FR2605006A1 - 5-FLUOROURACIL DERIVATIVES, PROCESS FOR THEIR PREPARATION, ANTICANCER COMPOSITION CONTAINING THEM AND THEIR USE FOR THE PREPARATION OF A COMPOSITION FOR THE TREATMENT OF CANCER - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION IS DERIVATIVES OF 5-FLUOROURACIL REPRESENTED BY THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS AN ALKOXYMETHYL CC GROUP, THESE COMPOUNDS HAVE AN ANTI-CANCER ACTIVITY AND THEY ARE SUITABLE TO BE USED FOR THE TREATMENT .

Description

The present invention relates to derivatives of 5-fluo

  rouracile, to a process for their preparation, to their use

  and in particular anticancer compositions.

  European patent application published under No. 180897 discloses

  a derivative of 5-fluorouracil with anti-cancer activity

  reuse. European patent application published under the number 180188 de-

  wrote a composition containing a pyridine derivative for

  to increase the anti-cancer activity of an anticancer compound selected from 5-fluorouracil and a compound capable of providing

in vivo 5-fluorouracil.

  Extensive research on derivatives of 5-

  fluororuracil and we found that some compounds that are not

  not specifically described in the European patent applications.

  the above-mentioned, have a significantly higher therapeutic index than the compounds which are specifically described in the European patent application published under No. 180 897, and that the -fluorouracil and the compound capable of providing in vivo 5-fluorouracil which the anticancer activity is increased by the

  pyridine derivative according to the European patent application.

published under No. 180188.

  The present invention provides a 5-fluorouracil derivative, represented by the formula:

CN O

O X 0 F

/ C00 N O-C -Qoz I (Ra

  wherein Ra is a C1-C6 alkoxymethyl group.

  The 5-fluorouracil derivatives of formula (1) have an effect

  anticancer drugs, they have low toxicity and ef-

  Attenuated side effects, such as loss of body weight, and derivatives of formula (1) are therefore very useful as 26050o06 anti-tumor agent for the treatment of cancer in humans and animals. The compounds of the present invention have the following remarkable characteristics: (1) they are easily absorbed, (2) they have a prolonged effect, (3) they are very stable, (4) they have little or no gastrointestinal toxicity, intestinal

  such as diarrhea, anemia, or bleeding.

  gastrointestinal tract and (5) have a significant safety margin (ie, a significant difference between the dose at which anti-cancer activity occurs and the dose at

  side effects such as toxicity are caused by

  drés), while having an excellent therapeutic index and being

particularly harmless.

  The present invention provides an anti-cancer composition

  comprising an effective amount of a 5-fluorouracil derivative

  of formula (1) and a pharmaceutically acceptable carrier.

  The subject of the present invention is also the use of a 5-fluorouracil compound as defined above for the

  preparation of a composition for the treatment of cancer.

  Examples of the C1-C6 alkoxymethyl groups in the

  finishing and in particular with regard to formula (1), include

  methoxymethyl, ethoxymethyl, 1-propoxymethyl, iso-

  propoxymethyl, 1-butoxymethyl, 2-butoxymethyl, tert-butoxymethyl

  thyl, 1-pentyloxymethyl, 1-hexyloxymethyl and the like.

  Among the compounds of formula (1), the compounds

  in which the Ra group is an ethoxymethyl or methoxy group

  methyl. Among the compounds of the present invention, there is particularly preferred a compound which will be described hereinafter in the example

  1, that is 3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)

  nyl) benzoyl) -1-ethoxymethyl-5-fluorouracil.

  The compounds of formula (1) of the invention may be prepared according to the methods illustrated below by the diagrams

Reactions 1 or 2.

<Reaction Scheme 1> Step A on

H O

N 1 1 C-X

0D

Ra O

O F

0 I

Ra (4) Step B CN

-

(4) + CO-O-N oRb.

