JPS6330482A - 5-fluorouracil derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is pyridyloxy (which may contain substituent group such as halogen, cyano, nitro, lower alkyl, carboxyl, lower alkoxycarbonyl, OH, etc.); R<2> is (phenyl)lower alkoxy lower alkyl, group shown by formula II or formula III (R<3> is H, lower alkanoyloxy; R<4> is H, lower alkanoyloxy, phenyl lower alkoxy, etc; R<5> is H, methyl, tec.)]. EXAMPLE:3-{[ 3-Cyano-6-(2,4-dichlorobenzoyloxy)-2-pyridyloxy ]carbonyl}-5-fluoro-1-( 2-tetrahydrofuranyl )uracil. USE:A carcinostatic agent having improved absorption, improved stability and low side effects such as reduction in weight, etc. PREPARATION:For example, first a compound shown by formula R<1>H is reacted with a compound shown by formula IV (X is halogen) and then the prepared compound shown by formula V is reacted with a compound shown by formula VI (R<2a> is R<2> except group shown by formula III).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 5-fluorouracil derivatives.

traditional techniques The derivative of the present invention is a novel compound not yet published in the text.

Problems to be Solved by the Invention The present inventors have conducted intensive studies to improve the antitumor activity of 5-fluorouracil and reduce its toxicity. In addition to successfully synthesizing a new compound in which a pyridyloxycarbonyl group with or without a specific substituent is attached to We have found that it is extremely useful.

Means for Solving the Problems The present invention is based on the general formula [wherein R1 is a substituent, a halogen atom, a cyan group, a nitro group, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a phenyl lower alkoxy group, and 1 to 3 of groups selected from the group consisting of acyloxy groups
Indicates a pyridyloxy group that may have . R2 is lower alkoxy lower alkyl group, phenyl lower a3
RA R3 is a hydrogen atom or a lower alkanoyloxy group, R4
is a hydrogen atom, a lower alkanoyloxy group, or a lower alkoxy group (which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group) on the phenyl ring. R5 represents a hydrogen atom, a methyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group), or a group R1-C- (R1 is the same as above). ] This relates to a 5-fluorouracil derivative represented by:

In each group used in the above general formula (1) and in the present specification below, the terms "lower alkyl group" and "lower alkoxy group" are used either as they are or in the form contained in various functional groups. When used in methyl,
Straight chain or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, inpropyl, butyl, t-butyl, pentyl, hexyl groups, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy , pentyloxy, hexyloxy, and other linear or branched alkoxy groups having 1 to 6 carbon atoms. Also,
The term "halogen atom", whether used as is or included in various functional groups, exemplifies fluorine, chlorine, bromine, and iodine atoms, respectively. Furthermore, the term "lower alkanoyl group" also refers to straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, isopropionyl, butyryl, t-butyryl, pentanoyl, hexanoyl, etc. I will give an example.

Specific examples of each group used in this specification include the following groups.

Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
t-butoxycarbonyl, pentyloxycarbonyl,
A carbonyl group having an alkoxy group having 1 to 6 carbon atoms such as a hexyloxycarbonyl group can be exemplified.

Examples of phenyl lower alkoxy groups include benzyloxy, 2-phenylethoxy, 2-phenylpropoxy, 4-phenylbutoxy, 1-methyl-2-phenylpropoxy, 3-phenylpemethyloxy, 5-phenylpentyloxy, 4- Examples include alkoxy groups having 1 to 6 carbon atoms having a phenyl group as a substituent, such as phenylhexyloxy.

Examples of the lower alkoxy lower alkyl group include methoxymethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl, 5-isopropoxypentyl, 1.1-dimethyl-2-butoxyethyl, 2-methyl-3- Examples include alkoxyalkyl groups in which the alkoxy and alkyl portions each have 1 to 6 carbon atoms, such as t-butoxypropyl, 2-pentyloxyethyl, and 2-hexyloxyethyl groups.

