DK163124B - N-Benzoyl-N'-pyrimidinyloxyphenylurea compounds, process for preparing them, and anti-tumour preparations which comprise the compounds - Google Patents

Description

DK 163124 B

in

The present invention relates to novel N-benzoyl-N'-pyrimidinyloxyphenylurea compounds, a process for their preparation and antitumor preparations containing the compounds as active ingredients.

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It is known that certain benzoyl urea compounds have the formula: ^ oVcONHCONH- ^ oVo- ^ oVzi 10 It N_ <Z2 wherein X represents a halogen atom or a nitro group, Y and Z ^ each represent a hydrogen atom or a halogen atom, Z halogen atom or a trifluoromethyl group, and T represents = CH- or 15 = N-, are useful as anti-tumor drugs. More specifically, it has been described that when cancer cells were inoculated intraperitoneally in mice and the drugs were also administered intraperitoneally in mice, antitumor effects were obtained (unexamined Japanese Patent Application Publication No. 109721/1982).

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However, these known compounds are generally poorly soluble in both water and the organic solvent and are poorly absorbed in the gut. Therefore, depending on the manner in which the drug is administered, they sometimes exhibit almost no antitumor activity, and there is a limit to the amount of intraperitoneal administration of these drugs for healing purposes.

Therefore, there is a desire to obtain compounds which can exhibit good antitumor effects without causing side effects in a convenient and simple mode of administration in a convenient and simple formulation for the purpose of curing cancer.

This object is achieved with the N-benzoyl-N'-pyrimidinyloxophenylurea compounds of the invention, characterized in that they have the formula: / oV ^ ONHCONH- / oVo-γD ^ -A (I) 1 * 02 ^ C1 35

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2 where A represents a bromine atom or a chlorine atom.

The process of the invention for the preparation of the above compounds of formula (I) is characterized in that a substituted nitrobenzene compound of formula: / oV-COR, 1 (II) NO2

wherein R 2 represents an isocyanate group, an amino group or the group -NHCONH- / OOH

15 Cl is reacted with a substituted pyrimidine compound having the formula: N - \ 20 where A has the same meaning as given above * and R 2 - when R 1 represents an isocyanate group or amino group - represents the group 25 wherein R 9 represents an isocyanate group or an amino group other than R 2, while R 2 - when R 1 represents the group 30 -NHCONH- 2 O 2 OH, represents a halogen atom.

The antitumor composition of the invention is characterized in that it contains a compound of formula I as active ingredient.

Comprehensive studies have been carried out on the compounds represented by the general formula IV and detailed studies on the chemical structures and antitumor activities, and as a result

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3 of which, it has been found that desirable antitumor activities are obtainable with the two novel compounds, wherein X in the above Formula IV is a nitro group, Y is a chlorine atom, T is = N-, Zj is chlorine or bromine, and Z is a hydrogen atom. With these compounds 5, when the portion in which the cancer cells are inoculated and the portion into which the drug is administered is different, surprisingly it has been found that substantially better activity is obtained than when Z whether there is no significant difference in antitumor activity when the above parts are identical. In particular, the present invention is based on the finding that the compounds of the invention have better antitumor activity than those specifically mentioned in the above publication.

The reason for the difference in antitumor activity for various halogen atoms such as Zj is not fully understood. However, it is believed that depending on the mode of administration of the drug, the absorption of the drug in the intestine, the concentration of the drug in the blood, and the drug's transferability to the target may vary depending on the different halogen atom types, whereby a substantial difference in the drug's appearance to the diseased portion may occur. and there is thus a substantial difference in antitumor activity. Thus, it appears that some specific property of the compounds of the present invention is to some extent associated with the antitumor activity. According to the present invention, excellent antitumor activity can be achieved by a method of indirectly administering the drug to the diseased part, e.g. by a method in which the drug is administered throughout the body and the diseased portion is at a distance from the portion in which the drug is administered, such as oral administration, intravenous administration (intravenous injection), suppository (rectal) administration, intramuscular administration or percutaneous administration, preferably by oral, intravenous or suppository administration, more preferably by oral administration. According to the present invention, the administration of the drug can be further simplified, and as the amount of the drug can be reduced, there will be the advantages that the patient's pain during the administration time can be reduced and the side effects can be reduced.

