DD243025A5 - METHOD FOR PRODUCING BENZOYL UREA COMPOUNDS - Google Patents

Abstract

There are provided benzoylurea compounds of the following general formula in which A represents a bromine atom or a chlorine atom.

Description

where A is a bromine atom or a chlorine atom and Hal is a halogen atom. \

10. The method according to item 9, characterized in that the reaction is carried out in the presence of an alkaline substance and a solvent. j

11. The method according to item 9, characterized in that the reaction is carried out at a temperature of ^{0 0} C to reflux temperature. j

Field of application of the invention;

The invention relates to novel benzoylurea compounds and to a process for their preparation.

Characteristic of the known technical solutions i

It is known that Benzoylha.rnstoff compounds of the following formula I.

(IV)

wherein X represents a halogen atom or a nitro group and wherein Y and Z ₂ each represents a hydrogen atom or a halogen atom and Z _{1 represents} a halogen atom or a trifluoromethyl group and wherein T represents = CH- or = N-, are useful as an anti-tumor agent. In particular, it is known that anti-tumor effects are observed in mice after prior intraperitoneal inoculation of cancer cells and subsequent intraperitoneal administration of these drugs (Japanese Patent Laid-Open No. 109721/1982). , ';.

However, these compounds are generally sparingly soluble in water and organic solvents and thus difficult to absorb from the intestine. Thus, depending on the mode of administration, they often show little anti-tumor effects, and the intraperitoneal administration for medical purposes, of course, has its limitations. It is therefore desirable to further develop this class of binding so that the anti-tumor effects are enhanced without side effects. It should be a viable and simple administration possible and a simple composition of the cancer treatment agent.

Object of the invention

It is therefore an object of the present invention to provide novel benzoylurea compounds which, while falling within the above general formula IV but have not yet been specifically disclosed, as well as processes for their preparation and anti-tumor agents containing the same.

Explanation of the essence of the invention

According to the invention, a benzylurea compound of the following formula is given the general formula:

O V-CONHCONH- / OV ° ~ \ P / ^k IO <

(D

'2 y ¹

where A is a bromine atom or a chlorine atom.

Further, according to the invention, there is provided a process for the preparation of the compounds of the formula I, which comprises reacting a nitro-substituted benzene compound of the following general formula

O) -COR ₁ NO "

-3- 243 UZ5

-NHCONH- (Q) -OH,

Reacts with a substituted pyrimidine compound of the following formula

N-

wherein A has the meaning given above and wherein R _{2 is} a halogen atom or a group of the formula

Cl

wherein R _{3 represents} an isocyanate group or an amino group other than R ₁ , with the proviso that when R _{1 represents} an isocyanate group or an amino group, R _{2 represents} a group of the formula

• 0 Cl

is and that when R _{1 is} a group of the formula

-NHCONH- ^ V-OH Cl

R _{2 is} a halogen atom.

