JPS6122015A - N-benzoyl-n'-phenylurea based compound and anticancer agent containing same - Google Patents

Abstract

NEW MATERIAL:An N-benzoyl-N'-phenylurea based compound expressed by formula I (X1 and X2 are H, halogen or NO2; Y is H or halogen; Z is H, halogen or CF3; Z is H when X1 is H and X2 is halogen or NO2). EXAMPLE:N-( 2,4-Dinitrobenzoyl )-N'-[3-chloro-4-( 5-trifluoromethyl-2-pyridyloxy ) phenyl]urea. USE:An anticancer agent administered in preferably 10-400mg/kg/day dose. The above-mentioned agent can be administered by a method, e.g. oral, intravenous, intramuscular, subcuterneous route, etc. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III in the presence of a solvent, e.g. benzene or toluene, at 0-120 deg.C for 0.1-24hr to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel N-benzoyl-Nl-yenyl urea compounds and anticancer agents containing them, and more specifically, the general formula (summer); (in the formula, %Xl and Xt are hydrogen atoms, a halogen atom or a nitro group, Y is a hydrogen atom or a halogen atom,
z is a hydrogen atom, a halogen atom, or a trifluoromethyl group; The present invention relates to an anticancer agent containing N-benzoyl-N1-phenylurea compounds and at least one thereof as an active ingredient.

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

(A) e) Examples of the solvent used in the above reaction include benzene, toluene, xylene, pyridine, dioxane, and dimethyl sulfoxide. (B) (In the formula, X 1 * X 2 # Y and 2 is the above-mentioned number 9.) Examples of the solvent used in the above reaction include toluene, xylene, 7-chlorobenzene, 2-ethyl acetate, and dioxa v.

Further, the raw material aniline compound or phenyl isocyanate compound used in each of the above reactions can be produced, for example, by the following method.

(C) (in the formula, % HalI is a halogen atom, C1Y and zt
i Same as above n) The alkaline substances used include sodium hydroxide,
Examples include potassium hydroxide, sodium carbonate, potassium carbonate, etc., and examples of solvents include aprotic polar solvents such as dimethylnulphoxide, dimethylformamide, hexamethylphosphoramide, a7tone, methyl ethyl ketone, and methyl isobutyl ketone. In addition, it is a desirable method to carry out this condensation reaction in the presence of nitrogen gas.

(D) (In the formula, Y and z are as defined above.) The solvent used is one that is inert to phosgene, such as toluene, xene, monochlorobenzene, ethyl acetate, dioxane, etc. is kicked for 2 hours.

Next, a specific synthesis example of the wood compound "11" will be described below. Synthesis of -2-pyridyloxy)phenyl urethane 2-chloro-5-) II fluoromethyl "?' l)
') / l Og 7.9 g of 12-chloro-4-7 minophenol and 15.2 g of potassium carbonate in 100 l of dimethyl sulfoxide were heated at 120°C under a nitrogen atmosphere.
The mixture was stirred for 3 hours. After the reaction was completed, the reaction product was poured into water and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over anhydrous sodium sulfate, ethyl acetate was distilled off, and purified by silica gel column chromatography to give 3-chloro-4-(5-trifluoride) having a melting point of 73-74.5°C. Fluoromethyl-2-pyridyloxy)aniline 14.2 g
'e got it.

10 ml of dioxane and 0.95 g of C):3-/coro-4-(5-)lifluoromethyl-2-pyridyloxy)aniline were charged into a flask and dissolved. To this, 2,4-dinitrobenzoyl isocyanate 1.
A solution prepared by dissolving 40 g of dioxane in dioxane was added dropwise over 5 minutes with stirring, and the mixture was reacted at room temperature for 15 hours. After the reaction was completed, the product was poured into hot water, and the precipitate was filtered and washed with methanol to obtain 0.72 g of the target product having a melting point of 203-207°C.

Synthesis? ! 12 N-(4-=)lobenzoyl)-N'
-(3-Chloro-4-(5-)trifluoromethyl-2-pyridyloxy)phenyltourea synthesis flask was charged with the 3-chloro-4-(5-trifluoromethyl-2-pyridyloxy)aniline 1. .14gJ-
Add a solution dissolved in 10 mJ of dioxane, and add 4
A solution of 1.30 g of -nitrobenzoyl isocyanate) dissolved in dioxane 5- was added dropwise over 5 minutes with stirring, and then reacted at room temperature for 18 hours. After the reaction is completed, the product is poured into hot water, and the precipitate is washed with cold methanol and dried to obtain the desired product 1.2 with a melting point of 220-225°C.
Representative examples of compounds according to the present invention synthesized according to the M-adic method or Synthesis Examples 1 and 2 are as follows:
-(4-nitrobenzoyl)-N'-(3-chloro-4
-(5-)Lifluoromethyl-2-pyridyloxy)phenyltourea Melting point 220-225℃ Compound NO,2N-(2,4-dinitrobenzoyl)-N
'-(3-chloro-4-(5-trifluoromethyl-2
-Pyridyloxy)phenyl Melting point 20
3-207°C Compound No, (N-(2-chloroa-4-
nitrobenzoyl)-N'-(3-chloro-4-(5-
Trifluoromethyl-2-pyridyloxy) phenyltourea Melting point 184-1906C Compound NO,4N-(
2,4-dichlorobenzoyl)-N'-(3-chloro-
4-(5-)lifluoromethyl-2-pyridyloxy)
Phenyl]Urero Melting point 192-193℃ Compound NO, 5N-(4-chlorobenzoyl)-N'-(3-
Chloro-4-(5-trifluorome≦2-pyridyloxy)phenyl Melting point 214
~216°C Compound NO,6i'J -(2-nitrobenzoyl)-ze-[3-chloro-4-(2-pyridyloxy)fe,? ) Urea Melting point 200-20
2°G Compound NO,7N-(2,4-dinitrobenzoyl)-N'-(3-chloro-4-(5-iodo°-2-
pyridyloxy)phenyl]urea melting point 219-223
°C Compound NO,8N-(4-chloro-2-nitodibenzoyl)-N-rich-[3-chloro-4-(5-)I+ FluoVmethyl-2-pyridyloxy)phenyltourea 9
The anticancer activity, acute toxicity, dosage, and method of administration of the Beni I-Silium-Noa compound according to the present invention will be described below.

(1) Anticancer activity test example CDF, p-388 leukemia cells were injected 1x into mice.
N3 was intraperitoneally transplanted at a ratio of 10 mice/mouse, and the test drug was intraperitoneally administered twice on the 1st and 4th day after transplantation.
The survival rate of each treatment group was determined by observing whether the mice were alive or dead for 0 days, and assuming that the survival days of mice in the control group to which physiological saline was administered was 100, and the results are shown in Table 1. The drug is a small amount of surfactant (for example, Tween-8) added to the test compound.
0) is added as a suspending agent.

pi-1 Table A (2) Acute i'? LD by intra-abdominal administration. The bfn of compound N0-1-8 was also 100 mg/kHz or higher.

(3) Dose and administration method Dosage of the anticancer agent of the present invention - 1 Although it cannot be absolutely defined due to differences in administration conditions, the active ingredient is usually about 5 to about 500 mg per kg of body weight per day, Yuko Masashi. is about 10
~400mg.

At the time of drug administration, the dosage 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, drug administration can be carried out by oral, intravenous, intramuscular, or subcutaneous routes. They are most suitably formulated with carriers, such as inert diluents or assimilable edible carriers, and are administered orally. In this case, it may be enclosed in a soft gelatin capsule or compressed into a tablet.
Or you can dry it with oily wild waves.

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

Formulation Example 1 70 rng of the amorphous powder of Compound No. 2 was thoroughly mixed with 30 mg of lactose, and 100 mg of the mixture was filled into capsules to prepare oral capsules.

Formulation Example 2 Amorphous powder 85M of the above compound No. 3, 1 part of sucrose, 1 part of corn starch, and 5%
The mixture was uniformly mixed with 1.5 parts of corn starch paste liquid and made into granules by a wet method, and then 1 ft., p part of magnesium stearate was added and compressed into tablets for oral use.

Formulation Example 3 After dissolving 5 g of the above compound No. 4 in 5M of dimethyl esterate'7mid, Coconut oil 25d1 Begnol HC
-17C manufactured by Toho Kagaku Co., Ltd.) and 6 g of HO-ioM (manufactured by Toho Chemical Co., Ltd.) were added to form an emulsion. This emulsion is accompanied by a
'JR distilled water was added and subjected to ultrasonic treatment for 20 to 30 seconds to obtain an oily suspension.

for patent1 person Ishihara Sangyo Co., Ltd.

Claims (1)

[Claims] 1. General formula; ▲ Numerical formulas, chemical formulas, tables, etc. Z is a hydrogen atom, a halogen atom or a trifluoromethyl group, and when X_1 is a hydrogen atom and X_2 is a halogen atom or a nitro group, Z is a hydrogen atom), N-benzoyl-N'- Phenylurea compounds. 2. General formula; ▲ There are mathematical formulas, chemical formulas, tables, etc. atom or trifluoromethyl group, and when X_1 is a hydrogen atom and X_2 is a halogen atom or a nitro group, Z is a hydrogen atom). An anticancer drug that contains one type of cancer as an active ingredient.