CH671578A5 - - Google Patents

Description

DESCRIPTION The invention relates to a 5-fluorouracil derivative, a process for its preparation, a composition containing this derivative as an anti-cancer agent and a use thereof for the preparation of anti-cancer agents.

In patent application EP-180897 a 5-fluoroacil-wherein Rb publishes a hydrogen atom or a tri (lower alkyl) silyl-65 derivative, which is a cancer-fighting activity rest, in an organic solvent; or has. In patent application EP-180188 there is a

b) reacting a compound of the following composition published, which contains a pyridine derivative, to inhibit the cancer-fighting activity of a cancer

3rd

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fighting compound selected from the group consisting of 5-fluorouracil and a compound capable of forming 5-fluorouracil in vivo.

The inventors have carried out extensive research on 5-fluorouracil derivatives and found that some compounds which have not been expressly published in the abovementioned EP patent applications have a significantly higher therapeutic index than the compounds expressly published in patent application EP180897 and those for Formation of 5-fluoroura-cil in vivo-capable compound if its anti-cancer activity has been increased according to the patent application EP-180188 by the pyridine derivative.

With the invention, a 5-fluorouracil derivative of the formula below

Reaction scheme 1

C-N

C \ ^ 7

Step A

O

H

10th

15

O ^ N-

Rc

(2)

X-C

F 20

C-X

Step B

25th

(1)

provided wherein Ra is a Cr-C6 alkoxymethyl group.

The 5-fluorouracil derivatives of formula (1) have an excellent anti-cancer activity, low toxicity and minor side effects such as weight loss, so the 5-fluorouracil derivatives of formula (1) are anti-tumor agents for the treatment of cancer in humans and very useful in animals. The compounds according to the invention have the remarkable properties that they (1) are well absorbed, (2) have a long-term effect, (3) are highly stable, (4) have little or no gastrointestinal toxicity such as diarrhea, anemia or gastrointestinal bleeding, and (5 ) have a broad safety margin (ie a large difference between the dose that causes cancer-fighting activity and the dose that causes side effects such as toxicity) and an excellent therapeutic index and are significantly safe.

The invention provides a composition consisting of an effective amount of the 5-fluorouracil derivative and a pharmaceutical carrier as an anti-cancer agent.

(4) + // \\

co-o

N ^ 0-Rb

30th

35

40

(5)

co-o

45

50

Examples of Q-Q-alkoxymethyl radicals in this description and in particular with reference to the formula (1)

are methoxymethyl, ethoxymethyl, 1-propoxymethyl, iso-propoxymethyl, tert-butoxymethyl, 1-pentyloxymethyl, 55 1-hexyloxymethyl and the like.

Of the compounds of formula (1), those in which Ra is ethoxymethyl or methoxymethyl are preferred.

Among the derivatives according to the invention, one is preferred, which is described in more detail below in Example 1, namely 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -l-ethoxymethyl-5-fluorouracil.

60

65

The compounds of the formula (1) are prepared in accordance with the invention in accordance with one of the reaction schemes 1 or 2 given below.

(1)

In the above formulas, the meaning of Ra is as given above, X represents a halogen atom such as fluorine, chlorine, bromine and the like, and Rb represents a hydrogen atom or a tri (lower alkyl) silyl radical. Examples of lower alkyl radicals in the tri (lower alkyl) silyl radical are Q-Cg-alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl etc.

(i) Step A

According to the process shown in reaction scheme 1, the known compound (2) is reacted with the known compound (3), whereby the intermediate compound (4) is obtained.

The reaction is carried out in the presence of an acid scavenger and in an organic solvent. Examples of useful acid scavengers 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-dimethylaminopyridine , Pyridine and the like. Examples of solvents that can be used are organic solvents that do not interfere with the reaction

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4th

Take effect and include ethers such as dioxane, tetra-hydrofuran 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) is not particularly limited in relation to the amount of the compound (2), but is generally about 1 mole and preferably about 1 to about 3 moles per mole of the compound (2). The reaction is carried out at a temperature from about -30 to about 100 ° C, preferably at room temperature to about 100 ° C, and is complete in about 10 minutes to 20 hours.