Further, an anti-tumor agent is provided according to the invention, which contains a compound of formula I as an active ingredient. Extensive studies were conducted in the above class of compounds of general formula IV, and details of chemical structure and anti-tumor effects were examined in detail. It has been found that excellent antitumor effects are obtained in the case of particular substituent combinations, wherein in the compound of formula IV X represents a nitro group, Y represents a chlorine atom, T = N-, Z _{1 represents} a halogen atom and Z ₂ for a hydrogen atom. In such a substituent combination, there are significant differences in anti-tumor effects due to different halogen atoms than Z ₁ when the body part into which the cancer cells are inoculated and the parts of the body where the drug is administered are different. We compare the case that Z _{1 represents} a chlorine or bromine atom with the case that Z _{1 represents} an iodine atom. In the former case, one obtains much higher effects than in the latter case, when the two parts of the body are different. However, when the two body parts are the same, there is essentially no difference in anti-tumor activity. The present invention is therefore based on the finding that these specific compounds, which were not mentioned in the above-mentioned publication, have superior anti-tumor effects in comparison to the compounds specifically mentioned in the publication. The reason for the differences in anti-tumor effect due to the different halogen atoms in PoSItIOnZ ₁ is not completely clear. However, it is believed that depending on the administration of these agents, the absorption of the active ingredients in the intestine and the concentration of the active ingredients in the blood and the conversion of the active ingredients to the target organ depend on the nature of the halogen atom, so that there are considerable differences in the transport of the drug result in diseased area and thus have considerable anti-tumor effects. Thus, there is a correlation between certain, specific, structural properties of the compounds of the invention with their anti-tumor effects. According to the invention, excellent anti-tumor effects can be obtained by administering the remedy indirectly. This means that when the remedy is administered to the whole body at a point remote from the diseased spot, the curative effect is still extremely high. As such administration routes are: oral administration, intravenous administration (intravenous injection), suppository (rectal) administration, intramuscular administration or percutaneous administration. Preferred are oral administration, intravenous administration or administration by suppository. Particularly preferred is oral administration. Thus, according to the invention, the administration of the remedy can be substantially simplified, and the amount of the remedy can be reduced. This leads to a considerable reduction in side effects and in particular to a reduction in the pain that the patient has to endure during administration.

The benzoylurea compounds according to the invention can be prepared, for example, by the following methods.

* ^X- JONCO + H ₂ N- (O Vo- (O

NO ₂

in the presence of one

-4- Z43UZU

wherein A has the meaning given above. Octane, benzene, toluene, xylene, pyridine, dioxane, dimethyl sulfoxide, monochlorobenzene or ethyl acetate can be used as the solvent.

[B]

O) -CONH ₂ + OCN'NO,

/ ν Ν

ONHCONH

in the presence of a solvent .

50 ° C-reflux temp .; _{wu o} 0.1-24 h ²

where A has the meaning given above. It is possible to use the same solvent as in the above reaction [A].

cc]

(θ VcONHCONH ^N0 2

in the presence of an alkaline substance and a solvent

O ⁰ C reflux temp. 0.1-24 h

-OH + Hal- (Q Χ

ONHCONH- (OO ₂ Cl

wherein Hal is a halogen atom and A has the above meaning.

As the alkaline substance, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate may be used. As the solvent, it is possible to use an aprotic polar solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide and sulfolane, or a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or a halogenated hydrocarbon such as methylene chloride or chloroform.

The aniline compound, the phenyl isocyanate compound and the n-substituted phenyl-N'-benzoylurea, which are used as a starting material, may, for. B. can be obtained by the following methods.

[D]

in the presence of an alkaline substance and a solution by means of>

0-20O ⁰ C; O, 5-1O h

> Cl

wherein Hai and A are as defined above. It is possible to use the alkaline substances and solvents mentioned in reaction [C]. This condensation reaction is preferably carried out in the presence of nitrogen gas.

in the presence of a solvent

50-15O ⁰ C; 0.1-24 h

OCN

where A has the meaning given above. It is possible to use a solvent which is inert with respect to phosgene, e.g. As toluene, xylene, monochlorobenzene, ethyl acetate or dioxane.

'- * -: onco

in the presence of / ÖYcONHCONH

Solvent. \ - <

CM20 ° C, · 0.1-24 h ' ^N0 2

You can use the same solvent as in the reaction [A].

embodiments

In the following the invention will be explained in more detail by means of examples.

Production Example 1 Synthesis of Compound No. 1: N- (2-nitrobenzoyl) -N '- [4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl] -urea

(1) To a flask is added 7.00 g B-Bromo ^ -chlorpyrimidin, 5,19g 4-Amino-2-chloro phenol, 9,98g of potassium carbonate and 70 ml of dimethyl sulfoxide, and sets the whole 1.5 h under a nitrogen atmosphere at 12O ⁰ C with stirring. After completion of the reaction, the product is poured into water and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then purified by silica gel column chromatography to obtain 6.80 g of oily 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline.

