JPH0156065B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides novel benzoyl urea compounds,
The present invention relates to a method for producing the same and an anticancer agent containing the same as an active ingredient. [Prior art] Conventionally, the following general formula: (In the formula, X is a halogen atom or a nitro group, Y
and Z ₂ is a hydrogen atom or a halogen atom, Z ₁ is a halogen atom or a trifluoromethyl group, respectively,
It is generally disclosed that benzoylurea compounds represented by the group =CH- or =N- are useful as anticancer agents. Specifically, cancer cells are inoculated intraperitoneally into mice, and the drug is also administered. It has been disclosed that an anticancer effect was obtained by administering the drug to this area (Japanese Patent Application Laid-open No. 109721/1983). [Problems to be solved by the invention] However, these compounds are inherently poorly soluble in both water and organic solvents and have poor drug absorption in the gastrointestinal tract, so depending on the administration method, they may not have sufficient anticancer activity. Intraperitoneal administration of drugs has its own limitations in terms of treatment. Therefore, there is a need for further improvements in order for these compounds to exhibit excellent anticancer effects without causing side effects by using administration methods and forms that are more practical and easier for cancer treatment. Although the object of the present invention is included in the above general formula,
The object of the present invention is to provide a novel benzoyl urea compound that is not specifically disclosed in the specification, a method for producing the same, and an anticancer agent containing the same as an active ingredient. [Means for Solving the Problems] To summarize the present invention, the first invention of the present invention is an invention relating to a benzoyl urea compound,
General formula below: (wherein A is the group =CH- or =N-, and B
is a bromine atom or a chlorine atom. ). Further, the second invention of the present invention relates to a method for producing a compound represented by the above general formula, which comprises the following general formula: (wherein R ₁ is an isocyanate group or an amino group) and the following general formula: (wherein A and B have the same meanings as the formula, R ₂ is an amino group or an isocyanate group, and is different from R ₁ ) to obtain a compound of the above formula. Features. Furthermore, the third invention of the present invention relates to an anticancer agent, and is characterized in that it contains at least one compound of the above formula as an active ingredient. The present inventors first studied in detail the chemical structure and anticancer activity of the compound represented by the above general formula (), and found that in the above general formula (), X is a nitro group and Y is a chlorine atom _Z1 . halogen atoms and
It was found that a combination in which Z ₂ is a hydrogen atom provides more desirable anticancer activity. Next, it was found that when the cancer cell inoculation site and the drug administration site were changed with respect to the halogen atom as Z ₁ in the above combination, a significant difference in anticancer activity was observed due to the difference in the halogen atom.
In other words, when Z ₁ is a chlorine atom, a bromine atom, and an iodine atom, if both sites are the same, there is not much difference in anticancer activity, but there is a gap between the two sites. When heated, the former was found to have extremely superior activity compared to the latter. The present invention was completed based on the knowledge that those whose anticancer effects are not specifically described in the above-mentioned publication have superior effects. Regarding the present invention, the cause of the difference in anticancer activity due to the halogen atoms of Z ₁ has not yet been fully elucidated, but depending on the dosage form of the drug, the difference in the type of halogen atom may cause Differences occur in the absorption of drugs in the gastrointestinal tract, drug concentration in the blood, and transferability of drugs to target areas, resulting in differences in the ability of drugs to reach the affected area.
This is presumed to be the reason for the superiority and inferiority of the anticancer activity, and it is presumed that the inherent properties of the compounds of the present invention are related to the anticancer activity. According to the present invention, a method of indirectly supplying a drug to an affected area, that is, a method of systemic administration of a drug in which there is a distance between the affected area and the drug administration site, such as oral administration, intravenous injection, suppository (rectal injection), etc. ) administration, intramuscular administration,
Extremely excellent anticancer activity can be obtained by methods such as transdermal administration, preferably oral, intravenous or suppository administration, and more preferably oral administration. Further, according to the present invention, it is possible to easily administer the drug, and by reducing the amount of the drug, the patient's pain during administration can be reduced, and side effects can be reduced. In the above general formula (), =N- is desirable as A in terms of anticancer activity. The benzoyl urea compound according to the present invention can be produced, for example, by the following method. (In the formula, A and B are as described above.) Examples of the solvent used in the above reaction include benzene, toluene, xylene, pyridine, dioxane, dimethyl sulfoxide, and the like. (In the formula, A and B are as described above.) Examples of the solvent used in the above reaction include toluene, xylene, monochlorobenzene, ethyl acetate, and dioxane. Further, the aniline compound or phenyl isocyanate compound used as a raw material in each of the above reactions is produced, for example, by the following method. (In the formula, Hal represents a halogen atom, A and B
(as mentioned above) Examples of alkaline substances used include sodium hydroxide, potassium hydroxide, sodium carbonate,
Examples of solvents include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoramide, acetone, methyl ethyl ketone,