(ii) Step B

The intermediate compound (4) thus obtained is reacted with the known or new compound (5), which gives the desired compound of the 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 the compound (5) used and especially when the compound (5) is used, in which Rb Is hydrogen.

If a compound (5) is used in which Rb is a tri (lower alkyl) silyl radical, the reaction can be carried out in the presence of a suitable solvent, such as an aprotic organic solvent, for example ethers such as diethyl ether, dioxane, tetra-hydrofuran 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 the dry state.

In both cases, the reaction is carried out at a temperature from about -30 to about 100 ° C, preferably at room temperature to about 60 ° C, and is complete in about 1 to 20 hours. In the reaction between the intermediate compound (4) and the compound (5) in which Rb represents a tri (lower alkyl) silyl group, a catalytic amount of a Lewis acid such as aluminum chloride, tin (II) chloride, zinc chloride, and the like can also be used be used.

The amount of the compound (5) can be appropriately determined, and is generally about 1 mole, and preferably about 1 to about 3 moles, per mole of the intermediate compound (4).

Reaction scheme 2

Step A

Oc ° - ° -sXh ♦ JL0rx

(6) (3)

CN

Step B

O

(2)

CN O

(1)

In the above formulas, Ra and X have the same meaning as in Reaction Scheme 1.

(i) Step A

The reaction shown in Reaction Scheme 2 between compound (6) and compound (3) is carried out in the same manner as the reaction shown in Reaction Scheme 1 between compound (2) and compound (3).

(ii) Step B

The reaction between the intermediate compound (7) and the compound (2) can also be carried out in the same way as the reaction shown in the reaction scheme 1 between the compound (2) and the compound (3).

Compounds (2) and (3) to be used as starting compounds in Reaction Schemes 1 or 2 are both readily available known compounds. On the other hand, the compounds (5) and (6) to be used in the reaction schemes 1 or 2 include new compounds. These compounds can be prepared, for example, by any of the methods (a) and (b) described below or by a combination thereof.

(a) Reaction to introduce a benzoyl residue

The reaction for the preparation of compounds (5) and (6) whose pyridyl radical is substituted by a benzoyloxy radical is carried out by using a corresponding pyridine compound as the starting compound which has a hydroxyl radical or a tri (lower alkyl) silyl radical, with which a suitable Acylation agent (Benzoylie-rungsagens) is implemented. This acylation reaction can be carried out in the same manner as the reaction between the compound (2) and the compound (3) shown in Reaction Scheme 1.

(b) Reaction to introduce a tri (lower alkyl) silyl group

The reaction for producing a compound (5) in which Rb is a tri (lower alkyl) silyl radical can be carried out by reacting a corresponding pyridine compound which has a hydroxyl radical with a silylation agent. Examples of silylating agents that can be used are those commonly used in the art and include hexa- (lower alkyl) disilazanes such as 1,1,1,3,3,3-hexamethyldisilazane

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

and the like, tri (lower alkyl) halogenosilanes such as trimethylchlorosilane and the like, silylated acetamides such as N, 0-bis (trimethylsilyl) acetamide and the like. The silylating agent is generally used in an amount of about 1 to 3 moles per mole of the starting compound. 5 If a tri (lower alkyl) halogenosilane is used as the silylation agent, the reaction system should preferably contain about 1 to about 3 moles of an amine such as triethylamine, dimethylaniline, diethylaminopyridine and the like, or pyridine per mole of the starting compound. In In this case, or if a silylated acetamide is used as the silylating agent, it is preferred to carry out the reaction in a suitable solvent which comprises, for example, 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. If a hexa (lower alkyl) disilazane is used as the silylation agent, it can also serve as a solvent, eliminating the need to use a different solvent. The silylation reaction is carried out at a temperature between room temperature and about the boiling point of the solvent and is complete in about 1 to about 15 hours.

