NL8700742A - 5-fluorouracil derivative, process for its preparation; PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION WITH ANTI-CANCER EFFECT AND USE OF A 5-FLUORURACIL DERIVATIVE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION WITH ANTI-CANCER EFFECT. - Google Patents

Description

»IÉ ;; 87.3017 / Ba / vL ly '-1-

Short indication; 5-Fluorouracil derivative, process for its preparation; a method of preparing a pharmaceutical composition having an anticancer effect and the use of a 5-fluorouracil derivative to prepare a pharmaceutical composition having an anticancer effect

The invention relates to 5-fluorouracil derivatives, a process for their preparation, and more particularly a process for the preparation of compositions having an anti-cancer effect.

European patent application 180 897 discloses a 5-fluorouracil derivative, which has anti-cancer activity. European patent application 180188 teaches a composition comprising pyridine derivative to enhance the cancer-fighting activity of a cancer-fighting compound selected from 5-fluorouracil and a compound capable of forming 5-fluorouracil in vivo.

Extensive research has been conducted on 5-fluorouracil derivatives and it has been found that some compounds not specifically disclosed in the aforementioned European Patent Applications have a considerably higher therapeutic index than the compounds specifically disclosed in the published European Patent Application. 180 897 and 5-fluorouracil as well as the compound capable of forming 5-fluorouracil in vivo, the cancer fighting activity being enhanced by the pyridine derivative according to European patent application 180 188.

The invention provides a 5-fluorouracil derivative represented by the formula (1) of the formula sheet wherein Ra represents a C 1 -C 6 alkoxymethyl group.

The 5-fluorouracil derivatives of formula (1) have excellent anti-cancer activity, low toxicity and exhibit reduced side effects such as a decrease in body weight, and thus the derivatives of formula (1) of the formula sheet are extremely useful as anti-tumor agents -30 parts for treating cancer in humans and animals. The compounds of the invention have the remarkable properties of the invention: (1) they are absorbed quickly (2) they exhibit delayed activity 5 (3) they are very stable (4) they exhibit little or no gastrointestinal toxicity such as diarrhea, enemia, or gastrointestinal bleeding and (5) they have a wide safety limit (ie a large difference between the dose in which cancer fighting activity is shown and the dose in which side effects such as toxicity manifest themselves and furthermore they are excellent in terms of their therapeutic index and they are significantly safe.

The present invention also provides a method of preparing a pharmaceutical composition having an anti-cancer activity which is characterized by introducing an effective amount of a 5-fluorouracil derivative of the formula (1) into a pharmaceutical form suitable for pharmaceutical purposes. the formula sheet wherein Ra is a C 1 -C 6 alkoxymethyl group and optionally a pharmaceutically acceptable carrier.

The invention also relates to the use of a 5-fluorouracil derivative of the formula (1) of the formula sheet for the preparation of a pharmaceutical composition with anti-cancer activity.

Examples of C 1 -C 6 alkoxymethyl groups in the description and in particular with regard to formula (1) of the formula sheet are: methoxymethyl, ethoxymethyl, 1-propoxymethyl, isopropoxymethyl, 1-butoxymethyl, 2-butoxymethyl, tertiary butoxymethyl, 1-pentyloxymethyl, 1-hexyloxymethyl and the like. Of compounds of formula (1), compounds wherein R is ethoxymethyl or methoxymethyl are preferred.

Of the compounds of the invention, most preferred is a compound to be described later in Example 1, namely 3- / 3- (6-benzyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl7-1-ethoxymethyl-5 -fluorouracil.

The compounds of formula (1) according to the invention can be prepared by methods indicated in reaction scheme 1 or reaction scheme 2 of the formula sheet.

0 <·. ~ · · O ',' · ".

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Discussion of reaction scheme 1 as indicated in the formula sheet In the formulas indicated in reaction scheme 1, Ra is as defined above, X is a halogen atom such as fluorine, 3d chlorine, bromine and the like and R is a hydrogen atom or a tri (lower alkyl) silyl group. Examples of the lower alkyl group in the tri (lower alkyl) silyl group are C 1 -C 8 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl etc.