Examples of the phenyl lower alkoxy lower alkyl group include benzyloxymethyl, 2-benzyloxyethyl,
5-(2-phenylpentyloxy)pentyl, 6-
Benzyloxyhexyl, 6-(4-phenylhexyloxy)hexyl, phenylmethoxymethyl, 2'-(
1-phenylpropoxy)ethyl, 2-(benzyloxy)propyl, 4-(benzyloxy)butyl, 5-(
benzyloxy)pentyl, 6-(2-phenylethoxy)hexyl, 2-(2-phenylethoxy)ethyl,
It has a phenyl group as a substituent, such as 2-(4-phenylbutoxy)ethyl, 4-(4-phenylbutoxy)butyl, 6-phenylhexyloxymethyl group, and the alkoxy moiety and alkyl moiety each have 1 carbon number. -6 phenylalkoxyalkyl groups can be exemplified.

Examples of the phenyl lower alkoxy group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group on the phenyl ring include benzyloxy, 2-methylbenzyloxy,
3-methylbenzyloxy, 4-methylbenzyloxy, 2-ethylbenzyloxy, 3-ethylbenzyloxy, 4-ethylbenzyloxy, 2-propylbenzyloxy, 3-propylbenzyloxy, 4-propylbenzyloxy, 4- Butylbenzyloxy, 2-t-butylbenzyloxy, 3-t-butylbenzyloxy,
2-pentylbenzyloxy, 3-hexylbenzyloxy, 4-hexylbenzyloxy, 2.3-dimethylbenzyloxy, 2.4-dimethylbenzyloxy, 2
．． 5-dimethylbenzyloxy, 2.6-dimethylbenzyloxy, 2.3.4-trimethylbenzyloxy,
2.3.5-trimethylbenzyloxy, 2.4゜6-
Trimethylbenzyloxy, 3.4.5-trimethylbenzyloxy, 3.4-diethylbenzyloxy, 3,
5-dipropylbenzyloxy, 2-methyl-4-ethylbenzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-(2-methylphenyl)ethoxy, 2
-(3-methylphenyl)ethoxy, 1-(2,4-dimethylphenyl)ethoxy, 2-(2,4,6-drimethylphenyl)ethoxy, 3-phenylpropoxy, 5
- (3-methylphenyl)pentyloxy, 6-phenylhexyloxy, 6-(4-methylphenyl)hexyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 2-
Ethoxybenzyloxy, 3-ethoxybenzyloxy, 4-propoxybenzyloxy, 2-t-butoxybenzyloxy, 3-t-butoxybenzyloxy, 2-
pentyloxybenzyloxy, 3-pentyloxybenzyloxy, 4-hexyloxybenzyloxy,
2.3-dimethoxybenzyloxy, 2.4-dimethoxybenzyloxy, 2゜5-dimethoxybenzyloxy, 3.4-dimethoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2.6-dimethoxybenzyloxy, 2. 3.4-Trimethoxybenzyloxy, 2゜4
．． 6-1-rimethoxybenzyloxy, 3.4゜5-trimethoxybenzyloxy, 1-(4-methoxyphenyl)ethoxy, 2-(3,4-dimethoxyphenyl)
Ethoxy, 4-(2-methoxyphenyl)butoxy, 6
- (4-methoxyphenyl)hexyloxy, 6-(
2-pentyloxyphenyl)hexyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy,
4-fluorobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2.3-dichlorobenzyloxy, 2.4-dichlorobenzyloxy, 2-bromobenzyloxy, 3-
Bromobenzyloxy, 4-bromobenzyloxy, 2
-iodobenzyloxy, 3-iodobenzyloxy,
4-iodobenzyloxy, 2,4-dibromobenzyloxy, 3,5-dibromobenzyloxy, 3- (2
-chloro)phenylbutoxy, 4-(3-bromo)phenylbutoxy, 6-<4-ri0)phenylhexyloxy, 3-(4-fluoro)phenylhexyloxy, 6-(2,6-dichloro)phenyl Hexyloxy, 3-(2,4-dibromo)phenylbutoxy, 2.
4.6-drichlorobenzyloxy, 3.4.6-dribromobenzyloxy, 2-bromo-4-chlorobenzyloxy, 6-<2-chloro-3-fluoro)phenylhexyloxy, 2-methyl-3 -methoxybenzyloxy, 3-ethyl-4-propoxybenzyloxy, 2
-chloro-6-nitrobenzoloxy, 3-chloro-5
-Selected from halogen atoms, alkyl groups having 1 to 6 carbon atoms, and alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as methylbenzyloxy and 4-(2-bromo-4-ethoxy)phenylbutoxy groups. Examples include phenylalkoxy groups, which may have 1 to 3 groups, and whose alkyl moiety has 1 to 6 carbon atoms.