The end compound produced in each step and the compound according to the invention thus obtained can be separated from the reaction product by known processes and then purified. Usable separation methods and purification methods include repeated precipitation, recrystallization, silica gel chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, and the like.

The compounds of the invention are generally administered to mammals, including humans, in the form of generally acceptable pharmaceutical compositions made using diluents and excipients such as filters, integration agents, binders, disintegration agents, surfactants, lubricants and the like. The forms of the administration units of these pharmaceutical compositions according to the invention can be varied and selected in such a way that they correspond to the various therapeutic purposes. Typical forms of pharmaceutical compositions are illustrated by examples such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions and others), ointments and the like.

In the case of shaping in the form of tablets, usable carrier materials are, for example, excipients such as 50 lactose, purified sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica and others; Binders such as syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone and others; Disintegrating agents such as dried starch, sodium alginate, agar powder, lamina powder, sodium hydrogen carbonate, calcium carbonate, a fatty acid ester of polyoxyethylene sorbitan, sodium lauryl sulfate, a monoglyceride of stearic acid, starch, lactose 60 and others; Disintegration inhibitors such as purified sugar, stearin, cocoa butter, hydrogenated oils and others; Absorption accelerators such as a quaternary ammonium base, sodium lauryl sulfate and others; Wetting agents such as glycerin, starch and others; Adsorption accelerators such as 65 lactose, kaolin, bentonite, colloidal silica and others; and lubricants such as purified talc powder, salts of stearic acid, boric acid powder, polyethylene glycol and others.

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If necessary, the tablets can also be coated with a conventional coating layer in order to make tablets coated therefrom, for example tablets coated with sugar, a gelatin layer, an enteric layer or double-coated tablets, multi-coated tablets and others. In the case of shaping in the form of pills, usable carrier materials are, for example, excipients such as glucose, lactose, cocoa butter, hydrogenated vegetable oils, kaolin, talcum and others; Binders such as gum arabic in powder form, gum tragacantha, gelatin in powder form, gelatin and others; Disintegration agents such as laminaran, agargar powder and others. Carrier materials that can be used in the form of suppositories are, for example, polyethylene glycol, cocoa butter, a higher alcohol, an ester of a higher alcohol, gelatin, semisynthetic glycerides and others. Capsules are produced in a conventional manner by admixing various of the foregoing carriers with the compound according to the invention and encapsulating the mixture in hard gelatin capsules, soft gelatin capsules and the like. In the manufacture of injections, solutions, emulsions and suspensions are sterilized and are preferably chosen to be isotonic with the blood. When prepared in the form of solutions, emulsions and suspensions, useful diluents are, for example, water, ethanol, macro-gol, propylene glycol, ethoxylated isostearyl alcohol, poly-oxylated isostearyl alcohol, a fatty acid ester of polyoxyethylene sorbitan and others. When producing isotonic solutions, sufficient amounts of sodium chloride, glucose or glycerin can be added to make the solution isotonic with the blood. The pharmaceutical compositions for the production of injections can furthermore contain customary solution auxiliaries, buffer solutions, analgesic agents and the like, if necessary. The pharmaceutical compositions according to the invention can also contain colorants, preservatives, fragrances, flavors, sweeteners and other, as well as other drugs if necessary. When shaped in the form of pastes, creams and gels, thinners such as white petroleum jelly, paraffin, glycerin, cellulosic compounds, polyethylene glycols, silicones, bentonite and the like can be used.

The amount of the desired product according to the invention, which is to be contained as an active ingredient in the pharmaceutical composition, is not particularly restricted and can be selected in a wide range, generally between 1 and 70% by weight.

The administration method for the above-mentioned pharmaceutical compositions is not particularly limited, and these can be administered by a method suitable for the respective administration forms, depending on the age of the patient, the gender and other circumstances, the condition of the patient and others. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally; Injections are administered intravenously, individually or as a mixture with conventional injectable transfusions such as glucose solution, amino acid solutions and others; if necessary, the injections can be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally; and the suppositories are administered rectally.

