SE464303B - 5-FLUOROURACIL DERIVATIVES, PROCEDURES FOR PREPARING THIS AND ANTICANCER COMPOSITION - Google Patents

Description

The substances of the invention have remarkable characteristics of: (1) being readily absorbed, (2) exhibiting a prolonged action, (3) being highly stable, (4) exhibiting little or no gastrointestinal toxicity, such as diarrhea, anemia or gastrointestinal bleeding and <5) to have a large safety margin (ie a large difference between the dose at which the anticancer effect is exhibited and the dose at which side effects such as toxicity are caused) and to be excellent in therapeutic index and significant safety.

The present invention provides an anticancer composition comprising an effective amount of a 5-fluorouracil derivative of formula (1) and a pharmaceutically acceptable carrier.

The present invention relates to the use of a fluorouracil derivative of the formula (1) for the preparation of a composition for the treatment of a cancer.

Examples of C1-C5 alkoxymethyl groups in the description and especially with respect to formula (1) are methoxymethyl, ethoxymethyl, methyl, 1-propoxymethyl, isopropoxymethyl, 1-butoxymethyl, 2-butoxy-tert-butoxymethyl, 1-pentyloxymethyl, 1- hexyloxymethyl and the like.

Of the compounds of formula <1), compounds are suitable in which Ra represents ethoxymethyl or methoxymethyl.

Of the compounds of the invention, more suitable is a compound described later in Example 1, i.e. 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil.

The compounds of formula (1) of the invention may be prepared by methods shown below by Reaction Scheme-1 or Reaction Scheme-2. hv 10 15 20 25 30 35 40 3 464 503 Reaction Scheme-1 äEQL / š O O F H 0 H \ N n C-X 4L \ | + XC ° T Ra (2) (3) 0 OR onu XQ CN \ Ra (4) Steg B CN (4) _ * <::: >> Co_O \\ N o-Rb "" "__ '> (5 ) CN OFO fi: LN, N 0 -c4 <: šÉïï'O¿L \ T Ra (1) In the foregoing formulas, Ra is as defined above, X represents the halogen atom, such as fluorine, chlorine, bromine and the like and Rb represents the hydrogen atom or tri (1-alkyl) silyl group.

Examples of the lower alkyl group in the tri (lower alkyl) silyl group are e.g. Propvl, isøprøpvl.

C 1 -C 5 alkyl groups such as methyl, butyl, tert-butyl, pentyl, hexyl, etc.

Ci) Step A According to the procedure shown in Reaction Scheme 1, the known compound (2) is reacted with the known compound (3) to give the intermediate (4).

The reaction is carried out in the presence of a suitable acid scavenger and in a suitable solvent. Examples of useful acid scavengers are those conventionally used in the art and include inorganic basic compounds such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like, and organic basic compounds such as triethylamine, N, N-dimethylaminopyridine, pyridine and the like.

Examples of useful solvents are organic solvents which do not adversely affect the reaction and include ethers such as dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile and the like, aromatic hydrocarbons such as benzene, toluene and the like halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, pyridine, N, N-dimethylformamide, etc.

The amount of the compound (3) relative to the compound (2) is not specifically limited but is usually at least about 1 mole, preferably about 1 to about 3 moles, per mole of the compound (2).

The reaction is carried out at a temperature of about -30 to about 100 ° C, preferably room temperature to about 100 ° C and is completed within about 10 minutes to about 20 hours. (ii) Step B The intermediate (4) thus obtained is reacted with the known or novel compound (5) to produce the intended compound of formula (1) according to the invention.

The reaction can be carried out under the same conditions as in the reaction between the compounds (2) and (3) in step (A) depending on the kind of compound (5) used or more specifically, when using the compound (5), wherein Rb represents hydrogen.

When the compound (5), wherein Rb represents tri (lower alkyl) silyl group is used, the reaction can be carried out in the presence of a suitable solvent, such as aprotic organic solvents, e.g. ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile and the like, aromatic hydrocarbons such as benzene, toluene and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like. similar. These solvents are suitably used in the dry state.