(2) To a flask is added a solution obtained by dissolving 6.80 g of the above 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 30 ml of dioxane, dropping thereto by dissolving 5.76 g of 2-nitrobenzoyl isocyanate in 30 ml of dioxane, and the mixture is reacted for 9 h at room temperature. After completion of the reaction, the product is poured into water, filtered and washed with hot water. The resulting crystals are added to methanol, stirred and refiltered to give 9.42 g of the desired product, m.p. 234-236 ° C.

Production Example 2 Synthesis of Compound No. 2: N- (2-nitrobenzoyl) -N '- [3-chloro-4- (5-chloro-2-pyrimidinyloxy) -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 dimethylsulfoxide are added to a flask, and the mixture is placed under a nitrogen atmosphere at 100 ° C for 1.5 hours Stirring around. After completion of the reaction, the product is poured into water and extracted with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off, the resulting crude product is purified and isolated by silica gel column chromatography. This gives 2.20 g of 3-chloro-4- (5-chloro-2-pyrimidinyloxy) -aniline, mp. 95 to 96 ° C.

(2) To a flask is added a solution obtained by dissolving 1.50 g of 2-nitrobenzoyl isocyanate in 6.5 ml of dioxane. To this is added dropwise a solution prepared by dissolving 1.00 g of the 3-chloro-4- (5-chloro-2-pyrimidinyloxy) -aniline obtained in the above step in 6.5 ml of dioxane, and the mixture is reacted at room temperature for 3 hours. After completion of the reaction, pour the product into water and collect the precipitated crystals by filtration. The crystals are washed with water of about 5O ⁰ C, dried and suspended in ethyl acetate. A small amount of η-hexane is added, the precipitated crystals are collected by filtration and dried. This gives 1.05 g of the desired product, mp. 222 to 225 ⁰ C. ♦

Production Example 3 Synthesis of Compound No. 1

(1) To a flask is added a solution of 0.02 mole of phosgene in 30 ml of ethyl acetate. This solution is added dropwise at room temperature with a solution of 3g of 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 10 ml of ethyl acetate. The mixture is reacted with stirring for 3 h at room temperature and further for 1 h under reflux. After completion of the reaction, the ethyl acetate is distilled off under reduced pressure and the residue is dried in vacuo. This gives 3.10 g of 4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl isocyanate, mp. 63 to 68 ° C.

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

Production Example 4 Synthesis of Compound No. 1

(1) To a flask is added a solution of 5.19 g of 4-amino-2-chlorophenol in 100 ml of dioxane. This solution is added dropwise at room temperature with a solution of 5.78 g of 2-nitrobenzoyl isocyanate in 10 ml of dioxane. The mixture is reacted with stirring at room temperature for 12 hours. After completion of the reaction, the reaction product is added to water. The precipitated crystals are collected by filtration and washed with methanol. 8.60 g of N- (2-nitrobenzoyl) -N '- (3-chloro-4-hydroxyphenyl) urea, mp 237 to 239 ^° C. are obtained.

(2) To a flask is added a solution of 1 g of the N- (2-nitrobenzoyl) -N '- (3-chloro-4-hydroxyphenyl-urea) obtained in the above step in 10 ml of dimethyl sulfoxide and thereto 0.14 g of potassium hydroxide and Finally, 0.58 g of 5-bromo-2-chloropyrimidine.The mixture is reacted for 5 hours at 50 ° C. When the reaction is complete, 20 ml of methanol are added to the reaction product and the precipitated crystals are collected by filtration and washed with water and methanol , 81 g of the desired product.

In the following, once again special compounds of the invention are to be put together.

Connection no. 1:

N- (2-nitrobenzoyl) -N '- [3-chloro-4- (5-bromo-2-pyrimidinyloxy) phenyl] urea; Mp 234-236 ° C.