(5)

CN O

O F

C cNIo-o <o_

(03> O-C and C-N C

Ra

()

  In the above formulas, the group Ra is as defined above, X is a halogen atom, such as fluorine, chlorine, bromine and the like, and the Rb group is a hydrogen atom or a group tri (lower alkyl) silyl. Examples of the lower alkyl group in the tri (lower alkyl) silyl group include C1-C6 alkyl groups, such as

  methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,

  tyl, hexyl, etc. (i) Step A In accordance with the process illustrated by Reaction Scheme 1, the known compound (2) is reacted with the known compound (3)

  to obtain the intermediate compound (4).

  The reaction is carried out in the presence of an acid blocking agent and in a suitable solvent. Examples of useful acid blocking agents include those which are usually

  used in the art, namely inorganic compounds

  such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like, and

  organic basics, such as triethylamine, N, N-dimethyl

  minopyridine, pyridine and the like. Examples of useful solvents include organic solvents having no adverse effect on the reaction, namely ethers, such as dioxane, tetrahydrofuran and the like, nitriles, such as acetonitrile and the like, aromatic hydrocarbons, such

  benzene, toluene and the like, halogenated hydrocarbons

  such as methylene chloride, chloroform, tetra-

  carbon monoxide and the like, pyridine, N, N-dimethyl

  mamma, 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

  from about -30.degree. to about 100.degree. C., preferably from room temperature.

  ambient temperature at about 100 C, and is completed in about 10

minutes to about 20 hours.

  26050o6 (ii) Step B The intermediate compound (4) thus obtained is reacted with the new or known compound (5) to obtain the target compound.

  of formula (1) according to the present invention.

  The reaction can be carried out under the same conditions as

  the reaction for compounds (2) and (3) in step A as a function of

  type of the compound (5) used, or in particular when using the compound (5) in which the Rb group is a hydrogen atom. When using the compound (5) in which the Rb group is

  a tri (lower alkyl) silyl group, the reaction can be effected

  in the presence of a suitable solvent, such as a solvent

  aprotic, for example an ether such as diethyl ether,

  ethyl, dioxane, tetrahydrofuran and the like, a

  such as acetonitrile and the like, an aromatic hydrocarbon

  such as benzene, toluene and the like, a hydrocarbon

  halogen such as methylene chloride, chloro-

  carbon trachloride and the like. These solvents are preferably

used in the anhydrous state.

  In each case, the reaction is carried out at a temperature

  from about -30 to about 100 ° C, preferably from ambient temperature.

  approximately 60 C, and is completed in approximately one

  20 hours. In the reaction between the intermediate compound (4) and the compound (5) in which the Rb group is a tri (lower alkyl) silyl group, it is also possible to use a catalytic amount of a Lewis acid, such as sodium chloride. 'aluminum,

  stannic chloride, zinc chloride and the like.

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

intermediate of formula (4).

<Reaction Scheme 2> EtaDe A O

:)-WE

Ilo IlO-D

0 NO

(Z)

- + "1" (/ 1

  H oz ed433 (9) x-D N: I j! O D Oso9z In the formulas above, the groups Ra and X are such

  as defined in reaction scheme 1.

  (i) Step A The reaction between the compound (6) and the compound (3) illustrated in the reaction scheme 2 is carried out in the same manner as the reaction between the compound (2) and the compound (3) illustrated in

the reaction scheme 1.

  (ii) Step B The reaction between the intermediate compound (7) thus obtained and the compound (2) can also be carried out in the same manner as the reaction between the compound (2) and the compound (3) illustrated

in the reaction scheme 1.

  Compounds (2) and (3) which must be used as

  Starting feeds in Reaction Scheme 1 or 2 are both known readily available compounds. On the other hand,

  compounds (5) and (6) for use in the reaction scheme.

  1 or 2, include novel compounds. These compounds can be prepared for example according to any one or

  combination of processes (a) and (b) below.

  (a) Reaction for the introduction of a benzoyl group.

  The reaction to prepare the compound (5) or (6) comprising

  a pyridine group substituted with a benzoyloxy group is

  killed by using as starting material a corresponding compound

  pyridine having a hydroxyl group or a tri (lower alkyl) syliloxy group with which a

  suitable acylating agent (a benzoylation agent). This re

  acylation action can be performed in the same way as the reaction

  between component (2) and component (3), illustrated in

reaction scheme 1.