The benzoyl urea compounds of the present invention may e.g. is prepared by the following reaction:

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4 [A] N / qVcONCO + H2N ~ / oVo ”(O ^ -a

^ no2 ^ C1 N

5 in the presence of a solvent. / —Y / —y n — y

(O VCONHCONH- / O / -0-fO) -A

0 - 120 ° C n ° 2 Cl 0.1-24 hours where A is as defined above.

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As the solvent in the above reaction may be mentioned octane, benzene, toluene, xylene, pyridine, dioxane, dimethyl sulphoxide, monochlorobenzene or ethyl acetate.

[B] 20 (o \ com2 + ocn- / oVo -ΛoVa Wno2 Wci 25 1 presence of a solvent. __ .-> »-,

- * \ Oy ^ OrøCONH - * / oVoHp VA

50 ° C - reflux temp. 0.1-24 hours where A is as defined above.

The solvent used in the above reaction is the same as that used in reaction [A].

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5 [C] O ^ CONHCONH- ^ 0 ^ -OH + Hal 2 5 in the presence of an alkaline substance and a solvent. _ «-> -> / oVconhconh- / o / 0) PyA 0 ° C - for reflux temp. 0.1 - 24 hours 15 where Hal represents a halogen atom and A is as defined above.

For use as an alkaline substance in the above reaction may be mentioned sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. As a solvent may be mentioned an aprotic, polar solvent such as dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoramide and sulfolane, a ketone such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and a halogenated hydrocarbon such as methylene chloride or chloroform.

The aniline compound, the phenyl isocyanate compound or the N-substituted phenyl-Ν'-benzoylurea compound used as the starting material in each of the above reactions can be e.g. is prepared by the following reaction: [D]

30 / _N

A- ^ O ^ -Hal + 35 in the presence of an alkaline substance and a solvent. / TTl / T \ _> αλ? ^ ° λ2 / nh2

Cl

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6

0 - 200 ° C

0.5 - 10 hours where Hal and A are as defined above.

5

The alkaline substance and solvent used are the same as those used in the reaction [C]. Furthermore, this condensation reaction is preferably carried out in the presence of nitrogen gas.

[E] N ^ N - <(oV0- ^ O> -A + COC12 15 1 in the presence of a solvent. ^ - vn - s, -> OCN ^ / oVo -CO Va 20 50 - 150 ° C ^ ci 0 , 1 - 24 hours - where A is as defined above.

The solvent used may be mentioned a solvent which is inert to phosgene such as toluene, xylene, monochlorobenzene, ethyl acetate or dioxane.

[F] 30 UdV-conco + h2n- / oV ° h> i02 ^ C1 35 in the presence of a solvent. .-. - ^

-> / oVcONHCONH-YoVoH

0 - 120 ° C N 2 NO 2 XI

0.1 - 24 hours

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7 where A is as defined above.

The solvent used in the above reaction is the same as that used in reaction [A].

The present invention will be described in more detail in the following by way of examples.

Synthesis Example 1:10

Synthesis of Compound No. 1 N- (2-Nitrobenzoyl) -Ν '- [4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl] urea.

(1) 7.00 g of 5-bromo-2-chloropyrimidine, 5.19 g of 4-amino-2-chlorophenol, 9.98 g of potassium carbonate and 70 ml of dimethyl sulphoxide were charged to a flask and reacted in a nitrogen atmosphere at 120 ° C for 1.5 hours with stirring. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then purified by silica gel column chromatography to give 6.80 g of oily 4- (5-bromo-2-pyrimidinyl-oxy) -3-chloroaniline.