In both cases, the reaction is carried out at a temperature of about -30 to about 100 ° C, preferably room temperature to about 60 ° C and is completed within about 1 to about 20 hours. In the reaction between the intermediate (4) and the compound (5), wherein Rb represents tri (alkylalkyl) silyl group, a catalytic amount of a Lewis acid, such as aluminum chloride, tin (IV) chloride, The amount of the compound (5) can be suitably determined and zinc chloride and the like are also used. usually at least about 1 mole, preferably about 1 to about 3 moles, per mole of the intermediate of formula (4).

Reaction Scheme -2 step AQO, / CN OH CO-O \\ + XC Ö '"_ N oH (6) (3) cn. / OI ° I' ___? Co-o \ II <3 cx N oc (7) 10 15 20 25 30 35 464 303 6 Steg_§ OH \ F \\ N / L: fl // ________ à <7) + O ,, \\ NI Ra 'J (2) cm OIF _0 (ü gN CO \\ N In the foregoing formulas, Ra and X are defined as in Reaction Scheme 1. (i) Step A Reaction between the compound (6) and the compound (3), as shown in Reaction Scheme-2, is carried out on the same as in the reaction between the compound (2) and the compound (3), as shown in Reaction Scheme 1. (ii) Step B The reaction between the intermediate (7) thus obtained and the compound (2) can also be carried out in the same manner as in the reaction between the compound (2) and the compound (3), as shown in Reaction Scheme-1.

The compounds (2) and (3) to be used as starting materials in Reaction Schemes 1 and -2 are both readily available known compounds. On the other hand, the compounds (5) and (6) to be used in Reaction Scheme-1 or -2 comprise new compounds. These compounds can be prepared, for example, by any of or a combination of methods M (a) and (b), as described below. (a) Reaction to introduce benzoyl group; The reaction for preparing the compound (5) or (6) having a pyridyl group substituted by benzyloxy group is carried out using as a starting material a corresponding pyridine compound having a hydroxyl group or tri group, with which a suitable acylating agent (benzoylating agent) brought to react. This acylation reaction can be carried out in the same manner as in the reaction between the compound (2) and the compound (3), as shown in Reaction Scheme-1. (b) Reaction to introduce tri (lower alkyl) silyl group For example, the reaction to prepare the compound <5), wherein R b represents tri to react the corresponding pyridine derivative with hydroxyl group with a silylating agent. Examples of useful silylating agents are those commonly used in the art and include hexa (lower alkyl) disilazanes such as 1,1,1,3,3,3-hexamethyldisilazane and the like, tri-trimethylchlorosilane and the like, silylated acetamides such as N , O-bis (trimethylsilyl) acetamide and the like. The silylating agent is usually used in an amount of about 1 to about 3 moles per mole of the starting compound. When tri (lower alkyl) halososilane is used as the silylating agent, the reaction system suitably further contains about 1 to about 3 moles of an amine, such as triethylamine, dimethylaniline, diethylaminopyridine or the like or pyridine per mole of the silylating agent. In this case or when silylated acetamide is used as the silylating agent, it is convenient to carry out the reaction in a suitable solvent comprising ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile and the like halogenated hydrocarbons such as methylene chloride, chloro shape and the like. Hexa (lower alkyl) disilazane, when used as a silylating agent, can also act as a solvent and eliminate the need to use another solvent.

The silylation reaction is carried out at a temperature between room temperature and approximately the boiling point of the solvent and is completed within about 1 to about 15 hours.

The final compound prepared in each step, and thus obtained compound of the present invention, can be separated from the reaction product by conventional methods followed by purification. Useful separation and purification methods include reprecipitation method, recrystallization method, silica gel column chromatography, ion exchange column chromatography, gel chromatography, affinity chromatography, etc. is prepared by using diluents and extenders, such as filters, fillers, binders, disintegrants, surfactants, lubricants and the like. Dosage unit forms of these pharmaceutical compositions of the present invention may be varied and selected to meet various therapeutic purposes. Typical forms of the pharmaceutical compositions may be exemplified, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions and others), ointments and the like.

