JPS625959A - Benzoylurea compound - Google Patents

Abstract

NEW MATERIAL:A benzoylurea compound shown by the formula I (X is halogen, nitro or trifluoromethyl; Y and Z<2> are H or halogen; Z<1> is halogen or trifluoromethyl; Z is CH or N; when X is halogen and A is CH, Z<2> is halogen). EXAMPLE:N-( 2-Chlorobenzoyl )-N'-[3-chloro-4-(5-trifluoromethyl-6- chloro-2-pyri dyloxy)phenyl]urea. USE:Useful as a drug effective for remedying cancers, being administered orally, intravenously, intramuscularly or hypodermically. PREPARATION:For example, a starting raw material is reacted in a solvent such as benzene, toluene, dimethyl sulfoxide, etc., under heating at 0-120 deg.C as shown by the reaction formula to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to benzoylurea compounds.

In detail, the general formula (1) (wherein, and the AFi group = CH- or =N-, provided that X
When is a halogen atom and A is a group =CH-, Z8 is a halogen atom. ) is related to a benzoylurea compound represented by

The halogen atoms include fluorine, chlorine, bromine, and iodine.

BACKGROUND ART Conventionally, a number of anticancer substances, extracts from lily pads, or synthetic substances have been used as anticancer agents. Examples include mitomycin, adriamycin, pleomycin, vincristine, PSK, nitrogen mustards, and 5-fluorouracil.

As a result of intensive research on numerous synthetic substances, the inventors obtained the novel finding that the benzoyl urea compound represented by the general formula (I) above is effective in the treatment of cancer. This led to the proposal of an inventive compound.

The benzoyl urea compound according to the present invention can be produced, for example, by the following method.

[A]

(In the formula, X, Y, Zj, Z' and A are as described above.) Examples of the solvent used in the above reaction include benzene, toluene, xylene, pyridine, dioxane, and dimethyl sulfoxide.

CB) (In the formula, X, Y, Zl, Z2, and A are as described above.) Examples of the solvent used in the above reaction include toluene, xylene, monochlorobenzene, 6[ethyl, dioxane, etc.].

Further, the raw material aniline compound or phenyl isocyanate compound used in each of the above reactions is left behind, for example, by the following method.

[C]

(In the formula, Y, Zl, Z" and A are as described above.) Examples of the alkaline substance used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and the solvent includes dimethyl sulfoxide. , aprotic polar solvents such as dimethylformamide and hexamethylphosphoramide, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone.In addition, this condensation reaction is carried out in the presence of kffl gas. This is the preferred method.

[D]

(In the formula, Y, Zl, Zj and A are as described above.) The solvent used is one that is inert to phosgene, such as toluene, xylene, monochlorobenzene, ethyl acetate, dioxane, etc. It will be done.

Synthesis example 1. N-(2-chlorobenzoyl)-N'-[5
-Chloro-4-1(5-)lifluoromethyl-6-chloro-2-pyridyloxy)phenylcochlear synthesis flask was preliminarily charged with
．． A solution dissolved in dimethyl sulfoxide 20- and 1.12 f of potassium hydroxide were added to 43f' and heated at 140°C for 1 hour to generate potassium salt. This was cooled to room temperature, and 2,6-dichloro-5-)! A solution of 2.161 J fluoromethylbidine dissolved in 10-dimethyl sulfoxide was added dropwise over 10 minutes, and the mixture was reacted at 100° C. for 2 hours. After the reaction was completed, the product was poured into water and extracted with methylene chloride.

The extract was washed with water, dried over anhydrous sodium sulfate, and the methylene chloride was distilled off to give 3-chloro-4-(5-)1jfluoromethyl-6-chloro-2-pyridyloxy)aniline (melting point 7).
6-78°C) 2°16ft was obtained.

In a flask, dissolve 6-chloro-4-(5-trifluoromethyl-6-chloro-2-pyridyloxy)aniline &2f in dioxane 40- and add 7IC solution.
To this, 1.8 2-chlorobenzoyl isocyanate
A bath solution in which f was dissolved in dioxane 20 - 10 minutes under stirring
After dropping the solution over a period of minutes, the mixture was allowed to react at room temperature for 5 hours.

After the reaction was completed, the product was poured into water, and the precipitate was filtered, washed with cold methanol, and dried to obtain 4.6f of the desired product with a melting point of 194-196°C.

Synthesis example 2. N-(2-nitrobenzoyl)-N'-[6
-Chloro-4-(5-trifluoromethyl-6-chloro-2-pyridyloxy)phenyltaurea synthesis flask was charged with dioxane 20- and 3-chloro-4-(
12 tf of 5-trifluoromethyl-6-chloro-2-pyridyloxy)aniline was added and dissolved. To this, 2-nitrobenzoylin 7-anate t 9 f
A solution dissolved in 'Jk dioxane 10- was added dropwise over 15 minutes with stirring, and then reacted at room temperature for 6 hours.

After the reaction is completed, the product is poured into total water, filtered to form a precipitate, and washed with methanol to obtain the desired product having a melting point of 187-190°C.4.
8g was obtained.

Synthesis Example A N-(2-bromobenzoyl)-N'-[
Synthesis of 3-chloro-4-(5-1lifluoromethyl-6-chloro-2-pyridyloxy)phenyltaurea 75- toluene was placed in a flask, saturated by blowing in dry phosgene gas, and then 3-chloro- 4-(5-)IJ
A solution of fluoromethyl-6-chloro-2-pyridyloxy)aniline 9f) toluene 75- was added dropwise at a reaction temperature of 80° C. while passing phosgene so that the system contained excess phosgene. After dropping, add 5 more
After passing phosgene for 10 minutes, increasing the temperature and distilling off excess phosgene, 6-chloro-4-(5-
) ') Fluoromethyl-6-terro-2-pyridyloxy) phenyl isocyanate was obtained. Furthermore, 2-
A toluene solution of 30 mm of bromobenzamide was added, the temperature was raised, and the reaction was carried out under reflux (110° C.) for 20 #f.

The reaction product was poured into 200 liters of water, and 1 liter of ethyl acetate was added.
After adding ov'l and extracting, drying the organic layer with Glauber's salt,
IE was distilled off. Melting point: 168 after washing with a small amount of toluene
1a5ft of the target material was obtained at ~171°C.

Synthesis example 4. N-(2-nitrobenzoyl)-N'-[3
-Synthesis of chloro-4-(5-iodo-2-pyrimidyloxy)phenyltaurea 3-chloro-4-(5-iodo-2-pyrimidyloxy)aniline 1.7 f 'lf Dissolved in dioxane 10- and stirred. Meanwhile, a solution of 1.1 f' of 2-dito-μbenzoyl isocyanate dissolved in dioxane 10- was added dropwise to the bath solution and allowed to react for 200 hours. After the reaction was completed, the product was poured into water and filtered to obtain crystals.

After adding an appropriate amount of ethyl acetate to the crystals and stirring, the crystals were mixed with P again to obtain the desired product 2.1 having a melting point of 234-236°C.

The production method or synthesis fI11. ~4. Representative examples of compounds according to the present invention synthesized according to the following are shown in Table 1.

Table 1 Next, the anticancer activity, acute toxicity, dosage and administration method of the benzoylurea thread compound 9 according to the invention are described.

+11 Anticancer activity test example 1 CDF, p-588 day pedicel histocysts total 1 x 1 in mice
The mice were intraperitoneally transplanted at a rate of 0.06 mice/mouse, and administered intraperitoneally twice on day 1.1 and on day 4 after transplantation of the test drug. The survival of the mice was observed for 60 days, and the survival rate (%) of each treatment group was determined by setting the survival days of mice in the control group to which physiological saline was administered as 100. In addition, the drug is the test compound yc
This is a suspension agent to which a small-scale surfactant (for example, Twθθn-80) is added.

Table 2 (2) Acute toxicity LD by intraperitoneal administration Values for compounds N001-1
Both 1.15 and 14 were 9 or more in 500 μ/. In addition, the LD value of compound No. 12 is 100
~200TIII/hour.

(3) Dosage and administration method The dose of the anticancer agent of the present invention cannot be unconditionally defined due to differences in administration conditions, but usually the active ingredient is about 1 to about 2 ml per 9 Ikg of body weight per day, Preferably about 5
~ Approximately 1.0 mouths OW.

More preferably, it is about 5←about 5ooq.

When administering the cross-drug, the above-mentioned dose [1' (i = one dose) may be administered all at once or in divided doses, or may be increased or decreased depending on the exigencies of the therapeutic condition.

In addition, cross-medium administration can be carried out by oral, intravenous, intramuscular, subcutaneous routes, and other methods.

The anticancer agent of the present invention is formulated in the same manner as ordinary pharmaceuticals, for example, it is formulated from an active ingredient and a pharmacologically acceptable carrier, such as an inert diluent or an assimilable edible carrier, and these are administered orally. It is most appropriate to administer the drug. In this case, it may be encapsulated in a hard or soft gelatin capsule, compressed into a tablet, or made into an oil suspension. Next, examples of formulations of the anticancer agent of the present invention will be given.

Example of flattening 1゜The above compound No. 10 amorphous powder 85-layer lid part,
Dextrose 1-layer needle capital, cornstarch 10 parts by weight and 5%
The mixture was uniformly mixed with 1.5 parts by weight of a corn starch paste solution, granulated by a wet method, and 1 coulometric part of magnesium stearate was added thereto and compressed into tablets for oral use.

formulation? ! I 2゜ 5f of the above compound NO61 was replaced with dimethylacetamide 5
After intoxication with sdK, coconut oil 25-, pegnol HC
-17 (manufactured by Toho Katei) 72 and HO-10M (manufactured by Toho Katei) 6t' were added to prepare an emulsion. The same amount of kill in this emulsion! 111 distilled water was added and subjected to ultrasonic treatment for 20 to 30 seconds to obtain an oily suspension.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, X is a halogen atom, nitro group or trifluoromethyl group, Y and Z^2 are a hydrogen atom or a halogen atom, Z^1 is a halogen atom or a trifluoromethyl group, and A is a group =CH- or =N-.However, X
When is a halogen atom and A is a group =CH-, Z^2 is a halogen atom. ) A benzoyl urea compound represented by