The dosage of the desired products according to the invention can be chosen depending on the form of administration, the age of the patient, the sex and other circumstances, the state of the symptoms, and in general the pharmaceutical according to the invention can be chosen

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6

Composition in an amount of about 0.5 to about 20 mg per kg body weight and per day, based on the compound (active ingredient) according to the invention, administered in 1 to 4 doses.

The following reference examples illustrate the preparation of the starting materials used for the preparation of the compounds according to the invention, and the following examples illustrate the preparation of the compound according to the invention. In addition, pharmaceutical tests relating to the compound according to the invention are given below.

In connection with the NMR data in the reference examples and examples, the digits which are subscripted to the right of the symbol “C” are used to designate the position in the connection. Thus, for example, the term "C6-H" refers to hydrogen attached to the carbon atom in position 6.

Reference Example 1 Preparation of 6-benzoyloxy-3-cyano-2-hydroxypyridine

0.51 ml of triethylamine and 0.43 ml of benzoyl chloride were added to a solution of 1.00 g of 3-cyano-2,6-dihydroxypyridine in 40 ml of N, N-dimethylacetamide. 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 reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with chloroform and water, whereby 1.06 g of the title compound was obtained in a yield of 60%.

'H NMR (DMSO-d6) 5 (ppm): 12.76 (IH, bs, OH or NH), 8.33 (1H, d, J = 8Hz, C4-H from the pyridine ring),

8.17-8.07 (2H, m-C, 94-7.58 (3H, m, -CO - ^ -),

6.95 (IH, d, J = 8Hz, C5-H from the pyridine ring)

Reference Example 2 Preparation of 6-benzoyloxy-3-cyano-2-trimethylsilyloxypyridine

20 ml of 1,1,1,3,3,3-hexamethyldisilazane were added 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and the mixture was stirred at 140 ° C for 20 minutes. The mixture was concentrated under reduced pressure, whereby the title compound was obtained quantitatively.

'H NMR (CDCI3) 5 (ppm): 8.23-8.13 (2H, m,

0-CO-), 7.96 (1H, d, J = 8Hz, C4-H), 7.68-7.43 (3H, m, -0-CO-), 6.85 (IH, d, J = 8Hz, C5-H) 0.40 (9H, s,

CH3x3)

example 1

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -1-ethoxymethyl-5-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-fluorouracil in 50 ml of dry dioxane. The mixture was refluxed for 1 hour.

The reaction mixture was filtered, the filtrate concentrated and the residue dissolved in 50 ml of acetonitrile. 3.46 ml of triethylamine and 2.10 g of 6-benzoyl-oxy-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 chromatography with chloroform as an eluent, to obtain 860 mg of the title compound. Yield 25%. Melting point 162-164 ° C. , ■ H-NMR (CDCI3) § (ppm): 8.66-8.14 (6H, m. (\ CO-

and- ^ CO- and C4-H from the pyridine ring) 7.82-7.33 (6H, m, -CO

Q-H and-0-CO- and and C5-H from pyridine

-CO

ring) 5.15 (2H, s, N-CH2) 3.62 (2H, q, J = 7Hz, -CH2CH 3) 1.22 (3H, t, J = 7Hz, -CH3)

Example 2

Preparation of 3- [4- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

The title compound was obtained by the general procedure of Example 1. Yield 24%. Form: Pul-ver. .

'H NMR (CDCI3) 5 (ppm): 8.39-8.02 (7H, m, Q-CO-

and CO- ^ CO- and C4-H from the pyridine ring) 7.67-7.39

(5H, m, -0-CO- and C6-H, and C5-H from the pyridine ring)

5.14 (2H, s, N-CH,) 3.61 (2H, q, J = 7Hz, -CH2CH3) 1.22 (3H, t, J = 7Hz, CH3)

Example 3

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -5-fluoro-1- (methoxymethyl) fluorouracil

The title compound was obtained by the general procedure of Example 1. Yield 25%. Form: powder.