Connection no.2:

N- (2-nitrobenzoyl) -N '- [3-chloro-4- (5-chloro-2-pyrimidinyloxy) phenyl] urea; Mp 222 to 225 ^° C.

Specific intermediates of the invention are given below.

4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline, m.p. 52 to 61.5 C ^0.; 3-chloro-4- (5-chloro-2-pyrimidinyloxy -aniline, m.p. 95 to 96 ⁰ C;!. 4- (5-bromo-2-pyrimidinyloxy) -3-chlorophenylisocyanate, m.p. 63 to 68 ° C. N- (3-chloro-4-hydroxyphenyl) -N '- (2-nitrobenzoyl) -urea, m.p. 237-239 ° C.

In the following, comparative compounds are to be given

 Comparative Compound No. 1:

N- (2-nitrobenzoyl) -N '- [3-chloro-4- (5-iodo-2-pyrimidinyloxy) -phenyl] -urea (Japanese Patent Laid-Open No. 109721/1982).

In the following, the specific antitumor effects of the benzoylurea compounds according to the invention will be explained.

Comparative Compound No. 1 was mentioned by name in the above publication as well as antitumor effects. With this compound, compounds 1 and 2 of the present invention are compared. In Experimental Example 1, the compounds of the invention show no significant superiority in anti-tumor activity. In this Experimental Example 1, the body area in which the cells are inoculated and the area in which the drug is administered are the same. However, there are extreme improvements in the effects of Test Examples 2 and 3, in which the administration examples are different.

Test Example 1

Both the cancer cells and the drug are intraperitoneally administered as in Test Example 1 of the above publication.

In BDF _r mice, p-388 leukemia cells are inoculated intraperitoneally, in an amount of 1 × 10 ⁶ cells / mouse. An active ingredient is administered twice intraperitoneally, ie on the first day and on the fourth day after inoculation. Mice are now observed for 30 days and the number of surviving mice is determined. The ratio (%) of the mean survival time (MST) of the test and control mice is determined. In the comparison group, a physiological saline solution is administered. This receives the rating of 100. The agent administered is a dispersion containing a minor amount of a surfactant (e.g., Tween-80, Atlas Powder Co.) and the active ingredient (Table 1).

Table 1

Compound No. Dose (drug mg / kg / day) T / C (%) of the MST

1 25 168

12.5 173

2 25 210

12.5 150

Vergleichsverb. 1 25 230

12.5 171

Test Example 2

The p-388 leukemia cells are administered intraperitoneally and the drug is administered orally.

In BDF ₁ mouse, p-388 leukemia cells are inoculated intraperiotoneally in an amount of 1 × 10 ⁶ cells / mouse. The active substance is administered orally twice, ie one day and four days after vaccination. The mice are observed for 30 days and the survival rate is determined. The ratio (%) of the mean survival time of the experimental animals and the control animals is determined for each treated group (10 animals / group). The survival days of the control group mice (physiological saline was administered) are given as 100 (Table 2). The active compounds were formulated according to preparation 1.

Table 2

Connection no.

Dose (active ingredient mg / kg / day)

T / C (%) derMST

1 2 comparative 1

100 50 50 25

1600 800 400

173 157 178 139 186 143 116

Test Example 3

The p-388 leukemia cells are administered intraperitoneally while the drug is administered orally.

The ratio (%) of the mean survival time of the experimental animals and the comparison animals is determined in the same manner as in Test Example 2, but formulating the active compounds according to Preparation 2. The results are shown in Table 3.

Table 3

Connection no.

Dose (active ingredient mg / kg / day)

T / C (%) derMST

Vergleichsverb. 1

400

300

200

3200

1600

235 180 143 183 141

Test Example 4

The L-1210 leukemia cells are administered intraperitoneally and the drugs intravenously. ►

In BDF _r mice, L-1210 leukemia cells are inoculated intraperitoneally in an amount of 1 × 10 ⁵ cells / mouse. The remedies are formulated according to preparation 2 and administered intravenously. The mice are observed for 30 days to determine the survival rate. The ratio (%) of the mean survival time of the test animals and the control animals was determined, each treated group comprising 10 animals. The number of survival days of the mice of the control group (physiological saline was administered) receives the rating of 100. The results are shown in Table 4.

Table 4

Connection no.

Dose (active ingredient mg / kg / day)

T / C (%) derMST

12.5

195

Test Example 5

The L-1210 leukemia cells are administered intraperitoneally and the active ingredients are administered orally.

In BDF-i mice, L-1210 leukemia cells are inoculated intraperitoneally in an amount of 1 × 10 ⁵ cells / mouse. The drug formulated according to preparation 1 is administered orally on the first day and on the fourth day after inoculation. The mice are observed for 30 days and the survival rate is determined. The ratio (%) of the mean survival time of the test animals and the control animals is determined with respect to each treated group (10 animals / group). The survival days of the control group mice (physiological saline treatment) were scored 100. The results are shown in Table 5.

Table 5

Connection no.

Dose (active ingredient mg / kg / day)

T / C (%) derMST

100 50

213 165

Test Example 6

The B-16 melanoma cells are administered intraperitoneally and the active ingredients are administered orally.

In BDF _r mice, 0.5 ml of a fluid obtained by dispersing 1 g of B-16 melanoma cells in 8 cc of physiological saline is inoculated intraperitoneally in an amount of 0.5 ml / mouse. The test compound is formulated according to Preparation 1 and administered orally three times, ie one day, seven days and fourteen days after vaccination. The mice are observed for 60 days and the ratio (%) of the mean survival time of the test and control animals is determined, each group comprising 10 animals. The number of survival days of the mice of the control group (physiological saline was administered) is taken as 100%. The results are shown in Table 6.

Table 6

Compound No. Dose (drug T / C (%) of the MST

mg / kg / day)

1 100 139

Test Example 7

The M-5074 ovarian larcoma cells are administered intraperitoneally and the active ingredients are administered orally.

In BCFi mice, M-5074 ovarian larcoma cells are inoculated intraperitoneally in an amount of 1 × 10 ⁶ cells / mouse. The active substance is formulated according to preparation 1 and administered orally three times, ie on the first day, on the seventh day and on the fourteenth day after the vaccination. The mice are observed for 60 days and the ratio (%) of the mean survival time of the test animals and the control animals is determined, treating 10 animals per group. The survival days of the control group mice receiving the physiological saline solution are taken as 100%. The results are shown in Table 7.

table 7

Compound No. Dose (drug T / C (%) of the MST

mg / kg / day)

1 25 139

In the following, the acute toxicity, the dosages and the routes of administration of the benzoylurea compounds according to the invention will be explained.

(1) Acute toxicity

Compound Nos. 1 and 2 of the invention were formulated in accordance with Preparation 1 and intravenously administered groups of 10 animals each (ddY mice) in an amount of 100 mg / kg. None of the animals died. Thus, the acute toxicity (LD ₅₀ ) of compounds Nos. 1 and 2 is at least 100 mg / kg.

(2) dosages

The active substances may be administered continuously or intermittently, in an area where the total dose does not exceed a certain value. This area is determined by animal experiments under different conditions. However, the dose may be varied depending on the route of administration as well as the conditions of the patient or animal being treated (eg age, body weight, sex, sensitivity, diet or the like). The dose may also depend on the interval of administration as well as other agents used in combination and the degree of the disease. The optimal dose and the number of administrations under certain conditions should be determined by the specialist.

(3) Routes of administration

The anti-tumor agents of the invention may be administered orally, intravenously, rectally, intramuscularly or subcutaneously. Oral, intravenous or rectal administration is preferred. Particularly preferred is the oral route. The active compounds of the invention can be formulated using a variety of pharmacologically acceptable carriers; suitable carriers are inert diluents or anabolic foods, as in the case of conventional drugs. Preferred are the additives for oral, intravenous or suppository administration, especially for oral administration.

The compounds of the invention are sparingly soluble in water and organic solvents. Therefore, the formulation is preferably carried out in an aqueous suspension which may contain phospholipids. As a method of preparing an aqueous suspension without phospholipids, the active ingredient may be previously pulverized into a fine powder, followed by adding the fine powder of the active ingredient to an aqueous solution containing a surface-active agent and, if necessary, an antifoaming agent. This mixture is then pulverized in the wet system until 80% of the particles have a particle size of not more than 5 / xm and preferably not more than 2μηι. If necessary, you can add a thickener. Specific examples of surfactants which may be mentioned are: nonionic,

Phosphoric acid esters, hydrogenated castor oil polyoxyethylene, polyoxyethylene sorbitan hydride fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block polymers or the like. As an antifoaming agent, z. Dimethylpolysiloxane, methylphenylsiloxane, a sorbitan-hydride fatty acid ester, a polyoxyethylene-polyoxypropylene cetyl ether, silicone or the like. As a thickener can be z. As guar gum, alginic acid, gum arabic, pectin, starch, xanthan gum, gelatin or the like. Use.

On the other hand, it is also possible to prepare an aqueous suspension containing a phospholipid. Mentioned z. For example, methods in which a phospholipid such as soybean phospholipid or egg yolk phospholipid is used in place of a surfactant using an antioxidant such as α-tocopherol in place of the thickening agent. As another method for producing an aqueous suspension containing a phospholipid, the following method may be mentioned. A phospholipis and an active ingredient of the present invention are dissolved in an organic solvent such as chloroform and, if necessary, an antioxidant is added. Then, the solvent is distilled off under reduced pressure so that a thin layer of the phospholipid is deposited on the inner wall of the container containing the compound of the present invention. Then, a physiologically acceptable aqueous solution is added to the obtained thin layer, followed by shaking or stirring to destroy the thin layer. The suspension obtained is then subjected to ultrasound treatment and centrifugal separation. Then, the residue of the lowermost layer is recovered and washed in the centrifuge with an aqueous solution of a phospholipid (particle size: at most 5 μm, for example, 0.2 to 2 μm).

The active ingredients can be made into tablets, capsules, enteric agents, granules, powders, injectable solutions or suppositories by known methods

 In the following, special preparations are given.

Preparation 1 '

The compound No. 1 is previously pulverized in a centrifugal pulverizer. 5 parts by weight of a compound of polyoxyethylene (60) and hydrogenated castor oil, O, 2 parts by weight of silicone, and 0.3 part by weight of polyoxyethylene-polyoxypropylene block polymer are added to 79.5 parts by weight of a physiological saline solution. whereby one receives an aqueous solution. To this is added 10 parts by weight of the above pulverized compound No. 1 of the invention. The mixture is pulverized in the wet system with a sand mill using glass beads. 80% of the particles then have a particle size of not more than 2μττ>. Then, 5 parts by weight of xanthan gum (2% solution) is added to the obtained aqueous suspension.

Preparation 2

O, 24 parts by weight of Compound No. 1 of the invention and 2.4 parts by weight of purified egg yolk phospholipid and 0.0024 part by weight of α-tocopherol are dissolved in 48.7576 parts by weight of chloroform. Then, the chloroform is distilled off under heating and under reduced pressure in a rotary evaporator. A thin layer of a phospholipid containing the compound no. 1 of the invention is obtained. 48.6 parts by weight of an aqueous, physiological saline solution are added to this thin layer. The flask is immediately shaken vigorously at room temperature and then subjected to ultrasonic treatment for 1 hour while cooling with ice. It is a Sonycator used. This is followed by centrifugal separation at room temperature. The residue of the bottom layer is recovered and washed several times in the centrifuge using the above aqueous physiological saline. Then it is filtered for the purpose of removing bacteria. This gives an aqueous suspension having a particle size of 0, "2 to 2ftm, which contains phospholipid.

Preparation 3

The aqueous suspension of the preparation 2 is freeze-dried to obtain a dry agent containing a phospholipid.

In accordance with the present invention, compounds are provided which exhibit extremely beneficial anti-tumor effects, and even with the choice of routes of administration in which the body area of administration of the drug is far removed from the diseased body area. Further, according to the present invention, the administration can be simplified and the dose can be reduced, so that the pain burden of the patient at the time of administration and the side effects of the agent can be significantly reduced.

Preparation 4

To an aqueous solution obtained by dissolving 1.5 parts by weight of an oxyethylated polyallylphenol phosphate and 0.2 parts by weight of silicone in 53.3 parts by weight of a physiological salt solution are added 40 parts by weight of Compound No. Figure 2 of the invention, which was pulverized in a centrifuge pulverizer. The mixture is then pulverized in a wet system using a sand mill with glass beads. 90% of the particles then have a particle size of not more than 2μπ \. Then 5 parts by weight of xanthan gum (2% solution) are added and an aqueous suspension is obtained.

Preparation 5

The compound No. 1 of the invention is previously pulverized in a centrifugal pulverizer. 5 parts by weight of powdered Compound No. 1 of the invention are added to an aqueous solution obtained by stirring and dispersing 2 parts by weight of egg yolk phospholipid, 0.001 parts by weight of a-tocopherol and 92.999 parts by weight. Sharing a physiological saline solution.

The mixture is then pulverized in a wet system using a sand mill with glass beads. 80% of the particles have a particle size of not more than 2μ, ηη. An aqueous suspension is obtained.

Claims (9)

Claim: where A is a bromine atom or a chlorine atom, characterized in that a substituted nitrobenzene compound of the formula <O> - ^C0R i (II) NO ₂ wherein Ri is an isocyanate group, an amino group or -NHC0NH- / q) -0H- is reacted with a substituted pyrimidine compound of the following formula N ^\: ι ' R ₂ - <O) - A (III) wherein A has the meaning given above and R _{2 is} a halogen atom or a group of the formula Cl wherein R _{3 represents} an isocyanate group or an amino group other than R i, with the proviso that when R 1 represents an isocyanate group or an amino group, R _{2 represents} a group represented by the following formula is and that if Ri is a group of the following formula ; --NHCONH - ^ - OH R _{2 is} a halogen atom. 2. The method according to item 1, characterized in that the substituted nitrobenzene compound is a 2-nitrobenzoyl compound of the following formula : o> - ^coRi i NO ₂ wherein R'i represents an isocyante group or an amino group, and that the substituted pyrimidine compound is a pyrimidinyloxybenzene compound of the following formula ^R 3 Cl where A represents a bromine atom or a chlorine atom and R _{3 represents} an amino group or an isocyanate group other than R'i. 3. The method according to item 2, characterized in that R'i is an isocyanate group and R _{3 is} an amino group. 4. The method according to item 3, characterized in that the reaction is carried out in the presence of a solvent. 5. The method according to item 3, characterized in that the reaction is carried out at a temperature of from 0 to 120 ⁰ C. 6. The method according to item 2, characterized in that R'i is an amino group and R _{3 is} an isocyanate group. 7. The method according to item 6, characterized in that the reaction is carried out in the presence of a solvent. 8. The method according to item 6, characterized in that the reaction is carried out at a temperature of 50 ^c C to reflux temperature. 9. The method according to item 1, characterized in that the substituted nitrobenzene compound is N- (2-nitrobenzoyl) -N '- (3-chloro-4-hydroxyphenyl) urea and that the substituted pyrimidine compound has the following formula: Hawg)