JPH0429979A - Substituted benzoylurea compound or its salt, preparation thereof and anticancer drug containing the same - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, halogen, nitro; R<2>, R<3> are H, alkyl, COR<6> (R<6> is alkyl, alkoxy), SO2R<6>, or R<2> and R<3> form a heterocyclic ring together with the adjacent N; R<4> is halogen, (substituted)alkyl, (substituted)alkoxy, (substituted)alkyltio, nitro; R<5> is halogen, nitro, (substituted) alkyl]. EXAMPLE:N-[4-(5-Bromo-2-pyrimidinyloxy)-3-methylphenyl]-N'-[2-(dimethy lamino) benzoyl]urea. USE:An anticancer drug useful for treating leukemia, melanoma, sarcoma, carcinoma, etc. PREPARATION:A compound of formula II (Hal is halogen) is made to react with a compound of formula III.

Description

Detailed Description of the Invention "Field of Industrial Application" The present invention relates to novel substituted benzoyl urea compounds having an N-substituted benzoyl group on one side of the urea chain and a substituted pyrimidinyloxyphenyl group on the other side, and salts thereof. , intermediates thereof, and anticancer agents containing the substituted benzoyl urea compounds or salts thereof.

[Means for solving the problems of the prior art] Substituted benzoyl urea compounds of the present invention are similar to those described in JP-A-61
-218569, but they have different chemical structures in the substituents bonded to the phenyl ring directly bonded to the urea group, and the present invention has a different anticancer activity compared to the compound described in the above publication. Compound or superior. In addition, JP-A-2-9855 describes benzoyl urea compounds, but the presence or absence of a substituent on the carbon atom or nitrogen atom of the carbonyl urea chain and the type of substituent of the amino group as a substituent of the benzoyl group The two have different chemical structures.

In addition, the compound of the present invention is a conventional benzoyl urea 1] Solubility in non-aqueous solvents is improved compared to other compounds.

The present inventors have determined whether the substituted benzoyl urea compound represented by the general formula (I) or its salt exhibits high anticancer activity and also shows a tendency to be difficult to dissolve in non-aqueous solvents compared to conventional benzoyl urea compounds. The inventors have discovered that this tendency can be improved and have completed the present invention.

The present invention provides - formation (I) l [wherein R1 is a hydrogen atom, a halogen atom or a nitro group, and R2 and R3 are a hydrogen atom, an argyl group,
COR6 group (Rr' is an alkyl group or alkoxy group) or 502R6 group (R6 is as described above), R2 and R3 may form a heterocycle together with adjacent N atoms, and R4 is a halogen group. atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a 21.4 group, and R5 is a halogen atom, a 21.4 group, or an optionally substituted The present invention relates to a substituted benzoyl urea compound or a salt thereof represented by [alkyl group], a method for producing them, an intermediate thereof, and an anticancer agent containing the substituted benzoyl urea compound or salt thereof.

In the above-mentioned -formation (I), the substituents for the optionally substituted alkyl group, optionally substituted alkoxy group, and optionally substituted alkylthio group contained in R4 include:
Halogen atom: alkoxy group: alkylthio group diano group: thiocyan-1 group: alkoxycarbonyl group: carboxyl group-alkylthiocarbonyl group, etc. Substituents for the optionally substituted alkyl group included in R5 include halogen atoms, etc., and the number of substituents contained in R4 and R5 may be one or more.

Examples of the heterocyclic group formed by R2 and R3 together with the adjacent N atom include a morpholino group, an aziridinyl group, a pyrrolidinyl group, a piperidino group, and a pyrrolyl group.

The salt of the hensyl urea compound may be used as a pharmaceutical compound.
Any permissible substance may be used, such as salts of hydrogen halides such as hydrochloric acid and hydrobromic acid, salts of alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium and calcium. can be mentioned.

The halogen atoms contained in R1, R4 and R5 are:
Examples include fluorine atom, chlorine atom, bromine atom, and iodine atom.