Examples include ketones such as methyl isobutyl ketone. Moreover, it is a desirable method to carry out this condensation reaction in the presence of nitrogen gas. (In the formula, A and B are as described above.) Examples of the solvent used are those inert to phosgene, such as toluene, xylene, monochlorobenzene, ethyl acetate, and dioxane. [Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. Synthesis Example 1 N-(2-nitrobenzoyl)-
N′-[3-chloro-4-(5-bromo-2-
Synthesis of pyrimidinyloxy)phenyl]urea 5-bromo-2-chloropyrimidine in a flask
7.00g, 4-amino-2-chlorophenol
5.19 g of potassium carbonate, 9.98 g of potassium carbonate, and 70 ml of dimethyl sulfoxide were added, and the reaction was carried out under a nitrogen atmosphere at 120° C. for 1.5 hours with stirring. After the reaction was completed, the product was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous salt water, and purified by silica gel column chromatography to obtain 6.80 g of oily 4-(5-promo-2-pyrimidinyloxy)-3-chloroaniline. I got it. A solution of 6.80 g of the above 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline dissolved in 30 ml of dioxane was placed in a flask, and into this,
A solution of 5.76 g of 2-nitrobenzoyl isocyanate dissolved in 30 ml of dioxane was added dropwise, and the mixture was allowed to react at room temperature for 9 hours. After the reaction was completed, the product was poured into water and washed with filtrate and boiling water. The obtained crystals were poured into methanol, stirred, and filtered again to obtain 9.42 g of the desired product having a melting point of 234-236°C. Synthesis Example 2 N-(2-nitrobenzoyl)-
N′-[3-chloro-4-(5-bromo-2-
Synthesis of pyridinyloxy)phenyl]urea 25 g of 2,5-dibromopyridine in a flask, 4
- Add 16.7 g of amino-2-chlorophenol, 21.8 g of potassium carbonate, and 50 ml of dimethyl sulfoxide, and stir at 150°C under nitrogen atmosphere.
A time reaction was performed. After the reaction is complete, transfer the product to ice water.
The mixture was poured into a 500 ml volume and extracted twice with 200 ml of diethyl ether. The extracted layer was washed with a 10% aqueous sodium hydroxide solution, then water and saturated brine, dried over anhydrous sodium sulfate, the ether was distilled off under reduced pressure, and purified by silica gel chromatography to obtain 4-
16.35 g of (5-bromo-2-pyridinyloxy)-3-chloroaniline was obtained. A solution of 16.35 g of the above 4-(5-bromo-2-pyridinyloxy)-3-chloroaniline dissolved in 90 ml of dioxane was placed in a flask, and 2
10 ml of a solution of 11.5 g of nitrobenzoyl isocyanate in dioxane was gradually added dropwise at room temperature, followed by stirring and reaction at room temperature for 15 minutes. After the reaction was completed, dioxane was distilled off under reduced pressure, and the residue was washed with methanol, filtered, and dried to obtain 26.5 g of the target product having a melting point of 207-208°C. Synthesis Example 3 N-(2-nitrobenzoyl)-
N′-[3-chloro-4-(5-chloro-2-
Synthesis of pyrimidinyloxy)phenyl]urea 1.50 g of 2.5-dichloropyrimidine in a flask, 4
-Add 1.45 g of amino-2-chlorophenol, 2.76 g of potassium carbonate, and 15 ml of dimethyl sulfoxide, and stir at 100℃ under nitrogen atmosphere for 1.5 g.
A time reaction was performed. After the reaction was completed, the product was poured into water and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous salt water, and the solvent was distilled off. The obtained crude product was purified and isolated by silica gel column chromatography to obtain 2.20 g of oily 3-chloro-4-(5-chloro-2-pyrimidinyloxy)aniline. A solution of 1.50 g of 2-nitrobenzoyl isocyanate dissolved in 6.5 ml of dioxane is placed in a flask, and the 3-chloro-4- obtained in the above step is added to the flask.
A solution of 1.00 g of (5-chloro-2-pyrimidinyloxy)aniline dissolved in 6.5 ml of dioxane was added dropwise, and the mixture was allowed to react at room temperature for 3 hours. After the reaction is complete,
The product was poured into water, and the precipitated crystals were separated. The crystals were washed with water at about 50°C, dried, and suspended in ethyl acetate. A small amount of n-hexane was added to this, and the precipitated crystals were separated and dried to obtain 1.05 g of the desired product having a melting point of 222-225°C. Specific compounds included in the present invention are listed below. Compound No. 1 N-(2-nitrobenzoyl)-
N'-[3-chloro-4-(5-bromo-2-pyrimidinyloxy)phenyl]urea melting 234-236℃ Compound No. 2 N-(2-nitrobenzoyl)-
N'[3-chloro-4-(5-chloro-2-pyrimidinyloxy)phenyl]urea Melting point 222-225℃ Compound No. 3 N-(2-nitrobenzoyl)-
N'-[3-chloro-4-(5-bromo-2-pyridinyloxy)phenyl]urea Melting point 207-208℃ Compound No. 4 N-(2-nitrobenzoyl)-
N'-[3-chloro-4-(5-chloro-2-pyridinyloxy)phenyl]urea Melting point 191-195°C Next, the names of comparative compounds used in the following examples are shown. Comparative compound No. 1: N-(2-nitrobenzoyl)-N'-[3-chloro-4-(5-iodo-
2-pyrimidinyloxy)phenyl]urea (described in JP-A-57-109721). Comparative compound No. 2: N-(2-nitrobenzoyl)-N'-[3-chloro-4-(5-trifluoromethyl-2-pyridinyloxy)phenyl]
Urea (described in the above publication). Comparative compound No. 3: N-(2-nitrobenzoyl)-N'-[3-chloro-4-(5-iodo-
2-pyridinyloxy)phenyl]urea (included in the general formula of the above publication). Next, it will be shown that the benzoyl urea compound according to the present invention has specific anticancer activity. For example, Compounds No. 1 and No. 2 of the present invention are more effective in Test Example 1 than Comparative Compound No. 1, which specifically describes the name of the compound and its anticancer effect in the above-mentioned publication.
(the site of cancer cell inoculation and drug administration site are the same), it does not show very good anti-cancer activity, but
In the case of Test Examples 2 and 3 (both sites are different), extremely excellent activity is shown. Test Example 1 (Cancer cell inoculation site and drug administration site are both intraperitoneal: same as in Test Example 1 of the above publication) CDF ₁ mice were injected with 1 x 10 ⁶ p-388 leukemia cells.
After transplantation, the test drug was intraperitoneally administered twice on the 1st and 4th day after transplantation. The survival of the mice was observed for 30 days, and the survival rate (%) of each treatment group was determined by setting the number of days of survival of mice in the control group to which physiological saline was administered as 100. In addition,
The drug is added to the test compound with a small amount of surfactant [e.g. Tween-80 (Atlas Powder)].
Company)] is added as a suspending agent (No. 1).
table).