(2) A solution obtained by dissolving 6.80 g of the above 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 30 ml of dioxane was charged to a flask and a solution which was obtained by dissolving 5.76 g of 2-nitrobenzoyl isocyanate in 30 ml of dioxane was added dropwise, and the mixture was then reacted at room temperature for 9 hours. After completion of the reaction, the product was poured into water, subjected to filtration and washed with warm water. The crystals thus obtained were transferred to methanol, stirred and then subjected again to filtration to give 9.42 g of the desired product with a melting point of 234 to 236 ° C.

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Synthesis Example 2:

Synthesis of Compound No. 2 N- (2-Nitrobenzoyl) -Ν '- [3-chloro-4- (5-chloro-2-pyrimidylloxy) phenyl] urea.

(1) 1.50 g of 2,5-dichloropyrimidine, 1.45 g of 4-amino-2-chlorophenol, 2.76 g of potassium carbonate and 15 ml of methyl sulphoxide were charged to a flask and reacted in a nitrogen atmosphere at 100 ° C for 1.5 hours with stirring.

After completion of the reaction, the product was poured into water and extracted with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was then distilled off. The crude product thus obtained was purified and isolated by silica gel column chromatography to give 2.20 g of 3-chloro-4- (5-chloro-2-pyrimidinyloxy) aniline having a melting point of 95 to 96 ° C.

(2) A solution obtained by dissolving 1.50 2-nitrobenzoyl-isocyanate in 6.5 ml of dioxane was charged to a flask and a solution obtained by dissolving 1.00 g of 3-chloro -4- (5-Chloro-2-pyrimidinyloxyjaniline, obtained in the above steps, in 6.5 ml of dioxane was added dropwise and the mixture was reacted at room temperature for 3 hours. Upon completion of the reaction, the product was poured into water and the precipitated crystals were collected by filtration, these crystals were washed with 50 ° C hot water, dried and suspended in ethyl acetate, a small amount of n-hexane was added, and the precipitated crystals were collected by filtration and dried to give 1.05 g of the desired product with a melting point of 30 from 222 to 225 ° C.

Synthesis Example 3:

Synthesis of Compound No. 35 (1) A solution of 0.02 mol of phosgene in 30 ml of ethyl acetate was charged to a flask. To this solution was added dropwise at room temperature a solution of 3 g of 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 10 ml of ethyl acetate. The mixture was reacted at room temperature.

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9 for 3 hours with stirring and further under reflux for 1 hour. After completion of the reaction, the ethyl acetate was distilled off under reduced pressure and the residue was vacuum dried to give 3.10 g of 4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenylisocyanate, m.p. 68 ° C.

(2) 1.22 g of 4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl isocyanate obtained in the above step were charged to a flask and then 20 ml of toluene was added. 0.62 g of 2-nitrobenzamide 10 was further added with stirring. The mixture was refluxed for 4 hours. After completion of the reaction, 5 ml of methanol was added to the reaction product and the mixture was cooled. The precipitated crystals were collected by filtration to give 0.79 g of the desired product.

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Synthesis Example 4:

Synthesis of Compound No. 20 (1) A solution of 5.19 g of 4-amino-2-chlorophenol in 100 ml of dioxane was charged to a leolbe. To this solution was added dropwise at room temperature a solution of 5.78 g of 2-nitrobenzoyl isocyanate in 10 ml of dioxane. The mixture was reacted at room temperature for 12 hours with stirring. After completion of the reaction, the reaction product was poured into water. The precipitated crystals were collected by filtration and washed with methanol to give 8.6 g of N- (2-nitro-benzoyl) -Ν '- (3-chloro-4-hydroxyphenyl) urea, m.p. from 237 to 239 ° C.

(2) A solution of 1 g of N- (2-nitrobenzoyl) -N '- (3-chloro-4-hydroxyphenylurea) obtained in the above step in 10 ml of dimethyl sulphoxide was charged to a flask, and 0.14 g of potassium hydroxide and then 0.58 g of 5-bromo-2-chloropyrimidine were added, and the mixture was reacted at 50 ° C for 5 h. The crystals were washed with water and methanol to give 0.81 g of the desired product.