When forming into tablet form, such carriers are useful, e.g. excipients such as lactose, purified sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and others; binders, such as simple syrup, a glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and others; disintegrants such as dried starch, sodium alginate, agar-agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, a fatty acid ester of polyoxyethylene sorbitan, sodium lauryl sulphate, stearic acid monoglyceride, starch, lactose; decomposition inhibitors such as purified sugar, stearin, cocoa butter, hydrogenated oils and others; absorption accelerators, such as quaternary ammonium base, sodium lauryl sulfate and others; wetting agents such as glycerol, starch and others, adsorption accelerators such as starch, lactose, kaolin, bentonite, colloidal silicic acid and others and lubricants such as purified talc powder, stearic acid salts, boric acid powder, polyethylene glycol and others. If necessary, the tablets can be further coated with ordinary coating film to make them coated tablets, e.g. sugar-coated tablets, gelatin-film-coated tablets, enteric-film-coated tablets, film-coated tablets, or double-layered tablets, multiple-layer tablets and others. When forming into pill form, useful as carriers are e.g. excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc and others; binders, such as powdered a: biscuit rubber, powdered dragant rubber, gelatin and others; sf dividers, such as laminaria, agar-agar powder and others. When forming into suppository form, useful as carriers are e.g. polyethylene glycol, cocoa butter, a higher alcohol, an ester of a higher alcohol, gelatin, semi-synthesized glyceride and others. Capsules are prepared in a conventional manner by mixing the compound of the invention with the foregoing various carriers and encapsulating the mixture into hard gelatin capsules, soft gelatin capsules, etc. In case injections, solutions, emulsions and suspensions are prepared, they are sterilized and are conveniently prepared. isotonic to the blood. In the preparation of the form of solutions, emulsions and suspensions are useful as diluents e.g. water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester and others. In the case of isotonic solutions, a sufficient amount of sodium chloride, glucose or glycerol may be added to make the solution isotonic to the blood. The pharmaceutical compositions for injection may further contain customary solvents, buffer solutions, analgesics and the like, if necessary. The pharmaceutical composition of the present invention may also contain coloring agents, preservatives, perfumes, spices, sweeteners and others, as well as containing other medicines if necessary. When forming into paste, cream and gel form, diluents such as white petroleum jelly, paraffins, glycerol, cellulose derivatives, polyethylene glycols, silicones, bentonite and the like can be used.

The amount of the desired product of the present invention, which is contained as the active ingredient in the pharmaceutical composition, is not specifically limited and can be selected from a wide range, usually 1 to 70% by weight can be used.

Method of administration of the above pharmaceutical composition is not specifically limited and may be administered by a suitable method for respective types of administration depending on the age of the patient, the difference in sex and other conditions, the condition of the patient and others. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally; injections are administered intravenously alone or as a mixture with common injectable transfusions, such as a glucose solution, an amino acid solution and others; and if necessary, the injections alone are administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally and the suppositories are administered in the rectum.

The dosage of the desired products of the present invention may be suitably selected depending on the method of administration, the age of the patient, the difference in sex and other conditions and the condition of the symptoms, and usually the pharmaceutical composition of the invention may be administered in an amount of about 0.5 to about 20 mg / kg body weight / day, calculated as the compound of the invention (active ingredient) in 1 to 4 divided doses.

The following reference examples illustrate the preparation of starting materials used to prepare the compounds of the invention and the examples illustrate the preparation of the compound of the invention. Furthermore, pharmaceutical tests performed with respect to the compound of the invention will be given below.

In connection with NMR data in the reference examples and the examples, the numbers eà as a lower index to the right of the symbol "C", were used to refer to the position in the compound.Thus, for example, the expression "C5-H" refers to hydrogen bonded to the carbon atom at the 6-position.

Reference Example 1 Preparation of 6-benzoyloxy-3-cyano-2-hydroxypyridine To a solution of 1.00 g of 3-cyano-2,6-dihydroxypyridine in 40 ml of N, N-dimethylacetamide was added 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride. The mixture was stirred at room temperature for 15 minutes. To the reaction mixture were added 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with chloroform and water to give 1.06 g of the title compound in a yield of 60%. 1 H-NMR δ = 12.76 (1H, bs, OH or NH), 8.33 (1H, d, J = 8Hz, C4-H in the pyridine ring), s, 17- e, o7 <2H, m, -co-QL 7, e4-7, sa (an, m, -COQ-L 6.95 (1H, d, J = 8Hz, C5-H in the pyridine ring) Reference Example 2 Preparation of 6-Benzoyloxy-3-cyano-trimethylsilyloxypyridine A 20 ml quantity of 1,1,1,3,3,3-hexamethyldisilazane was added to 2.00 g of 6-benzooyloxy-3-cyano-2-hydroxypyridine and the mixture was stirred at 140 g. The reaction mixture was concentrated under reduced pressure to quantitatively give the title compound: 1 H-NMR δ Cppmn 8.23 ~ 8.13 (2H, m, <: §CO3), δ, 7.96 ( 1H, d, J = 8Hz, C4-H), δ 7.68-7.43 (3H, m, -CO-), 6.85 (1H, d, J = 8Hz, C5-H) 0, (SH, s, CH 3 x 3) Example gel 1 Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil To a solution of 1.17 g 1 - (ethoxymethyl) -5-fluorouracil in 50 ml of dry dioxane was added 5.53 ml of triethylamine and 1.52 g of isophthaloyl chloride and the mixture was refluxed for 1 hour.

The reaction mixture was filtered, the filtrate was concentrated and the residue was dissolved in 50 ml of acetonitrile. To the solution were added 3.46 ml of triethylamine and 2.10 g of 6-benzooyloxy-3-cyano-2-hydroxypyridine. The mixture was stirred at room temperature for 464,303 hours. The reaction mixture was filtered and concentrated and the residue was subjected to silica gel column chromatography using chloroform as an eluent to give 860 mg of the title compound. Yield 25 X. mp = 162-164 ° C. 1 H-NMR εcnc13> δ = '/ 8.66 - α, 14 can, m, <:> - co- ooh - <: 2Bco- ooh \ -co / C4-H in the pyridine ring) CO- and C5-H in the pyridine ring) -C 5.15 <2H, O, N-cH2> 3.62 <2H, q, J = 7Hz, -cH2cH3> 1, Example Gel 2 Preparation of 3- [N- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil The title compound is prepared following the general procedure of Example 1.

Yield 24%.

Form: powder in NMR δ = / \ / 1) co- ooh co-š:> ~ co- ooh \ \ C4-H in the pyridine ring) 8.39-8.02 cvx, m, \ 7.67-7 , 39 (sn, m, -š:> - co- ooh cs-H ooh cs-H 1 pyridine rings) 5.14 (2H, s, N-CH2) 3.61 (2H, q, J = 7Hz, - CH 2 CH 3) 1,22 (3H, t, J = 7Hz, CH 3) Example 3 Preparation of 3-La- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -5-fluoro-1- (methoxymethyl) uracil The title compound is prepared following the general procedure of Example 1.

Yield 26% Form: powder in-NMR = NC \ / a, s7-7.63 <12H, m, -š: j§co-, \ I - \ _ N -oc - <: É- and ce-H ), CO- s, 10 <2H, 8, cH2>, 3.37 can, s, cH3> O- Example 4 Preparation of 3-L3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl -1-Ethoxymethyl-5-fluorouracil To a solution of 1.07 g of 1-ethoxymethyl-5-fluorouracil in 40 ml of dioxane was added 1.39 g of isophthaloyl chloride and 3.15 ml of triethylamine. The mixture was stirred at BO ° C for 30 minutes. The reaction mixture was filtered and concentrated.

To the residue were added 30 ml of acetonitrile and 2.60 g of 6-benzoyloxy-3-cyano-2-trimethylsilyloxypyridine, and the mixture was stirred overnight at room temperature.

The reaction mixture was filtered and concentrated again, and the residue was placed on a silica gel column and eluted with ethyl acetate-methylene chloride to give 0.43 g of the title compound (compound of Example 1).

Example 5 Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil To a solution of 1.53 g of 6-benaoyloxy-3-cyano-2- hydroxypyridine in 30 ml of dioxane was added 1.30 g of isophthaloyl chloride and 2.68 ml of triethylamine. The mixture was stirred at room temperature for 3 hours. Insoluble material was filtered off and the filtrate was concentrated 464, concentrated to give an intermediate, i.e. 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl chloride.

The intermediate was dissolved in 30 ml of dioxane. To the solution were added 1.00 g of 1-ethoxymethyl-5-fluorouracil and 2.68 ml of triethylamine and the mixture was stirred at 60 ° C for 1 hour. Insoluble material was filtered off and the filtrate was concentrated. The residue was placed on a silica gel column and eluted with dichloromethane to give 0.62 g of the desired 3-L3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil (compound of Example 1). Yield 21 X.

Pharmacological test In Sarcoma-180 subcultured in an ascites in ICR mice, it was diluted with a physiological saline solution and implanted in the sub-epidermal tissues of the spine of ICR mice in an amount of 2 x 107 cells each. 24 hours after implantation, a suspension of the test compound was orally administered to each of the mice once a day for 7 consecutive days.

The suspension of the test compound was prepared by uniformly mixing the test compound with polyvinylpyrrolidone by precipitating and suspending the mixture in 5% gum arabic.

The solid tumor was removed from under the dorsal skin of mice on the tenth day after implantation to measure the weight of the tumor. The ratio (T / C) of the weight of tumor (T) excised from the group of mice treated with the test compound was determined to the weight of tumor (C) from the control group of mice not treated therewith. The dose with 50% tumor inhibition (ED50 value), in which the T / C is 0.5, was determined from the dose-response curve of dose and ratio (T / C).

The results are shown in Table 1, which also lists the results given by administering as a comparative drug an anticancer composition comprising 5-fluoro-1- (2-tetrahydrofuranyl) uracil and uracil in a ratio of 1: 4 (molar ratio) to a group of mice in the same way. pl m1 10 15 20 25 30 35 464 303 15 Table 1 Test compound ED50 (mg / kg) Compound in Example 1 Comparative drug _ 30 Pharmacological test II Yoshida sarcoma subcultured in an ascites in Donryu strain rats was diluted with a physiological saline solution and were implanted in subepidermal tissues of the backs of Donryu rats in an amount of 1 x 104 cells each. 24 hours after implantation, a suspension of the test compound was orally administered to each of the rats once a day for 7 consecutive days. The suspension of the test compound was prepared by uniformly mixing the test compound with polyvinylpyrrolidone by precipitation and suspending the mixture in 5% gum arabic.

The solid tumor was removed under the dorsal skin of the dishes on the tenth day after implantation to measure the weight of the tumor. The ratio (T / C) of the weight of tumor (T) excised from the group of rats treated with the test compound to the weight of tumor (C) from the control group of rats not treated therewith was determined. The dose for 50% tumor inhibition (ED5g_ value), in which the T / C is 0.5, was determined from the dose-response curve of the dosage and the ratio (T / C).

During the above test, a dose (given once, mg / kg) was also determined, which was effective in suppressing the increase in body weight of the rats treated with the test compound by 10%, compared with the increase in the body weight of the rats in the control group, which did not The dose will hereinafter be referred to as "10 Z body weight-suppressing dose".

A therapeutic index was calculated from the value of ED50 and 10 Z body weight suppressive dose according to the following equation: 10 15 20 25 30 464 so: 16 10 X body weight suppressing dose Therapeutic index = ED50 Table 2 below shows the result together with the results, which obtained when the following comparative drugs A to E listed below were administered in place of the compound of the invention. Table 2 also indicates the relative potency of each of the test drugs, which is a ratio of therapeutic index of each of the test drugs to the therapeutic index of comparative drug C (expressed as 1). (1) Comparative drug A 3- {3- [B-benzooyloxy-3-cyano-2-pyridyloxycarbonyl] benzoyl} -1-L2-Ctetrahydrofuranyl17-5-fluorouracil <2) Comparative drug B 3- {3- [ S-chloro-4-benzoyloxy-2-pyridyloxycarbonyl-benzoyl-2'-deoxy-3'-O-benzyl-5-fluorouridine (3) Comparative drug C 3- {3-fluoro-benzoyloxy-3-cyano-2-pyridyloxy- carbonyl 7-benzoyl-2'-deoxy-3'-O-benzyl-5-fluorouridine (4) Comparative drug D 3- [3- [β-benzoyloxy-5-chloro-2-pyridyloxycarbonyl] benzoyl] -5-fluoro-1-ethoxymethyluracil (5) Comparative drug E Combination of 1-ethoxymethyl-5-fluorouracil and 3-cyano-2,5-dihydroxypyridine. 10 15 20 25 30 464 305 17 Table 2 Experimental ED50 10% body weight- Therapy Relative drug mg / kg suppressive technical strength In dose index Compound in ex 1 10 10 1 2.7 Compound Drug A 30 15 0.5 1, 3 Compound Medicines B 260 20 í0.3 20.8 Compound Medicines C 40 15 0.375 1 Compound Medicines D 240 18 (0.5 <1.3 Compound _ - Medicines E 8 3 0.375 1 As can be seen from Table 2, the compound according to the invention significantly higher therapeutic index than comparative drugs A to E.