[Table] Test Example 2 (Cancer cell inoculation site is intraperitoneal, drug administration site is oral) (1) N'-pyrimidinyloxyphenyl-N-benzoylurea compound BDF ₁ mice were injected with P-388 leukemia cells 1x 10 ⁶
The test drug was intraperitoneally transplanted at a ratio of one mouse per mouse, and the test drug was orally administered twice on the 1st and 4th day after transplantation. The survival of mice was observed for 30 days, and the number of survival days of mice in the control group administered with physiological saline was determined by 100 days.
As, the survival rate (%) of each treatment group (10 animals per group)
was calculated (Table 2-1). The test drug was prepared in Formulation Example 1 described below.

[Table] Based on the dosage and survival rate in the table, the compound No. of the present invention.
1 and No. 2 are each about approx. compared to comparative compound No. 1.
It can be seen that the anticancer activity is 16 times and about 32 times higher. (2) N'-Pyridinyloxyphenyl-N-benzoylurea compound A test was conducted in the same manner as in (1) above, and the results shown in Table 2-2 were obtained.

[Table] Also, from the above table, the present invention compounds No. 3 and No. 4 show excellent anticancer activity, whereas the comparative compound No. 4 shows excellent anticancer activity.
It can be seen that No. 2 and No. 3 do not show anticancer activity. Test Example 3 (Cancer cell inoculation site is intraperitoneal, drug administration site is oral) The same test as described above was performed in Test Example 2 except that the test drug formulated in Formulation Example 1 was replaced with the test drug formulated in Formulation Example 4. The life extension rate (%) was determined in the same manner as in Example 2 (Table 3).

[Table] Test Example 4 (Cancer cell inoculation site is intraperitoneal, drug administration site is intravenous) 1 x 10 ⁵ L-1210 leukemia cells were injected into BDF ₁ mice.
The test drug prepared in Formulation Example 4 was intraperitoneally implanted at a ratio of 2 mice/mouse, and the test drug formulated in Formulation Example 4 was administered intravenously. The survival of mice was observed for 30 days, and the number of survival days of mice in the control group administered with physiological saline was set as 100, and each treatment group (11 groups
The survival rate (%) of 10 animals was calculated (Table 4).

〔Effect of the invention〕

As explained in detail above, according to the present invention,
A compound has been provided that has extremely excellent anticancer activity even when an administration method involves a distance between the affected area and the drug administration site. Furthermore, since the drug of the present invention can be easily administered, the amount of the drug can be reduced, and the patient's pain and side effects during administration can also be reduced.

Claims (1)

[Claims] 1. The following general formula: (wherein A is the group =CH- or =N-, and B
is a bromine atom or a chlorine atom). 2 General formula below: (wherein R ₁ is an isocyanate group or an amino group) and the following general formula: (wherein A is a group =CH- or =N-, B is a bromine atom or a chlorine atom, _R2 is an amino group or an isocyanate group, and is different from _R1 ) to react,
General formula below: A method for producing a benzoyl urea compound, which comprises producing a benzoyl urea compound represented by the formula (where A and B are as described above). 3 General formula below: (wherein A is the group =CH- or =N-, and B
is a bromine atom or a chlorine atom) as an active ingredient.