Specific intermediate compounds are listed below:

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οο 4- (5-bromo-2-pyrimidyloxy) -3-chloroaniline.

Melting point 52-61.5 ° C.

3-chloro-4- (5-chloro-2-pyrimidinyloxy) aniline.

Melting point 95-96 ° C.

4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenylisocyanate.

Melting point 63-68 ° C.

N- (3-chloro-4-hydroxyphenyl) -Ν '- (2-nitrobenzoyl) urea.

Melting point 237-239 ° C.

The following is used as Comparative Compound No. 1: N- (2-Nitrobenzoyl) -Ν '- [3-chloro-4- (5-iodo-2-pyrimidinyloxy] phenyl] urea.

15 (disclosed in the disclosure to Japanese Unexamined Patent Application Publication No. 109721/1982).

The particular anti-tumor activities of the N-benzoyl-N'-pyrimidinyloxyphenylurea compounds of the present invention will now be described.

Compounds Nos. 1 and 2 of the present invention show e.g. Compared to Comparative Compound # 1, whose name and antitumor effects are specifically described in the above publication, no significant advantage in antitumor effect in Test Example 1 (wherein the portion into which the cancer cells were inoculated and the portion to which the drug was administered , were the same), but they showed much better activities in Test Examples 2 and 3 (where the above 2 parts were different).

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Afroofinase Example 1 (Inoculation of cancer cells and administration of the drug were both made intraperitoneally, as was the case in Test Example 1 of the above publication).

BDF1 mice were intraperitoneally inoculated with p-388 leukemia cells in 6 at a rate of 1 x 10 6 cells / mouse. A test drug was administered intraperitoneally twice, namely one day and four days thereafter

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11 inoculation. The mice were observed for 30 days to determine whether they survived or died. The ratio (%) of mean survival time (MST; median survival time) for experimental and control animals was obtained from the number of survival days for the 5 mice in the control group who had been administered a physiological saline solution, which number was set to 100. The drug was a dispersion obtained by adding a small amount of a surfactant (e.g., Tween-80, which is sold by Atlas Powder Co.) to the test compound (Table 1).

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Table 1

Compound No. Dose (Active ingredient mo / kq / dao) T / C% of MST

15 j 25 168 12.5 173 2 25 210 12.5 150 20 ______

Comparative Example 2 (p-388 leukemia cells were inoculated intraperitoneally while the drug was administered orally).

BDF1 mice were intraperitoneally inoculated with p-388 leukemia cells in * 1 6 30 at a rate of 1 x 10 6 cells / mouse. A test drug was administered orally twice, namely one day and four days after inoculation.

The mice were observed for 30 days to determine whether they survived or died, and the ratio (%) of mean survival time for trial and control animals was obtained for each treated group (10 animals per group) based on the number of survival days for the mice in the control group that had been administered a physiological saline solution were added to 100 (Table 2).

The test drugs were formulated accordingly

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12 formulation example 1, which will be discussed later.

Table 2

Compound No. Dose (Active ingredient mq / kq / drop T / C% of MST

j 100 173 50 157 10 __ 2 50 178 25 139

Comparative 1600 186 15 Compound No. 800 143 400 116

Test Example 3 (p-388 leukemia cells were inoculated intraperitoneally while the drug was administered orally).

The ratio (%) of mean survival time of test and control animals was obtained in the same manner as in test example 2 except that the test drugs formulated in accordance with formulation example 1 were replaced by test drugs formulated according to formulation example 2 (Table 3).

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Table 3

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Compound No. Dose (Active ingredient ma / ka / drop T / C% of MST

5 400 235 1 · 300 180 200 143 10 Comparative 3200 183 Example No. 1 1600 141

Test Example 4 (L-1210 leukemia cells were inoculated intraperitoneally while the drug was administered intravenously).