Furthermore, the acyloxy group includes a wide variety of groups. Examples of the acyl group constituting the acyloxy group include those belonging to the following groups (1) to (3).

(1) Lower alkanoyl group: Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, etc. having 1 to 6 carbon atoms.
Examples include straight chain or branched chain alkanoyl groups.

(2) A benzoyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a nitro group as substituents on the phenyl ring: Examples thereof include, Benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2,4-dimethylbenzoyl, 3゜4.5-trimethylbenzoyl, 4-ethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4- Methoxybenzoyl, 2,4-dimethoxybenzoyl, 3,4゜5-trimethoxybenzoyl, 4-ethoxybenzoyl, 2-methoxy-4-ethoxybenzoyl, 2-propoxybenzoyl, 3-propoxybenzoyl, 4-propoxybenzoyl, 2 .4-dipropoxybenzoyl,
3.4.5-tripropoxybenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2.3-dichlorobenzoyl, 2.4-dichlorobenzoyl, 2゜4.6-drichlorobenzoyl, 2 - Halogen atom, carbon number 1 as a substituent of bromobenzoyl, 4-bromobenzoyl, 4-fluorobenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 2-nitro-4-methoxybenzoyl group, etc. Examples include benzoyl groups that may have 1 to 3 groups selected from the group consisting of ~6 alkyl groups, C1-6 alkoxy groups, and nitro groups.

2C [In the formula, R2C represents a lower alkoxy lower alkyl group.

] In addition, as the pyridyloxy group that may have a specific substituent defined by R1 in the general formula (1) representing the compound of the present invention, specifically, the following general formula (A)
An example is the residue of a pyridine derivative represented by (a derivative from which a hydrogen atom has been removed).

(In the formula, Re, R7, and R9 each represent a hydrogen atom, a hydroxyl group, a phenyl lower alkoxy group, or an acyloxy group, and R8 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group, a carboxyl group, or a lower alkoxycarbonyl group. (However, at least one of Re, R7 and R9 shall represent a hydroxyl group.) The compound of the present invention represented by the general formula (1) can be produced, for example, by the method shown in the following reaction scheme -1 or -2. can do.

Reaction scheme-1> (2) <3) (4) (4
) R2a R2, (1) (In the formula, R1 and R2 are the same as above. X represents a halogen atom. R2a represents the same group as IR2 (excluding the R1-C0- group) or a hydrogen atom.] Reaction According to the method shown in process formula-1, first, a known compound (2) and a known compound (
Intermediate (4) is obtained by reacting with 3).

This reaction can be carried out in a suitable solvent in the presence of a suitable deoxidizing agent. As the deoxidizing agent, commonly used ones can be used, such as inorganic basic compounds such as sodium bicarbonate, sodium carbonate, and potassium carbonate, and organic basic compounds such as triethylamine, N,N-dimethylaminopyridine, and pyridine. As a solvent, various solvents that do not adversely affect the reaction, such as ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, aromatic hydrocarbons such as benzene and toluene, methylene chloride, chloroform, carbon tetrachloride, etc. Halogenated hydrocarbons, pyridine, N,N-dimethylformamide, etc. can be used.

The ratio of compound (3) to compound (2) to be used is not particularly limited and can be determined as appropriate, but it is usually selected from the range of at least an equimolar amount, preferably from an equimolar amount to about 4 times the molar amount. . The reaction temperature is generally about -30°C to
The temperature is selected from around room temperature, preferably from about -5 to 5°C, and the reaction is completed in about 30 minutes to 5 hours.