In the above-mentioned -formation (I), the alkyl moiety constituting the alkyl group and alkoxy group contained in R2 and R3, R
an alkyl moiety constituting an optionally substituted alkyl group, an optionally substituted alkoxy group, and an optionally substituted alkylthio group contained in 4, an alkyl moiety constituting an optionally substituted alkyl group contained in R5, and Alkyl constituting an optionally substituted argyl group, an optionally substituted alkoxy group, and an alkoxy group as a substituent of an optionally substituted alkylthio group, an alkylthio group, an alkoxycarbonyl group, and an alkylthiocarbonyl group contained in R4 The part preferably has a carbon number of 1 to 1.
10, such as methyl group, ethyl group, propyl group,
Examples include butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, dedyl group, and more preferably those having 1 to 4 carbon atoms. They also include structural isomers of straight or branched fatty chains.

In the above-mentioned -Formation (1), a substituted benzoyl urea compound represented by the following -Formation (I)'' or a salt thereof is preferred.

General formula (I)': [In the formula, R1, R2, R3, R4 and R5 are as described above. ] Preferred substituents included in R1 include hydrogen atoms, and preferred substituents included in R2 and R3 include alkyl groups. It is also desirable that R2 and R3 form a heterocycle together with the adjacent N atom. Desirable substituents included in R4 include a halogen atom or an optionally substituted alkyl group, and more desirable ones include an optionally substituted alkyl group. Desirable substituents included in R5 include halogen atoms. Said-formation (I)
Among the substituted benzoyl urea compounds or salts thereof, the most desirable compound is N-(4-(
5-Bromo-2-pyrimidinyloxy)-3-methylphenyl)-N[2-(dimethylamino)benzoyltourea, N-(1-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl)- N'-(2-(dimethylamino)benzoyltourea hydrochloride, N[4=(
5-bromo-2-pyrimidinyloxy)3-1-lifluoromethylphenyl)-N[2-(dimethylamino)benzoyltourea, N-(1-(5-ri-4-2-pyrimidinyloxyL-): 3-1-lifluoromethylphenyl)-N' [2-(dimethylamino)benzoyltourea, N-(4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl) -N' -(2 -(dimethylamino)benzoyltourea, N-[4(5-bromo-2-pyrimidinyloxy)-3methylphenyl) -
N'-(2-(ditylamino)benzoyltourea,
N-(4-(5-chloro-2-pyrimidinyloxy)-
Examples include 3-methylphenyl)-N'-(2-(dithylamino)benzoyltourea.

The benzoyl urea compound of the above-formation (I) can be produced by the following method.

(A) (In the formula, R1, R2, R3, R4, and R5 are as described above, and Hal is a halogen atom) This reaction is usually carried out at a temperature of 0°C to reflux temperature, and the reaction time is usually 1 to 24
It's time. Further, a solvent may be used in this reaction, and examples of the solvent include benzene, toluene, xylene, chlorobenzene, hexadi, chloroform, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, Examples include hexamethylphosphoric acid 1-helamide, water, and the like.

(B) ■ (In the formula, R1, R4 and R5 are as described above, and A1
and A2 is -NCO group or -Ni2 group, and A1 or -
In the case of NGO group, A2 is -NH2 group, and A1 or Ni2
In the case of a group, A2 is an -NGO group, R2" and R3' are an argyl group, a C0R6 group (R6 is an alkyl group or an alkoxy group) or a 5O2R6 group (R6 is as described above), and R" and R3' may form a heterocycle together with the adjacent N atom.] This reaction is usually carried out in the presence of a solvent at a temperature of 0°C to reflux, and the reaction time is usually 1 to 1.
It is 24 hours. As a solvent, benzene, toluene,
xylene, tetralobenzene, hexane, chloroform,
Examples include methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and the like.

[CD (I-2) (wherein Rl, R4 and R5 are as described above,
B1 is a phthaloyl group) Examples of the hydrazines include hydrazine, alkylhydrazine, and phenylhydrazine.

This reaction is usually carried out in the presence of a solvent at a temperature of 0°C to reflux, and the reaction time is usually 1 to 24 hours. Examples of the solvent include methanol, ethanol, chloroform, methylene chloride, and the like.

CD) (I-3) (wherein, R1' is a hydrogen atom or a halogen atom, and R
``represents a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group, and R'' represents a halogen atom or an optionally substituted alkyl group) This reaction It is carried out according to the usual reduction method.

Examples of the reduction method include a reduction method using metals such as reduced iron and zinc, and a catalytic reduction method using a catalyst such as platinum and palladium on carbon.