BDF1 mice were intraperitoneally inoculated with L-1210 leukemia cells in an amount of 1 x 10 celler cells / mice. A test drug formulated in accordance with Formulation Example 2 was administered intravenously. The mice were observed for 30 days to determine whether they survived or died, and the ratio (%) of mean survival time for trial and control animals was obtained for each treated group (10 animals per group) based on the number of survivors. six days for the mice in the control group who had been administered a physiological saline solution, which number was set at 100 (Table 4).

Table 4 30

Compound No. Dose (Active ingredient ma / kq / daal T / C% of MST 1 12.5 195 35

Test Example 5 (L-1210 leukemia cells were inoculated intraperitoneally while the drug was administered orally).

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14 BDF, -Mice were intraperitoneally inoculated with L-1210 leukemia cells in -1 at a rate of 1 x 10 celler cells / mice. A test drug formulated in accordance with Formulation Example 1 was administered orally 2 times, namely one day and four days after inoculation.

The mice were observed for 30 days to determine whether they survived or died, and the ratio (%) of mean survival time for experimental and control animals was obtained for each treated group (10 animals per group) based on the number of survival days for the mice. in the control group, a physiological saline solution was administered, which number was added to 100 (Table 5).

Table 5

Compound No. Dose (Active ingredient ma / ka / drop T / C% of MST 15 1 100 213 50 165 20 Test vaccine exemple 6 (B-16 melanoma cells were inoculated intra-peritoneally while the drug was administered orally).

BDFj-Mice were intraperitoneally inoculated with 0.5 ml of a liquid obtained by dispersing 1 g of B-16 melanoma cell in 8 ml of physiological saline solution at a rate of 0.5 ml / mouse. A test drug formulated in accordance with Formulation Example 1 was administered orally 3 times, namely 1 day, 7 days and 12 days after inoculation. The mice were observed for 60 30 days to determine whether they survived or died and the ratio (%) of mean survival time of the test and control animals was obtained for each treated group (10 animals per group) based on the number of survival days for the mice in the control group that had been administered a physiological saline solution, which number was added to 100 (Table 6).

Table 6

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Compound No. Dose (Active ingredient mq / kq / dao) T / C% of MST 5 1 100 139

Test Example 7 (M-5074 ovarian sarcoma cells were inoculated intraperitoneally while the drug was administered orally).

BCFT Mice were inoculated intraperitoneally with M-5074 ovarian sarcoma.

* C

cells in an amount of 1 x 10 celler cells / mice. A test drug formulated in accordance with Formulation Example 1 was administered orally 3 times, namely 1 day, 7 days and 14 days after inoculation. The mice were observed for 60 days to determine whether they survived or died, and the ratio (%) of mean survival time for the test and control animals was obtained for each treated group (10 animals per group) based on the number of survival days. for the mice in the control group who had been administered a physiological saline solution, which number was added to 100 (Table 7).

Table 7 25 Compound No. Dose (Active ingredient ma / ko / daa) T / C% of MST 1 25 139 30 Acute toxicity, dose and mode of administration of the N-benzoyl-N'-pyrimidinyloxyphenylurea compounds of the present invention will now be described.

(1) Acute Toxicity: 35 ddY-Mice (10 animals) were administered intravenously a drug containing compound # 1 or # 2 of the present invention, formulated in accordance with formulation example 1, in an amount of the compound of 100 mg / kg, at which

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16 no mice died. Thus, this shows that the acute toxicity values (LD ^ q) of compounds # 1 and # 2 are at least 100 mg / kg.

5 (2) Amount of dose.

As to dose, the compounds are administered continuously or at intervals to the extent that the total dose does not exceed a certain level, taking into account the results of animal experiments and other conditions. However, the dose may, of course, be suitably varied depending on the mode of administration and the circumstances of a patient or animal being treated (e.g., age, body weight, gender, sensitivity, food and the like), administration intervals, medications used in conjunction with the compounds, and the disease state.

An optimal dose and the number of administrations under certain conditions should be determined by medical specialists.

(3) Modes of administration.