'H-NMR (DMSO-d6) 5 (ppm): 8.87-7.63 (12H, m, ~ Ö ~ C0 ~ tV' - ° C ^ and Q-H),

At \

-O O-

5.10 (2H, s, CH2), 3.37 (3H, s, CH3).

Example 4

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -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.

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

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

Example 5

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

1.30 g of isophthaloyl chloride and 2.68 ml of triethylamine were added to a solution of 1.53 g of 6-benzoyloxy-3-cyano-2-dihydroxy pyridine in 30 ml of dioxane. The mixture s

10th

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25th

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was stirred at room temperature for 3 hours. The insoluble portions were filtered off and the filtrate was concentrated to give an intermediate, 3- (6-benzoyloxy -3-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 80 ° C. for 1 hour. The insoluble parts were filtered off and the filtrate was concentrated. The residue was placed in a silica gel column and eluted with dichloromethane, whereby 0.62 g of the desired title compound (compound of Example 1) was obtained. Yield 21%.

Pharmacological test I

Sarcoma-180 subcultivated on ascites from ICR mice was diluted with physiological saline and implanted on the back of ICR mice in subepidermal tissue in amounts of 2 × 107 cells each. 24 hours after implantation, a suspension of the test compound was orally administered to each mouse once a day for 7 consecutive days. The test compound suspension 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 the mice on the 10th day after implantation to determine the weight of the tumor. The ratio (T / C) of the weight of the tumor (T) cut out from the mouse group treated with the test compound to the weight of the tumor cut out from the reference mouse group not treated with the test compound (C) was determined. The 50% tumor inhibitory dose (ED50 value) at which T / C is 0.5 was determined from the dose response curve for the dose and the ratio (T / C).

The results are given in Table 1, which also gives the results obtained by similarly giving a mouse group 5: fluoro-1 - (2-te-trahydrofuranyl) uracil and uracil in a 1: 4 ratio (molar ratio ) containing cancer-fighting composition administered as a comparative drug.

Table 1

Test compound ED50 (mg / kg)

Connection of example 1 5

Comparative compound 30

Pharmacological test II

Yoshida sarcoma subcultured on an ascites from Donryu-type rats was diluted with physiological saline and implanted on the back of Donryu-type rats in subepidermal tissue in amounts of 2 × 104 cells each. 24 hours after implantation, a suspension of the test compound was orally administered to each rat once a day for 7 consecutive days. The test compound suspension 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 on the 10th day after implantation under the rat dorsal coat to determine the weight of the tumor. The ratio (T / C) of the weight of the tumor (T) cut out from the group of rats treated with the test compound to the weight of the tumor cut out from the untreated reference group of rats (C) was determined. The 50% tumor inhibitory dose (ED50 value) at which T / C is 0.5 was determined from the dose response curve for the dose and the ratio (T / C).

During the previous test, a dose (mg / kg) (to be administered once) was determined that was effective to increase the body weight gain of the test compound-treated rats by 10% compared to the body weight gain of the test compound-untreated rats suppress. This dose is referred to below as the «dose suppressing 10% body weight gain».

A therapeutic index was calculated from the values of ED50 and the 10% body weight suppressing dose according to the following equation:

10% body weight suppressive dose

Therapeutic index

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

Table 2 also shows the relative efficacy of each of the test drugs, namely the ratio of the therapeutic index of each of the test drugs to the therapeutic index (assumed 1) of the comparative drug C.