  (b) Reaction for the introduction of a tri (lower alkyl) silyl group. The preparation reaction of the compound (5) in which the Rb group is a tri (lower alkyl) silyl group may for example be carried out by reacting the corresponding derivative of

  pyridine having a hydroxyl group with a silylating agent

  lation. Examples of useful silylating agents include those commonly used in the art, namely

  hexa (lower alkyl) disilazanes, such as 1,1,1,3,3,3-

  hexamethyldisilazane and the like, tri (lower alkyl) halo

  genosilanes, 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 from about 1 to about 3 moles per mole of the starting compound. When the tri (lower alkyl) halosilane is used as the silylating agent, the reaction system preferably further contains from about 1 to about 3 moles of an amine,

  such as triethylamine, dimethylaniline, diethylene glycol,

  thylaminopyridine 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 carry out the reaction in a suitable solvent, including ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, nitriles and the like. such as acetonitrile and the like, halogenated hydrocarbons, such as methylene chloride, chloroform and the like. Hexa (lower alkyl) disilazane,

  may, when used as a silylating agent, also act

  as a solvent by eliminating the need to use another solvent. The silylation reaction is carried out at a temperature from room temperature to about the boiling point of the solvent and is complete in about 1 to about

hours.

  The final compound prepared during each step and the

  of the present invention thus obtained, can be separated from the reaction mixture by conventional methods followed by purification. Useful separation and purification methods include reprecipitation, recrystallization, silica gel column chromatography, ion exchange column chromatography, gel chromatography, affinity chromatography, and the like. The compounds of the present invention are usually administered to mammals, including humans, in the form of

  pharmaceutical compositions which are generally acceptable

  and which are prepared using diluents and excipients

  such as fillers, packing agents,

  binding agents, disintegrating agents, surfactants,

  scummers and the like. The unit dosage forms of these pharmaceutical compositions of the present invention may be

  to be diverse and they are chosen in such a way as to satisfy the

  therapeutic applications. Examples of typical shapes

  characteristics of the pharmaceutical compositions, include the

  tablets, pills, powders, liquids, suspensions

  ions, emulsions, granules, capsules, suppositories

  injection preparations (liquids, suspensions

  and the like) ointments and the like.

  Examples of useful vehicles for tabletting include excipients such as lactose, purified sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dehydrated starch, sodium alginate, agarose powder, laminar powder, sodium hydrogencarbonate, calcium carbonate, an ester

  of a fatty acid with polyoxyethylene sorbitan, lauryl sulphonyl

  sodium fate, a monoglyceride of stearic acid, starch, lactose and the like; disintegration inhibitors such as purified sugar, stearin, cocoa butter, dehydrogenated oils and the like; absorption accelerators such as a quaternary ammonium base, sodium lauryl sulphate or the like; wetting agents such as glycerine, starch and the like; adsorption accelerators such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like, and lubricants such as purified talc powder, stearic acid salts , powder

  boric acid, polyethylene glycol and the like. If this is born

  In addition, the tablets may be further coated with a conventional coating film to form them in the form of coated tablets, for example coated tablets, gelatin film-coated tablets, enteric-coated film-coated tablets, compressed tablets, and the like. coated with a film, two-layer tablets or multi-layer tablets, and the like. For the preparation

  of pills, it is possible, for example, to use as vehicles, ex-

  containers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as powdered gum arabic, spray gum tragacanth, gelatin and the like; disintegrating agents such as laminar, agar powder and others. For putting into the form of suppositories, it is possible for example to use as vehicles, polyethylene glycol,

  cocoa butter, a higher alcohol, an ester of a higher alcohol

  jelly, semi-synthetic glyceride and others.

  capsules are prepared in a conventional manner by mixing the

  of the invention with the various vehicles mentioned above and in

  capsulating the mixture in hard gelatin capsules, cap-

  soft gelatine sules, etc. For the preparation of compositions

  injectables, solutions, emulsions and suspensions

  are sterilized and are preferably isotonic

  compared to the blood. For the preparation in the form of

  tions, emulsions and suspensions, usable diluents

  include, for example, water, ethanol, macrogol, propylene

  glycol, ethoxylated isostearyl alcohol, isostearyl alcohol

  Polyoxylated acid, a fatty acid ester with polyoxyethylene

  sorbitan and others. For the preparation of isotonic solutions

  In addition, a sufficient amount of sodium chloride may be added

  dium, glucose, or glycerin to make the solution isotonic

  in relation to blood. The pharmaceutical compositions intended

  injections may further contain, if necessary, solubilizing agents,

  buffer solutions, conventional analgesic agents or the like.