The antitumor compositions of the invention may be administered orally, intravenously, rectally, intramuscularly and subcutaneously, preferably orally, intravenously or rectally, more preferably orally *. In this case, the compositions of the invention may be formulated using various pharmacologically acceptable carriers, such as inert diluents or anabolic food carriers, as is the case with ordinary medicine, and are preferably administered orally, intravenously or suppository, preferably especially by oral administration.

The compounds of the present invention are heavily soluble in both water and organic solvents. Therefore, they are preferably formulated in an aqueous suspension which may further contain phospholipids. As a process for preparing an aqueous suspension without phospholipids, there may be mentioned a process in which the active compound is pre-pulverized to a fine powder, whereupon the fine powder of the active compound is added to an aqueous solution containing a surfactant and, if necessary, an antifoam agent. and the mixture is comminuted in a wet system until 80% of the particles have a particle size not greater than 5 microns, preferably not greater than 2 microns, and a thickening agent.

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17 is added if necessary. As specific examples of surfactants may be mentioned a non-ionic phosphoric acid ester, a polyoxyethylene-cured castor oil, a polyoxyethylene sorbitan fatty acid ester, a sugar ester, a polyoxyethylene polyoxypropylene block polymeric acid, ethylene oxide, ethylene oxide, polyaniloxide, , a polyoxyethylene polyoxypropylene acetyl ether, silicone, etc. As specific examples of thickener may be mentioned guar gum, alginic acid, gum arabic, pectin, starch, xanthan gum, gelatin, etc.

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As a method for preparing an aqueous suspension containing a phospholipid, on the other hand, there is mentioned a process in which a phospholipid such as soybean phospholipid or egg yolk phospholipid is used in place of the surfactant used in the above process and an antioxidant such as α-tocopherol, is used instead of the thickener.

As another method for preparing an aqueous suspension containing a phospholipid, the following procedure may be further mentioned. A phospholipid and a compound of the present invention are dissolved in an organic solvent such as chloroform and an antioxidant is added if necessary. Thereafter, the solvent is distilled off under reduced pressure to thereby deposit a thin layer of phospholipid on the inside of the vessel to obtain a thin phospholipid containing the compound of the present invention. Then, a physiologically acceptable aqueous solution is added to the thin layer just formed, followed by shaking or stirring to destroy the thin layer, and the suspension obtained is subjected to supersonic treatment and centrifugal separation, thereby recovering the residue obtained from the bottom layer. and centrifugal is washed with an aqueous solution containing a phospholipid (particle size: maximum 5 µm, for example from 0.2 to 2 / wn).

In addition, these compounds may be formulated into tablets, capsules, intestinal agents, granules, powders, injection solutions or suppositories by conventional formulation methods.

Examples of specific formulation examples will now be described 18

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Vet.

Formulation Example 1 Compound # 1 of the present invention was previously pulverized by means of a centrifugal pulverizer. 5 parts by weight of polyoxyethylene (60) cured castor oil, 0.2 parts by weight of silicone and 0.3 parts by weight of polyoxyethylene-polyoxypropylene block polymer were added to 79.5 parts by weight of physiological saline to give a 10 aqueous solution to which 10 parts by weight of the above powdered compound was added. No. 1 of the present invention. The mixture was comminuted in a wet system using a sand grinder using glass goblets (80% of the particles had a particle size not exceeding 2 μπτ). Then 5 parts by weight of xanthan gum (2% solution) was added to give an aqueous suspension.

Formulase Example 2 20 0.24 parts by weight of compound # 1 according to the present invention, 2.4 parts by weight of purified egg biophospholipid and 0.0024 parts by weight of α-tocopherol were dissolved in 48.7576 parts by weight of chloroform, and the chloroform was then distilled off by heating under reduced pressure. pressure by means of a rotary evaporator to form a thin phospholipid layer containing compound # 1 of the present invention. To this thin layer was added 48.6 parts by weight of a physiological sodium chloride solution, which was immediately shaken vigorously at room temperature, and then supersonic treatment was performed for 1 hour while cooling with ice using a Sonycator. Centrifugal separation was further performed at room temperature, recovering the remainder of the bottom layer and centrifuging a few times with the above aqueous physiological sodium chloride solution and then filtering to remove bacteria to obtain an aqueous suspension containing 35 phospholipid (particle size: 0.2-2 μια).