Next, the desired compound (1) of the present invention is obtained by reacting the obtained intermediate (4) with a known compound (5) in a solvent in the presence of the same deoxidizing agent as above. can. The ratio of compound (4) and compound (5) to be used can be determined as appropriate, but usually the ratio of compound (4) to compound (5) is
4) in at least an equimolar amount, preferably an equimolar amount to about 2
It is best to set it to about twice the same amount. The reaction temperature for this reaction is usually around air temperature to about 100°C, preferably around air temperature to about 80°C.
The temperature is selected from a range of about 0.degree. C., and the reaction is completed in about 30 minutes to 5 hours.

In addition, in the above, when producing the compound of the present invention in which R2 represents a group R' -Go-, compound (4) is added in an amount of at least about twice the molar amount of compound (5), preferably about 2 times the molar amount of compound (5).
It is appropriate to use a double molar amount to about three times the molar amount.

<Reaction scheme-2> R2a (3) (In the formula, R'% R2, R2a and X are the same as above.

R2b represents the same group as the group R2 (excluding the R'-Go- group) or the group X-C0-. ] According to the method shown in Reaction Step-2, compound (5) and compound (3) are mixed in a suitable solvent in the presence of a suitable deoxidizing agent similar to that shown in Reaction Scheme-1 above. By reacting to obtain compound (6), and reacting compound (6) with compound (2), the desired compound (1) of the present invention
can be manufactured.

The reaction between the above compound (5) and compound (3) is a reaction between the compound (5) and the compound (3).
Compound (3) is used in at least an equimolar amount, preferably an equimolar amount to about 4 times the molar amount of compound (3), and usually about -30
It can be carried out at a temperature of about 50°C to about 50°C, preferably about 30°C to about seedling temperature, for about 30 minutes to 5 hours. In the above, if you want to obtain compound (6) in which R2b is an X-C0- group, compound (3) is replaced with compound (5).
at least about 2 times the molar amount, preferably about 2 to 6
It is desirable to have twice the mole in the same month.

The subsequent reaction between compound (6) and compound (2) is as follows:
Compound (2) and compound (3) shown in the reaction scheme-1 above
It can be carried out in a solvent in the presence of a deoxidizing agent in the same manner as the reaction with. The amount of compound (2) to be used relative to compound (6) is at least equimolar, preferably equimolar to
It is appropriate to set the amount to about twice the molar amount, and R2 is a group R′ −
When producing a compound of the present invention exhibiting CO-, the amount should be at least about 2 times the molar amount, preferably about 2 to 3 times the molar amount.

The target compound and the compound of the present invention obtained by the methods shown in each of the above reaction schemes can be separated from the reaction system by conventional separation means and further purified. As this separation and purification means, for example, reprecipitation method, recrystallization method, silica gel column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, etc. can be employed.

The compounds of the present invention thus obtained have excellent anticancer effects, are well absorbed, exhibit rapid medicinal efficacy, have good stability, and have few side effects such as weight loss. Due to its excellent characteristics, it is very effective as an anticancer agent for the treatment of cancer in humans and their patients.

The compound of the present invention is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders, binders,
It is adjusted using diluents or excipients such as 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, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, skewers, injections (liquids, suspensions, etc.), ointments, etc. When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as grade ammonium bases and sodium lauryl sulfate, moisturizing agents such as glycerin and starch, starch,
Adsorbents such as 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 provided with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, or double layered or multilayered tablets. When forming into an emulsion, carriers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin,
Excipients such as talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar can be used. When forming into a skewer, for example, polyethylene glycol, cacao butter, higher alcohol, ester base of higher alcohol, gelatin, semi-synthetic glyceride, etc. can be used as the carrier. Capsules are usually 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 sterilized and isotonic with blood, and when molded into these forms, diluents such as water, ethyl alcohol, macrogol, etc. , propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene turgortan fatty acid esters, and the like 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, buffers, 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, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone,
Bentonite etc. can be used.