  The pharmaceutical composition of the present invention may also

  contain, if necessary, coloring agents, preservatives, flavoring agents, desiccants, sweetening and other agents and other medicaments. For the preparation of pastes, creams and gels, diluents such as white petrolatum, paraffins,

  glycerin, cellulose derivatives, polyethylene glycerol

  collars, silicones, bentonite and the like.

  The quantity of the required product that must be contained as

  active ingredient in the pharmaceutical composition of the present invention.

  invention, is not specifically limited and can be selected in a wide range, from 1 to 70% by weight.

  weight that can be used in general.

  The method of administering the pharmaceutical composition mentioned above is not specifically limited and can be administered by a method appropriate to the types

  respective forms of administration according to the age of the

  sex and other distinctive conditions as well as

  the condition of the patient and others. For example, tablets,

  quides, suspensions, emulsions, granules and

  lules are administered orally, the injections

  tables are administered alone or intravenously

  with injectable classical compositions for transfusion

  such as glucose solutions, acid solutions

  amines, and others, and if necessary,

  jectables are administered alone intramuscularly.

  tracutaneous, subcutaneous, intraperitoneal; and suppositories

are administered by the rectum.

  The dosage of the required products of the present invention may be suitably selected according to the method

  administration, age of the patient, sex and other conditions

  and the state of the symptoms, the pharmaceutical composition of the invention being generally administrable in an amount of from about 0.5 to about 20 mg / kg of body weight per day, calculated on the basis of composed of

  the invention (active ingredient) in one to four individual doses

  Dual. The following reference examples illustrate the preparation of the starting materials used for the preparation of the compounds

  of the invention, and examples illustrate the preparation of the

  posed of the invention. In addition, pharmaceutical tests of

  compound of the invention are given below.

  In the NMR data, reference examples and

  examples, the numbers used as an index to the right of the sym-

  "C", are used to designate the position in the

  posed. Thus, the expression "C6-H" designates, for example, hydrogen

  bound to the carbon atom at position 6.

Reference Example 1

  Preparation of 6-benzoyloxy-3-cyano-2-hydroxypyridine

  To a solution of 1.00 g of 3-cyano-2,6-dihydro-

  droxypyridine in 40 ml of N, N-dimethylacetamide, 0.51 ml of

  triethylamine was 43mn of benzoyl chloride. We stirred the

  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. We have washed the

  sidu with chloroform and water to obtain 1.06 g of

  posed mentioned in the title with a yield of 60%.

  1 H-NMR (DMSO-d6) d (ppm): - 12.76 (1H, broad OH, or NH) - 8133 (1H, d, J = 8Hz, C4-H-8; 17-8t07 (2H); , m, -CO) -7.94-7 (3H, m, -CO->), 6t95 (1H, d, J = 8Hz, C5-H Reference example 2

  Preparation of 6-benzoyloxy-3-cyano-trimethylsililoxypyridine

  20 ml of 1,1,1,3,3,3-hexamethyl disilazane in 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine were added and the mixture was stirred at 140 ° C for 20 minutes. The reaction mixture was concentrated under reduced pressure to obtain quantitatively

  this way the compound mentioned in the title.