The reaction is usually carried out at a temperature of 0°C to reflux, and the reaction time is usually 1 to 100 hours.

(E) ■ (In the formula, R', R'', R4 and R5 are as described above) This reaction is usually carried out at a temperature of 0°C to reflux, and the reaction time is usually 0.1 to 24 hours. In addition, a solvent and a base may be used in this reaction, and examples of the solvent include benzene, toluene, xylene, chlorobenzene, pyridine,
Hexane, cyclohexane, chloroform, methylene chloride, dichloroethane,.

diethyl ether, tetrahydrofuran, dioxane,
Examples include ethyl acetate, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, etc.
Examples of bases include organic lithiums such as n-butyllithium, tert-butyllithium, and phenyllithium; inorganic bases such as thorium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases such as triethylamine and n. Can be mentioned.

CF) Pyridine (in the formula, R1, R2", R3", R4 and R5 are as described above) The reaction conditions may be the same as in (E) above.

Note that the compounds represented by -formation (■) and (■) can be produced according to the method of CB) above. In the above-mentioned -formation (IV), the compound having A1 or -NH2 group is obtained by, for example, reacting 2-halogenobenzamides with the secondary amines represented by the above-mentioned -formation (I) according to the method of the above-mentioned (A). It can be manufactured by A1 or -N
For the CD group compound, the benzamide obtained by the above method is mixed with oxanyl chloride in the presence of the same solvent as mentioned in the above method CB) at O'C to reflux temperature for 1 to 10 minutes.
It can be produced by reacting for 0 hours. The compound represented by the above-formation (VI) can be obtained by reacting 2-aminobenzamides with phthalic anhydride in the presence of a solvent such as chloroform, methylene chloride, or pyridine at O'C to reflux temperature for 1 to 100 hours. or the benzamides obtained by the above method and oxanyl chloride at 0°C to reflux temperature in the presence of the same solvent as mentioned in the above method CB) for 1-100 hours. It can be produced according to the method [B] above using isocyanates obtained by the reaction.

Further, the salt of the substituted benzoyl urea compound can be easily obtained by a conventional manufacturing method.

In the compound represented by the above-formation (IV), R2 and R
A compound (shown below in -formation (XII)) in which " is a C0R6 group (R6 is an alkyl group or an alkoxy group) or a 502R6 group (R' is as described above) is new. Also, this - A1 or NH2 in the compound of formation (IV)
The base is preferred.

-Formation (XII): [In the formula, R2''' and R3'' are an alkyl group, C0R6
group (R6 is an alkyl group or an alkoxy group) or 5
is an O2R6 group (R6 is as described above), and R2''
and R3′′ is a COR@ group or 502
R6 group, and R1 and A1 are as described above.] [Example] Next, a specific synthesis example of the compound of the above-mentioned -formation (I) will be described.

Synthesis Example I Synthesis of N-(4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]N'-(2-(dimethylamino)benzoyl)urea (compound No. l below) 4-(5 -bromo-2-pyrimidinyloxy)3-methylphenylisocyaner) 3.73 g, 2(dimethylamino)/\lentusmid 2.0 g and toluene 457
The mixed solution of np was refluxed for 4 hours to react.

After the reaction was completed, the mixed solvent was cooled and insoluble materials were removed by filtration. The obtained filtrate was concentrated and subjected to silica gel column chromatography (n-hexane:ethyl acetate-6,
4) to obtain the desired product (melting point 98-104°C)
3.9 g was obtained (compound No. 1 described later).

Synthesis Example 2 Synthesis of N-(4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl)N'-(2-(dimethylamino)benzoyl)urea hydrochloride (compound No. 2 described later) The target product obtained in Example 1 (compound No. described below).

1) 1.5 g was dissolved in 20 ml of diethyl ether and 50 ml of methylene chloride, and the solution was saturated with hydrochloric acid gas.

Thereafter, the saturated solution was stirred for 1 hour and cooled, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ether to obtain 1.55 g of the target compound (melting point: 117 to 123°C) (compound No. 2 described below).