(i) Step A

According to the method indicated in reaction scheme 1, the known compound (2) is reacted with a known compound (3) to form the intermediate (4).

The reaction is carried out in the presence of a suitable acid binding agent and in a suitable solvent.

Examples of useful acid binding agents are those commonly used in the art and include inorganic basic compounds such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and the like and organic basic compounds such as triethylamine, N, N-20 dimethylaminopyridine, pyridine, and such. Examples of suitable solvents are organic solvents which do not show any adverse effect on 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 methyl chloride, chloroform, carbon tetrachloride and the like, pyridine, Ν, Ν-dimethylformamide etc.

The amount of compound (3) relative to compound (2) is not particularly limited, but is generally at least 1 mole, preferably from about 1 to about 3 moles, per mole of compound (2). The reaction is carried out at a temperature from about -30 to 100 ° C; preferably room temperature to about 100 ° C and is completed in about 10 minutes to about 20 hours.

i '· «-4- t

(ii) Step B

The intermediate (4) thus obtained is reacted with the known or new compound (5) to form the compound of formula (1) contemplated 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 type of Compound (5) used, or more particularly when the compound (5) is used. in which R ° represents hydrogen.

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When the compound (5), wherein R 0 represents a tri (lower alkyl) -silyl group, the reaction can be carried out in the presence of a suitable solvent, such as aprotic organic solvents, for example 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. These solvents are preferably used in an anhydrous state.

In any case, the reaction is conducted at a temperature from about -30 to about 100 ° C, preferably room temperature to about 60 ° C, and is completed in about 1 to about 20 hours. In the reaction between the intermediate 25 (4) and the compound (5), wherein R ° represents a tri (lower alkyl) silyl group, a catalytic amount of a Lewis acid, such as aluminum chloride, tin (IV) chloride, zinc chloride and the like are used.

The amount of compound (5) can be suitably determined and is usually at least 1 mole, preferably from about 1 to about 3 moles, per mole of intermediate of formula (4).

Discussion of reaction scheme 2 as indicated in the formula sheet

In the formulas indicated in reaction scheme 2, Ra and X are 35 as defined in reaction scheme 1.

tl J ·, C '- /, 1}' -. · V ··· '··' · -5- ï

(i) Step A

The reaction between compound (6) and compound (3) as indicated in reaction scheme 2 is performed in the same manner as the reaction between compound (2) and compound (3), as shown in reaction scheme 1.

(ii) Step B

The reaction between the intermediate (7). thus obtained and the compound (2) can be carried out in the same manner as the reaction between compound (2) and compound 10 (3) shown in reaction scheme 1.

The compounds (2) and (3), to be used as the starting materials in reaction scheme 1 or 2, are both readily available known compounds. Otherwise, compounds (5) and (6) can be used in reaction scheme 1 or 2 new compounds. These compounds can be prepared, for example, by any or all of the methods (a) and (b), which will be described below.

(a) Reaction for entering the benzoyl group

The reaction to form compound (5) or (6) having a pyridyl group substituted with a benzoyloxy group is carried out using, as a starting material, a corresponding pyridine compound with a hydroxyl or a tri ( lower alkyl) silyloxy group, which is reacted with a suitable acylating agent (benzoylating agent). The acylation reaction can be performed in the same manner as the reaction between the compound (2) and compound (3), as shown by reaction scheme 1.

(b) Reaction for introducing a tri (lower alkyl) silyl group The reaction for preparing the compound (5), wherein R is a tri (lower alkyl) silyl group, may be performed, for example, by a corresponding pyridine derivative, which has a hydroxyl group to react with a silylation group. * tm (% -6 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 such tri (lower alkyl) halo-5 silanes such as trimethylchlorosilane and the like, silylated acetamides such as Ν, Ο-bis (trimethylsilyl) acetamide etc. The silylating agent is usually used in an amount of about 1 to about 3 moles per mole of the starting compound When the tri (lower alkyl) halosilane 10 is used as the silylating agent, the reaction system preferably further contains about 1 to about 3 moles of an amine such as triethylamine, dimethylaniline, diethylamino-pyridine or the like or pyridine per mole of silylating agent.

In this case, or when silylated acetamide is used as the silylating agent, it is preferable to carry out the reaction in a suitable solvent, including ethers such as diethyl ether, dioxane, tetrahydrofuran, and the like, nitriles such as acetonitrile and the like halogener the hydrocarbons, such as methylene chloride, chloroform and the like. Hexa (lower alkyl) disilazane, when used as a silylating agent, can also serve as a solvent, thereby eliminating the need to use a different solvent. The silylation reaction is carried out at a temperature of between room temperature and about the boiling point of the solvent and is completed in about 1 to about 15 hours.

The final compound prepared in each step and the compound of the present invention thus obtained can be separated from the reaction product by conventional methods followed by purification. Useful separation and purification methods include a reprecipitation method, recrystallization method, silica gel column chromatography, ion exchange column chromatography, gel chromatography, affinity chromatography, etc.

The compounds of the present invention are usually administered to mammals, including humans, Ϋ. In the form of generally acceptable pharmaceutical compositions, which are prepared using diluents and excipients, such as filters, fillers, binders, disintegrants, surfactants, glidants and such.

Administration unit forms of these pharmaceutical compositions of the present invention can be varied and selected to meet various therapeutic objectives. Typical forms of the pharmaceutical compositions may include, for example, tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions and others), ointments and the like.

In the form of tablets useful as carriers, for example, excipients such as lactose, purified sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica and the like are used; binders such as simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and others; disintegrants such as dried starch, sodium alginate, agar agar powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, a fatty acid ester of polyoxyethylene sorbitan, sodium lauryl sulfate, glycerol monostearate, starch, lactose and others; anti-breakdown agents 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 glycerine, starch and others, adsorption accelerators such as starch, lactose, kaolin, bentonite, colloidal silicic acid and others; and lubricants such as purified talcum powder, stearic acid salts, boric acid powder, polyethylene glycol and others. If necessary, the tablets may further be coated with a conventional coating to form coated tablets, for example, sugar coated tablets, gelatin coated tablets, gut film coated tablets, 870C 7 '.

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hl * -8- film-coated tablets or double-layer tablets, multi-layer tablets and others. In the form of pills useful as carriers, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc and others are used; further binders such as powdered gum arabic, powdered gum tragacanth, gelatin and others; disintegrants such as laminaran, agar agar powder and others. In the form of suppositories useful as carriers, use is made, for example, of polyethylene glycol, cocoa butter, a higher alcohol, an ester of a higher alcohol, gelatin, semisynthetic glyceride and others. Capsules are manufactured in the usual manner by joining together the compound of the invention with the aforementioned various carriers and encapsulating the mixture into hard gelatin capsules, soft gelatin capsules, etc. In the case of preparation of injection liquids, liquids , emulsions and suspensions that are manufactured sterilized, and preferably they are isotonic with the blood. For example, when prepared in the form of solutions, emulsions and suspensions, water, ethanol, macrogol, propylene glycol, ethoxylated iso-stearyl alcohol, polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester and others can be used as diluents. In the case of preparing isotonic solutions, a sufficient amount of sodium chloride, glucose, or glycerine can be added to make the solution isotonic with the blood. The pharmaceutical compositions for injection preparations may further contain the usual solvents, buffer solutions, analgesics or the like, if necessary. The pharmaceutical composition of the present invention may also contain colorants, preservatives, fragrances, seasonings, sweeteners and others and may also contain other medicaments, if necessary. When in the form of pastes, creams and gels, diluents such as white petroleum jelly, paraffins, glycerine, cellulose-8 o n? ?

- · '· - ”» -i »C

9-9 derivatives, polyethylene glycols, silicones, bentonite and the like are used.

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

The mode of administration of the above pharmaceutical composition is not particularly limited, it can be administered by an appropriate method for the different types of dosage forms, depending on the age of the patient, gender discrimination and other circumstances, conditions of the patient and others. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules can be administered orally; injections are administered single intravenously or as a mixture with the usual injectable liquids such as glucose solution, amino acid solutions and others; and if necessary, the injections are administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, while the suppositories are introduced into the rectum.

The dosage of the desired products, according to the invention, may be suitably selected depending upon the mode of administration, the age of the patient, gender distinction and other conditions and symptom conditions; generally, the pharmaceutical composition of the invention is administered in an amount of from about 0.5 to about 20 mg per kg of body weight per day, calculated as the compound of the invention (active ingredient) in 1-4 divided doses.

The following reference examples illustrate the preparation of the starting materials used to prepare the compounds of the invention, while the examples illustrate the preparation of the compound of the invention.

Furthermore, hereinafter pharmaceutical tests carried out with respect to the compound according to the invention, f *; '/' - V 'V- i w * ♦ -10- are given.

In connection with the NMR data in the reference examples and examples, the numbers used as appendix numbers on the right side of the symbol "C" are used to refer to the location in the compound. The term "Cg-H", for example, refers to the hydrogen atom, which is attached to the 6-position carbon atom.

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 Ν-dim-dimethylacetamide, 0.51 ml of triethylamine and 0, 43 ml of benzoyl chloride are added. The mixture was stirred at room temperature for 15 minutes. 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride were added to the reaction mixture. 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 yield 1.06 g of the title compound in 60% yield.

20 1 H NMR (DMSO-dg) $ (ppm): 12.76 (1H, bs, OH or NH), 8.33 (1H, d, J = 8Hz, C4-H of the pyridine ring), 8.17 -8.07 (2H, m,) r 7.94-7.58 (3H, m, -CO- <£ ^ -), 6.95 (1H, d, J = 8Hz, C | --H) of the pyridine ring)

Reference example 2

Preparation of 6-Benzoyloxy-3-cyano-trimethylsilyloxy-pyridine

20 ml of 1,1,1,3,3,3-hexamethyldisilazane was added to 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and the mixture was stirred at 140 ° C for 20 minutes. The reaction mixture was concentrated under reduced pressure, '' '. ir? / - λ.

1-lion of the quantitative yield of the title compound, 1 H-NMR (CDCl 3) ((ppm): 8.23-8 / 13 (2H, m, J J ~ CO), 7.96 (1H, d, J = 8Hz, C4-H) / 5 7.68-7.43 (3H, m, - ^> - CO-), 6.85 (1H, d, J = 8Hz, Cc-H>

D

0.40 (9H, s, CH3x3)

Example 1

Preparation of 3- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) -10 benzoyl-1 ^ ethoxymethyl-S-fluorouracil

5.53 ml of triethylamine and 1.52 g of isophthaloyl chloride were added to a solution of 1.17 g of 1- (ethoxymethyl) -5-fluoro-uracil in 50 ml of dry dioxane. The mixture was allowed to reflux for 1 hour.

The reaction mixture was filtered, the filtrate concentrated and the residue dissolved in 50 ml acetonitrile.

3.46 ml of triethylamine and 2.10 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine were added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated and the residue was subjected to silica gel column chromatography using chloroform as the eluent to give 860 mg of the title compound. Yield 25%. Melting point = 162-164 ° C.

1 H-NMR (CDCl 3) 4 (ppm):.

25 8.66-8.14 (6H, m, ^ ~ ^ -C0- and CO- and C ^ -H of the

pyridine ring) -CO

7.82-7.33 (6H, m, Cg-H and - ^^ - CO- and ^ ~ ^) - C0- and Cg-H of the pyridine ring) 5.15 (2H, s, N-CH2) '' - 7 h 1 -12- 3f62 (2H, q, J = 7Hz, -CH2CH3) 1.22 (3H, t, j = 7Hz, -CH ^)

Example 2

Preparation of 3- / 4- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) -5 benzoyl-7-ethoxymethyl-5-fluorouracil

The title compound was prepared according to the general procedure of Example 1.

Yield 24%.

Form: powder 10 1 H NMR (CDCl 3) $ (ppm): 8.39-8.02 (7H, m, ^ ~ ^ -CO- and CO -e -CO- and C ^ -H of the pyridine ring) 7 .67-7.39 (5H, m, - ^ J ^ -CO- and Cg-H, and C ^ -H of the pyridine) 15 5.14 (2H, s, N-CH2) 3.61 (2H, q, J = 7Hz, -CH2CH3) 1.22 (3H, t, J = 7Hz, CH ^ "

Example 3

Preparation of 3- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) -20 benzoyl7-5-fluoro-1- (methoxymethyl) uracil

The title compound was prepared according to the general procedure from Example 1.

Yield 26%

Form: powder 25 1 H NMR (DMSO-d) 6 (ppm):.

Ύύ 8.87-7.63 (12H, m, "O-CO-,) \ Λ -0 0- -OC-jQ- and Cg-H), CO-5.10 (2H, s, CH) , 3.37 (3H, s, CH3) β *? Η ni / ft a -13-

Example 4

Preparation of 3- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) -benoyl / -1-ethoxymethyl-5-fluorouracil

1.39 g of isophthaloyl chloride and 3.15 ml of triethylamine were added to a solution of 1.07 g of 1-ethoxymethyl-5-fluorouracil in 40 ml of dioxane. The mixture was stirred at 80 ° C for 30 minutes. The reaction mixture was filtered and concentrated.

To the residue, 30 ml of acetonitrile and 2.60 g of 6-ben-10-zoylaxy-3-cyano-2-trimethylsilyloxy-pyridine were added and the mixture was stirred at room temperature overnight.

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 from Example 1).

Example 5

Preparation of 3- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) -benoyl 7 "1-ethoxymethyl-5-fluorouracil

To a solution of 1.53 g of 6-benzoyloxy-3-cyano-2-hydro-20-xypyridine 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. The insolubles were filtered off and the filtrate was concentrated to form an intermediate, namely 3- (6-benzoyloxy-3-25 cyano-2-pyridyloxycarbonyl) benzoyl chloride.

The intermediate was dissolved in 30 ml of dioxane. 1.00 g of 1-ethoxymethyl-5-fluorouracil and 2.68 ml of triethylamine were added to the solution and the mixture was stirred at 60 ° for 1 hour. The insolubles were 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- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl} benzoyl7-1-ethoxymethyl-5-fluorouracil ( compound of example 1) Yield 21% V.A 7 L 9 tr -14-

Pharmacological test I

Sarcoma-180, which was grown in an ascites of ICR mice, was diluted with physiological saline and introduced into the subepidermal tissues of the backs of ICR mice in an amount of 2 x 10 cells each. 24 hours after implantation, a suspension of the test compound was administered orally 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 coprecipitation and suspending the mixture in 5% gum arabic.

The solid tumor was removed from under the back skin of the mice on the tenth day after implantation to determine the weight of the tumor. The ratio (T / C) of the weight of the tumor (T) cut from the group of mice treated with the test compound was determined to the weight of the tumor (C) from the control group of mice not were treated. The 50% tumor inhibition dose (ED .... value)

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where T / C is 0.5 was determined from the dose response curve of the dose and the ratio (T / C).

The results are shown in Table 1, which also lists the results obtained by administering as a comparative drug an anti-cancer composition comprising 5-fluoro-1- (2-tetrahydrofuranyl) uracil and ura-25 cyl. of 1: 4 (mol. ratio) to a group of mice in the same manner.

6 / i / /% 2.

-15- TABLE 1

Test compound ®D50

Compound from example 1 5

Comparative medicine 30

5 Pharmacological test II

Yoshida sarcoma, which was grown in an ascites of Donryu strain rats, was diluted with physiological saline and implanted into the subepidermal tissues of 4 ridges of Donryu rats in an amount of 1 x 10 cells each. Twenty-four hours after implantation, a suspension of the test compound was administered orally 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 coprecipitation and suspending the mixture in 5% gum arabic.

The solid tumor was removed from under the rats' skin on the tenth day after implantation to determine the weight of the tumor. The ratio (T / C) of the weight of the tumor (T) cut from the group of rats treated with the test compound to the weight of the tumor (C) of the control group was determined. rats that had not been treated with them. The 50% tumor inhibition dose (EDj-q value) in which T / C is 0.5 was determined from the dose response curve of dose and the ratio (T / C).

During the above test, a dose (given at once, mg / kg), which was effective in suppressing the body weight gain of the rats treated with the test compound by 10%, was also determined. with the increase in body weight of the rats in the control group, who were not treated with it.

The dose will hereinafter be referred to as the "10% body weight suppression dose".

A therapeutic index was calculated from the value of '2

V

-16- ED ^ q and 1Ö% body weight suppression dose, according to the following equation:

Therapeutic index = lit, body weight suppression dose ED50

Table 2 given below shows the results together with the results obtained when the following comparative drugs A to E, indicated below, were administered in place of the compound of the invention.

Table 2 also indicates the relative potency of each of 10 of the test drugs, which is a ratio of the therapeutic index of each of the test drugs to the therapeutic index of comparative drug C (indicated as 1).

(1) Comparative Medication A

3- {3- [6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl] benzoyl} -15 1- / 2- (tetrahydrofuranyl) _7-5-fluorouracil

(2) Comparative drug B

3- {3- / 5-chloro-4-benzoyloxy-2-pyridyloxycarbonyl7benzoyl} -2'-deoxy-3'-0-benzyl-5-fluorouraidine

(3) Comparative drug G

20 3- {3- / 6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl7benzoyl} - 2'-deoxy-3'-0-benzyl-5-fluorouraidine

(4) Comparative Medication D

3- {3- / 4-Benzoyloxy-5-chloro-2-pyridyloxycarbonyl7benzoyl} -5-fluoro-1-ethoxymethyluracil 25 (4) Comparative drug E

Combination of l-ethoxymethyl-5-fluorouracil and 3-cyano-2,6-dihydroxypyridine £ *. f "?.. v.; * 3 '-17- TABLE 2

Test- ED_n 10% body Therapeutic Relative medicament weight under-index potency ng / kg Icings.

5 ___ dose _; __

Compound of example 1 10 10 1 2.7

Comparative drug A 30 15 0.5 1.3 10 Comparative drug B £ 60 20 ^ 0.3 £ 0.8

Comparative medicament C 40 15 0.375 1

Comparative medicament D £ 40 18 ^ 0.5 11.3

Comparative medicine E 8 3 0.375 1

As can be seen from Table 2, the compound of the invention has a significantly higher therapeutic index than the comparative medicaments A to E.

Pharmacological test III

Comparative drug C, which was used in the pharmacological test II or the compound of example 1, (25 mg / kg each) was administered orally to each of normal rats. The rats were bled at fixed times. The concentration of the test compound in the blood was observed by measuring the concentration of the metabolite in the blood as an index (3,0-benzyl-2'-deoxy-5-fluorouraid as the metabolite for rats treated with the comparative drug C and the 1-ethoxymethyl-5-fluorouracil as the rat metabolite treated with the compound of Example 1), and the maximum concentration in the blood was determined. Table 3 below gives results.

p; f: n v / o * · f v v J 'i ά »TABLE 3 -18- to»

Test compound Maximum concentration in high blood (yug / ml)

Compound of Example 1 9.2 5 Comparative Medicament C 1.8

Table 3 shows that the compound of Example 1.5 was absorbed 5 times higher than comparative drug C.

Some of the examples of preparations according to the invention are given below.

10 Preparation example 1

Compound of Example 1 25 mg

Starch 112 mg

Magnesium stearate 18 mg

Lactose_ 45 mg 15 Total 200 mg

Tablets were prepared in the usual manner and each had the above composition.

Preparation example 2

Compound of Example 2 10 mg 20 Starch 125 mg

Magnesium stearate 20 mg

Lactose 45 mg

Total 200 mg

Tablets were prepared in the usual manner and each had the previous composition.

: · * · - 1 L 9 *. · .. * 6

Claims (6)

A process for the preparation of a 5-fluorouracil derivative, of formula (1) of the formula sheet wherein Ra represents a C 1 -C 6 alkoxymethyl group, wherein 10 (a) is a compound of formula (2) of the formula sheet wherein sl. R is as defined above to react with a compound of formula (3) of the formula sheet wherein X represents a halogen atom in an organic solvent in the presence of an acid binding agent to form an intermediate product of formula (4) of the formula sheet wherein X and Ra are as defined above and the intermediate of formula (4) of the formula sheet is reacted with a compound, of formula (5) of the formula sheet wherein R 0 represents a hydrogen atom or a tri (lower alkyl) ) silyl group, in an organic solvent? or otherwise (b) reacting a compound of formula (6) of the formula sheet with a compound of formula (3) of the formula sheet wherein X represents a halogen atom in an organic solvent in the presence of an acid binding agent to form an intermediate of formula (7) of the formula sheet wherein X is as defined above and the intermediate of formula (7) is reacted with a compound of formula (2) of the formula sheet wherein R is as defined above, in a organic solvent in the presence of an acid-binding agent. A process for the preparation of a pharmaceutical composition having an anti-cancer effect, characterized in that a 5-fluorouracil derivative of the formula (1) of the formula sheet in which R is a C 1 -C 8 alkoxymethyl group in •: 4 z * -20- en dosage form suitable for pharmaceutical application. 5. Process according to claim 4, characterized in that the 5-fluorouracil derivative used is 3- / 3- (6-benzoyloxy-5-cyano-2-pyridyloxycarbonyl) benzoyl-7-ethoxymethyl-5-fluorouracil. The use of a 5-fluorouracil derivative according to claim 1 for the preparation of a pharmaceutical composition with cancer-fighting effect. Use according to claim 6, characterized in that the 5-fluorouracil derivative used is 3- / 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl-7-ethoxymethyl-5-fluorouracil. ► * Response schedule 1 0 Step a II. F O H \ A /. o II XX "Ra (2) (3) O 0 li F b / rxh'y '-> (4) Step b CN (4) + f \ Vco-0-L ^ \ —- / ^ N xO-Rb > (5) CN O ___, 0 [JF 0-c ° - ° \ Aoi /> lxV \ - / O ^ N ^ Ra (1) 6. o C "": 2 0 Reactions 2 step a 0, __ I '0 »χχ, * (6) CN o II (7) ο step b HN | SF, 7) + <aJ ia (2) CN O / V o II F / T * \\ | o II Λ / la Ra 0 “? N λ 7 / <* 4 t> J uf / 4 / ^ .V f t'.ui (1). Formula sheet CN 0 ^ \ / o II F AT ~ \ I II o _ II // \ Vco ~ oL JL || Π \ _ / ^ N ^ ocf Y YY (!) N '\ - / Cj ^ N' f ia 0 Η μ F \ A / | o ^ J t2) Ra O o II II ^ VCX ( 3) x ~ c ~ v O 0 LI / F 0 Η Λ / 11 /> C-N I 141 ia Λ 7 Λ Λ 7 A Ο i) / V v / * '%% * // \! i v Vco-o- ^ A (5) \ _ / ^ ϊΓ ^ 0-Rb a ^ \ ^ CN <; T-co-o-L · JL (6) \ - / N OH CN j,., Rt λ • '• i ί λ%! y 0 / H L