(1) Comparative drug A

3- [3- (6-Benzoyloxy-3-cyano-2-pyridyloxycarbonyl) ben-zoyl] -l - [2- (tetrahydrofuranyl) -5-fluorouracil

(2) Comparative drug B

3- [3- (5-chloro-4-benzoyloxy-2-pyridyloxycarbonyl) ben-zoyl] 2 '-deoxy-3'-0-benzyl-5-fluorouridine

(3) Comparative drug C

3- [3- (6-Benzoyloxy-3-cyano-2-pyridyloxycarbonyl) ben-zoyl] -2'-deoxy-3'-0-benzyl-5-fluorouridine

(4) Comparative drug D

3- [3- (4-Benzoyloxy-5-chloro-2-pyridyloxycarbonyl) ben-zoyl] -5-fluoro-1-ethoxymethyl uracil

(5) Comparative drug E

Combination of l-ethoxymethyl-5-fluorouracil and 3-cyano-2-dihydroxypyridine

Table 2

test

ED like this

10%

Therapist

realtive connect

Kgz.

Effective

(mg / kg)

u.D.

Index

example 1

10th

10th

1

2.7

Comparison. A

30th

15

0.5

1.3

Comparison. B

^ 60

20th

<0.3

<0.8

Comparison. C.

40

15

0.375

1

Comparison. D

^ 40

18th

<0.5

<1.3

Comparison. E

8th

3rd

0.375

1

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

Pharmacological test III

The comparative drug C used in pharmacological test II or the compound of Example 1 (25 mg / kg in each case) were administered orally to a normal rat5

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enough. Blood was drawn from the rats at predetermined 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 in the rats treated with the comparative drug C and 1-ethoxyme -thyl-5-fluorouracil as a metabolite in the rats treated with the compound of Example 1), and the maximum concentration in the blood was determined. Table 3 shows the results.

Table 3

Test Connection

Compound of Example 1 Comparative Drug C

Max. Concentration in blood ((ig / ml)

9.2 1.8

10th

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

Example 1 of a composition

Compound of Example 1 25 mg

Starch 112 mg

Magnesium stearate 18 mg

Lactose 45 mg

Total 200 mg

Tablets were made in a known manner, each of which had the above composition.

Table 3 shows that the compound of Example 1 was absorbed five times more than the comparative drug C.

Example 2 of a composition

15 compound of example 2 10mg

Strength 125 mg

Magnesium stearate 20 mg

Lactose 45 mg

Total 200 mg

20th

Tablets were made in a known manner, each of which had the above composition.

C.

Claims (7)

671 578 PATENT CLAIMS 1. 5-fluorouracil derivative of the formula below CO-O- (I) where Ra is a Q-Q alkoxymethyl radical. (2) O ^ N To obtain (2) wherein X has the meaning given above, and reacting the intermediate compound of the above formula (7) with a compound of the following formula 30th O wherein Ra is a Q-Co alkoxymethyl group, with a compound of the formula below H V N X-C 35 k, 2. 3- [3- (6-Benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -l -ethoxymethyl-5-fluorouracil as 5-fluorouracil derivative according to claim 1. (3) 40 wherein X is a halogen atom in an organic solvent in the presence of an acid scavenger to form an intermediate of the formula below 45 (3) 15 wherein X is a halogen atom in an organic solvent in the presence of an acid scavenger to form an intermediate of the formula below CO-CH H \ N (7) 25th O ^^ N Rc 3. A process for the preparation of a 5-fluorouracil derivative according to claim 1, comprising the alternative a) reacting a compound of the formula below CO-CH 4. Composition consisting of an effective amount of the 5-fluorouracil derivative according to claim 1 and a pharmaceutical carrier material, as an anti-cancer agent. (4) 50 to obtain where X and Ra have the meaning given above, and reacting the intermediate compound of the above formula (4) with a compound of the following formula 60 5. The composition according to claim 4, wherein the 5-fluorouracil derivative is 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -l-ethoxymethyl-5-fluorouracil. (5) O-R wherein Ra has the meaning given above, in an organic solvent in the presence of an acid scavenger. 6. Use of a 5-fluorouracil derivative according to claim 1 for the preparation of anti-cancer agents. (6) N 'OH with a compound of formula O below X-C C-X 7. Use according to claim 6, wherein the 5-fluoro-rouracil derivative is 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxy-carbonyl) benzoyl] -l-ethoxymethyl-5-fluorouracil.