Synthesis Example 3N-(2-aminobenzoyl)-N'(4-(
Synthesis of 5-bromo-2-pyrimidinyloxy)-3-chlorophenyl urea (compound No. 26 below) N-(4-
A mixture of 1.0 g of (5-bromo-2-pyrimidinyloxy)-3-chlorophenyl)-N'-(2-nitrobenzoyl)urea and 30 ml of glacial acetic acid is heated to 80°C, and reduced iron is added to it. .57 g was added to the stoppers under stirring. Thereafter, the mixture was stirred and reacted at the same temperature for 30 minutes.

After the reaction was completed, the reaction mixture was poured into water, and insoluble matter was filtered off. The insoluble matter collected by filtration was vacuum dried and purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate - 7:3) to obtain the desired product (melting point: 196-2
00°C) 0.4g (compound No. 26 described later) was obtained.
.

Synthesis Example 4 Synthesis of N-(4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl)N'-(2-morpholinobenzoyl)urea (compound No. 34 below) (1) 5 g of 2-fluorobenzamide and 25 ml of morpholine were reacted for 18 hours at 00°C.

After the reaction, the reaction product was cooled, excess morpholine was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate = 3:7) to obtain 2-morpholinobenzamide (melting point 112~
119°C) 2.8 g was obtained.

(2) 4-(5-bromo-2-pyrimidinyloxy)-
A solution of 3.28 g of 3-methylphenylisocyanate dissolved in 30 m of toluene (!) was added dropwise to 2.21 g of 2-morpholinobenzamide obtained in step (1) with stirring. Then, the mixture was heated at 100°C. The mixture was allowed to react for 3 hours.

After the reaction, toluene was distilled off, and silica gel column chromatography (developing solvent: n-hexane: ethyl acetate) was performed.
1:1) to obtain the desired product (melting point 67-70°C
1.25 g of amorphous (compound No. 34 described below) was obtained.
).

Synthesis Example 5 N-(4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl]N'-(2-(
dimethylamino)benzoyl]urea (compound No.
, 11) Synthesis of 4-(5-chloro-2-pyrimidinyloxy)-3-
Methylphenyl isocyaner'r-3, 33 g, 2(dimethylamino)benzamide 2.1 g and toluene 30
The mixed solution of m1 was reacted at 100°C for 4 hours.

After the reaction was completed, the mixed solution was cooled and insoluble matter was removed by filtration. The obtained filtrate was concentrated and subjected to silica gel column chromatography (n-hexane:ethyl acetate-6=
4) to obtain 2.84 g of the target product (melting point: 48-52° C1, in an unfinished form) (compound No., Il, described later).

Synthesis Example 6 Synthesis of N-(4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]N'-(2-(diethylamino)benzoyl)urea (compound No. 33 below) 4-(5- 3.27 g of bromo-2-pyrimidinyloxy)-3-methylphenyl-isocyanate, 2.05 g of 2-(diethylamino)benzamide and 30 g of toluene.
The mixed solution of m1 was reacted at 100°C for 3 hours.

After the reaction was completed, the mixed solution was cooled and insoluble matter was removed by filtration. The obtained filtrate was concentrated and subjected to silica gel column chromatography (n-hexane:ethyl acetate = 7
: 3) to obtain the desired product (melting point 39-43°C1
Amorphous form) 1.45g was obtained (compound No. 33 described later).
).

Synthesis Example 7N-(2-(acetylamino)benzoyl)
Synthesis of -N' -C4-(5-bromo2-pyrimidinyloxy)-3-methylphenyl]urea (Compound No. 49 below) N-(2-aminobenzoyl)- synthesized according to Synthesis Example 3 above 1.3 g of N'-(4-(5-bromo2-pyrimidinyloxy)-3-methylphenyl)urea (compound No. 27 described below) was added to 30 ml of pyridine, and 0.25 mj of acetyl chloride was added dropwise under water cooling. .

After stirring at room temperature for 2.5 hours, pyridine was distilled off and purified by silica gel column chromatography (methylene chloride: ethyl acetate = 7:3) to obtain the desired product (melting point 18
6-191'C) 1.18g (compound N described below) was obtained.
o, 49).

Next, representative examples of the compounds of the above-mentioned -formation (I) are shown in Table 1.