  1H NMR (CDCl3):? 13.28-8; 13 (2H, m, -rCO-), -7t96 (1H, d, J = 8Hz, C4-H), -7168-7; 3H, m, -CO-), -6t85 (1H, d, J = 8Hz, C5-H) 1-5 Exemol -040 (9H, s, CH3x3) Example 1

  Preparation of 3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)

  nyl) benzoyl) -l-ethoxymethyl-5-fluorouracil. 5.53 ml of triethylamine and 1.52 g of chloride were added

  isophthaloyl in a solution of 1.17 g of 1- (ethoxymethyl) -5-

  fluorouracil in 50 ml of anhydrous dioxane. We put the mixture

at reflux for one hour.

  The reaction mixture was filtered, the filtrate was concentrated

  and the residue was dissolved in 50 ml of acetonitrile. We have

  added in the solution 3.46 ml of triethylamine and 2.10 g of 6-

  benzoyloxy-3-cyano-2-hydroxypyridine. The mixture was stirred at room temperature for 2 hours. The reaction mixture

  filtered, concentrated, and the residue was chromatographed

  silica gel column using chloroform as eluent to obtain 860 mg of the compound

title with a yield of 25%.

Mp = 162-164 ° C .;

  1 H-NMR (CDCl 3) (ppm): - 8/6 -, - (OHa,:,; - Cr - and - -C-- and

-

  C4-H pyridine ring - 7,82-7,33 (6H, m, C6-H and, -: co- and 0 "-4COet c -H of the cycle of P> pyridine -co -5; (2H, s, N-CH2) -3t62 (2H, a, J = 7Hz, -CH2CH3) -1.22 (3H, t, J = 7Hz, -CH3)

Example 2

  Preparation of 3- (4- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)

  nyl) benzoyl) -1-ethoxymethyl-5-fluorouracil. The compound mentioned in the title was prepared by following

the general method of Example 1.

  Yield 24% Form: 1H-NMR (CDCl3) (ppm) -8.39-8; 02 (7H, mi, COe Co eJ CO- and C4-H pyridine ring

> C-H

  -7; 67-7; 39 (5H, n, -CO-and-C6-H, and C5 of the pyridine ring -5t14 (2: -, s, N-CH2) -3t62 (2H, c, j = 7Hz, -CH 2 CH 3) -, 22 (3H, t, J = 7Hz, CH 3)

Example 3

  Preparation of 3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)

  nyl) benzoyl) -5-fluoro- 1- (methoxymethyl) uracil.

  The title compound was prepared according to the general procedure of Example 1; Yield: 26% Form: 1H-NMR powder (DMSO-d6) 6 (ppm): NC -8t87-7t63 (12H, m, CO-, NC-

-O 0-

  -OC V and C6-H), co- -5.10 (2H, s, CH2), 3.37 (3H, s, CH3) Example 4

  Preparation of 3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)

  nyl) benzoyl) -1-ethoxymethyl-5-fluorouracil.

  1.39 g of isophthaloyl chloride and 3.15 ml of

  triethylamine in a solution of 1.07 g of 1-ethoxymethyl-5-

  fluorouracil in 40 ml of dioxane. The mixture was stirred at C for 30 minutes. The reaction mixture was filtered and

concentrated it.

  30 ml of acetonitrile and 2.60 g of 6-benzoyloxy-3-cyano-2-trimethylsilyloxy-pyridine were added to the residue and

  The mixture was stirred overnight at room temperature.

  The reaction mixture was filtered and concentrated again and the residue was placed on a column of silica gel and

  eluted with a mixture of ethyl acetate and methylene chloride

  thylene 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)

  nyl) benzoyl) -l-ethoxymethyl-5-fluorouracil. 1.30 g of isophthaloyl chloride and 2.68 ml of

  triethylamine in a solution of 1.53 g of 6-benzoyloxy-3-cyano-

  2-hydroxypyridine in 30 ml of dioxane. The mixture was stirred at

  room temperature for three hours. We separated by

  the insoluble residue and the filtrate was concentrated to

  hold an intermediate compound, ie 3- (6-

  benzoyl-oxy-3-cyano-2-pyridyloxycarbonyl) benzoyl. The intermediate compound was dissolved in 30 ml of dioxane. 1.00 g of 1-ethoxymethyl-fluorouracil and 2.68 ml of triethylamine were added to the solution, and the mixture was stirred at 60 ° C. for one hour. The insoluble residue has been separated

  by filtration and the filtrate was concentrated. The residue was discarded

  placed on a column of silica gel and eluted with dichloro-

  thane to obtain 0.62 g of 3- (3- (6-benzoyloxy-3-cyano-2-pyridyl)

  loxy-carbonyl) benzoyl) -1-ethoxymethyl-5-fluorouracil expected

  (compound of Example 1). Yield: 21%.

  Pharmacological test I-180 sarcoma was diluted in ICR mouse ascites with physiological saline and implanted into the subcutaneous tissues of the ICR mouse back in an amount of 2 x 107 cells each. Twenty-four hours after implantation, the test compound was orally administered to each mouse once daily for seven consecutive days. The test suspension was prepared by uniformly mixing the test compound with polyvinylpyrrolidone by co-precipitation and suspending the mixture in

gum arabic at 5%.

  The solid tumor was removed under the dorsal skin of the mouse on the 10th day after implantation to measure the tumor weight. The (T / C) weight ratio of tumors (T) taken from the group of mice treated with the test compound was determined relative to the tumor weight (C) of a group of control mice that did not been treated with this one. The 50% inhibitory dose of tumor formation (ED 50 value) for which T / C is 0.5 was determined from the dose-effect curve and the T / C ratio.

  The results are shown in Table 1 which men-

  the results obtained by administering the same

  way to a group of mice an anti-cancer composition com-

  taking 5-fluoro-1- (2-tetrahydrofuranyl) uracil and uracil

  at a ratio of 1: 4 (molar ratio) as a combination drug

parative.

Table 1

  Test Compound DE50 (mg / kg) Compound of Example 1 5 Comparative Drug 30 Drug Test II Yoshida sarcoma was transplanted into rat ascites of Donryu strain with physiological saline and was implanted in the subcutaneous tissues of Donryu rats back in an amount of 1 x 104 cells each. Twenty four

  hours after implantation, it was administered orally

  one of the rats, once a day for seven consecutive days, a suspension of the test compound. 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 under the dorsal skin of the rats on the tenth day after implantation to measure the tumor weight. The T / C weight ratio of tumors (T) taken from the group of rats treated with the test compound was determined relative to the weight of tumors (C) taken from the group of rats.

  witnesses who have not been treated with this one. The inhibitory dose

  50% of tumor formation (ED 50 value) in the

  which T / C is equal to 0.5, was determined from the curve

  dose-response and T / C ratio.

  During the test above, the dose was also determined

  (to be administered in one single dose, in mg / kg) which has proved to be effective

  to reduce by 10% the increase in body weight of rats treated with the test compound compared to the increase in body weight of the control group rats which were not

  treated with it. The dose is hereinafter referred to as "dose

  yielding 10% of the increase in body weight ".

  A therapeutic index was calculated from the OES value and the 10% reduction dose of the increase in body weight according to the following equation: Therapeutic index = 10% reduction dose of body weight increase

ED50

  Table 2 below lists the results and the results obtained when the following comparative drugs A to E, mentioned below, were used in place of

compound of the invention.

  Table 2 also shows the relative efficiency of each

  one of the test drugs in the form of a ratio of the therapeutic index of each of the test drugs to the comparative drug therapeutic index C (indicated as

being equal to 1).

(1) Comparative drug A.

  3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl) -1- (2-

  (Tetrahydrofuranyl) -5-fluorouracil. (2) Comparative drug B.

  3- (3- (5-chloro-4-benzoyloxy-2-pyridyloxy-carbonyl) benzoyl) -2'-des-

  oxy-3'-O-benzyl-5-fluorouridine. (3) Comparative drug C.

  3- (3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl) -2'-des-

oxy-3'-0-benzyl-5-fluorouridine.

(4) Comparative drug D.

  3- (3- (4-benzoyloxy-5-chloro-2-pyridyloxy-carbonyl) benzoyl) -5-

  fluoro-1-éthoxyméthyluracile. (5) Comparative drug E.

  Combination of 1-ethoxymethyl-5-fluorouracil and 3-cyano-2,6-

dihydroxypyridine.

Table 2

  Drug ED50 Reducing dose Tea-Efficiency Index

  test mg / kg of 10% of the cited increase

  mg / kg test for body weight loss Composed of ex. 1 10 10 1 2.7 Comp. A 0.5 0.5 Comp Comp. B> 60 20 <0.3 <0.88 Comp. C 40 15 0.375 1 Comp. D> 40 18 <0.5 <1.3 Comp. As can be seen from Table 2, the compound of the invention has a significantly higher therapeutic index than Comparative Drugs A through E. Dharmacoloqioue III Test

  Oral rats were given normal

  Comparative Table C used in Pharmacological Test II or the compound of Example 1 (25 mg / kg each). The rats were bled at measured time intervals. The concentration of the test compound in the blood was monitored by measuring as

  index, the concentration of the metabolite in the blood (the 3'-O-

  benzyl-2'-deoxy-5-fluorouridine as metabolite for rats

  treated with comparative drug C and 1-ethoxymethyl-5-

  -5 fluorouracil as a metabolite for rats treated with

  example 1) and the maximum concentration was determined

  in the blood. Table 3 below illustrates the results.

Table 3

  Compound Maximum Test Concentration in Blood (9g / ml) Compound of Example 1 9.2 Comparative Drug C 1.8 Table 3 shows that the compound of Example 1 was found to be five times more absorbed. than comparative drug C.

  Some examples of preparation in accordance with

in accordance with the present invention.

  Example of DreDaration Compound of Example 1 25 mg Starch 112 mg Magnesium Stearate 18 mg Lactose 45 mg Total 200 mg Tablets were prepared conventionally having each

the previous composition.

  Preparation Example 2 Compound of Example 2 10 mg Starch 125 mg Magnesium Stearate 20 mg Lactose 45 mg Total 200 mg Tablets were prepared conventionally having each

the composition quoted.

Claims (7)

  1. Derivative of 5-fluorouracil represented by the formula: CN 0 0 F O 0N X O-Ck (1) Ra   wherein Ra is a C1-C6 alkoxymethyl group.   2. Derivative of 5-fluorouracil according to claim 1,   characterized in that it is 3- (3- (6-benzoyloxy-3-cyano-2-pyridyl)   yloxy-carbonyl) benzoyl) -l-ethoxymethyl-5-fluorouracil. A process for the preparation of a 5-fluorouracil derivative as defined in claim 1, characterized in that (a) reacting a compound represented by the formula: I F N 11 (2) o0; N the Ra   in which Ra is as defined above with a compound   presented by the formula: ol IC-x (3)   wherein X is a halogen atom, in an organic solvent,   in the presence of an acid blocking agent to obtain an intermediate compound represented by the formula: ## STR5 ## wherein R and X are as defined above, and   reacting the intermediate compound of formula (4) with a compound of   represented by the formula: XCO - (5) wherein Rb is a hydrogen atom or a tri (lower alkyl) silyl group in an organic solvent; or alternatively (b) reacting a compound represented by the formula: CN / co-o (6) N OH (6)   with a compound represented by the formula: o O i1 x-c e c-x (3).   Wherein X is a halogen atom in an organic solvent in the presence of an acid blocking agent to obtain an intermediate compound represented by the formula: CN we C-1: 'N 0 -C_ -   wherein X is as defined above, and the intermediate compound of formula (7) is reacted with a compound represented by the formula: 0 H (2) Ra   wherein Ra is as defined above, in a solvent or   in the presence of an acid blocking agent.   4. Anti-cancer composition, characterized in that it comprises an effective amount of a 5-fluorouracil derivative such as   as defined in claim 1 and a pharmaceutical carrier-   acceptable: 5. Anti-cancer 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. 6. Use of a 5-fluorouracil derivative as defined   in claim 1 for the preparation of a composition of for the treatment of cancer.   7. Use according to claim 6, characterized in that   what the 5-fluorouracil derivative is 3- (3- (6-benzoyloxy) -3-   cyano-2-pyridyloxycarbonyl) benzoyl) -l-ethoxymethyl-5-fluoroura- cult.