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Formulase Example 3

The aqueous suspension obtained in Formula Example 2 was lyophilized to give a dry formulation containing a phospholipid.

Formulation Example 4

To an aqueous suspension obtained by dissolving 1.5 parts by weight of 10 oxyethylated polyallylphenol phosphate and 0.2 parts by weight of silicone in 53.3 parts by weight of physiological saline solution, 40 parts by weight of compound # 2 of the present invention was added which was powdered. using a centrifugal pulverizer and the mixture was partitioned into a wet system in a sand mill using glass spheres (90% of the particles had a particle size not exceeding 2 μηι). Five parts by weight of xanthan gum (2% solution) was then added to give an aqueous suspension.

Formulation Example 5 20

Compound No. -1 of the present invention was previously pulverized by means of a centrifugal pulverizer. Five parts by weight of the powdered compound # 1 of the present invention was added to an aqueous solution obtained by stirring and dispersing 2 parts by weight of egg biophospholipid, 0.001 parts by weight of α-tocopherol and 92,999 parts by weight of physiological saline. The mixture was then comminuted in a wet system in a sand mill using glass goblets (80% of the particles had a particle size of not more than 2 inches) to obtain an aqueous suspension.

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Claims (9)

N-Benzoyl-N'-pyrimidinyloxyphenylurea compounds, characterized in that they have the formula: 5 OVCONHCONH-ZoV O (I) NO2 'Ό1 where A represents a bromine atom or a chlorine atom. 10 N-Benzoyl-N'-pyrimidinyloxyphenylurea compound according to claim 1, characterized in that the compound is N- (2-nitro-benzoyl) -Ν '- [4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl] urea. 15 N-Benzoyl-N'-pyrimidinyloxyphenylurea compound according to claim 1, characterized in that the compound is N- (2-nitro-benzoyl) -Ν '- [3-chloro-4- (5-chloro-2-pyrimidinyloxy) phenyl ] urea. A process for the preparation of N-benzoyl-N'-pyrimidinyloxy-phenyl urea compound having the formula: / OV-CONHCONH- / OV 0 NO 2 Ol 25 wherein A represents a bromine atom or a chlorine atom, characterized in that a substituted nitrobenzene compound of the formula: (2'-CORl (H) no2 where Rj represents an isocyanate group, an amino group or the group 35 -NHCONH- / OV-OH ^ C1 is reacted with a substituted pyrimidine compound of the formula: DK 163124B R2-O) - a-N-7 5 where A has the same meaning as given above and - when R 1 represents an isocyanate group or amino group - the group 10 wherein R 9 represents an isocyanate group or an amino group different from R 1, while R 2 - when R 1 represents the group -NHCONH- ^ O ^ -OH represents a halogen atom. Process according to claim 4, characterized in that the substituted nitrobenzene compound is a 2-nitrobenzoyl compound of the formula: 20 - y - (θλ-CORat no compound of the formula: wherein A represents a bromine atom or a chlorine atom and R 9 represents an amino group or an isocyanate group other than R 1. Process according to Claim 5, characterized in that R 1 represents an isocyanate group and R 8 represents an amino group. A process according to claim 5, characterized in that R 1 represents an amino group and R 8 represents an isocyanate group. DK 163124B Process according to claim 4, characterized in that the substituted nitrobenzene compound is N- (2-nitrobenzoyl) -N '- (3-chloro-4-hydroxyphenyl) urea and the substituted pyrimidine compound has the formula: Hail-fo A where A represents a bromine atom or a chlorine atom and Hal represents a halogen atom. 10 An antitumor composition, characterized in that it contains an N-benzoyl-N'-pyrimidinyloxyphenylurea compound of the formula: 15 q q -conhconh- / qV NO 2 Cl where A represents a bromine atom or a chlorine atom. 20 25 1 35