The compound of the present invention to be contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected from a wide range, but it is usually preferable to contain the compound in an amount of 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 are administered intravenously alone or mixed with conventional replacement fluids such as glucose and amino acids, and further intramuscularly, intradermally, subcutaneously, or intraperitoneally, if necessary. The skewer is administered rectally.

The administration rate of the above-mentioned pharmaceutical preparations is appropriately selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc., but usually the active ingredient, the compound of the present invention, is administered at a dose of 1 kg of body weight per day.
The dosage is preferably about 0.5 to 2011 g/day, and the preparation can be administered in 1 to 4 divided doses per day.

EXAMPLES Hereinafter, production examples of the compounds of the present invention will be given as examples, followed by examples of pharmacological tests conducted on the compounds of the present invention, but the present invention is not limited thereto.

Example 1 3-([3-cyano-6-(2,4-dichlorobenzoyloxy)-2-pyridyloxy]carbonyl)-5
-Production of fluoro-1-(2-tetrahydrofuranyl)uracil A solution of 5.34 g of phosgene in 60 mQ of methylene chloride, -
3-cyano-6-(2,4-dichlorobenzoyloxy)-2-hydroxypyridine 1.
840 and 0.83 mg of triethylamine were added and stirred for 5 minutes.

After returning the reaction solution to air temperature and removing excess phosgene,
2.38 g of -fluoro-1-(2-tetrahydrofuranyl)uracil and 4.11 g of triethylamine were added, and the mixture was stirred at room temperature for 2 hours.

After the reaction solution was filtered and concentrated, the residue was purified using a silica gel column and eluted with methylene chloride to obtain the target compound.
66 g (yield 21%) was obtained.

'H-NMR (COCO2): δ 8.27 (IH, d, J-8Hz, pyridine ring)
C,-H) 8,11 (1H,d, J-9Hz, CsH of benzene ring) 7.58-7.34 (4H,m, Cs-H and Cs-H of pyridine ring and 03+5 of benzene ring -H) 6.02-5.93 (1H, m, C+' -H)
4.38 3.89 (2H,l,Ct'-H)2
．． 58 1.77(4H,11,C2',3'-H) Example 2 3-[(6-penzoyloxy-3-cyano-2-pyridyloxy)carbonylcy-2',3'-di-0-acetyl Production of -5-fluorouridine The target compound was produced in the same manner as in Example 1.

'H NMR (COCO2): δ8, 29-8.
10 (3H, ra, CaH of the pyridine ring and 02, s-H of the benzene ring) 7, 70-7.35 (5H
,m, Ca-H and Cs H of the pyridine ring and C3+4 of the benzene ring, 5 8) 6,01 (1H.dd.J-1Hz, J-5Hz
.

C+'-H) 5, 34 5.00 (2H.II, C2'.3'-H
) 4, 39-4.1 2 (1H.ra, CA'-
H) 2, 10. ! :2.09 (3H.s each, COC
H3) 1,47 (3H,d, J-6Hz, Cs
' -H) Example 3 3- [ (6-penzoyloxy-3-cyano-2-
pyridyloxy)carbonyl]-2'-deoxy3'-
Preparation of 〇-benzyl-5'-〇-7cetyl-5-fluorouridine The target compound was prepared in the same manner as in Example 1.

Electron H NMR (CDC(! 3):
δ8.29-8.15 (3H,m, 6.24 (1H,t, J-6Hz, Ca
' -H) 4.30 (3H,S, Ch'
, s' -H) 4.19 4.00 (1H,
II, C3'-H)2, 76-1.97
(5H, I, C2'-H.

COCH3) Example 4 1-benzyloxymethyl-3-([5-chloro-4-
Production of (3-methylbenzoyloxy)-2-pyridyloxy]carbonyl)-5-fluorouracil The target compound was produced in the same manner as in Example 1.

'H-NMR (CDCG! 3)': δ8.51
(1H,s, Cs H of pyridine ring)7.48-
7.29 (9H, In, Chh C of pyridine ring: +
H, Cs H.

4,65 (2H,S, -CH2QC ratio 20) Example 5 3-([3-cyano-6-(2-nitrobenzoyloxy)-2-pyridyloxy]carbonyl)-1-ethoxymethyl-5-fluorouracil The target compound was produced in the same manner as in Production Example 1.

'H-NMR (DMSOds): δ8
．． 86 (IH, d, J-8Hz, C of pyridine ring
A-H) 8.38 (IH, d, J=7Hz, Cs
H) 8.23-8.05 (28,11, C2H of benzene ring, C5'-H) 8.01-7.91 (2H,m, 03 of benzene ring
H,C4-H) 7.79 (1H,d, J=8Hz, C5-H of pyridine ring) 5, 13 (2H,s, N-CH2) 3.59
(2H,Q, J-7t-+z, CH2CH
3) 1, 14 (3H,t, J-7Hz,
CH3) Example 6 3-C(6-penzoyloxy-3-cyano-2-pyridyloxy)carbonyl]-1-ethoxymethyl-5-
Production of Fluorouracil The target compound was produced in the same manner as in Example 1.

'HNMR (CDCQ3): δ8.28-8
．． 13 (3H, m, Ca-H of the pyridine ring and 02, s-H of the benzene ring) 7.68-7.08 (
5H, ra, Cr, -H and Cs H of the pyridine ring and C3+ t C5-H of the benzene ring) 5.16 (2H, S, N CR2) 3.62 (2H, Q, J=7Hz, CH20H3
)1.21 (3H,t, J-7Hz, CH3) Example 7 3- ([6-(2-chlorobenzoyloxy)-3-
Production of cyano-2-pyridyloxy]carbonyl-1-ethoxymethyl-5-fluorouracil The target compound was produced in the same manner as in Example 1.

'H-NMR (CD CQ 3): δ8.27
(1H, d, J=8Hz, Ct-H of pyridine ring
) 8.20-8.09 (1H, m, Cs of benzene ring
H) 7.60-7.36 <5H,m, Cs-H and Cs-H of the pyridine ring and C31A of the benzene ring.

5-H) 5.19 (2H,S,N-CH2)3.65 (2
H, q, J=7Hz, CH20H3) 1.24 (3
H, t, J-7Hz, CHa) Example 8 3-[[3-cyano-6-(2,4-dichlorobenzoyloxy)-2-pyridyloxy]carbonyl)-1-
Production of ethoxymethyl-5-fluorouracil The target compound was produced in the same manner as in Example 1.

'H-N MR (CD CQ 3 ): δ8.3
1 (1H, d, J-8Hz, Ca- of pyridine ring
H) 8.10 (1H, d, J-8Hz, Cs H of benzene ring) 7.54-7.34 (4H, m, Cs H and Cs'H of pyridine ring and Cs of benzene ring, 5-H ) 5.18 (2H,S,N-CH2)3.63 (2
H, q, J=7Hz, CH20H3) 1.22 (3
H,t, J-7Hz, CH3) Example 9 5-fluoro-3-([4-(4-propoxybenzoyloxy)-2-pyridyloxy]carbonyl)-1-
Production of (2-tetrahydrofuranyl)uracil The target compound was produced in the same manner as in Example 1.

H-NMR (CDCQ3): δ8.46
(IH, d, J-6Hz, C5-H of pyridine ring
) 8.19-8.02 (2H,m, 02 of benzene ring
, s -H) 7.49 (IH, d, J-6Hz, Ca -
H) 7.37-7.27 (2H,ra, C3,5H of the pyridine ring) 7.06-6.93 (2H,m, 03 of the benzene ring
．． 5 H) 6.00-5.91 (IH, m, C+'
-H) 4.35 3.85 (4H,m, Ct' H and -0CH2) 2.59-1.66 (6H,m, C2', 3
'-H and C ratio 2 CH3) 1.06 <38. t, J=7Hz, CH3) Example 10 3-([3-cyano-6-(2,4-dichlorobenzoyloxy)-2-pyridyloxy]carbonyl)-5-
Preparation of fluoro-1-(2-tetrahydrofuranyl)uracilPhosgene4. A solution of OOg in methylene chloride in 50m
Cool with ice and add 5-fluoro-1-(2-tetrahydrofuranyl)uracil 2. 00 was added, followed by the gradual addition of triethylamine 1,4o-. After addition,
The mixture was stirred for 1 hour under water cooling, and then excess phosgene was removed under reduced pressure.

3.1 g of 3-cyano-6-(2,4-dichlorobenzoyloxy)-2-hydroxypyridine and 2.0 omf2 of triethylamine were added thereto, and the mixture was stirred at air temperature for 1 hour. Insoluble materials were removed, the filtrate was concentrated, and the residue was purified using a silica gel column in the same manner as in Example 1 to obtain the target compound 0.33 (1 (yield: 6%)).

This product can be used for thin layer chromatography (developing solvent; chloroform:methanol = 39:1), high performance liquid chromatography (eluent: niacetonitrile:water = 7).
:3) and 'H-NMR spectrum analysis, it was found to be the same as the compound obtained in Example 1.

Pharmacological test example ■ Sarcoe subcultured in ICR mice as ascites? (S
arcoma)-180 was diluted with physiological saline to 1
2×10' m per mouse were subcutaneously transplanted into the backs of syngeneic mice and used for experiments. Starting 24 hours after tumor implantation, a drug suspended in 5% gum arabic was orally administered once a day for 7 days.

On the 10th day after tumor implantation, a solid tumor under the skin of the back was removed, the tumor weight was measured, and the S of the drug administration group was determined. Tumor severity 1T) and tumors in the control group without drug administration! Find the ratio (T/C) with I(C),
From the drug dose and analogy (T/C) dose-response curve, T/
A 50% tumor-inhibiting dose (ED50 value) at which C was 0.5 was determined.

The results are shown in Table 1 below.

Table 1 Test compounds EDs o (1
110/kg) Compound of Example 1 12 Compound of Example 6 10 Examples of formulations using the compounds of the present invention are listed below.

Formulation Example 1 Compound of Example 1 0.025mg
Bun Bun 132ma Magnesium Stearate 18mg Lactose
50mg total
Tablets of 200 mq each were prepared at the above blending ratio of about 200 mΩ.

Formulation Example 2 Compound of Example 2 0.25ma Denbun 130ma Magnesium Stearate 20ma Lactose
50n.

Total approximately 200Il1
g Tablets of 200 no each were prepared at the above mixing ratio.

Formulation Example 3 Compound of Example 3 12.5 bias polyethylene glycol 0.3 g (molecules!:
4000) Sodium chloride 0.9 (1 Polyoxyethylene sorbitan monooleate 0.49 Sodium metabisulfite 0.1 g Methyl paraben
0.180 propylparaben
0.020 Distilled water for injection 10
0m12 The above parabens, sodium metabisulfite and sodium chloride were dissolved in distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, the compound of the present invention, polyethylene glycol, and polyoxyethylene sorbitan monooleate were sequentially dissolved therein, and then distilled water for injection was added to the solution to adjust the final volume. The mixture was sterilized by sterile filtration using an appropriate filter paper, and 11,112 doses were dispensed into ampoules to prepare injections.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a halogen atom, a cyano group, a substituent,
1 to 1 of groups selected from the group consisting of nitro group, lower alkyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, phenyl lower alkoxy group, and acyloxy group
Indicates a pyridyloxy group which may have three groups. R^2 is a lower alkoxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, the following group ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ (R^3 is a hydrogen atom or a lower alkanoyloxy group, R^4 is a hydrogen atom, a lower alkanoyloxy group, or a phenyl ring on which a halogen atom, a lower alkyl group, and a lower alkoxy group are selected. a phenyl lower alkoxy group that may have 1 to 3 substituents, R^5 represents a hydrogen atom, a methyl group, a hydroxymethyl group, or a lower alkanoyloxymethyl group), or a group ▲ mathematical formula, chemical formula, There are tables etc. ▼ (R^1 is the same as above). ] 5-fluorouracil derivative represented by these.