Compound No., 56 Compound No., 57 Compound No., 58 Compound No., 59 Compound No., 6O N-(3-(5-chloro-2-pyrimidinyloxy)-4-methylphenyl) -N'-[:2-( dimethylamino)benzoyl]urea Melting point: 134-136.5°C N-(1-(5-chloro-2-pyrimidinyloxy)-4-methylphenyl) -N' -(2-(diethylamino)benzoyl]urea N-(3-(5-bromo-2-pyrimidinyloxy)- 4-methylphenyl) -N'-1: l-(diethylamino)benzoyl]urea N-(3-(5-bromo-2-pyrimidinyloxy)-4-1-lifluoromethylphenyl)-N [2-( dimethylamino)benzoyltourea compound No. 61 N-(3-(5-bromo-2-
P-3880 Ikemia, L-1210 Leukemia, B-
16 melanoma, M-5076 monkey: ]-ma (sarc
oma, ), Colon 38, Colon (C
olon) 26, Lewis Lang Carcinoma (L
euis lung carcin.

It is effective against cancers such as ma). On the other hand, in order to determine the stability of test compounds as antineoplastic agents, certain in vivo test systems and process test sheets have been developed by the National Institute of Diseases
ational Cancer In5 position
) has been developed by. These are r Caner C
Hemotherapy Reports, I [Part, Volume 3, No. 2. (1972), Plan (Der
an), Greenberg
, MacDonald, Schumacher and Abo
tt).

These in-process test charts measure standardized preliminary tests commonly performed in the testing field for anti-tumor drugs.

Of these systems, lymphocytic leukemia P388 is of particular significance to the present invention. These neoplasms were discovered in mice. - Good anti-tumor activity in human leukemia, generally indicated by a % increase in mean survival time of treated (T) animals compared to control (C) animals in these process test tables. suggesting similar results.

Next, the anticancer activity, solubility in non-aqueous solvents, dosage, and method of administration of the compound (1) will be described.

(1-1) Anticancer activity test example 1 (intraperitoneal - intraperitoneal) After intraperitoneal transplantation of P-388 leukemia cells into BDF mice at a ratio of 1X10' mice/mouse, on the 1st day of the month and the 8th day of the 2nd day. The test drug was administered intraperitoneally over several times.

The survival rate of mice in the control group administered with physiological saline was increased by 8 days (ILS,
%), the increased life extension rate (ILS, %) of each treatment area was determined, and the results are shown in Table 2.

In addition, among the test drugs, Compound N002 was formulated according to Formulation Example 9 described later, and the others were formulated according to Formulation Example 8 described later.

Table 2 (continued from Table 2) (Note) *Increase life span (ILS, %)...Increase Life 5p
an) and can be calculated using the following formula.

Increased survival rate (ILS, %) (1-1) Anticancer activity test example 2 (intraperitoneal-intravenous injection) P-388 leukemia cells were injected into BDF and mice lXl0'
2 on day 1 and 8 after intraperitoneal transplantation
The test drug (prepared according to Formulation Example IO below) was administered into the tail vein over several times.

The life and death of mice were observed for 30 days, and the number of survival days of mice in the control group administered with physiological saline was increased. Survival prolongation rate (ILS, %)
Assuming 0, the incremental life extension rate 1 (ILS, %) of the treatment area was calculated. Dosage of compounds No. 1 and 11 (active ingredient m
g/kg/day) or 10 mg/kg, ILS (
%) were 46 and 27, respectively.

(Note) *The method of calculating the increased life extension rate is the same as in Test Example 1 above.

(2) Dissolution pressure test example 3 in non-aqueous solvent A magnet for stirring was placed in a 10 ml or 10 ml eggplant flask with a stopper, and the test compound 50
m1, and then an appropriate amount of the desired solvent was added thereto to determine the solubility, and the results are shown in Table 3 (the temperature at the time of solubility measurement was 18 to 20°C).

Table 3 (Note) Medium-chain fatty acid triglyceride has the trade name 0DO1
Nisshin Oil Co., Ltd. (made in Japan) was used.

(3) Dosage and method of administration In the case of animals, the method of administration is intraperitoneal injection, intravenous injection, local administration, etc., or oral administration, and in the case of humans, intravascular injection into veins or arteries, or , as injections for local administration, or as oral preparations, herbal medicines, etc.
The dosage is determined by taking into account the results of animal tests and various circumstances, and the total dosage is administered continuously or intermittently within a range that does not exceed a certain amount. However, the dose may be changed as appropriate depending on the administration method, the condition of the patient or treated animal, such as age, weight, sex, sensitivity, diet, administration time, concomitant drugs, and the degree of the patient or the disease. Of course, the appropriate dose and frequency of administration under certain conditions must be determined by a specialist's appropriate dose determination test based on the above guidelines.

The anticancer agent of the present invention is formulated in the same manner as ordinary pharmaceuticals, for example, by containing the active ingredient and various pharmacologically acceptable adjuvants, such as inert diluents, and administering these orally. It can be injected intravenously or administered as a herbal medicine.

Further, the content of the active ingredient in the anticancer agent of the present invention varies depending on various conditions and cannot be unconditionally defined, and it is sufficient to contain the active ingredient in the same manner as in the case of ordinary anticancer agents, for example, at least 0.1% or less. It is possible to contain the above effective ingredients.

The compound of -formation (I) can be formulated into halves or capsules, for example by direct admixture with polyethylene glycol, or into an aqueous suspension. When preparing an aqueous suspension, the method for manufacturing an aqueous suspension that does not contain phospholipids is, for example, by first pulverizing the active ingredient, then adding a surfactant and, if necessary, an antifoaming agent to an aqueous solution. The above-mentioned pulverized active ingredient compound is added and wet-pulverized to reduce the particle size to 5 μm or less, for example, 2 μm.
One method is to make it as follows or 8096 and add a thickener if necessary. Examples of surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sucrose ester, polyoxyethylene polyoxyethylene block polymer, oxyethylated polyallylphenol phosphate l-, etc. Examples of antifoaming agents include:
dimethylpolysiloxane, methylphenylsiloxane,
Examples of thickeners include sorbitan fatty acid ester, polyoxyethylene, polyoxypropylene cetyl ether, and silicone. Examples of thickeners include guar gum, alginic acid, gum arabic, pectin, starch, xanthan gum, and seratin. On the other hand, as a method for producing an aqueous suspension containing phospholipids, for example, a phospholipid such as soybean phospholipid or egg yolk phospholipid is used instead of the surfactant in the above method, and α1 is used instead of using a thickener.
~An example is a method using an antioxidant such as coferol.

Furthermore, these can be made into tablets, capsules, enteric coated formulations, powders, injections, halved, etc. by conventional pharmaceutical methods.

Compared to conventional benzoyl urea compounds, the compounds of the present invention can be prepared using pharmacologically acceptable non-aqueous solvents such as medium-chain fatty acid trigylcerite, soybean oil, sesame oil, olive oil, camellia oil, rapeseed oil, corn oil, and peanut oil. Since it is easily dissolved in menjitsu oil, etc., it can be easily formulated into a fat emulsion for intravenous injection. As a method for preparing this fat emulsion, for example, the compound of the present invention and phospholipids, and if necessary, an emulsification auxiliary agent, an emulsion stabilizer, etc. are added, these are dissolved in the non-aqueous solvent, water is added, and the mixture is heated in a homogenizer. There is a method of homogenizing the dispersion liquid so that the average particle size is 1.0 μm or less. The phospholipids used here are:
Examples include purified egg yolk phospholipids and purified soybean phospholipids.
Examples of emulsification aids include fatty acids having 6 to 22 carbon atoms, which are commonly used in pharmaceuticals, their alkali metal salts such as thorium and potassium, and their alkaline earth metal salts such as calcium. Examples of emulsification stabilizers include cholesterol, etc. , phosphatidic acid and the like.

G In order to make the fat emulsion isotonic, an isotonic agent such as glycerin or glucose may be added. Examples of the homogenizer used here include a pressurized injection type homogenizer and an ultrasonic homogenizer.

Next, specific formulation examples of the anticancer agent of the present invention will be given.

Preparation: 70 mg of amorphous powder of compound No. I was mixed with lactose 3
Mix well with 0mg and fill each loomg into capsules to prepare oral capsules.

Formulation Example 2 86.5 parts by weight of the amorphous powder of Compound No. 3 was added to 1 part by weight of glucose, 10 parts by weight of cornstarch, and 5%
The mixture is uniformly mixed with 1.5 parts by weight of corn starch paste liquid and made into granules by a wet method, and then 1 part by weight of magnesium stearate is added and compressed into tablets for oral use.

Formulation Example 3 5 g of the above compound No. 4 was added to 5 g of dimethylacetamide.
ml and then 25 ml of coconut oil. Pegnol HC,
Add 7 g of -17 (Toho Chemical Industry Co., Ltd.) and 6 g of HO-10M (Toho Chemical Industry Co., Ltd.) to prepare an emulsion. The same amount of sterilized distilled water is added to this emulsion and subjected to ultrasonic treatment for 20 to 30 seconds to form an emulsion.

Formulation Example 4 The compound No. 26 was previously pulverized using a centrifugal pulverizer, and then polyoxyethylene (Go), 5 parts by weight of hydrogenated castor oil, 0.2 parts by weight of silicone, and polyoxyethylene.
Add 0.3 parts by weight of polyoxypropylene block polymer to 79.5 parts by weight of physiological saline to make an aqueous solution, add 10 parts by weight of the above-mentioned pulverized compound No. 3, and wet-process with a sand mill using glass beads. crushed (
After 80% particles with a particle size of 2 μm or less), xanthan gum (2%
Add 5 parts by weight of liquid) to make an aqueous suspension.

Formulation Example 5 Oxyethylated polyallylphenol phosphate
1 to 1.5 parts by weight and 0.2 parts by weight of silicone were dissolved in 53.3 parts by weight of physiological saline.
, 140 parts by weight were added, and the mixture was wet-milled in a sand mill using glass beads (particle size of 2 μm or less or 90%), and then 5 parts by weight of xanthan gum (2% solution) was added to prepare an aqueous suspension.

Formulation Example 6 The compound NO44 is pulverized in advance using a centrifugal pulverizer. 5 parts by weight of the pulverized compound No. 4 was added to an aqueous solution prepared by stirring and dispersing 2 parts by weight of egg yolk phospholipids, 0.0 parts by weight of α-tocopherol, and 92.999 parts by weight of physiological saline, and the mixture was sand milled using glass beads. (particle size: 2 μm or less (80%)) and form an aqueous suspension.

Formulation Example 7 The above-mentioned compound No. 3 was previously pulverized using a centrifugal pulverizer, and then 5 parts by weight of polyoxyethylene (60) hydrogenated castor oil was added to 60 parts by weight of physiological saline to form an aqueous solution, and the above-mentioned fine powder was added thereto. After adding 30 parts by weight of Compound No. 3 and wet-pulverizing it in a sand mill using glass beads (particle size of 2 μm or less or 80%), xanthan gum (2% liquid) 5
Add parts by weight to form an aqueous suspension.

Formulation Example 8 Oxyethylated polyallylphenol phosphate
1-1.5 parts by weight of Compound No. 1, 0.2 parts by weight of silicone, and 0.3 parts by weight of polyoxyethylene/polyoxypropylene block polymer dissolved in 81 parts by weight of physiological saline, 10 parts by weight of the above compound No. 1 was added. In addition, after wet grinding with a sand mill using glass beads (particle size of 2 μm or less or 90%), 7 parts by weight of xanthan gum (296 liquid) was added to prepare an aqueous suspension.

Formulation Example 9 1 part by weight of Compound No. 2 to polyethylene glycol #400 (Gyudon Chemical Co., Ltd., Chemical Use, M).

Add 100 parts by weight of W, 380-420) and dissolve to form a uniform solution.

Formulation Example 1O 2.4 parts by weight of egg yolk phospholipid and the above compound No. 10
．． 2 parts by weight of medium chain fatty acid triglyceride (product name 0D)
Add 40 parts by weight of O1 Nisshin Oil and dissolve it using a homomixer, add 57.4 parts of distilled water, coarsely emulsify using a homomixer, and emulsify using a sonic homogenizer to obtain an average particle size of 1. .0 fat emulsion.

"Effects of the Invention" The present invention relates to a novel substituted benzoyl urea compound represented by -formation (I) ultraμl (wherein R1, R2, R3, R4 and R5 are as described above), and They are useful in the treatment of cancers such as leukemia, melanoma, sarcoma, and carcinoma in mammals.

Claims (1)

[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a hydrogen atom, a halogen atom, or a nitro group, and R^2 and R^3 are each a hydrogen atom, an alkyl group, a COR^6 group (R^6 is an alkyl group or an alkoxy group), or a SO_2R^6 group (R^6 is as described above), and R^2 and R^ 3 may form a heterocycle with the adjacent N atom, and R^4 is a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group. and R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group] or a salt thereof. 2. General formula (II): ▲ Numerical formulas, chemical formulas, tables, etc. group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group; R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group; Hal is a halogen atom] Compounds represented by and general formula (III): ▲ Numerical formulas, chemical formulas, tables, etc. or an alkoxy group) or SO_2R^6 group (R^6 is as described above), and R^2 and R^3 may form a heterocycle together with adjacent N atoms] General formula (I) characterized by reacting with a compound that is: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is as described above] or a salt thereof. 3. General formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A^1 is -NCO group or -NH_2 group,
R^1 is a hydrogen atom, a halogen atom or a nitro group,
R^2' and R^3' are alkyl groups, COR^6 groups (R
^6 is an alkyl group or an alkoxy group) or SO_
2R^6 groups (R^6 is as described above), and R^
2' and R^3' may form a heterocycle with the adjacent N atom] and general formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A^2 is -NH_2 group or -NCO group,
When A^1 is -NCO group, A^2 is -NH_2 group, when A^1 is -NH_2 group, A^2 is -NCO group, and R^4 is a halogen atom, which may be substituted. an alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group, and R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group] General formula (I-1) characterized by reaction: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2', R^3', R^4 and R^
5 is as described above] or a salt thereof. 4. General formula (VI): ▲ Numerical formulas, chemical formulas, tables, etc. group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group, R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group, and B^1 is a phthaloyl group. A general formula (I-2) characterized by reacting a compound represented by ] with hydrazines: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^4 and R^ 5 is as described above] or a salt thereof. 5. General formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1' is a hydrogen atom or a halogen atom,
R^4' is a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group, and R^5' is a halogen atom or an optionally substituted alkyl group. [In the formula, R^1', R^4' and R^5' is as described above] or a salt thereof. 6. General formula (I-2): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a hydrogen atom, a halogen atom, or a nitro group, and R^4 is a halogen atom, even if substituted. is an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group, and R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group] General formula (VIII): Hal. -R^2" [In the formula, R^2" is an alkyl group, COR^6 group (R^6
is an alkyl group or an alkoxy group) or SO_2R
^6 groups (R^6 is as described above), and Hal.
is a halogen atom] General formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2'', R ＾4 and R＾5 are as described above.] 7. General formula (IX): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R＾1 is It is a hydrogen atom, a halogen atom, or a nitro group, and R^2'' is an alkyl group, a COR^6 group (R^6
is an alkyl group or an alkoxy group) or SO_2R
^6 group (R^6 is as described above), R^4 is a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group and R^5 is a halogen atom, a nitro group, or an optionally substituted alkyl group] and a compound represented by the general formula (X): Hal. -R^3" [In the formula, R^3" is an alkyl group, COR^6 group (R^6
is an alkyl group or an alkoxy group) or SO_2R
^6 groups (R^6 is as described above), and Hal.
is a halogen atom] General formula (X I) characterized by reacting with a compound represented by: ▲There are numerical formulas, chemical formulas, tables, etc.▼ ^3”, R^4 and R^
5 is as described above] or a salt thereof. 8. General formula (I): ▲ Numerical formulas, chemical formulas, tables, etc. group, COR^6 group (R^6 is an alkyl group or alkoxy group) or SO_2R^6 group (R^6 is as described above), and R^2 and R^3 are adjacent N atoms may form a heterocycle with R^4, R^4 is a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or a nitro group, and R^5 is 1. An anticancer agent comprising a substituted benzoyl urea compound or a salt thereof as an active ingredient. 9. General formula (X II): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A^1 is -NCO group or -NH_2 group,
R^1 is a hydrogen atom, a halogen atom or a nitro group,
R^2"' and R^3"' are an alkyl group, a COR^6 group (R^6 is an alkyl group or an alkoxy group), or S
O_2R^6 groups (R^6 is as described above),
Either R^2"' or R^3"' is COR^6
or SO_2R^6 group].