 40 (2H, m.

H2') Elemental analysis HCN Measured value (%) 4.15 53.42 5.85
Calculated value (%) 4.07 53.39 5.68
Q Compound 11 Yield 78.3 pg Amorphous nuclear magnetic resonance spectrum (measured in DMSO-d6) 699
m: 11.85 (IH, bs, NH), 8.20
(IH, d, J=7Hz.

H6), 7, 40 (4H, S, aromatic), 6.13 (IH, t, J=7Hz.

)(+’), 4.0-4.4 (2H, m, H3'.

H4′), 3.60 (2H, m, H5'), 2, 10-2.40 (2H, m.

H2') Example 5 03'-p-'Fo/IzbenzyruFudR0,74
Dissolve 5 g of pyridine and 0.55 g of mesyl chloride.
was added dropwise under water cooling, and after stirring for 5 hours, the mixture was concentrated, 50 g of water was added to the residue, extracted with methylene chloride, and dried over sodium sulfate. This was concentrated and the residue was purified by column chromatography to obtain Compound 12.

Yield 0.61g (yield 74.0%) Amorphous nuclear magnetic resonance spectrum (DMS Ods width measurement)
δpI)m: 11.84 (IH, b s, NH
), 7.94 (IH, d, J=8Hz.

H6), 7.39 (4H,s, aromatic), 6.15 (IH, t, J=8Hz.

Hl'), 4, 55 (2H,s, -CH2-□), 4, 09
~4.49 (2H, m.

H3', H4'), 3.90-4.00 (2H, m.

H5'), 1; 3.21 (3H', s, S CH3
), 2, 18-2.41 (2H, m.

H2') Example 6 In a similar manner to Example 5, compound 13.14.17.1
8.19 was synthesized.

O compound 13 Yield 68% Oil nuclear magnetic resonance spectrum (measured in CDCI23) δppL
Il: 9.30 (LH, bs, NH), 7.65
(IH, d, J=7Hz.

H6), 7.29 (5H,s, aromatic), 7.25 (4H,s, aromatic), 6.22 (IH, t, J”7Hz.

H1’), 4.05-4.40 (2H, m.

H3t, H4t), 3.78-3.80 (2H, m.

H5'), 1.99-2.21 (2H, m.

H2') 0 Compound 14 Yield 76.3% Amorphous nuclear magnetic resonance spectrum (measured in DMS〇-d5) δpp
m: 11.86 (IH, bs, NH), 8,
21 (IH, d, J=7Hz.

H6), 7.20-7.60 (4H, m, aromatic), 6, 13 (LH, t, J = 7Hz.

H1'), 4, 54 (2H, s, -CH2-C)), 4.
0-4.30 (2H, m.

H3', H”), 3.62 (2H, bs, H5'), 3, '21 (3H, s, -8-CH3), 2.0
~2.40 (2H, m.

H2') O compound 17 Yield 65% Oil nuclear magnetic resonance spectrum (DMSO-dG medium measurement) 69
9m: 10.42 (IH, bs, NH), 7.7
0 (LH, d, J=7Hz.

H6), 7, 22 (4H,s, aromatic), 6.25 (IH, t, J=8Hz.

H1'), 4, 49 (2H, s, -CH2X), 3.9
0-4.40 (4H, m.

(CH3CH20) 2), 3.90-4.40 (4H, m.

H3t, H4t, H5t), 1.80-2.
80 (2H, m.

H2'), 1.00-1.49 (6H, m.

(CH3CH20)2 ) 0 Compound 18 Yield 78% Oil nuclear magnetic resonance spectrum (D, MSO-ds medium measurement δp
prn: 11.80 (LH, bs, NH), 7.
85 (IH, d, J=7Hz.

H6), 7.38 (4H,s, aromatic), 6.09 (LH, t, J=7Hz.

H1'), 4, 52 (2H,s, CH2SeD), 4.20
(3H, bs, H3'.

H4t, H5t), 3.20 (4H, q, J=8Hz.

-N (C[2CH3)2), 2.20-2.40 (2H, m.

H2'), 1.02 (6H, t, J=8Hz.

N (CH20H3) 2 ) 0 Compound 19 Yield 68.3% Amorphous nuclear magnetic resonance spectrum (D M S Od s width measurement)
699m: 11.84 (IH, bs, NH), 7
．． 93 (IH, d, J=7Hz.

Hs), 7, 48 (4H,s, aromatic), 6.13 (IH, t, J=7Hz.

) (1'), 4.5 B (2H, s, -CH2-CJ) ),
4.0-4.30 (2H, m.

H3', H4'), 3.67 (2H, m, H5'), 3, 21 (3H, s.

SO2CH3), 2, 10-2.40 (2H, m.

H2') Example 7 3.2 g of barium salt of 2-cyanoethyl phosphate was suspended in 10 parts of water, Dowex 50 [H"] (manufactured by Dow Chemical Company) was added until the barium salt was dissolved, filtered, and Concentrate the solution below room temperature, and add pyridine 25T1 to the residue.
112 was added and concentrated. This operation was repeated again, and the resulting residue was added to 03'-p-chlorobenzyl-FudRl.
, 86g was dissolved in 25g of pyridine, and DCC6,
0 g was added thereto, and the mixture was stirred at room temperature for three days. Next, 25 parts of water was added to the reaction solution and filtered, and 1N-NaOH aqueous solution was added to the synovial fluid.
The mixture was heated under reflux for 40 minutes. After cooling, Dowex
50 [H”] on an ion exchange resin column, and
a ions were removed and the effluent was adjusted to pH 5 with saturated NaHCO3.
. Further, the effluent was adjusted to pH 7.5 using an IN-NaOH aqueous solution, and purified with an MCI gel column to synthesize disodium salt Compound 16.

Yield Compound 15: 0.97g (Yield 41.1%) Compound 1
6: 0.89g (Yield 36.0%) 0 Compound 15 Amorphous nuclear magnetic resonance spectrum (measured in DMSO-d6) δpp
m: 8.03 (IH, d, J=7Hz.

H6), 7.41 (4H,s, aromatic), 6.26 (IH, t, J=7Hz.

H1'), 4, 62 (2H, s, 'CH2@), 4.
0-4.50 (2H, m.

Ha’, H”), 3.80-3.90 (2H, m.

H5′), 2, 20-2.60 (2H, m.

H2') Q compound 16 amorphous nuclear magnetic resonance spectrum (measured during D20) δppm:
7. 92 (IH, d, J=7Hz.

Hs), 7.42 (4H,s, aromatic), 6, 30 (IH, t, J = 7Hz.

H1′), 4, 60 (2H, s, -4 over ◎), 4.20-4.50 (2H, m.

H3’, H”), 3.80-4.00 (2H, m.

H5'), 2.12-2.50 (2H, m.

H2′) Next, examples of formulations of the compounds of the present invention will be shown.

Formulation Example 1 Capsule Compound 3, lactose, crystalline cellulose, and corn starch were mixed in the following proportions, and magnesium stearate was further added and mixed in the following proportions.

This mixture was filled using an appropriate capsule filling machine so that each capsule weighed approximately 293 mg to obtain a product.

Capsule formulation IT1g/T1 Compound 3 200.0 Lactose
30.0 Crystalline Cellulose 50.0 Corn Starch 10.0 Magnesium Stearate 3.0293, 0 Formulation Example 2 Granule Compound 7, lactose, crystalline cellulose and corn starch were mixed in the following proportions. A 10% ethanol solution of heptadroxypropyl cellulose was added to this, and the mixture was kneaded and then made into granules using a suitable granulation device. After drying, this was sized into 12 to 42 meshes. The sized particles were coated with hydroxypropyl methyl cellulose in the proportions shown below using an appropriate coating device. 1
The product was prepared after sieving to a size of 2 to 42 meshes.

Granule formulation mg/- Compound in package 7 200.0 Lactose
200.0 Crystalline Cellulose 311.0 Corn Starch 200.0 Hydroxypropyl Cellulose 10.0 Hydroxypropyl Methyl Cellulose 70.0 Fatty Acid Monoglyceride 3.5 Titanium Dioxide
5.51000.0 Formulation Example 3 Tablet Compound 1, corn starch and calcium cellulose glycolate were mixed in the following proportions.

Add a 10% ethanol solution of hydroxypropylcellulose to this, knead it, granulate it with a suitable granulator, dry it, add magnesium stearate and silicic anhydride in the proportions shown below, mix it, and pulverize it in a suitable manner. The tablets were compressed using a tablet machine and coated with hydroxypropyl methylcellulose to produce a product.

Tablet formulation mg/tablet compound 1 200.0 Corn starch 5.0 Calcium glycolate 20.0 Hydroxypropyl cellulose 2.0 Magnesium stearate 2.
5 Silicic anhydride 2.5 Hydroxypropyl methylcellulose 19.999 Macrogol 6000 0.001 Titanium oxide 2.0 Formulation example 4 After melting half-split Witepsol W-35 (trade name, manufactured by Dynamite Nobel) at about 60°C The temperature was maintained at approximately 45°C. This was mixed with Compound 5 in the proportions shown below, and then molded into 1-g halves using a suitable full-open manufacturing device.

Half-split prescription mg/suppository half-open 5 400. 0 Witepsol W-35600.0 1000.0 (or more)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, one of R_1 and R_2 is a halogen-substituted benzyl group, and the other is a lower alkyl group, lower alkenyl group, thienylmethyl group, pyridylmethyl group. , carbamoylmethyl group, lower alkylsulfonyl group, phenylsulfonyl group, thienylmethylcarbonyl group, lower alkyl-substituted thienylcarbonyl group, thiazolidinylcarbonyl group, linolenyl group, N,N-dilower alkylcarbamoyl group, or ▲mathematical formula, chemical formula , tables, etc.▼Indicates the group.Here, R
_3 and R_4 are the same or different and represent a hydrogen atom, a lower alkyl group, or an alkali metal. ) A 2'-deoxyuridine derivative represented by: