JPS61109719A - Enhancer for antitumor activity - Google Patents

Abstract

PURPOSE:The titled enhancer strengthening excellently activity of antitumor agent, having no side effects such as loss in weight, etc., and low toxicity, containing a pyridine derivative as an active ingredient. CONSTITUTION:An enhancer containing a pyridine derivative shown by the formula (R<1> is H, halogen, lower alkyl, or amino; R<2> is H, or hydroxyl group; R<3> is H, halogen, lower alkyl, carboxyl, lower alkoxycarbonyl, cyano, nitro, or carbamoyl; R<4> is H, or hydroxyl group, with the proviso that R<1>, R<3>, and R<4> should not be H when R<2> is hydroxy group) as an active ingredient. For example, 1-(2-tetrahydrofuryl)-5- fluorouracil, etc. may be cited as an antitumor agent whose antitumor activity is enhanced. A blending ratio of the compound shown by the formula as the active compound and the compound of the active ingredient of the antitumor agent is preferably about 0.1-10mol compound shown by the formula based on 1mol compound of the active ingredient of the antitumor agent.

Description

[Detailed description of the invention] L1 Retired Emperor Yu 11 This invention is anti! This invention relates to a tumor activity enhancer.

The active ingredient compounds of the antitumor activity enhancer of the present invention have not been known at all to have such an antitumor activity enhancement effect.

Problems to be Solved by the Invention The present inventors have conducted intensive studies to improve the efficacy and reduce the toxicity of antitumor agents such as 5-fluorouracil (5-FU), and as a result, they have discovered that certain pyridine derivatives However, it has been found that when this compound is used in combination with the active ingredient compound of the antitumor agent 5-FU8, it exhibits an effect of extremely strongly enhancing the antitumor activity of the compound. The present invention was completed based on this knowledge.

The present invention is based on the general formula (where R1 is a hydrogen atom, a halogen atom, a lower alkyl group, or an amino group, R2 is a hydrogen atom or a hydroxyl group, and R3 is a hydrogen atom, a halogen atom, a lower alkyl group, or a carboxyl group). , a lower alkoxycarbonyl group, a cyano group, a nitro group or a carbamoyl group, and R represent a hydrogen atom or a water group.However, when R2 is a hydroxyl group, R1, R3 and R4 must not be hydrogen atoms.) The present invention relates to an anti-am activity enhancer containing the pyridine 11 conductor shown below.

In this specification, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms, and examples of lower alkyl groups include straight chain groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl groups. Or a branched alkyl group having 1 to 6 carbon atoms, and lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Lower alkoxycarbonyl in which the flukoxy moiety is a linear or branched flukoxy group having 1 to 6 carbon atoms, such as isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group, etc. Examples include groups.

The above general formula (
The pyridine derivative represented by 1) 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.Also, the pyridine ll conductor represented by the above general formula (1) has keto-type and enol-type tautomers, but in the present invention, these tautomers Any of these can be used.

Particularly suitable compounds as anti-Fl disease activity enhancers include:
In the above general formula (1), (Ia) a compound in which one of R2 and R1 is a hydrogen atom and the other is a water group, and (1b
) Examples include compounds in which R1 is a hydrogen atom and R3 is a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, or a nitro group. These particularly exhibit the effect of significantly enhancing anti-B1'4 activity.

When the pyridine derivative represented by the above general formula (1) is used in combination with an anti-tumor agent such as 5-FU, it significantly enhances the activity of the anti-tumor agent, and this combination also increases weight loss. It has the characteristics of low toxicity and low risk of causing side effects such as dehydration.

Antitumor agents whose antitumor activity is enhanced by the anti-N-selective activity enhancer of the present invention include 5-FU and the 5-F
Compounds that release U are included.

Specific examples of the compound (antitumor agent or anti-IITM active compound) 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-〇-(4
-methoxyphenoxycarbonyl)-3-(n-propoxybenzoyl)uridine (FF-707), ethyl (
±)-6-tert-butoxy-5-fluoro-2,4-dioxohexahydropyrimidine-γ-5-carboxylate (TAC-278), 1-phthalidyl-5-fluorouracil, 2'-deoxy-5- Fluorouridine (F
LIDR), etc. can be exemplified.

Furthermore, according to the research conducted by the present inventors, the compound whose group 11s activity is enhanced by the antitumor activity enhancer of the present invention has excellent anti-tumor activity, which was newly synthesized by the present inventors. 2'-deoxy-5 represented by general formula (2)
- Fluorouridine derivatives are included.

[Formula I+3R5 represents a phenyl lower alkyl group, R@ represents a hydrogen atom or a lower alkanoyl group, and R7 represents a hydrogen atom or a benzoyl group] In the above general formula (2), the phenyl lower alkyl group includes, for example, benzyl, α-phenethyl , β-7enethyl, 3-phenylpropyl, 1-phenyl-1-methylethyl, 4-phenylpropyl, 2-phenyl-1,
Examples include phenyl lower alkyl groups in which a phenyl group is bonded to a linear or branched alkylene group having 1 to 6 carbon atoms such as 1-dimethylethyl, 5-phenylpentyl, and 6-phenylhexyl groups, and lower alkanoyl groups. Basically,
For example, formyl, acetyl, propionyl, butyryl,
Examples include alkanoyl groups having 1 to 6 carbon atoms such as isobutyryl, pentanoyl, and hexanoyl groups.

The anti-am 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 process formula a> [In the formula, R5 and R7 are the same as above, IIR' is a hydrogen atom,
Indicates lower alkanoyl group or retention 5g. X represents a halogen atom. ] In the above, the protective group represented by R8 is, for example, a triaryl W1-substituted methyl group represented by the general formula % (in which Ar represents an aryl group); more specifically, a halogen atom, a nitro Examples include methyl groups substituted with three aryl groups such as phenyl groups, which may have lower alkyl groups, lower alkyl groups, or lower alkoxy groups.

In this reaction, a phenyl lower alkyl halide (
R" be.

In the above, the reaction for introducing the R5 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. As a specific example,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Examples include potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., 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 solvent, any customary inert solvent can be used, such as water, tetrahydrofuran (THF), etc.
), ethers such as dioxane, benzene, toluene,
Aromatic hydrocarbons such as xylene and chlorobenzene, ketones such as acetone and methyl ethyl ketone, nitrites such as acetonitrile and 7O bionitrile, dimethylformamide, dimethyl sulfoxide and the like are advantageously used. Compound (3) and phenyl lower alkyl halide (R5X)
The proportion of the latter to be used is not particularly limited and may be appropriately selected from a wide range; however, it is usually preferable to use at least the same molar amount of the latter as the former, preferably from an equimolar amount to twice the molar amount of the former. The reaction temperature is also not particularly limited and can be appropriately selected from a wide range, but generally from 0 to 100°C, preferably from room temperature to 80°C.
The temperature is preferably selected from the range of 0.degree. 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 target compound can be obtained by subsequently performing an elimination reaction of the retainer. This deprotecting group 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, and perchloric acid, m-acids, lower alkanoic acids such as acetic acid and propionic acid, benzoic acid, This is usually carried out in a solvent using an appropriate amount of an organic sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or 4-methylbenzenesulfonic acid.

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, and xylene. , aromatic hydrocarbons such as 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 121 to 80°C.
The temperature may be about .degree. 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 m, preferably in an excess amount.

<Reaction scheme b>(4') (5) (In the formula, R5 and R8 are the same as above. R71 represents a benzoyl group.) This reaction is a reaction for introducing a benzoyl group into the 3-position of the pyrimidine skeleton (benzoylation). reaction) and can be carried out according to conventional methods, such as the acid chloride method. According to the acid chloride method, benzoyl halide (
The target compound (5) is obtained by reacting R7'X) in a suitable solvent in the presence of an acid deoxidizing agent.

In the above, as the deoxidizing agent, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine, etc. can be used. Examples of solvents used include benzene, chloroform, methylene chloride, carbon tetrachloride, dioxane, and tetrahydrofuran. The dose of benzoyl halide is preferably at least equimolar, preferably equimolar to about 3 mol, relative to compound (4'). The reaction temperature is usually -30 to 100°C, preferably! The temperature is about 80° C., and the reaction is completed in about 20 minutes to 20 hours.

In the above reaction, when compound (4') has a free hydroxyl group at the 5' position, these sites may also be benzoylated at the same time as the 3' position.

Therefore, in the above-mentioned benzoylation of a secondary compound, it is preferable to protect the 5'-position hydroxyl group in advance, and then remove the protecting group after 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.

<Reaction Scheme C> [In the formula, R5 and R7 are the same as above. R81 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). This acylation reaction can be carried out using conventional acylation reactions and methods, such as acid chloride method, acid anhydride method, mixed acid anhydride method, N, N-
Any method such as the dicyclohexylcarbodiimide method (DOG method) can be applied, and the acid anhydride method and the acid chloride method are particularly advantageously applied.

The organic hydrate method is carried out by heating compound (6) together with an acid anhydride in a suitable solvent.

As the fi anhydride, an anhydride of an 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. Such r! Ifi hydrate is at least equimolar to compound (6), preferably 1
It is preferable to use about 1 to 3 times the mole. As rgts, various inert solvents such as pyridine, chloroform,
Halogenated hydrocarbons such as dichloromethane, dioxane,
Ethers such as THF, aromatic hydrocarbons such as benzene and toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, etc. can be used. The reaction temperature is usually -30 DEG C. to 100 DEG C., preferably room temperature to 80 DEG 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 organic bases such as tertiary amines such as pyridine, triethylamine, and N,N-dimethylaniline, and inorganic basic compounds such as sodium hydrogen carbonate, potassium carbonate, and sodium acetate.

In the acid chloride method, 7-syl halide (R
"X) in the presence of a deoxidizing agent in a suitable solvent. The method can be carried out in the same manner as shown in the above reaction scheme.

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.

In addition, the retention r! used in the reaction process formula a-C above! A starting material compound having one group can be obtained, for example, by the method shown in the following reaction scheme d.

<Reaction scheme d> (In the formula, R7 is the same as above. R9 represents a protecting group.) According to the above, by carrying out the reaction of directly introducing a retaining group into compound (8), a protecting group is added to the 5'' position. The introduced compound (9
) is obtained. For this protective group insertion reaction, the general formula (A
) Triaryl that provides a protecting group represented by! The reaction is carried out using \-exchanged methyl halide under the same conditions as the dehydrohalogenation reaction shown in the reaction scheme a above. However, the amount of sample M0 is 1 to 2 times the mole of compound (8), preferably 1 to 1
．． It is preferable to use 5 times the molar amount and to adjust the reaction temperature to 0° C. to moderate.

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 can be used as an anti-Il tumor agent for cancer treatment in humans and animals. Very useful.

The anti-111 tumor 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.
Further, it can be processed into the same formulation as the active ingredient compound of the anti-l1rs agent and put to practical use. In either case, the combined ratio of the pyrimidine derivative represented by the general formula (1), which is the active ingredient of the anti-tibial agent active ingredient, and the active ingredient compound of the anti-tumor agent is 1 mol of the active ingredient compound of the anti-tumor agent. For,
It is preferable that the maximum temperature of the pyrimidine derivative is 0.1 to 10 moles.

Each of the above formulations contains commonly used fillers, extenders, binders,
It is adjusted using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Forms of these pharmaceutical preparations can be selected depending on the therapeutic purpose, and representative examples include tablets, gunpowder, powders, liquids, suspensions, emulsions, granules, capsules, tablets, and injections ( Examples include liquid preparations, retsuen drugs, etc.), soft mouth preparations, etc. When forming into a tablet form, excipients such as whey, sucrose, sodium chloride, glucose, urea, starch, charcoal free calcium, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, etc. are used as carriers. Simple syrup, grape vIFe! , starch liquid, gelatin mFfl, carboxymethyl cellulose,
Binders such as shellac, methylcellulose, potassium phosphate, bonipinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride , disintegrants such as starch and lactose, disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants 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. In addition, tablets may be coated with a normal coating if necessary.
For example, sugar-coated tablets, gelatin-coated tablets, melt-coated tablets, film-coated tablets, double tablets, and multilayer tablets can be used. When molding into the form of gunpowder, carriers such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil,
Excipients such as kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar can be used. When molding into a clay form, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into Ni gelatin capsules, soft capsules, etc. according to conventional methods. Fl as an injection! When used, solutions, emulsions and suspensions are preferably sterile and isotonic with blood, and when formed into these forms, diluents such as water, ethyl alcohol, propylene glycol, ethoxylated Isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isodominant solution may be included in the pharmaceutical preparation, and usual solubilizing agents, III agents, soothing agents, etc. may be added. Good too. 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.

The amount of the compound of general formula (1) or the active ingredient compound of the antitumor agent to be contained in the pharmaceutical preparation of the present invention is as follows:
Although not particularly limited and appropriately selected from a wide range, it is usually 1 to 70 in pharmaceutical preparations. ! It is preferable to set it to ffi%.

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, emulsions, solutions, QI preparations, emulsions, granules, and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, are administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Doyo is administered rectally.

The dosage m 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 usually the amount of the active ingredient compound of the anti-R1M drug is about 0.5 to 11 kQ per day. The amount is preferably about 20e+o, and the dosage M 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.

Example Production examples, pharmacological test examples, and formulation examples are listed below.

Production example 1 2.6-cyhydroxy-3-chloropyridine [general formula (
1'), R1-R"-H, R3-CQ 1R'-O
Production of H] Add 1.460 2.6-dipenzyloxypyridine and 1.45 a of potassium carbonate to 30 ml of carbon tetrachloride. Furthermore, a solution of sulfuryl chloride (0.4) dissolved in carbon tetrachloride (101f) was added dropwise at room temperature over 2 hours. After stirring for 1 hour, the reaction solution was filtered, the filtrate was concentrated, and the residue was passed through a silica column (n-hexane:benzene-7=1) to obtain a colorless oil.

Yield 1. 20 (74%) Calculated elemental analysis value (%): C70,05:H4,95;N4.30 Actual value (%): C70,02:H4,82:N4.25 Subsequently obtained 2,6 - Dissolve 6.5 g of dipendyloxy-3-chloro-pyridine in 130 - of ethanol,
Add 429% palladium on carbon and contact J11 at normal pressure.
Perform FI source. The reaction solution is filtered, and the filtrate is concentrated to obtain red crystals, which are recrystallized from methanol-ethyl acetate to obtain the target compound.

Yield 41018! J (14%), light-colored edge-like crystals IE
) -300°C or higher (decomposition) (Discoloration at 220°C or higher, blackening at 250°C or higher) Production example 2 3'-〇-benzyl-2'-deoxy-5-fluorouridine [General formula (2), R@-R ”=H,R'-O
s H5CH2) produced water 3501G and dioxane 10
Potassium hydroxide 11.4a was dissolved in a mixture with 011 and 2'-deoxy-5-fluorouridine 10.4a was dissolved under stirring at room temperature. OQ and 3.011Q of benzyl bromide were added.

After this, 1w of 5% potassium hydroxide water every 24Bits 1m.
1100- and benzyl bromide 3.0- were added three times and stirring continued for an additional night. Pour the reaction solution into ether 200111
After washing with 1) 2@, the aqueous layer was neutralized with 6N-HO2 and
Concentrated to 0-. E)H with 6N-HCl2 again.
It was adjusted to about 3-4 and extracted twice with ethyl acetate 100WIQ. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and then concentrated. The oily residue was collected using a silica gel column.
Elute with 2% methanol-chloroform and collect the fraction corresponding to 3'-〇-benzyl-2'-deoxy-5-fluorouridine, concentrate, and recrystallize from ethanol to obtain the target compound 3.57Q (26,1
%) was obtained.

Melting point 138-139°C' H-NMR (DMSO-ds) δ:
11.82 (IH, bs, disappeared by addition of -NH-1020), 8.21 (IH, d, J-7Hz, Cs -H)7.
35 (5H,S, phenyl-H)6-16 (I H
StNJ-6HZ, Ct'H)5.22
(IH, bs, 5'-OH, disappeared by addition of C20) 4, 54 (2H, S, ecH2-) 4.24-4.
19 (IHSm1C3'H) 4.09 4.06
(18% m, OA'-H) 3.65-3.53
(2H,m,Cs'-H)2.51-2.16(
2H,m,C2'-H) Elemental analysis value: Os s
Calculated value (%) for H+ y FN20S and Lt: C57
, 14:H5, 09:N8.33 Actual value (%): C57, 12:H5, 28:N8.24 Production example 3 3'-〇-benzyl-5'-〇-acetyl-2'-deoxy-5- Fluorouridine [general formula (2), R5=C
e Hs CH2, R' = CH3GO1R'-H) Production of 3'-〇-benzyl-2'-deoxy-5-fluorouridine 3.95Q of pyridine 30w [Add 3.331112 acetic anhydride to 1 solution and heat at 40°C. I left it overnight.

The solvent was distilled off, the residue was dissolved in 30% of ethyl acetate, and 1% of water was dissolved.
Washed twice with 5112. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and eluted with chloroform using a silica gel column to obtain the target compound, 3.62cy (81,
5%).

Melting point 87-88°C IH-NMR (DMSO-68) δ: 11.86 (IH%d, J-4Hz, -NH-102
0g! 7.93 (IH, d, J-7Hz, Cs-H)7.
35 (58% S, Phenyl-H) 6.15 (1) 1
．． t, J-6Hz, C+'-H)4,55 (2H
,5l-CHt-CJ) )4.32-4.20 (
4H, m.

C3t ・Mut, 5t H) 2.39-2.28 (2H,t, J-6H2゜C2'
-H)' 2.04 (3H, s, COCH3) Elemental analysis value: C+ 8H+ e Calculated value (%) as FN20S
C57,14; H5,06N7.40 Actual value (%) C56,99: H5,22N7.37 Production example 4 3'-〇-benzyl-3-benzoyl-2'-deoxy-5-fluorouridine (general formula % formula % Trimethylchlorosilane 0.751112 and triethylamine 2.00% were added to a dioxane 20% solution of 0.500% luorouridine, and after stirring at room temperature for 2 hours,
It was left at ℃ for 30 minutes. Then benzoyl bromide 0.42
0 and 1.001'lll 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 portions of ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated, compressed by 1 m, and the residue was dissolved in 30 methanol, to which 0.5 m 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 0.350 (54%) of the target compound in powder form.

Melting point - (glassy powder) Blind HNMR (CDC123) δ: 8.19 (I
H, d, J-7Hz, Cs H), 6-24 (I
H1t s J-6Hz, C1'-H)4,46
(2H,S,<C)-CHt)4.24-4.12
(2H, m.

03', straight'-H) 3.92 3.56 (2H, m, Os'
H) 2.60-1.96 (281ml C2'
-H) Formulation Example 1 Compound obtained in Production Example 1 20ma2'-deoxy-3'-0-benzyl-5'-〇-acetyl-5-fluorouridine 50ma Lactose 1 1 omg
Crystalline cellulose 67m.

Magnesium stearate 3 mQ Capsules containing 250 mQ per capsule are prepared using the above combination.

Formulation Example 2 Compound obtained in Production Example 1 10 mg 2'-deoxy-3'-〇-benzyl-5-fluorouridine 20 ma Lactose 107 ma Crystalline cellulose 60 ma 0 m Mystearinnesium 3 mG1 mG1 Capsules of 200 m0 per capsule are prepared on the above table.

Formulation Example 3 Compound obtained in Production Example 1 10mQ5-fluorouracil 10ma lactose
isom.

Corn starch 290mCJ Hydroxypropyl methylcellulose 10mQ Prepare granules of 500mQ per package using the above combination.

Formulation Example 4 Compound obtained in Production Example 1 20m02'-deoxy-3'-〇1 Benzyl-5'-〇-7 Cetyl-5-fluorouridine 10mQ Macrogol 300 500ma Distilled water for injection
Appropriate amount 51 per ampoule at the above blending ratio
Prepare 19 injectable preparations.

Formulation Example 5 Compound obtained in Production Example 1 10Q5-Fluorouracil 10g Lactose
10g cornstarch 240 crystalline cellulose
25Q methylcellulose
1.5G.

Magnesium stearate 1g The compound obtained in Preparation Example 1, 5-fluorouracil, lactose, corn starch and crystalline 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 to obtain 1000 tablets for oral use.

Pharmacological Test Example: Sarcov (S
arcoma)-180 was diluted with physiological saline and an amount of 2×10' cells per mouse was subcutaneously implanted into the backs of syngeneic mice and used for experiments. T! Starting 24 hours after tumor transplantation, a drug suspended in 5% gum arabic was orally administered once a day for 7 days.

On the 10th day after tumor implantation, a subcutaneous solid tumor was removed from the back, and the weight of the tumor was measured. (T/C) is determined, and T
A 50% cancer-inhibiting dose (ED5G value) at which /C was 0.5 was determined.

Various anti-l! Table 1 shows cases in which antitumor drugs are used alone, and pyridine derivatives (2
, 4-dihydroxypyridine (indicated as enhancer a in the table) and 1=1 (molar ratio) are shown in Table 2.
Tables 3 and 4 show the cases in which pyridine (1) of general formula (1) is used in combination at a molar ratio of 1:1, respectively.

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-F Ll-...5-fluorouracil FT-20
7...-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-〇-(4-methoxyphenoxycamebonyl)-3-(n-propoxybenzoyl)uridine Fu D R-2'-deoxy-5-fluorouridine compound 2 a-2'-deoxy-3 '-〇-benzy-5-fluorouridine [general formula (2), R5-benzyl, R'-R7-H) Compound 2b...2'-deoxy-3'-〇-benzy-3-benzoyl-5-fluorouridine [General formula (2
), R5-benzyl, R8-H.

R7-benzoyl] Compound 2C...2'-deoxy-3'-〇-benzyl-5'-〇-acetyl-5-fluorouridine (general formula (2), R5-benzyl, R8-acetyl, R7-H) Ku resistance fl! Pain activity enhancing compound> Enhancing agent A...2,4-dihydroxy-5-chloropyridine (general formula (1), R1-R'-H1R2-OH,R
3-CQ) Enhancer B...2,6-dihydroxy-3-90pyridine [General formula (1), R'-R2-HlR"-CQ
, R'-0H) Enhancer C...2,4-dihydroxy-5-bromopyridine [General formula (1), R1-R'-H, R"-OH, R
3-81 Enhancer D...2,4-dihydroxy-5-methylpyridine (general formula (1'), R1-RA-H, R'=OH
, R' = CH3) Enhancer E...2,6-cyhydroxy-3-cyanopyridine (general formula (1), R1-R2-H, R3-CN,
R'-0H) Enhancer F...2,6-cyhydroxy-3-nitropyridine [General formula (1), R1-R'-H, R'=NOt
, R' -0HI Enhancer G・-2,6-dihydroxypyridine [general formula
(1), R1-R2-R3-H, R'-0H
) Enhancer H-2,4-dihydroxy-5-carboxypyridine (general formula (1), R1-R'-H.

R2-OH, R3-COOH) Enhancer 1-...2,4-dihydroxy-5-ethoxycarbonylpyridine [General formula (1), R'-R' = H,
R2-0H1R” = COOC* Hs) Enhancer J・
-2,4-dihydroxy-3,5-dichloropyridine [
General formula (1), R1-R3-CQ, R'-OH, R'
-H) Enhancer K・-2,4-dihydroxy-3,5-dibromopyridine [General formula (1), R1-R3-Br, R'-=
OH, R' -H) Enhancing agent -2,4-dihydroxy-3-chloropyridine [General formula (1), R' -CI R' -OH,R
'-R' -H) Enhancer M...2,4-dihydroxy-3-bromopyridine [General formula (1), R'-Br, Rll -OH, R
3-R'-H) Enhancer N・-2,4-dihydroxy-3-methylpyridine [General formula (1), R' = CH5, R2-OH, R
3-R' -H) Enhancer 0-2,4-dihydroxy-3-aminopyridine [General formula (1), R' = NH2, R'' -OH, R3
-R"-H) Enhancer P...2,6-cyhydroxy-3-carbamoylpyridine [General formula (1), R1-R2-H.

R3-CONH2,R'-0H) Enhancer Q-2,4,6-drihydroxypyridine (general formula (1), R1-R3-H, R2-R'-OH) Table 1 Table 2 Table 3 Table 4 From the results shown in Table 4, when the pyridine derivative of the present invention is used in combination with an anticancer drug, an extremely superior effect of enhancing antitumor activity is observed.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a hydrogen atom, halogen atom, lower alkyl group, or amino group, R^2 is a hydrogen atom or a hydroxyl group, R^3
represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a nitro group, or a carbamoyl group, and R^4 represents a hydrogen atom or a hydroxyl group. However, when R^2 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: