JPH0564123B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to an antitumor activity enhancer. Prior Art The active ingredient compound of the antitumor activity enhancer of the present invention is
Hitherto, it has not been known at all that these have such an antitumor activity-enhancing effect. Problems to be Solved by the Invention The present inventors have discovered that 5-fluorouracil (5-FU)
As a result of intensive studies aimed at improving the efficacy and reducing toxicity of antitumor agents such as 5-FU, certain pyridine derivatives have been found to be used in combination with the active ingredient compounds of antitumor agents such as 5-FU. Therefore, it has been found that the compound exhibits an effect of extremely strongly enhancing the antitumor activity. The present invention was completed based on this knowledge. Means for Solving the Problems The present invention is based on the general formula (In the formula, R ¹ is a hydrogen atom, a halogen atom, a lower alkyl group, or an amino group, R ² is a hydrogen atom or a hydroxyl group, and R ³ is a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group. , a nitro group or a carbamoyl group, and R ⁴ represent a hydrogen atom or a hydroxyl group.However, R ²
When is a hydroxyl group, R ¹ , R ³ and R ⁴ must not be hydrogen atoms. ) An antitumor activity enhancer characterized by containing a pyridine derivative represented by the following. In this specification, halogen atoms include fluorine, chlorine, bromine, and iodine atoms, and lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl groups. Chain or branched alkyl groups having 1 to 6 carbon atoms, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl Examples include lower alkoxycarbonyl groups in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as pentyloxycarbonyl and hexyloxycarbonyl groups. The pyridine derivative represented by the above general formula (1), which is used as an active ingredient in the antitumor activity enhancer of the present invention, is known per se or can be easily produced by a known method. A specific example of this method is shown in the production example below. Further, the pyridine derivative represented by the above general formula (1) has keto-type and enol-type tautomers, and any of these can be used in the present invention. Particularly suitable compounds as antitumor activity enhancers include compounds in the general formula (1) above, in which (1a) one of R ² and R ⁴ is a hydrogen atom and the other is a hydroxyl group, and (1b) R ¹ is a hydrogen atom, and R ³ is a hydrogen atom,
Examples include compounds that are halogen atoms, lower alkyl groups, amino groups, or nitro groups. These particularly exhibit the effect of significantly enhancing antitumor activity. The pyridine derivative represented by the above general formula (1) is
By using this in combination with an anti-tumor agent such as 5-FU, the activity of the anti-tumor agent can be significantly enhanced, and this combination is also less likely to cause side effects such as weight loss. Moreover, it is characterized by low toxicity. Antitumor agents whose antitumor activity is enhanced by the antitumor activity enhancer of the present invention include 5-FU and compounds that release 5-FU in vivo.
Specific examples of the compound (antitumor agent or compound with antitumor activity) include 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), 1
-Hexylcarbamoyl-5-fluorouracil (HCFU), 1-ethoxymethyl-5-fluorouracil (OFU), 5-fluorouridine (FUR), 5'-deoxy-5-fluorouridine (5'DFUR), 2'-deoxy -5-fluoro-3-
(3,4-methylenedioxybenzoyl)uridine (TK-117), 2'-deoxy-5-fluoro-
3',5'-bis-0-(4-methoxyphenoxycarbonyl)-3-(n-propoxybenzoyl)uridine (FF-707), ethyl (±)-6-t-butoxy-5-fluoro- Examples include 2,4-dioxohexahydropyrimidine-γ-5-carboxylate (TAC-278), 1-phthalidyl-5-fluorouracil, and 2'-deoxy-5-fluorouridine (FUDR). Furthermore, according to the research conducted by the present inventors, the compound whose antitumor activity is enhanced by the antitumor activity enhancer of the present invention has an excellent antitumor activity that is newly synthesized by the present inventors. Included are 2'-deoxy-5-fluorouridine derivatives represented by the general formula (2). [In the formula, R ⁵ is a phenyl lower alkyl group, R ⁶ is a hydrogen atom or a lower alkanoyl group, and R ⁷ is a hydrogen atom or a benzoyl group] In the above general formula (2), the phenyl lower alkyl group is, for example, benzyl, α-phenethyl,
β-phenethyl, 3-phenylpropyl, 1-phenyl-1-methylethyl, 4-phenylpropyl, 2-phenyl-1,1-dimethylethyl, 5
Examples include phenyl lower alkyl groups in which a phenyl group is bonded to a linear or branched alkylene chain having 1 to 6 carbon atoms, such as -phenylpentyl and 6-phenylhexyl groups, and lower alkanoyl groups include, for example, formyl groups. , acetyl, propionyl,
Examples include alkanoyl groups having 1 to 6 carbon atoms such as butyryl, isobutyryl, pentanoyl, and hexanoyl. The antitumor active compound represented by the above general formula (2) can be produced by the methods shown in the following reaction schemes a to c. <Reaction formula a> [In the formula, R ⁵ and R ⁷ are the same as above. ^R8 is a hydrogen atom,
Indicates a lower alkanoyl group or a protecting group. X represents a halogen atom. ] In the above, as the protecting group represented by R ⁸ , for example, the protecting group represented by the general formula [In the formula, Ar represents an aryl group] A triaryl-substituted methyl group represented by, more specifically, an aryl group such as a phenyl group 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 three groups. In this reaction, phenyl lower alkyl halide (R ⁵ is substituted with the desired R ⁵ group, and then, if necessary, a deprotection reaction or a delower alkanoylation reaction is performed. In the above, the reaction for introducing the R ⁵ 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 bicarbonate, potassium bicarbonate, 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 (3) and phenyl lower alkyl halide (R ⁵ It is preferable to use 2 to 2 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 5' position, the desired compound can be obtained by subsequently performing an elimination reaction of the protecting group. This deprotecting group reaction can be carried out using suitable catalysts commonly used in ordinary acid hydrolysis reactions, such as inorganic acids such as hydrochloric acid, sulfuric acid, and perchloric acid, lower alkanoic acids such as formic acid, acetic acid, and propionic acid, benzoic acid, and methane. It is usually carried out in a solvent using an appropriate amount of an organic acid such as an organic sulfonic acid such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like. Examples of solvents include 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, benzene, toluene, xylene, and chlorine. Aromatic hydrocarbons such as benzene, 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 it is usually 0 to 100°C, preferably room temperature to 80°C, and the reaction is carried out for 3 minutes to 80°C.
It will be completed in about 20 hours. The acid used is usually in a catalytic amount to an excess amount, preferably in an excess amount. <Reaction process formula b> (In the formula, R ⁵ and R ⁸ are the same as above. R ⁷ ' represents a benzoyl group.) This reaction is a reaction (benzoylation reaction) that introduces a benzoyl group at the 3-position of the pyrimidine skeleton,
It can be carried out according to conventional methods such as the acid chloride method. According to the acid chloride method, the target compound (5) can be obtained by reacting benzoyl halide (R ⁷ 'X) with compound (4') in an appropriate solvent in the presence of a deoxidizing agent. Ru. In the above, examples of the deoxidizing agent include sodium hydrogen carbonate,
Sodium carbonate, potassium carbonate, pyridine, triethylamine, etc. can be used. As a solvent,
For example, benzene, chloroform, methylene chloride,
Carbon tetrachloride, dioxane, tetrahydrofuran, etc. are used. of the dose of benzoyl halide,
The amount should be at least equimolar, preferably equimolar to about 3 mol, relative to compound (4'). The reaction temperature is usually -30 to 100℃, preferably room temperature to 80℃
℃, and the reaction is completed in about 20 minutes to 20 hours. In addition, in the above reaction, if the compound (4') has a free hydroxyl group at the 5' position, these sites also have a 3' position.
may be benzoylated at the same time. Therefore, in the above benzoylation of such compounds, the hydroxyl group at the 5' position is protected in advance, and after acylation,
Preferably, the protecting group is removed. 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. <Reaction process formula c> [In the formula, R ⁵ and R ⁷ are the same as above. R ⁶ ' represents a lower alkanoyl group. ] According to this reaction, compound (7) is obtained by acylating the free hydroxyl group at the 5' position of compound (6). For this acylation reaction, the usual 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. Applicable. The acid anhydride direction is carried out by heating compound (6) together with an acid anhydride in a suitable solvent. As the acid anhydride, the anhydride of the acid corresponding to the acyl group (lower alkanoyl group) to be introduced at the 5' position is used. Specific examples include acetic anhydride, propionic anhydride, butyric anhydride, and the like. These acid anhydrides are preferably used in at least an equimolar amount, preferably about 1 to 3 times the molar amount of compound (6). As a solvent, various inert solvents such as halogenated hydrocarbons such as pyridine, chloroform, and dichloromethane, ethers such as dioxane and THF, aromatic hydrocarbons such as benzene and 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. Examples of the basic compound include pyridine, triethylamine,
Examples include organic bases such as tertiary amines such as N,N-dimethylaniline, and inorganic basic compounds such as sodium hydrogen carbonate, potassium carbonate, and sodium acetate. The acid chloride method is carried out by reacting compound (6) with an acyl halide (R ⁶ 'X) in the presence of an acid absorbing agent in a suitable solvent. The method can be carried out analogously to that shown in reaction scheme b above. The compound of the present invention is thus obtained. The resulting compound can be easily isolated and purified by conventional separation means such as reprecipitation, recrystallization, silica gel chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, etc. The starting material compound having a protecting group used in the reaction schemes a to c can be obtained, for example, by the method shown in the following reaction scheme d. <Reaction scheme d> [In the formula, R ⁷ is the same as above. R ⁹ represents a protecting group. ] According to the above, by directly performing a protecting group introduction reaction on compound (8), compound (9) 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 the dehydrohalogenation reaction shown in the reaction scheme a above using a triaryl-substituted methyl halide which provides a protecting group represented by the general formula (A). However, the amount of reagent is 1 to 2 times the mole of compound (8), preferably 1 to 1.5 times the mole,
The reaction temperature is preferably -30°C to room temperature. The raw material compound obtained by the reaction shown in the reaction scheme d above can be used as a raw material compound as it is, or can be used as a raw material compound after being separated from the reaction system according to a conventional method. Compound (2) obtained as described above has excellent anticancer activity, low toxicity, and few side effects such as weight loss, and is extremely useful as an antitumor agent for cancer treatment in humans and animals. It is useful for The antitumor activity enhancer of the present invention can be processed into a formulation alone and the resulting formulation can be used in combination with an antitumor agent, or it can be processed into a formulation that is the same as the active ingredient compound of the antitumor agent and put into practical use. You can also do that. In either case, the pyrimidine derivative represented by the general formula (1) as the active ingredient of the antitumor activity enhancer;
The proportion of the pyrimidine derivative used in combination with the active ingredient compound of the antitumor agent is preferably about 0.1 to 10 moles per 1 mol of the active ingredient compound of the antitumor agent. Each of the above formulations contains commonly used fillers, extenders,
It is adjusted using diluents or excipients such as binders, wetting agents, disintegrants, surfactants, and lubricants. 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, and injections ( (solutions, suspensions, etc.), ointments, etc. When forming into a tablet form, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate sugar excipients, water, ethanol, propanol, simple syrup, Glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan Fatty acid esters, sodium uralyl sulfate, stearic acid monoglyceride, starch,
Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin Adsorbents such as , bentonite and colloidal silicic acid, lubricants such as sugar 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,
Use gelatin, semi-synthetic glyceride, etc. Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules, etc. according to conventional methods.
When prepared as injections, solutions, emulsions, and suspensions are preferably sterilized and isotonic with blood, and when molded into these forms, diluents such as water, ethyl alcohol, and propylene glycol are used. , 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 to adjust the isotonic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. In addition, coloring agents, preservatives,
Flavoring agents, flavoring agents, sweeteners, etc. and other pharmaceutical agents may also be included in the pharmaceutical formulation. 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. General formula (1) to be contained in the pharmaceutical formulation of the present invention
The amount of the compound or the active ingredient compound of the antitumor agent is not particularly limited and may be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation. 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 can be administered intravenously alone or mixed with conventional replacement fluids such as grapes, amino acids, etc., and if necessary, can be administered alone intramuscularly, intradermally, subcutaneously, or intraluminally. 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 amount of the active ingredient compound of the antitumor agent is usually about 0.5 to 20 mg per 1 kg of body weight per day. The dosage of the compound of general formula (1) of the present invention is also determined according to this amount. The formulation can be administered in 1 to 4 divided doses per day. Examples Production examples, pharmacological test examples, and formulation examples are listed below. Production example 1 2,6-dihydroxy-3-chloropyridine [Production of general formula (1), R ¹ = R ² = H, R ³ = Cl, R ⁴ = OH] 1.46 g of 2,6-dibenzyloxypyridine and 1.45 g of potassium carbonate are added to 30 ml of carbon tetrachloride. Furthermore, a solution of 0.4 ml of sulfuryl chloride dissolved in 10 ml of carbon tetrachloride was added dropwise at room temperature over 2 hours. After stirring for 1 hour, the reaction solution was filtered, concentrated, and the residue was transferred to a silica gel column (n-hexane:benzene=7:
1) to obtain colorless oil. Yield 1.2g (74%) Elemental analysis Calculated value (%): C 70.05; H 4.95; N 4.30 Actual value (%): C 70.02; H 4.82; N 4.25 Subsequently obtained 2,6-dibenzyloxy -3
6.5 g of -chloro-pyridine was dissolved in 130 ml of ethanol, 429 mg of 5% palladium on carbon was added, and catalytic reduction was carried out in a conventional manner. The reaction solution is filtered and concentrated to obtain red crystals, which are recrystallized from methanol-ethyl acetate to obtain the target compound. Yield 410 mg (14%), pale green edge-shaped crystals mp = 300℃ or higher (decomposition) (discoloration at 220℃ or higher, blackening at 250℃ or higher) Production example 2 3'-0-benzyl-2'-deoxy-5 -Fluorouridine [general formula (2), R ⁶ = R ⁷ = H, R ⁵ = C ₆
H ₅ CH ₂ ] 11.4 g of potassium hydroxide was dissolved in a mixture 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 under 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 200ml of ether, the aqueous layer was washed with 6N-HC.
It was neutralized and concentrated to about 200 ml. This is again 6N−
Adjust the pH to about 3-4 with HC and add 100ml of ethyl acetate.
Extracted twice. 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, and the fraction that reacted with 3'-0-benzyl-2'-deoxy-5-fluorouridine was collected, concentrated, and recrystallized from ethanol. 3.57 g (26.1%) of the target compound was obtained. Melting point 138-139℃ ^1H -NMR (DMSO- _d6 ) δ: 11.82 (1H, bs, -
NH-, disappeared by addition of D ₂ O), 8.21 (1H, d, J = 7Hz, C ₆ -H) 7.35 (5H, s, phenyl-H) 6.16 (1H, t, J = 6Hz, 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 Production Example 3 3'-0-benzyl-5'-0-acetyl-2'-deoxy-5-fluorouridine [general formula (2),
Production of 3' ^- ₀ -benzyl _{- 2'} -deoxy- ⁵ _- fluorouridine (3.95 ^g of pyridine) and acetic anhydride.
3.33 ml was added and left at 40°C overnight. The solvent was distilled off, the residue was dissolved in 30 ml of ethyl acetate, and the mixture was diluted with 15 ml of water.
Washed twice. 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- _d6 ) δ: 11.86 (1H, d, J=4Hz, -NH-, disappeared by addition of _D2O ) 7.93 (1H, d, J=7Hz, _C6 -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 Production example 4 3'-0-benzyl-3- Benzoyl-2'-deoxy-5-fluorouridine [general formula (2), R ⁵
＝C ₆ H ₅ CH ₂ , R ⁶ = H, R ⁷ = C ₆ H ₅ CO] Production of 0.75 g of trimethylchlorosilane in 20 ml of dioxane solution of 0.50 g of 3'-0-benzyl-2'-deoxy-5-fluorouridine. 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) ^1H -NMR ( _CDCl3 ) δ: 8.19 (1H, d, J=7Hz, _C6 -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) Preparation Example 1 Compound obtained in Production Example 1 20mg 2'-deoxy-3'-0-benzyl-5'-0-acetyl-5-fluorouridine 50mg Lactose 110mg Crystalline cellulose 67mg Magnesium stearate 3mg 1 capsule with the above blending ratio Prepare 250 mg capsules per dose. Formulation Example 2 Compound obtained in Production Example 1 10 mg 2'-deoxy-3'-0 -benzyl-5-fluoro uridine 20 mg Lactose 107 mg Crystalline cellulose 60 mg Magnesium stearate 3 mg Capsules containing 200 mg per capsule were prepared at the above blending ratio. do. Formulation Example 3 Compound obtained in Production Example 1 10 mg 5-fluorouracil 10 mg Lactose 180 mg Corn starch 290 mg Hydroxypropyl methyl cellulose 10 mg Granules containing 500 mg per package are prepared at the above blending ratio. Formulation example 4 Compound obtained in Production example 1 20mg 2'-deoxy-3'-0-benzol-5'-0-acetyl-5-fluorouridine 10mg Macrogol 300 500mg Distilled water for injection Appropriate amount At the above blending ratio 1 Prepare 5 ml of injection per ampoule. Formulation Example 5 Compound obtained in Production Example 1 10g 5-fluorouracil 10g Lactose 10g Cornstarch 24g Crystalline cellulose 25g Methylcellulose 1.5g Magnesium stearate 1g The compound obtained in Production Example 1, 5-fluorouracil, lactose, cornstarch, and crystalline cellulose were thoroughly mixed. granulate with a 5% aqueous solution of methylcellulose, pass through a 200 mesh sieve and carefully dry. The dried granules are passed through a 200 mesh sieve and mixed with magnesium stearate and pressed into tablets to obtain 1000 tablets for oral use. Pharmacological test example Sarcoma-180, which had been passaged as ascites in ICR mice, was diluted with physiological saline and then transplanted subcutaneously into the back of syngeneic mice in an amount of 2 x ¹⁰⁷ cells per mouse. 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 cancer weight, calculate the ratio (T/C) between the tumor weight (T) of the drug administration group and the tumor weight (C) of the control group to which no drug has been administered, and calculate the drug administration amount and this ratio (T/C).
The 50% cancer-inhibiting dose (ED50 value) at which T/C was 0.5 was determined from the dose-response curve. Table 1 shows cases in which various tumor agents were used alone as test drugs, and 1:1 with pyridine derivatives (2,4-dihydroxypyridine, indicated as enhancer a in the table) for various anti-tumor agents as a control. Table 2 shows the cases in which the antitumor agent and the active ingredient compound of the antitumor activity enhancer of the present invention (pyridine derivative of general formula (1)) are used together in a 1:1 (molar ratio). Tables 3 and 4 show cases in which they are used in combination. The antitumor agent and the active ingredient compound of the antitumor activity enhancer used in combination with the antitumor agent are shown in each table using the following abbreviations or symbols. <Anti-tumor agent> 5-FU...5-fluorouracil FT-207...1-(2-tetrahydrofuryl)-5
-Fluorouracil TK-117...2'-deoxy-5-fluoro-3-
(3,4-methylenedioxybenzoyl)uridine HCFU...1-hexylcarbamoyl-5-fluorouridine OFU...1-ethoxymethyl-5-fluorouracil FUR...5-fluorouridine 5'-DFUR...5'- Deoxy-5-fluorouridine FF-707...2'-deoxy-5-fluoro-3',
5'-bis-0-(4-methoxyphenoxycamebonyl)-3-(n-propoxybenzoyl)uridine FUDR...2'-deoxy-5-fluorouridine compound 2a...2'-deoxy-3'- 0-benzyl-
5-Fluorouridine [General formula (2), R ⁵ = benzyl, R ⁶ = R ⁷ = H] Compound 2b...2'-deoxy-3'-0-benzyl-
3-Benzoyl-5-fluorouridine [General formula (2), R ⁵ = benzyl, R ⁶ = H, R ⁷ = benzoyl] Compound 2c...2'-deoxy-3'-0-benzyl-
5'-0-acetyl-5-fluorouridine [general formula (2), R ⁵ = benzyl, R ⁶ = acetyl,
R ⁷ =H] <Antitumor activity enhancing compound> Enhancer A...2,4-dihydroxy-5-chloropyridine [General formula (1), R ¹ = R ⁴ = H, R ² =
OH, R ³ = Cl] Enhancer B...2,6-dihydroxy-3-chloropyridine [General formula (1), R ¹ = R ² = H, R ³ = Cl,
R ⁴ =OH] Enhancer C...2,4-dihydroxy-5-bromopyridine [General formula (1), R ¹ = R ⁴ = H, R ² =
OH, R ³ = Br] Enhancer D...2,4-dihydroxy-5-methylpyridine [General formula (1), R ¹ = R ⁴ = H, R ² =
OH, ^R3 = _CH3 ] Enhancer E...2,6-dihydroxy-3-cyanopyridine [General formula (1), ^R1 = ^R2 =H, ^R3 =
CN, R ⁴ =OH] Enhancer F...2,6-dihydroxy-3-nitropyridine [General formula (1), R ¹ = R ² = H, R ³ =
NO ₂ , R ⁴ =OH] Enhancer G...2,6-dihydroxypyridine [General formula (1), R ¹ = R ² = R ³ = H, R ⁴ = OH] Enhancer H... 2,4 -Dihydroxy-5-carboxypyridine [General formula (1), R ¹ = R ⁴ = H, R ²
=OH, R ³ = COOH] Enhancer I...2,4-dihydroxy-5-ethoxycarbonylpyridine [General formula (1), R ¹ = R ⁴
= H, R ² = OH, R ³ = COOC ₂ H ₅ ] Enhancer J...2,4-dihydroxy-3,5-dichloropyridine [General formula (1), R ¹ = R ³ = Cl,
^R2 =OH, ^R4 =H] Enhancer K...2,4-dihydroxy-3,5-dibromopyridine [general formula (1), ^R1 = ^R3 =Br,
R ² = OH, R ⁴ = H] Enhancer L...2,4-dihydroxy-3-chloropyridine [General formula (1), R ¹ = Cl, R ² = OH,
R ³ = R ⁴ = H] Enhancer M...2,4-dihydroxy-3-bromopyridine [General formula (1), R ¹ = Br, R ² = OH,
^R3 = ^R4 =H] Enhancer N...2,4-dihydroxy-3-methylpyridine [General formula (1), ^R1 = _CH3 , ^R2 =OH,
R ³ = R ⁴ = H] Enhancer O...2,4-dihydroxy-3-aminopyridine [General formula (1), R ¹ = NH ₂ , R ² = OH,
R ³ = R ⁴ = H] Enhancer P...2,6-dihydroxy-3-carbamoylpyridine [General formula (1), R ¹ = R ² = H,
R ³ = CONH ₂ , R ⁴ = OH] Enhancer Q...2,4,6-trihydroxypyridine [General formula (1), R ¹ = R ³ = H, R ² , R ⁴ = OH]

【table】

【table】

【table】

【table】

[Table] From the above results, when the pyridine derivative of the present invention is used in combination with an anticancer drug, an extremely excellent antitumor activity enhancing effect is observed. Pharmacological test example Various compounds described on pages 37 to 38 of the specification were used as antitumor agents, and these N ¹ -(2'-tetrahydrofuryl)-4-hydroxy-2-pyridone (compound A) or 2,6-dihydroxy-3-
It was used in combination with cyanopyridine (enhancing agent E) at a molar ratio of 1:1, and the ED ₅₀ value was determined in the same manner as in the pharmacological test example. The results are shown in Table 5 below. The table also shows the ED ₅₀ value when the antitumor agent is used alone.

[Table] As can be seen from the above results, when Compound A is used in combination with an antitumor agent, almost no enhancement of the antitumor effect is observed.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a halogen atom, a lower alkyl group, or an amino group, R ² is a hydrogen atom or a hydroxyl group, and R ³ is a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group. , a nitro group or a carbamoyl group, and R ⁴ represent a hydrogen atom or a hydroxyl group.However, R ²
When is a hydroxyl group, R ¹ , R ³ and R ⁴ must not be hydrogen atoms. ) An antitumor activity enhancer characterized by containing a pyridine derivative represented by: