GB2192880A - Anti-cancer 5-fluorouracil derivatives - Google Patents

Description

SPECIFICATION 5-Fluorouracil derivatives, process for preparing the same and their use This invention relates to 5-fluorouracil derivatives, process for preparing the same and their use, and more particularly to anti-cancer compositions.

European patent application published under No. 180,897 discloses a 5-fluorouracil derivative having an anti-cancer activity. European patent application published under No.180,188 teaches a composition containing a pyridine derivative for increasing the anti-cancer activity of an anticancer compound selected from 5-fluorouracil and a compound capable of producing 5-fluorouracil in vivo.

We conducted extensive research on 5-fluorouracil derivatives and found that some compounds which are not specifically disclosed in the foregping European patent applications have significantly higher therapeutic index than the compounds specifically described in European Patent Application Published under No. 180,897, and than-5-fluorouracil and the compound capable of producing 5-fluorouracil in vivo with the anti-cancer activity increased by the pyridine derivative according to European Patent Application published under No. 180,188.

This invention provides a 5-fluorouracil derivative represented by the formula

wherein Ra is C1-C6 alkoxymethyl group.

The 5-fluorouracil derivatives of the formula (1) are outstanding in anti-cancer effect, and low in toxicity and deminished in side effects such as decrease of body weight, and therefore the derivatives of the formula (1) are very useful as anti-tumor agent for treating a cancer in humans and animals. The compounds of the invention have remarkable features of: (1) being readily absorbed, (1) exhibiting a sustained effect, (3) being highly stable, (4) exhibiting little or no gastro-intestinal toxicity such as diarrhea, enemia or gastro-intestinal bleeding and (5) having a wide safety margin (i.e., great difference between the dose at which anti-cancer activity is exhibited and the dose at which side effects such as toxicity are caused), and being excellent in therapeutic index and significantly safe.

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

This invention also provides a method for treating a cancer in a patient comprising administering to said patient an effective amount of a 5-fluorouracil derivative of the formula (1).

Examples of C,-C6 alkoxymethyl groups in the specification and particularly with respect to the formula (1) are methoxymethyl, ethoxymethyl, 1-propoxymethyl, isopropoxymethyl, 1-butoxymeethyl, 2-butoxymethyl, tert-butoxymethyl, 1-pentyloxymethyl, 1-hexyloxymethyl and the like.

Of the compounds of the formula (1), preferable are compounds wherein Ra is ethoxymethyl or methoxymethyl.

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

The compounds of the formula (1) according to the invention can be prepared by processes shown below by Reaction Scheme-1 or Reaction Scheme-2.

reaction Scheme-l > Step A

In the foregoing formulas, Ra is as defined above, X is halogen atom such as fluorine, chlorine, bromine and the like and Rb is hydrogen atom or tri(lower alkyl)silyl group. Examples of the lower alkyl group in the tri(lower alkyl) silyl group are C1-C6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.

(i) Step A According to the process shown by Reaction Scheme-1, the known compound (2) is reacted with the knwon compound (3), giving the intermediate (4).

The reaction is conducted in the presence of a suitable acid scavenger and in a proper solvent. Examples of useful acid scavengers are those conventionally used in the art and including inorganic basic compounds such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like, and organic basic compounds such as triethylamine, N,Ndimethylaminopyridine, pyridine and the like. Examples of useful solvents are organic solvents having no adverse effect on the reaction and including 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 generally 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 in about 10 minutes to about 20 hours.

(ii) Step B The intermediate (4) thus obtained is reacted with the known or novel compound (5), producing the contemplated compound of the formula (1) according to the invention.

The reaction can be performed 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 is hydrogen.

When the compound (5) in which Rb is tri(lower alkyl)silyl group is used, the reaction can be effected 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 aceto-nitrile 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 the dry state.

In either case, the reaction is conducted at a temperature of 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 (4) and the compound (5) wherein Rb is tri(lower alkyl)-silyl group, a cataiytic amount of a Lewis acid such as aluminium chloride, stannic chloride, zinc chloride and the like may also be used.

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

reaction Scheme-2 > Step A

In the foregoing formulas, Ra and X are as defined in Reaction Scheme-1.

(i) Step A The reaction between the compound (6) and the compound (3) shown by Reaction Scheme-2 is effected in the same manner as in the reaction between the compound (2) and the compound (3) shown by Reaction Scheme-i.

(ii) Step B The reaction between the intermediate (7) thus obtained and the compound (2) can be performed also in the same manner as in the reaction between the compound (2) and the compound (3) shown by Reaction Scheme-i.

The compounds (2) and (3) to be used as the starting materials in Reaction Scheme-l or -2 are both easily available known compounds. On the other hand, the compounds (5) and (6) to be used in Reaction Scheme-1 or -2 include novel compounds. These compounds can be prepared, for example, by any one of or a combination of processes (a) and (b) described below.

(a) Reaction for introducing benzoyl group The reaction for producing the compound (5) or (6) having pyridyl group substituted with benzoyloxy group is effected using as a starting material a corresponding pyridine compound having hydroxyl group or tri(lower alkyl)silyloxy group with which a suitable acylating agent (benzoylating agent) is reacted. This acylating reaction can be conducted in the same manner as in the reaction between the compound (2) and the compound (3) shown by Reaction Scheme-i.

(b) Reaction for introducing tri(lower alkyl)silyl group For example, the reaction for preparing the compound (5) wherein Rb is tri(lower alkyl)silyl group can be performed by reacting the corresponding pyridine derivative having hydroxyl group with a silylating agent. Examples of useful silylating agents are those conventionally used in the art and include hexa(lower alkyl)disilazanes such as 1,1,1,3,3,3-hexamethyldisilazane and the like, tri(lower alkyl)halogenosilanes such as 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 the tri(lower alkyl)halogenosiiane 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, 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 preferred to conduct the reaction in a suitable solvent including ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile and the like, halogenated hydrocarbons such as methylene chloride, chloroform and the like. Hexa(lower alkyl)disilazane, when used as the silylating agent, can act also as a solvent, eliminating the need to use another solvent.The silylating reaction is carried out at a temperature of between room temperature and approximately the boiling point of the solvent and is completed in about 1 to about 15 hours.

The end 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 methods and purification methods include reprecipitation method, recrystallization method, silica gel column chromatography, ion-exchange column chromatography, gel chromatography, affinity chromatorgraphy, etc.

The compound of the present invention are usually administered to mammals including humans in the form of generally acceptable pharmaceutical compositions which are prepared by using diluents and excipients such as filters, bulking agents, binders, disintegrating agents, surfactants, lubricants and the like. Administration unit forms of these pharmaceutical compositions of the present invention can be varied and selected so as to meet various therapeutical purposes.

Typical forms of the pharmaceutical compositions can be examplified such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions and others), ointments and the like.

In shaping into the form of tablets, usable as the carriers are, for example, 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, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and others; disintegrating agents such as dried starch, sodium alginate, agaragar powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, a fatty acid ester of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose and others; disintegration inhibitors such as purified sugar, stearin, cacao butter, hydrogenated oils and others; absorption accelerators such as quaternary ammonium base, sodium laurylsulfate and others; wetting agents such as glycerin, 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 further be coated with usual coating film to make them into coated tablets, for example sugar-coated tablets, gelatin film-coated tablets, enteric film-coated tablets, film-coated tablets, or double-layered tablets, multiple-layered tablets and others. In shaping into the form of pills, usable as the carriers are, for example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and others; binders such as powdered gum arabi, powdered tragacanth gum, gelatin and others; disintegrating agent such as laminaran, agar-agar powder and others.In shaping into the form of suppositories, usable as the carriers are, for example, polyethylene glycol, cacao butter, a higher alcohol, an ester of a higher alcohol, gelatin, semi-synthesized glyceride and others. Capsules are prepared in a conventional manner by admixing, the compound of the invention with the foregoing various carrier and encapsulating the mixture into hard-gelatin capsules, soft-gelatin capsules, etc.

In case of preparing injections, solutions, emulsion and suspensions being prepared are sterilized, and they are preferably isotonic to the blood. In preparing into the form of solutions, emulsions and suspensions, usable as the diluents are, for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester and others. In case of preparing isotonic solutions, suffient amount of sodium chloride, glucose or glycerin may be added to make the solution to be isotonic to the blood.

The pharmaceutical compositions for injection preparation may further contain usual dissolving agents, buffer solutions, analgesic agents or the like, if necessary. The pharmaceutical composition of the present invention may also contain coloring agents, preservatives, perfumes, seasoning agents, sweetening agents and others, as well as contain other medicines, if necessary.

In shaping into the form of pastes, creams and gels, diluents such as white vaseline, paraffins, glycerine, cellulose derivatives, polyethylene glycols, silicones, bentonite and the like can be used.

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

Administration method of the above-mentioned pharmaceutical composition is not specifically restricted and can be administered through a suitable method for the respective types of administration forms, depending upon age of the patient, distinction of the sex and other conditions, conditions of the patient and others. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally; injections are administered intraveneously singly or as a mixture with usual injectable transfusions such as a glucose solution, an amino acids solutions, and others; and if necessary the injections are administered singly intramuscularly, intracutaneously, subcutaneously or intraperitoneally; and the suppositories are administered into rectum.

The dosage of the desired products of the present invention may suitably be selected depending upon the method for administration, age of the patient, distinction of sex and other conditions, and conditions of the symptoms, and generally the pharmaceutical composition of the invention can be administered in an amount of about 0.5 to about 20 mg/kg of the 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 the starting materials used for preparing the compounds of the invention, and examples illustrate the preparation of the compound of the invention. Furthermore, pharmaceutical tests conducted with respect to the compound of the invention will be given below.

In connection with the NMR data in the reference examples and examples, the numerals used as a subscript at the right of the symbol "C" are used to refer to the position in the compound.

Thus the term "C5-H", for example, refers to the 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 were 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, giving 1.06 g of the title compound in a yield of 60%.

1H-NMR (DMSO-d6) 6(pom): 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, 7.94-7.58 (3H, m,

6.95 (1H, d, J=8Hz, C5-H of the pyridine ring) Reference Example 2 Preparation of 6-benzoyloxy-3-cyano-trimethylsilyloxypyridine A 20 ml quantity of 1,1,1,3,3,3-hexamethyl-disilazane was added to 2.00 g of 6-benzoyloxy3-cyano-2-hydroxypyridine, and the mixture was stirred at 1400C for 20 minutes. The reaction mixture was concentrated under reduced pressure, thereby quantitatively giving the title compound.

1H-NMR (CDCl3) J (ppm): 8.23-8.13 (2H, m,

7.96 (1H, d, J=8Hz, C4-H), 7.68-7.43 (3H, m,

6.85 (1H, d, J=8Hz, C5-H) 0.40 (9H, s, CH3x3) Example 1 Preparation of 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]- 1 -ethoxymethyl-5-fluo- rouracil To a solution of 1.17 g of 1-(ethoxymethyl)-5-fluorouracil in 50 ml of dry dioxane were added 5.53 ml of triethylamine and 1.52 g of isophthaloyl chloride. 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 6benzolyoxy-3-cyano-2-hydroxypyridine. 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 an eluant, giving 860 mg of the title compound.

Yield 25%.

M.p.=162--164"C 1H-NMR (CDC13) 6(ppm): 8.66 - 8.14 (6H, m,

and C4-H of the pyridine ring)

7.82-7.33 (6H, m, C6-H and HzCO- and CO- CO- and C5-H of the pyridine ring) -CO 5.15 (2H, s, N-CH2) 3.62 (2H, q, J=7Hz, -CH2CH3) 1.22 (3H, t, J=7Hz, -CH3) Example 2 Preparation of 3-[4-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]- 1 -ethoxymethyl-5-fluo- rouracil The title compound was prepared following the general procedure of Example 1.

Yield 24%.

Form: powder 1H-NMR (CDCl) 6(pom): 8.39-8.02 (7H, m,

and

and C4-H of the pyridine ring) 7.67-7.39 (5H, m,

and C6-H, and C5-H of the pyridine ring) 5.14 (2H, s, N-CH2) 3.61 (2H, q, J=7Hz, -CH2CH3) 1.22 (311, t, J=7Hz, CH3) Example 3 Preparation of 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-5-fluoro- 1 -(methoxyme- thyl)uracil The title compound was prepared following the general procedure of Example 1.

Yield 26% Form: powder 1H-NMR (DMSO-d6) d(ppm): 8.87-7.63 (12H, m,

and C6-H), 5.10 (2H, s, CH2), 3.37 (3H, s, CH3) Example 4 Preparation of 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]- 1 -ethoxymethyl-5-fluo- rouracil To a solution of 1.07 g of 1-ethoxymethyl-5-fluorouracil in 40 ml of dioxane were added 1.39 g of isophthaloyl chloride and 3.15 of triethylamine. The mixture was stirred at 80"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-benzoyioxy-3-cyano-2trimethylsiloxypyridine, 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, giving 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-fluo- rouracil To a solution of 1.53 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine in 30 ml of dioxane were 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, giving 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 1ethoxymethyl-5-fluorouracil and 2.68 ml of triethylamine, and the mixture was stirred at 60"C 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, giving 0.62 g of the desired 3-[3 (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl)benzoylj- 1 -ethoxymethyl-5-fluorouracil (compound of Example 1). Yield 21%.

Pharmacological Test I Sarcoma-180 subcultured in an ascites of ICR mice was diluted with a physiological saline solution and implanted into subepidermal tissues of the backs of ICR mice in an amount of 2x 107 cells each. Twenty-four hours after the 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 polyvinyl pyrrolidone by coprecipitation and suspending the mixture in 5% gum arabic.

The solid tumor was extirpated from under the dorsal skin of mice on the 10th day after the implantation to measure the weight of the tumor. There was determined the ratio (T/C) of the weight of tumor (T) cut out from the group of mice treated with the test compound to the weight of tumor (C) from the control group of mice not treated therewith. The 50% tumor inhibition dose (ED50) value) in which T/C is 0.5 was determined from the dose-response curve of dosage and the ratio (T/C).

The results are shown in Table 1 which also lists the results given by administering as a comparative drug an anti-cancer 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.

Table 1 Test Compound ED50 (mg/kg) Compound of Example 1 5 Comparative drug 30 Pharmacological Test II Yoshida sarcoma subcultured in an ascites of rats of Donryu strain was diluted with a physiological saline solution and implanted into subepidermal tissues of the backs of Donryu rats in an amount of 1 x 104 cells each. Twenty-four hours after the 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 polyvinyl pyrrolidone by co-precipitation and suspending the mixture in 5% gum arabic.

The solid tumor was extirpated from under the dorsal skin of the rats on the 10th day after the implantation to measure the weight of the tumor. There was determined the ratio (T/C) of the weight of tumor (T) cut out 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. The 50% tumor inhibition dose (EDso value) in which T/C is 0.5 was determined from the dose-response curve of dosage and the ratio (T/C).

During the above test, there was also determined a dose (to be given at one time, mg/Kg) which was effective in suppressing the increase of body weight of the rats treated with the test compound by 10%, compared to the increase of body weight of the rats in the control group not treated therewith. The dose will be hereinafter referred to as "10% body weight suppression dose." A therapeutic index was calculated from the value of EDso and 10% body weight suppression dose according to the following equation: 10% body weight suppression dose Therapeutic index= EDso Table 2 below shows the results, together with the results 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 (indicated as 1).

(1) Comparative drug A 3-{(3-[6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl]benzoyl}]- 1 -[2-(tetrahydrofuranyl)]-5-fluorouracil (2) Comparative drug B 3-{3-[5-chloro-4-benzoyloxy-2-pyridyloxywarbonyl]benzoyl}-2'-deoxy-3'-0-benzyl-5-fluorouridine (3) Comparative drug C 3-{3-[6-benzoylOxy-3-cyano-2-pyridyloxycarbonyl]benzoyl}-2'-deoxy-3'-0-benzyl-5-fluorouridine (4) Comparative drug D 3-{3-[4-benzoyloxy-5-chloro-2-pyridyloxycarbonyl]benzoyli-5-fluoro- 1 -ethoxymethyluracil (4) Comparative drug E Combination of 1-ethoxymethyl-5-fluorouracil and 3-cyano-2,6-dihydroxypyridine Table 2 Test ED50 10% Body Weight Therapeutic Relative Drug mg/Kg Suppression Dose Index Potency Compound of Ex. 1 10 10 1 2.7 Comp.

Drug A 30 15 0.5 1.3 Comp.

Drug B 260 20 #0.3 S0.8 Comp.

Drug C 40 15 0.375 1 Comp.

Drug D 240 18 S0.5 S1.3 Comp.

Drug E 8 3 0.375 1 As seen from Table 2, the compound of the invention has significantly higher therapeutic index than Comparative drugs A to E.

Pharmacological Test 111 Comparative drug C used in Pharmacological Test II or the compound of Example 1 (25 mg/kg each) was orally administered to each of normal rats. The rats were exsanguinated at timed intervals. The concentration of the test compound in the blood was monitored by measuring the concentration of the metabolite in the blood as an index (3'-0-benzyl-2'-deoxy-5-fluorouridine as the metabolite for the rats treated with the Comparative drug C and 1-ethoxymethyl-5-fluorouracil as the 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.

Table 3 Test Compound Maximum Concentration in Blood (ug/m1) Compound of Example 1 9.2 Comparative drug C 1.8 Table 3 shows that the compound of Example 1 was 5 times as highly absorbed as Comparative drug C.

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

Prepartion Example 1 Compound of Example 1 25 mg Starch 112 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets were prepared in a conventional manner which each had the foregoing composition.

Prepartion Example 2 Compound of Example 2 10 mg Starch 125 mg Magnesium stearate 20 mg Lactose 45 mg Total 200 mg Tablets were prepared in a conventional manner which each had the foregoing composition.

Claims (10)

1. A 5-fluorouracil derivative represented by the formula (1)

wherein Ra is C1-C6 alkoxymethyl group.

2. 3-[3-(6-Benzoyloxy-3-cyano-2-pyridyloxy-carbonyl)benzoyl]- 1 -ethoxymethyl-5-fluorouracil.

3. A process for preparing a 5-fluorouracil derivative represented by the formula (1)

wherein R" is C,-C6 alkoxymethyl group, the process comprising the steps of: (a) reacting a compound represented by the formula

wherein Ra is as defined above with a compound represented by the formula

wherein X is a halogen atom in an organic solvent in the presence of an acid scavenger to give an intermediate represented by the formula

wherein X and Ra are as defined above, and reacting the intermediate of the formula (4) with a compound represented by the formula

wherein Rb is a hydrogen atom or tri(lower alkyl)silyl group in an organic solvent; or alternatively (b) reacting a compound represented by the formula

with a compound represented by the formula

wherein X is a halogen atom in an organic solvent in the presence of an acid scavenger to give an intermediate represented by the formula

wherein X is as defined above, and reacting the intermediate of the formula (7) with a compound represented by the formula

wherein Ra is as defined above in an organic solvent in the presence of an acid scavenger.

4. A process for preparing a 5-fluorouracil derivative of the formula (1) defined in claim 1 according to any one of the Examples 1 to 5 hereinbefore.

5. An anti-cancer composition comprising an effective amount of a 5-fluorouracil derivative represented by the formula

wherein Ra is a C1-C6 alkoxymethyl group and a pharmaceutically acceptable carrier.

6. An anti-cancer composition according to claim 5 wherein the 5-fluorouracil derivative is 3 [3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)s,benzoyl]- 1 -ethoxymethyl-5-fluorouracil.

7. 5-fluorouracil derivative as defined in claim 1 for use in treating cancer.

8. 3-[3-(6-Benzoyloxy-3-cyano-2-pyridyloxyCarbonyl)benzOyl]-1-ethoxymethyl-5-fluorouracil for use in treating cancer.

9. Use of a 5-fluorouracil derivative as defined in claim 1 for the manufacture of a medicament for use in the treatment of cancer.

10. Use according to claim 9 wherein the 5-fluorouracil derivative is 3-[3-(6-benzoyloxy-3cyano-2-pyridyloxycarbonyl)benzoyl]- 1 -ethoxymethyl-5-fluorouracil.