Pharmacological Test III Comparative drug C, used in Pharmacological Test II, or the compound of Example 1 (25 mg / kg each) was orally administered to each of the normal rats. The rats were bled at selected intervals. The concentration of the test compound in the blood was recorded by measuring the concentration of the metabolite in the blood as an index (3'-O- -benzyl-2'-deoxy-5-fluorouridine as a metabolite for the rats, which were treated with comparative drugs C and 1- ethoxymethyl-5-fluorouracil as a metabolite for the rats treated with the compound of Example 1), and the maximum concentration in the blood was determined. Table 3 below shows the results. 10 15 20 25 30 35 464 303 18 Table 3 Test compound Maximum concentration in blood (gg / ml) _ Compound in Example 1 9.2 Comparative drug C 1.8 Table 3 shows that the compound in Example 1 was 5 times as strongly absorbed as a comparative drug C.

Given below are some of the examples of the compositions according to the invention.

Preparation Example 1 Compound of Example 1 25 mg Starch 112 mg Magnesium stearate 18 mg Lactose 45 mg A total of 200 mg Tablets were prepared in a conventional manner, each tablet having the foregoing composition.

Preparation Example 2 Compound of Example 2 10 mg Starch 125 mg Magnesium stearate 20 mg Lactose 45 mg A total of 200 mg Tablets were prepared in a conventional manner, each tablet having the foregoing composition.

Claims (7)

10 15 20 25 '”464 sus PATENTKRAV A 5-fluorouracil derivative, characterized by the formula cN 0 F O / - \ co-0 \ "[N O-C (ln Ra wherein Ra represents C1-C5 alkoxymethyl group. 5-Fluorouracil derivative according to claim 1, characterized in that 3-cyano-2-pyridyloxycarbonyl) benzoyl-1-ethoxymethyl-5-fluoro-thereof, that it consists of 3- [3- (6-benzoyloxyuracil) . 3. A process for the preparation of a 5-fluorouracil derivative corresponding to the formula 'CN O 0 F Ûí f: Ö * i If' I Ra wherein Ra represents C1-C5 alkoxymethyl group, characterized in comprises the steps of: (a) reacting a compound corresponding to the formula (2) wherein Ra is defined as above, with a compound corresponding to the formula (3) wherein X represents a halogen atom, in a organic solvent in the presence of an acid scavenger to give an intermediate corresponding to the formula OO _ | F 0 ll 'I C_N I <4) x-c 04k? J Ra wherein X and Ra are defined as above, and reaction of the intermediate of formula (4) with a compound corresponding to the formula // In CN co-o \ (S) wherein Rb represents a hydrogen atom or tri (lower alkyl) ) silyl group, in an organic solvent, or alternatively (b) reacting a compound corresponding to the formula / cm 2 CO-O 2 N OH corresponding to the formula (5) with a compound, (3) 10 15 20 25 30 35 Wherein X represents a halogen atom, in an organic solvent in the presence of an acid scavenger to give an intermediate corresponding to the formula CN / o IIH cx m, wherein X is defined as above, and reaction of the intermediate of formula (7) with a compound corresponding to formula <2), wherein Ra is defined as above, in an organic solvent in the presence of an acid scavenger. 4. Anticancer composition, characterized by an effective amount of a 5-fluorouracil derivative corresponding to the formula cN 0 F o 'I <5 than' CO-O \\ 'g I (1) N oc GÅ? ; Ra wherein Ra represents C1-C5 alkoxymethyl group, and a pharmaceutically acceptable carrier. An anticancer composition according to claim 4, characterized in that the 5-fluorouracil derivative is 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil. 22 464 303 Use of a 5-fluorouracil derivative of the formula cN 0 0 F _ (1) s Qcc-og (F LN I i / NOC o? L \?; Ra wherein Ra represents C for the treatment of a cancer. Use according to claim 6, characterized in that the 5-fluorouracil derivative is 3-E3- (8-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil.