JPH0446244B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a new antitumor agent containing a novel 2'-deoxy-5-fluorouridine derivative having antitumor activity together with a compound having an antitumor activity enhancing effect. PRIOR ART The derivative having antitumor activity used as an active ingredient in the antitumor agent of the present invention is a novel compound that has not been described in any literature. Problems to be Solved by the Invention As a result of extensive studies aimed at improving the antitumor potency and reducing the toxicity of 2'-deoxy-5-fluorouridine, the present inventors discovered that the 2'-deoxy-5-fluorouridine Succeeded in the synthesis of a new compound in which the 3' or 5' position of uridine is substituted with a specific phenyl lower alkyl group with or without a substituent, and the compound exhibits excellent antitumor activity. death,
Moreover, it has been found that this activity is significantly enhanced by certain pyrimidine derivatives or pyridine derivatives. Means for Solving the Problems The present invention is based on the general formula [In the formula, one of R ¹ and R ² represents a phenyl lower alkyl group which may have a substituent selected from a lower alkyl group and a halogen atom on the phenyl ring, and the other represents a hydrogen atom or a lower alkanoyl group. R ³ represents a hydrogen atom, a benzoyl group that may have a lower alkoxy group, a phenoxycarbonyl group, or a tetrahydrofuranyl group] 2'-deoxy-5-fluorouridine derivatives represented by the general formula [In the formula, R ⁴ is a hydrogen atom or a hydroxyl group, R ⁵ is a hydrogen atom, an amino group, a halogen atom, a mercapto group,
Nitro group, formyl group or lower alkyl group,
R ⁶ represents a hydrogen atom or a hydroxyl group] Pyrimidine derivatives and general formula represented by [In the formula, R ⁷ represents a hydrogen atom or a tetrahydrofuranyl group] At least one compound selected from pyridine derivatives represented by the following: In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl,
A straight or branched alkyl group having 1 to 6 carbon atoms such as butyl, t-butyl, pentyl, hexyl group,
Examples of lower alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy groups, and halogen atoms. Examples of the atom include fluorine, chlorine, bromine, and iodine atoms. The phenyl lower alkyl group which may have a substituent selected from a lower alkyl group and a halogen atom on the phenyl ring includes 1 to 3 of the above substituents.
Phenyl group that may have 1 to 6 carbon atoms
alkylene groups such as methylene, ethylene, trimethylene, 1-methylethylene, tetramethylene, 2-methyltrimethylene, pentamethylene,
An example is a phenyl alkyl group bonded to a hexamethylene group or the like. A specific example is shown below. Benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl,
2-propylbenzyl, 3-propylbenzyl,
4-propylbenzyl, 2-butylbenzyl, 3
-butylbenzyl, 4-butylbenzyl, 2-t
-butylbenzyl, 3-t-butylbenzyl, 4
-t-butylbenzyl, 2-pentylbenzyl,
3-pentylbenzyl, 4-pentylbenzyl,
2-hexylbenzyl, 3-hexylbenzyl,
4-hexylbenzyl, 2,3-dimethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6-dimethylbenzyl, 3,4
-dimethylbenzyl, 3,5-dimethylbenzyl, 2,3,4-trimethylbenzyl, 2,4,
5-trimethylbenzyl, 2,3,5-trimethylbenzyl, 2,4,6-trimethylbenzyl,
3,4,5-trimethylbenzyl, 2,3-diethylbenzyl, 2,4-diethylbenzyl, 2,
5-diethylbenzyl, 2,6-diethylbenzyl, 2,4,6-triethylbenzyl, 2,4-
Dipropylbenzyl, 3,4,5-triethylbenzyl, 3-methyl-4-ethylbenzyl, 1-
Phenylethyl, 2-phenylethyl, 2-phenyl-1-methylethyl, 1-(2-methylphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(4
-methylphenyl)ethyl, 1-(2,4-dimethylphenyl)ethyl, 2-(2,4-dimethylphenyl)ethyl, 1-(2,4,6-trimethylphenyl)ethyl, 2-(2 , 4,6-trimethylphenyl)ethyl, 3-phenylpropyl,
3-(4-methylphenyl)propyl, 4-phenylbutyl, 4-(2-methylphenyl)butyl,
5-phenylpentyl, 5-(3-methylphenyl)pentyl, 6-phenylhexyl, 6-(4
-methylphenyl)hexyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,3-difluorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 2-fluoro-3-chlorobenzyl, 2-fluoro-3-bromobenzyl, 2,6-difluorobenzyl, 2,3,4-trifluorobenzyl, 2,4,5-trifluorobenzyl, 2,
3,5-trifluorobenzyl, 2,4,6-trifluorobenzyl, 3,4,5-trifluorobenzyl, 1-(2-fluorophenyl)ethyl,
2-(2-fluorophenyl)ethyl, 3-(3-
fluorophenyl)propyl, 4-(2-fluorophenyl)butyl, 5-(2-fluorophenyl)pentyl, 6-(3-fluorophenyl)hexyl, 2-bromobenzyl, 3-bromobenzyl, 4 -bromobenzyl, 2,3-dibromobenzyl, 2-bromo-3-fluorobenzyl, 2-
Fluoro-4-bromobenzyl, 2,4-dibromobenzyl, 2,5-dibromobenzyl, 2,6
-dibromobenzyl, 2,3,4-tribromobenzyl, 2,4,5-tribromobenzyl, 2,
3,5-tribromobenzyl, 2,4,6-tribromobenzyl, 3,4,5-tribromobenzyl, 1-(2-bromophenyl)ethyl, 2-(2-bromobenzyl)
-bromophenyl)ethyl, 3-(2-bromophenyl)propyl, 4-(3-bromophenyl)
Butyl, 5-(2-bromophenyl)pentyl,
6-(4-bromophenyl)hexyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl,
2,6-dichlorobenzyl, 2-bromo-4-chlorobenzyl, 2-fluoro-4-chlorobenzyl, 2,3,4-trichlorobenzyl, 2,4,
5-trichlorobenzyl, 2,3,5-trichlorobenzyl, 2,4,6-trichlorobenzyl,
3,4,5-Trichlorobenzyl, 1-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3-(2-chlorophenyl)propyl, 4-(4-chlorophenyl)butyl, 5-(3
-chlorophenyl)pentyl, 6-(4-chlorophenyl)hexyl, 2-(3,4-dichlorophenyl)ethyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodobenzyl, 3,4-diiodobenzyl, 3,4,5-triiodobenzyl, 2-(3-iodophenyl)ethyl, 6-(2
-iodophenyl)hexyl group, etc. Lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl,
C1-6 pentanoyl, hexanoyl, etc.
Examples include straight chain or branched chain alkanoyl groups. Examples of the benzoyl group that may have a lower alkoxy group include benzoyl, 2-methoxybenzoyl, 3-ethoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 3,
4,5-trimethoxybenzoyl, 4-ethoxybenzoyl, 2-methoxy-4-ethoxybenzoyl, 2-propoxybenzoyl, 3-propoxybenzoyl, 4-propoxybenzoyl, 2,
Examples of substituents such as 4-dipropoxybenzoyl and 3,4,5-tripropoxybenzoyl groups include benzoyl groups that may have 1 to 3 lower alkoxy groups. Examples of the tetrahydrofuranyl group include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl. The compound represented by the above general formula (1) is a novel compound newly synthesized by the present inventors, and can be produced by the methods shown in the following reaction schemes a to d. [In the formula, R ³ is the same as above. At least one of R ⁸ and R ⁹ is a hydrogen atom, and the other is a lower alkanoyl group or a protective group. R represents a phenyl lower alkyl group which may have a substituent selected from a lower alkyl group and a halogen atom on the phenyl ring. One of R ^1a and R ^2a is a hydrogen atom or a lower alkanoyl group, and the other is the same group as R above. X represents a halogen atom. ] In the above protecting group represented by R ⁸ or R ⁹ ,
The following groups are included. (A) General formula [In the formula, Ar represents an aryl group] A triaryl-substituted methyl group represented by: Examples of such groups include aryl groups such as phenyl groups that may have a halogen atom, nitro group, lower alkyl group, or lower alkoxy group as a substituent.
An example is a methyl group substituted with . (B) General formula [In the formula, R' is a lower alkyl group and n is 2 or 3
] A cyclic ether residue represented by Examples of such groups include 2-tetrahydrofuranyl group and 2-tetrahydropyranyl group. (C) Lower alkoxymethyl group. Examples of such groups include methoxymethyl, ethoxymethyl, and hexyloxymethyl groups. (D) Tri-lower alkylsilyl group. The group is
Examples include trimethylsilyl and t-butyldimethylsilyl groups. In this reaction, phenyl lower alkyl halide (RX) is reacted with the compound of general formula (4) (hereinafter referred to as compound (4)), and the 3' or 5' position of compound (4) is reacted with phenyl lower alkyl halide (RX). Compound (5) is obtained by substituting the hydrogen atom with the desired R group, and then carrying out a deprotection reaction or a delower alkanoylation reaction as required. In the above, the reaction for introducing the R group is carried out under the reaction conditions of a normal dehydrohalogenation reaction. As the dehydrohalogenation agent, any of various basic compounds commonly used in this type of reaction can be used. Specific examples include sodium hydroxide,
Examples include potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metals such as sodium and potassium, and alkali metal hydrides such as sodium hydride and potassium hydride. The above reaction can be carried out without a solvent or in the presence of a solvent. As the solvent, any ordinary inert solvent can be used, such as water, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, and ketones such as acetone and methyl ethyl ketone. Nitriles such as acetonitrile, propionitrile, dimethylformamide, dimethyl sulfoxide and the like are advantageously used. The ratio of compound (4) and phenyl lower alkyl halide (RX) to be used is not particularly limited and may be appropriately selected from a wide range, but usually the former is used in at least an equimolar amount of the latter, preferably in an equimolar amount to It is preferable to use 5 times the molar amount. The reaction temperature is not particularly limited and is appropriately selected from a wide range, but it is generally selected from the range of 0 to 100°C, preferably room temperature to 80°C, and the reaction is usually completed in about 5 to 64 hours. . When the compound obtained by the above reaction has a protecting group at the 3' or 5' position, the desired compound (5) can be obtained by subsequently performing an elimination reaction of the protecting group. This deprotection reaction can be carried out using a suitable catalyst commonly used in ordinary acid hydrolysis reactions, such as inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, formic acid, acetic acid, etc.
Usually carried out in a solvent using an appropriate amount of an organic acid such as a lower alkanoic acid such as propionic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, organic sulfonic acid such as 4-methylbenzenesulfonic acid. be done. As a solvent, common inert solvents such as water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, THF, and dioxane,
Aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, lower alkanoic acids such as acetic acid and propionic acid, and mixed solvents thereof can be used. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but is usually 0 to 100°C,
Preferably, the temperature is from room temperature to about 80°C, and the reaction is completed in about 3 minutes to 20 hours. The acid used is usually in a catalytic amount to an excess amount, preferably in an excess amount. Also, the compound obtained in the above reaction scheme a
(5) Compounds having an acyl group in at least one of the 3-, 3'-, and 5'-positions are subjected to a hydrolysis reaction to convert any one or all of the acyl groups into hydrogen atoms. can be done. This hydrolysis reaction is carried out under conventional acid or alkaline hydrolysis conditions. As the catalyst used in this case, any catalyst used in ordinary acid or alkaline hydrolysis reactions can be used. Typical examples include basic compounds such as sodium hydroxide, potassium hydroxide, and barium hydroxide, and inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid. The amount of these catalysts to be used is not particularly limited and may be appropriately selected from a wide range. This reaction generally proceeds advantageously in a solvent, and a wide range of common inert solvents can be used as the solvent. For example, water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, and mixed solvents thereof can be advantageously used. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but it is usually 0 to 100°C, preferably room temperature to 80°C. This reaction is completed in about 30 minutes to 10 hours. [In the formula, R ¹ and R ² are the same as above. One of R ¹ ' and R ² ' is the above R group, and the other is a hydrogen atom, a lower alkanoyl group, or a protecting group. R ^3a represents a benzoyl group or a phenoxycarbonyl group that may have a lower alkoxy group. ] This reaction is a reaction (acylation reaction) for introducing a desired acyl group (substituted or unsubstituted benzoyl group or phenoxycarbonyl group) into the 3-position of the pyrimidine skeleton, and is carried out using a conventional method such as the acid chloride method. It can be implemented. According to the acid chloride method, the desired compound (7) is obtained by reacting compound (6) with an acyl halide (R ^3a In the above, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine, etc. can be used as a deoxidizing agent. Examples of solvents used include benzene, chloroform, methylene chloride, carbon tetrachloride, dioxane, and tetrahydrofuran. Dosage of acyl halide compound
The amount should be at least equimolar, preferably equimolar to about 3 mol, relative to (6). The reaction temperature is usually -30 to 100°C, preferably room temperature to about 80°C, and the reaction is completed in about 20 minutes to 20 hours. In the above reaction, compound (6) is at the 3' position or
When the 5'-position has a free hydroxyl group, these sites are also acylated at the same time as the 3-position. Therefore, in the above-mentioned acylation of such compounds, it is preferable to protect the 3'- or 5'-position hydroxyl group in advance, and then remove the protecting group after the acylation. The reaction for introducing this protecting group will be described later. Moreover, the elimination reaction of the protecting group can be carried out in the same manner as the method explained in the section of the reaction scheme a. (In the formula, one of R ^1b and R ^2b represents a hydrogen atom and the other represents the above R group. One of R ^1c and R ^2C represents a lower alkanoyl group and the other represents the above R group. R ³ is the same as above. ] According to this reaction, compound (9) is obtained by converting the free hydroxyl group at the 3' or 5' position of compound (8) into lower alkanoylation.This lower alkanoylation reaction can be carried out using a conventional acylation reaction method. For example, any of the acid chloride method, acid anhydride method, mixed acid anhydride method, N,N-dicyclohexylcarbodiimide method (DCC method), etc. can be applied, and the acid anhydride method and the acid chloride method are particularly advantageous. The acid anhydride method is carried out by heating compound (8) with an acid anhydride in a suitable solvent. The anhydride of the acid corresponding to the acyl group is used. Specific examples thereof include acetic anhydride, propionic anhydride, butyric anhydride, etc. These acid anhydrides can be used as compounds.
(8) at least in an equimolar amount, preferably from 1 to
It is preferable to use about 3 times the molar amount. As a solvent, various inert solvents such as pyridine, chloroform, halogenated hydrocarbons such as dichloromethane,
Ethers such as dioxane and THF, benzene,
Aromatic hydrocarbons such as toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, etc. can be used. The reaction temperature is usually about -30°C to 100°C, preferably about room temperature to 80°C, and the reaction is completed in about 20 minutes to 20 hours. Further, the above reaction is advantageously carried out in the presence of a basic compound. As the basic compound,
Examples include organic bases such as tertiary amines such as pyridine, triethylamine, and N,N-dimethylaniline, and inorganic basic compounds such as sodium bicarbonate, potassium carbonate, and sodium acetate. The acid chloride method is carried out by reacting compound (8) with a lower alkanoyl halide (R ^3a X) in a suitable solvent in the presence of an acid absorbing agent. The method can be carried out analogously to that shown in reaction scheme b above. In the above reaction scheme b and reaction scheme c,
When the amount of the reagent, i.e., acid anhydride or acid halide used is at least twice the molar amount relative to the raw material,
In some cases, a compound is obtained in which the 3' or 5' position (O-acyl form) and the 3-position (N-acyl form) are simultaneously acylated, but this O- and N-acyl form is
It can be easily separated from the -acyl form or the N-acyl form. [In the formula, R ¹ and R ² are the same as above. A represents a tri-lower alkylsilyl group and B represents a lower alkanoyl group. Furthermore, one of R ¹ ″ and R ² ″ represents the above R group, and the other represents the above A group or lower alkanoyl group. ] According to the above, compound (11) is obtained by reacting compound (10) with bis-N,O-trilower alkylsilylacetamide (trialkylsilylation reaction), and then 2-lower alkanoyloxytetrahydrofuran is reacted with compound (11). Reaction (tetrahydrofuranylation reaction)
By doing so, compound (12) can be obtained. The trialkylsilylation reaction can be carried out using a suitable inert solvent, such as dioxane, ethers such as THF,
Aromatic hydrocarbons such as benzene and toluene,
In a solvent such as DMF, DMSO, acetonitrile, etc., at a temperature of about 0 to 100℃, preferably room temperature to 50℃ for 30 minutes.
The process takes between minutes and 6 hours. In the above, the bis-N,O-trilower alkylsilylacetamide is preferably used in an amount of at least an equivalent, preferably 1 to 2 times equivalent, per functional group to be reacted. The subsequent tetrahydrofuranylation reaction is carried out in the same solvent as above at a temperature of about 0 to 100°C, preferably room temperature to 50°C, for 30 minutes to 6 hours. The amount of 2-lower alkanoyloxytetrahydrofuran to be used is at least equimolar to the raw material, preferably 1 to 2 times the molar amount.
This reaction also proceeds advantageously when a Lewis acid such as stannic chloride (SnCl ₄ ), aluminum chloride, zinc chloride, etc. is present in the reaction system in an amount of about 0.1 mol or more based on the raw materials. In addition, in the tetrahydrofuranylation reaction, when using a compound in which R ¹ '' or R ² '' is a tri-lower alkylsilyl group, the desired compound can be obtained by subsequently performing an elimination reaction of the tri-lower alkylsilyl group. (12)
is obtained. This elimination reaction is carried out in the same manner as the deprotecting group reaction described in the section of reaction scheme a. In this way, a compound of general formula (1) is obtained. The resulting compound can be separated by conventional separation methods such as reprecipitation, recrystallization, silica gel chromatography, ion exchange chromatography, gel chromatography,
It is easily isolated and purified by affinity chromatography and the like. The starting material compounds used in the reaction schemes a to d can be obtained, for example, by the methods shown in the following reaction schemes e to g. [R ³ a is the same as above. R ² c represents a lower alkanoyl group and R ¹⁰ represents a protecting group] The lower alkanoylation reaction of compound (13) is carried out in the same manner as that of compound (8) shown in reaction scheme c above. More preferably, the reaction uses an acid anhydride corresponding to the lower alkanoyl group to be introduced at the 5' position in a molar amount of about 1 to 1.5 times the amount of compound (13),
Approximately 1 to 6
It takes time. Compound acylated at the 5′ position by the above reaction (14)
is obtained as the main component, and a compound acylated at the 3' position is also obtained as a subcomponent. Compound (14) obtained above is then
It is used for the protection reaction of the 3'-hydroxyl group. This protection reaction is performed by converting the protecting group explained in reaction scheme a to compound (14).
The reagent for introducing the protecting group is a triaryl-substituted methyl halide which provides the protecting group represented by the above general formula (A), and a triaryl-substituted methyl halide which provides the protecting group represented by the above general formula (B). The following general formula provides a protecting group [In the formula, R' and n are the same as those in the general formula (B)] Unsaturated cyclic ethers, lower alkoxymethyl halides, and tri-lower alkylsilyl halides are used. The protecting group introduction reaction using a halide is carried out in the same manner as the dehydrohalogenation reaction shown in the reaction scheme a. However, the amount of reagent is 1 to 2 times the mole of compound (14), preferably 1 to 1.5 times,
The reaction temperature is preferably -30°C to 80°C. The protecting group introduction reaction using the unsaturated cyclic ether represented by the above general formula (B') is carried out in the presence of an acid catalyst, for example, in an aprotic inert solvent such as THF, dioxane, acetonitrile, etc.
As the acid catalyst, hydrohalic acids such as hydrogen bromide and hydrogen chloride, and Lewis acids such as aluminum chloride, boron fluoride, and zinc chloride can be used. The reaction was carried out using a reagent in a molar amount of 1 to 1.5 times that of compound (14) at -30°C to 60°C.
It takes about 2 to 5 hours at a temperature of 0.degree. The elimination reaction of the lower alkanoyl group at the 5' position of compound (15) thus obtained is carried out under alkaline hydrolysis conditions. The conditions are the same as those for the hydrolysis reaction described in the section of the reaction scheme a above using a basic compound as a catalyst. [In the formula, R ¹⁰ is the same as above] According to the above, by directly performing a protecting group introduction reaction on compound (13), compound (17) in which a protecting group is introduced at the 5' position can be obtained. This protecting group introduction reaction is carried out under the same conditions as shown in reaction scheme e. By the reactions shown in the above reaction schemes e and f,
A starting compound having a lower alkanoyl group or a protecting group introduced at either the 3'-position or the 5'-position can be obtained. [In the formula, A is the same as above] The trialkylsilylation reaction of compound (18) is carried out according to the reaction scheme, except that at least 3 mol of bis-O,N-trilower alkylsilylacetamide is used with respect to compound (18). The reaction is carried out in the same manner as the trialkylsilylation reaction of compound (10) shown in d. Tetrahydrofuranylation reaction at the 3-position of the resulting compound (19), followed by a reaction at the 3'-position of the compound (20) and
The elimination reaction of the tri-lower alkylyl group at the 5' position is carried out in the same manner as each reaction shown in reaction scheme d. In this way, a compound (21) having a tetrahydrofuranyl group at the 3-position is obtained. By subjecting the compound (21) to the reactions shown in the above reaction schemes e and f, it has a tetrahydrofuranyl group at the 3-position and a lower alkanoyl group or a protecting group at either the 3'-position or the 5'-position. It is possible to obtain a raw material compound into which . The raw material compounds obtained by the reactions shown in the above formulas can be used as raw material compounds as they are, or can be used as raw material compounds after being separated in a reaction system according to a conventional method. The compound (1) obtained in this way has excellent anticancer activity in itself, is low in toxicity, has few side effects such as weight loss, and is very useful as an antitumor agent for cancer treatment in humans and animals. Useful. The present invention provides that the anticancer effect of the compound (1) is further enhanced when it is used in combination with the pyrimidine derivative represented by the general formula (2) and/or the pyridine derivative represented by the general formula (3). This has been discovered and completed. The above compound (2) and/or compound (3) used in combination with compound (1) in the present invention are known or can be prepared according to a known method [Triv.Chem.Rec., 73 , 704 (1954)]. It can be easily manufactured. Compound (1) and compound (2) in the antitumor agent of the present invention
The blending ratio with compound (3) and (3) varies slightly depending on the type of compound, but usually 1 of compound (1)
Compound (2) and/or compound (3) per mole
The amount is preferably about 0.1 to 10 molar, and by this combination, significantly enhanced antitumor activity is expressed even though Compound (2) and Compound (3) themselves have substantially no antitumor activity. Moreover, side effects such as weight loss are reduced, and toxicity is also significantly weakened. The antitumor agent of the present invention is usually used in the form of a common pharmaceutical preparation. The formulation usually uses fillers,
Bulking agents, binders, wetting agents, disintegrants, surfactants,
It is adjusted using a diluent or excipient such as a lubricant. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules,
Capsules, suppositories, injections (liquids, suspensions, etc.),
Examples include ointments. When forming into a tablet, carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water, ethanol, propanol, simple syrup, Glucose solution, starch solution, gelatin solution,
Binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, ponyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, Disintegrants such as stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; and heat insulating agents such as glycerin and starch. Adsorbents such as , starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, carriers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil,
Excipients such as kaolin and talc, gum arabic powder,
Binders such as powdered tragacanth, gelatin and ethanol, and disintegrants such as laminaran and agar can be used. When forming into a suppository, carriers such as polyethylene glycol, cacao butter,
Higher alcohols, esters of higher alcohols,
Gelatin, semi-synthetic glyceride, etc. can be used.
Capsules are prepared by mixing the compound of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods.
When prepared as injections, solutions, emulsions and suspensions are preferably sterile and isotonic with blood, and when forming these forms, diluents such as water, ethyl alcohol, macrogol, etc. , propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to adjust the isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents. Compound (1) to be contained in the pharmaceutical formulation of the present invention
The amounts of compound (2) and (or) compound (3) are not particularly limited and may be appropriately selected within a wide range.
Usually, the total amount of compounds in pharmaceutical preparations is 1 to 70% by weight.
It is preferable to set the amount to be contained. The administration method of the above pharmaceutical preparation is not particularly limited, and is determined depending on various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with conventional replacement fluids such as glucose and amino acids, and furthermore, if necessary, are administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the compound (1) usually used in combination at the above-mentioned mixing ratio.
The amount should be approximately 0.5 to 20 mg per kg of body weight per day. The formulation can be administered in 1 to 4 divided doses per day. Examples Hereinafter, production examples of compound (1) used in the present invention will be given, followed by pharmacological test examples and formulation examples. Production Examples 1 and 2 3'-0-benzyl-2'-deoxy-5-fluorouridine [R ¹ = C ₆ H ₅ CH ₂ , R ² = R ³ = H] and 5'-0-benzyl-2' -Deoxy-5-fluorouridine [R ¹ = R ³ = H, R ² = C ₆ H ₅ CH ₂ ]
11.4 g of potassium hydroxide was dissolved in a mixed solution of 350 ml of water and 100 ml of dioxane, and 10.0 g of 2'-deoxy-5-fluorouridine and 3.0 ml of benzyl bromide were added while stirring at room temperature. Thereafter, 100 ml of a 5% aqueous potassium hydroxide solution and 3.0 ml of benzyl bromide were added three times every 24 hours, and stirring was continued overnight. After washing the reaction solution twice with 200 ml of ether, the aqueous layer was neutralized with 6N-HCl and concentrated to about 200 ml. This is again 6N−
The pH was adjusted to about 3-4 with HCl and extracted twice with 100 ml of ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and then concentrated. The oily residue was eluted with chloroform to 2% methanol-chloroform using a silica gel column to give 3'-0-benzyl-
The fraction corresponding to 2'-deoxy-5-fluorouridine was collected, concentrated, and recrystallized from ethanol to yield 3.57 g (26.1%) of the target compound. Melting point 138-139℃ ^1H -NMR (DMSO- _d6 ) δ: 11.82 (1H, bs, -NH-, disappeared by addition of _D2O ), 8.21 (1H, d, J=7Hz, _C6 -H ) 7.35 (5H, s, phenyl-H) 6.16 (1H, t, J = 6 Hz, C ₁ ′-H) 5.22 (1H, bs, 5′-OH, disappeared by addition of D ₂ O) 4.54 (2H, s ,

[Formula]) 4.24-4.19 (1H, m, C ₃ ′-H) 4.09-4.06 (1H, m, C ₄ ′-H) 3.65-3.53 (2H, m, C ₅ ′-H) 2.51-2.16 ( 2H, m, C ₂ '-H) Elemental analysis value: C ₁₆ H ₁₇ FN ₂ O ₅ Calculated value (%): C 57.14; H 5.09; N 8.33 Actual value (%): C 57.12; H 5.28; N 8.24 The fraction corresponding to the eluted 5'-0-benzyl-2'-deoxy-5-fluorouridine was then collected, concentrated and recrystallized from ethanol.
0.40 g (2.9%) of the target compound was obtained. Melting point 129-130℃ ^1H -NMR (DMSO- _d6 ) δ: 11.76 (1H, bs, -NH-, disappeared by addition of _D2O ) 7.95 (1H, d, J=7Hz, _C6 -H) 7.34 (5H, s, phenyl-H) 6.15 (1H, t, J=7Hz, C ₁ ′-H) 5.33 (1H, bs, 3′-OH, disappears with addition of D ₂ O) 4.55 (2H, s,

[Formula]) 4.34-4.16 (1H, m, C ₃ ′-H) 4.00-3.89 (1H, m, C ₄ ′-H) 3.69-3.63 (2H, m, C ₅ ′-H) 2.14 (2H, t, J = 6 Hz, C ₂ '-H) Elemental analysis value: C ₁₆ H ₁₇ FN ₂ O ₅ Calculated value (%): C 57.14; H 5.09; N 8.33 Actual value (%): C 57.29; H 5.30 ;N 8.26 Production Examples 3 and 4 3'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine [R ² = R ³ = H, R ¹ =
4-chlorobenzyl group] and 5'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine [R ¹ = R ³ = H, R ² = 4-chlorobenzyl group] 150 ml of water 4.0 g of potassium hydroxide was dissolved in a mixture of 2'-deoxy-5-fluorouridine and 40 ml of dioxane, and 2'-deoxy-5-fluorouridine 2.00 g and 4-chlorobenzyl chloride 5.5 g were added thereto under stirring at room temperature. After 2 days, post-treatment was carried out in the same manner as in Production Examples 1 and 2, and 3'-0-(4-chlorobenzyl) was eluted with chloroform to 2% methanol-chloroform using a silica gel column.
The fraction corresponding to -2'-deoxy-5-fluorouridine was collected and concentrated to yield 0.50% of the target compound.
g (17%) was obtained. Melting point 196-198℃ ^1H -NMR (DMSO- _d6 ) δ: 11.81 (disappeared by addition of 1H, bs, -NH-, _D2O ), 8.20 (1H, d, J=7Hz, _C6 -H ) 7.38 (4H, s, phenyl-H) 6.14 (1H, t, J = 7Hz, C ₁ '-H) 5.21 (1H, bt, J = 5Hz, 5'-OH, disappeared by addition of D ₂ O) 4.53 (2H,s,

[Formula]) 4.23-4.14 (1H, m, C ₃ ′-H) 4.10-4.03 (1H, m, C ₄ ′-H) 3.71-3.58 (2H, m, C ₅ ′-H) 2.41-2.02 ( 2H, m, C ₂ '-H) Elemental analysis value: C ₁₆ H ₁₆ ClFN ₂ O ₅ Calculated value (%): C 51.83; H 4.35; N 7.56 Actual value (%): C 51.82; H 4.60; N 7.41 5'-0-(4-chlorobenzyl) then eluted
The fraction corresponding to -2'-deoxy-5-fluorouridine was collected and concentrated to obtain 0.12 g (4.0%) of the target substance in powder form. ^1H -NMR (DMSO- _d6 ) δ: 11.79 (disappeared by addition of 1H, bs, -NH-, _D2O ), 7.91 (1H, d, J=7Hz, _C6 -H) 7.38 (4H, s , phenyl-H) 6.13 (1H, t, J = 6Hz, C ₁ ′-H) 5.33 (1H, bs, 3′-OH, disappeared by addition of D ₂ O) 4.53 (2H, s,

[Formula]) 4.38-4.21 (1H, m, C ₃ ′-H) 4.04-3.82 (1H, m, C ₄ ′-H) 3.78-3.74 (2H, m, C ₅ ′-H) 2.25-1.98 ( 2H, m, C ₂ '-H) Elemental analysis value: C ₁₆ H ₁₆ ClFN ₂ O ₅ Calculated value (%): C 51.83; H 4.35; N 7.56 Actual value (%): C 51.73; H 4.80; N 7.97 Production Example 5 2'-deoxy-5-fluoro-3'-(2-methylbenzyl)uridine [R ² = R ³ = H, R ¹ = 2
-Methylbenzyl group] Dissolve 1.14 g of potassium hydroxide in a mixture of 33 ml of water and 16 ml of acetonitrile, and stir at room temperature with 1.00 g of 2'-deoxy-5-fluorouridine and 1.50 g of 0-methylbenzyl bromide. added. Then production example 1
And after treatment in the same manner as in 2, 0.29g of the target compound
(20%). Melting point: 114-116℃ ^1H -NMR (DMSO- _d6 ) δ: 11.79 (1H, bs, -NH-, disappeared by addition of _D2O ), 8.19 (1H, d, J=7Hz, _C6- H) 7.30−7.17 (4H, m, phenyl-H) 6.11 (1H, t, J = 6Hz, C ₁ ′-H) 5.19 (1H, t, J = 5Hz, 5′-OH, by addition of D ₂ O disappearance) 4.45 (2H, s,

[Formula]) 4.22-4.02 (2H, m, C' ₃ , C ₄ -H) 3.66-3.62 (2H, m, C ₅ '-H) 2.29-2.21 (2H, m, C ₂ '-H and CH ₃ ) Elemental analysis value: C ₁₇ H ₁₉ FN ₂ O ₅ Calculated value (%): C 58.28; H 5.46 N 7.99 Actual value (%): C 58.12; H 5.64; N 8.01 Production example 6 Same as production example 5 The following compound was obtained. 3'-0-(4-methylbenzyl)-2'-deoxy-
5-Fluorouridine [R ² = R ³ = H, R ¹ = 4-
Methylbenzyl group] Yield 21% Melting point 178-180℃ ^1H -NMR (DMSO- _d6 ) δ: 11.81 (1H, bs, -NH-, disappeared by addition of _D2O ), 8.18 (1H, d, J=7Hz, _C6 -H) 7.30-7.13 (4H, m, phenyl-H) 6.12 (1H, t, J=6Hz, _C1' -H) 5.17 (1H, t, J=5Hz, 5'- 4.20-4.01 (2H, m, C _{3 ′} , C ₄ ′-H) 3.65-3.60 (2H, m, C ₅ ′-H) 2.29-2.12 (5H, m, C _2′ -H and CH ₃ ) Production Example 7 3′-0-benzyl-2′-deoxy-5-fluoro-3-phenoxycarbonyl uridine [R ¹
＝C ₆ H ₅ CH ₂ , R ² = H, R ³ = phenoxycarbonyl] Production of 3'-0-benzyl-2'-deoxy-5-fluorouridine 0.50 g dioxane 20 ml solution and trimethylchlorosilane 0.38 ml and triethylamine 1.04
ml and stirred at room temperature for 2 hours, then heated to 60℃ for 30 minutes.
I left it for a minute. Then, 0.40 g of phenoxycarbonyl chloride and 1.00 ml of triethylamine were added, and the mixture was further left at 60°C for 3 hours. The solvent was distilled off, the residue was dissolved in 50 ml of ethyl acetate, washed with saturated brine, and the ethyl acetate layer was separated. This was concentrated and the residue was dissolved in 30 ml of methanol. Acetic acid here 0.5
ml was added, left overnight, and concentrated. The residue was eluted with chloroform to 2% methanol-chloroform using a silica gel column to obtain 0.58 g of the target compound.
(86%). Melting point 110-112℃ ^1H -NMR ( _CDCl3 ) δ: 8.16 (1H, d, J=7Hz, _C6 -H), 7.34-7.22 (10H, m, phenyl-H) 6.27 (1H, t, J = 6Hz, C ₁ ′-H) 4.49 (2H, s,

[Formula]) 4.26-4.17 (2H, m, C ₃ ′, ₄ ′-H) 3.95-3.60 (2H, m, C ₅ ′-H) 2.63-1.98 (2H, m, C ₂ ′-H) Element Analytical value _{: C23H21FN2O7 Calculated} value (%): C 60.53; H 4.64; N 6.14 Actual value (%): C 60.60; _H 4.72; N 6.08 Production example 8 3'-0-benzyl- 3-benzoyl-2'-deoxy-5-fluorouridine [R ¹ =C ₆ H ₅ CH ₂ ,
R ² = H, R ³ = C ₆ H ₅ CO] 3'-0-Benzyl-2'-deoxy-5-fluorouridine 0.50 g in dioxane 20 ml solution, trimethylchlorosilane 0.75 ml and triethylamine 2.00
ml and stirred at room temperature for 2 hours, then left at 60°C for 30 minutes. Next, 0.42 g of benzoyl bromide and 1.00 ml of triethylamine were added, and the mixture was further left at 60°C for 1 hour. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate.
and washed with saturated saline. The ethyl acetate layer was separated and concentrated, and the residue was dissolved in 30 ml of methanol, to which 0.5 ml of acetic acid was added and left overnight at room temperature. After distilling off the solvent, the residue was eluted with chloroform to 2% methanol-chloroform using a silica gel column to obtain 0.35 g (54
%) was obtained. Melting point - (glassy powder) ¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, d, J=7Hz, C ₆ -H) 7.94-7.85 (2H, m,

【formula】) 7.64−7.21 (8H, m,

【formula】

[Formula]) 6.24 (1H, t, J=6Hz, C ₁ '-H) 4.46 (2H, s,

[Formula]) 4.24-4.12 (2H, m, C ₃ ′, ₄ ′-H) 3.92-3.56 (2H, m, C ₅ ′-H) 2.60-1.96 (2H, m, C ₂ ′-H) Manufacturing Example 9 3'-0-benzyl-2'-deoxy-3-(4-
Production of (propoxybenzoyl)-5-fluorouridine [R ¹ =C ₆ H ₅ CH ₂ , R ² =H, R ³ =4-propoxybenzoyl] The target compound was obtained in the same manner as in Production Example 8. Yield 65% Melting point - (glassy powder) ¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, d, J = 7Hz, C ₆ -H) 7.85 (2H, d, J = 9Hz,

【formula】) 7.27 (5H, s,

【formula】) 6.90 (2H, d, J=9Hz,

[Formula]) 6.25 (1H, t, J=6Hz, C ₁ '-H) 4.44 (2H, s,

[Formula]) 4.20−3.55 (6H, m, C ₃ ′, ₄ ′, ₅ ′−H, −CH ₂ C H ₂ O
−) 2.57−1.58 (4H, m _, C ₂ ′−H, CH ₃ C H ₂ CH ₂ O−) 0.99 (3H, t, J=7Hz, CH 3 CH ₂ −) Production example 10 3′−0 -benzyl-2'-deoxy-3-(2-
Production of (tetrahydrofuranyl)-5-fluorouridine [R ¹ = C ₆ H ₅ CH ₂ , R ² = H, R ² = 2-tetrahydrofuranyl] 3'-0-benzyl-2'-deoxy-5-fluorouridine To a suspension of 0.40 g in 30 ml of dry dichloromethane was added 0.54 g of N,O-bis(trimethylsilyl)acetamide while stirring at room temperature. 4 hours later,
A solution of 0.20 g of 2-acetoxytetrahydrofuran and 0.05 ml of stannic chloride in 0.5 ml of dry dichloromethane was added, and the mixture was further stirred for 1.5 hours. Next, 1.00 ml of triethylamine was added to neutralize the mixture, and the mixture was washed with water. The dichloromethane layer was concentrated, the residue was dissolved in 20 ml of methanol, 1.0 ml of acetic acid was added thereto, and the mixture was left at 40°C for 3 hours. The solvent was distilled off, and the residue was eluted with chloroform to 4% methanol-chloroform using a silica gel column to obtain 0.37 g (77 g) of the target compound as an oil.
%) was obtained. ^1H -NMR ( _CDCl3 ) δ: 8.01 (1H, d, J=6Hz, _C6 -H) 7.30 (5H, s, phenyl-H) 6.58 (1H, bt, J=6Hz,

[Formula]) 6.26 (1H, bt, J=6Hz, C ₁ ′-H) 4.51 (2H, s,

[Formula]) 4.39−3.50 (7H, m, C ₃ ′, ₄ ′, ₅ ′-H, C ₅ ′-OH,

[Formula]) 2.60−1.86 (6H, m, C ₂ ′−H,

[Formula]) Elemental analysis value: C ₂₀ H ₂₃ FN ₂ O ₆ Calculated value (%) C 59.11; H 5.70N 6.89 Actual value (%) C 59.02; H 6.11N 6.78 Production example 11 5'-0-acetyl -3'-O-benzyl-3-benzoyl-2'-deoxy-5-fluorouridine [R ¹ = C ₆ H ₅ CH ₂ , R ² = CH ₃ CO, R ³ =
Production of 5'-0-acetyl-3'-O-benzyl-2'-deoxy-5 _- fluorouridine in 10 ml of dioxane, add 0.29 g of benzoyl chloride and _0.73 ml of triethylamine, It was left at 80°C for 2 hours.
After evaporating the solvent, the residue was dissolved in 50 ml of ethyl acetate and washed with water. After drying the ethyl acetate layer over anhydrous sodium sulfate and concentrating, the residue was applied to a silica gel column and eluted with chloroform to obtain 0.20 g (78%) of the target compound as an oil. ^1H -NMR ( _CDCl3 ) δ: 7.95-7.27 (11H, m, phenyl-H, _C6 -H), 6.20 (1H, t, J=6Hz, _C1' -H) 4.45 (2H, s,

[Formula]) 4.23-4.08 (4H, m, C ₃ ′, ₄ ′, ₅ ′-H) 2.60-2.05 (5H, m, C ₂ ′-H, COCH ₃ ) Elemental analysis value: C ₂₅ H ₂₃ FN Calculated value (%) as ₂ O ₇ C 62.24; H 4.80; N 5.81 Actual value (%) C 62.34; H 5.06; N 5.77 Production example 12 3'-0-benzyl-5'-0-acetyl-2'- Deoxy-5-fluorouridine [R ¹ =
Production of C ₆ H ₅ CH ₂ , R ² = CH ₃ CO, R ³ = H] Add 3.33 ml of acetic anhydride to a solution of 3.95 g of pyridine containing 3'-0-benzyl-2'-deoxy-5-fluorouridine. The mixture was then left at 40°C overnight. The solvent was distilled off, and the residue was dissolved in 30 ml of ethyl acetate and washed twice with 15 ml of water. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and eluted with chloroform using a silica gel column to obtain 3.62 g (81.5 g) of the target compound.
%) was obtained. Melting point 87-88℃ ^1H -NMR (DMSO-d ₆ ) δ: 11.86 (1H, d, J = 4Hz, -NH-, disappeared by addition of D ₂ O) 7.93 (1H, d, J = 7Hz, C ₆ −H) 7.35 (5H, s, phenyl-H) 6.15 (1H, t, J = 6Hz, C ₁ ′-H) 4.55 (2H, s,

[Formula]) 4.32-4.20 (4H, m, C ₃ ′, ₄ ′, ₅ ′-H) 2.39-2.28 (2H, t, J=6Hz, C ₂ ′-H) 2.04 (3H, s, COCH ₃ ) Elemental analysis value: C ₁₈ H ₁₉ FN ₂ O ₆ Calculated value (%) C 57.14; H 5.06 N 7.40 Actual value (%) C 56.99; H 5.22 N 7.37 Formulation example 1 5-mercapto-2,4-dihydroxy Pyrimidine 20 mg 2'-deoxy-3'-0-benzyl-5-fluorouridine 50 mg Lactose 110 mg Crystalline cellulose 67 mg Magnesium stearate 3 mg Capsules containing 250 mg per capsule are prepared using the above blending ratio. Formulation example 2 2,4-dihydroxypyrimidine 10mg 2'-deoxy-3'-0-benzyl-3-benzoyl-5-fluorouridine 20mg Lactose 107mg Crystalline cellulose 60mg Magnesium stearate 3mg At the above blending ratio, 200mg per capsule. Prepare capsules. Formulation example 3 5-chloro-2,4,6-trihydroxypyrimidine 10mg 3'-0-benzyl-2'-deoxy-5-fluoro-3-phenoxycarbonyl uridine 10mg Lactose 180mg Cornstarch 290mg Hydroxypropylmethylcellulose 10mg Prepare 500 mg of granules per package using the above mixing ratio. Production example 4 5-chloro-4,6-dihydroxypyrimidine
20mg 2'-deoxy-3'-0-benzyl-3-(2-
Tetrahydrofuranyl)-5-fluorouridine 10 mg Macrogol 300 500 mg Distilled water for injection Appropriate amount Prepare 5 ml of an injection preparation per ampoule at the above mixing ratio. Formulation example 5 N-(2-tetrahydrofuranyl)-2,4-dihydroxypyridine 10g 5'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine 10g Lactose 40g Cornstarch 24g Crystalline cellulose 25g Methyl cellulose 1.5g Magnesium stearate 1g N-(2-tetrahydrofuranyl)-2,4-dihydroxypyridine, 5'-0-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine,
The lactose, cornstarch and microcrystalline cellulose are thoroughly mixed, granulated with a 5% aqueous solution of methylcellulose, passed through a 200 mesh sieve and carefully dried.
The dried granules are passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.
You get 1000 tablets for oral use. Pharmacological test example Sarcoma-180, which had been passaged in ICR mice as ascites, was diluted with physiological saline and an amount of 2 x ¹⁰⁷ cells per mouse was transplanted subcutaneously on the back of syngeneic mice and used for experiments. did. 1 from 24 hours after tumor implantation
The drug suspended in 5% gum arabic was orally administered once a day for 7 days. On the 10th day after tumor transplantation, a solid tumor under the skin of the back was removed.
Measure the tumor weight and calculate the ratio of the tumor weight (T) in the drug-administered group to the tumor weight (C) in the control group to which no drug was administered (T/C).
was determined, and the 50% tumor-inhibiting dose (ED50 value) at which T/C was 0.5 was determined from the dose-response curve of the drug dose and the ratio (T/C). Table 1 shows the cases where Compound (1) or other 2'-deoxy-5-fluorouridine derivatives were used alone as antitumor agents as test drugs.

【table】

[Table] Pharmacological test Compound (1) or a known antitumor drug active ingredient compound (FT-
207, 1-(2-tetrahydrofuryl-5-fluorouracil) was used alone or in combination with the following compound (2) or compound (3) in a molar ratio of 1:1. The results using the combination agents are shown in Table 2 below. Compound (1) in each table is indicated by the No. in Table 1 above. Also, compound (2) and compound (3)
are indicated using the following abbreviations. <Compound (2)> A...2,4-dihydroxypyrimidine B...5-nitro-2,4-dihydroxypyrimidine C...5-methyl-2,4-dihydroxypyrimidine D...5-mercapto-2,4-dihydroxypyrimidine E...5-chloro-2,4-dihydroxypyrimidine F...5-bromo-2,4-dihydroxypyrimidine G...5-iodo-2,4-dihydroxypyrimidine H...4-6-dihydroxypyrimidine I...5-chloro- 4,6-dihydroxypyrimidine J...5-bromo-4,6-dihydroxypyrimidine K...5-nitro-4,6-dihydroxypyrimidine L...5-methyl-4,6-dihydroxypyrimidine M...2,4,6- Trihydroxypyrimidine N...5-methyl-2,4,6-trihydroxypyrimidine O...5-chloro-2,4,6-trihydroxypyrimidine P...5-bromo-2,4,6-trihydroxypyrimidine Q... 5-nitro-2,4,6-trihydroxypyrimidine R...5-formyl-2,4,6-trihydroxypyrimidine <Compound (3)> S...2,4-dihydroxypyridine T...N-(2-tetrahydrofura nyl)-2,4-
Dihydroxypyridine (N position of compound S is 2-
Substituted with tetrahydrofuranyl group

【table】

[Table] From Tables 1 and 2 above, it can be seen that compound (1) used in the present invention has excellent antitumor activity by itself, and that it is used in combination with compound (2) or (3). It is clear that sometimes the antitumor activity is significantly enhanced.

Claims (1)

[Claims] 1. General formula [In the formula, one of R ¹ and R ² represents a phenyl lower alkyl group which may have a substituent selected from a lower alkyl group and a halogen atom on the phenyl ring, and the other represents a hydrogen atom or a lower alkanoyl group. R ³ represents a hydrogen atom, a benzoyl group that may have a lower alkoxy group, a phenoxycarbonyl group, or a tetrahydrofuranyl group] 2'-deoxy-5-fluorouridine derivatives represented by the general formula [In the formula, R ⁴ is a hydrogen atom or a hydroxyl group, R ⁵ is a hydrogen atom, an amino group, a halogen atom, a mercapto group,
Nitro group, formyl group or lower alkyl group,
R ⁶ represents a hydrogen atom or a hydroxyl group] Pyrimidine derivatives and general formula represented by [In the formula, R ⁷ represents a hydrogen atom or a tetrahydrofuranyl group] At least one compound selected from pyridine derivatives represented by the following.