JPS62135463A - N-benzoylurea compound, carcinostatic agent containing same and production thereof - Google Patents

Abstract

NEW MATERIAL:The benzoylurea compound of formula I (X is Br or Cl). EXAMPLE:N-( 2-nitrobenzoyl )-N-[4-( 5-bromo-2-pyrimidinyloxy )-3-fluorophe nyl]urea. USE:Useful as a carcinostatic agent. It is administered preferably by oral administration. It can be easily administered and is effective at a reduced dose. The pain of patient in administration and the side effect of medicine can be decreased. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II (R1 is isocyanate group or amino group) with the compound of formula III (R2 is amino group or isocyanate group different from R1) in a solvent such as octane, benzene, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to novel N-benzoyl urea compounds, anticancer agents containing them as active ingredients, and methods for producing them.

(Prior art) Conventionally, the following general 2■: (wherein, Q represents a halogen atom or a nitro group,
is a hydrogen atom or a halogen atom, Z is a halogen atom or a trifluoromethyl group, and A is a group -CH- or -N-), benzoyl urea compounds are used as anticancer agents. It is generally disclosed that cancer cells were inoculated into the 11th cavity of a mouse, and a drug was also administered thereto, and an anticancer effect was obtained (
JP-A-57-109721).

(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 they may not exhibit sufficient anticancer activity depending on the administration method. In addition, intraperitoneal administration of drugs naturally has its limits in terms of treatment. Therefore, there is a need for further improvement 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 in terms of cancer treatment.

The object of the present invention is to provide novel benzoyl urea compounds included in the general formula (rV) but not specifically disclosed in the above publications, anticancer agents containing these compounds as active ingredients, and methods for producing these compounds. It's about doing.

(Means for Solving the Problems) The present inventors first studied in detail the chemical structure and anticancer activity of the compound represented by the general formula (IV), and found that the compound represented by the general formula (rV) It has been found that a combination in which Q is a nitro group, Y is a fluorine atom, Z is a bromine atom or a chlorine atom, and Zt is a hydrogen atom provides more desirable anticancer activity. That is, when comparing the compound of the present invention and a chemically structurally similar compound, if the inoculation site of cancer cells h'd drug administration site is the same, there is no significant difference in anticancer activity, but both It has been found that when the above-mentioned site is changed, there is a significant difference in anti-cancer activity.The present invention has been found to be superior to those whose anti-cancer effects are specifically described in the above-mentioned publication. The reason why the compound of the present invention exhibits the desired anticancer activity has not yet been fully elucidated, but depending on the administration form of the drug, the central benzene ring and Differences in the types of halogen atoms that are substituents on the pyrimidine ring cause differences in drug absorption in the gastrointestinal tract, drug concentration in the blood, and drug migration to the target site, resulting in differences in drug delivery to the affected area. It is presumed that this difference in accessibility caused a difference in anticancer activity, and that the inherent properties of the compound of the present invention are related to the anticancer activity. For example, methods for indirectly supplying drugs to the affected area, i.e., methods for systemic administration of drugs in which there is a distance between the affected area and the drug administration site, such as oral administration, intravenous injection (intravenous injection), suppository (intrarectal) administration,
Extremely excellent anticancer activity can be obtained by intramuscular administration, transdermal administration, etc., preferably oral, intravenous injection, 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 and side effects during administration can be reduced.

(Disclosure of the Invention) The present invention relates to N-benzoyl urea compounds represented by the general formula (■): (wherein This is a method for producing a compound.

The N-benzoyl urea compound represented by the general formula (1) can be produced by the following method.

(n) CI[[) (wherein R+ is an incyanate group or an amino group, and R2 is an amino group or an isocyanate group different from R8) Specifically, the following method may be mentioned.

(A) 0 to 120°C for 0.1 to 24 hours (in the formula, , tetrahydrofuran, dimethyl sulfoxide, dimethyl acetamide, ethyl acetate, 7-setone, methyl ethyl ketone and the like.

0.1 to 24 hours (in the formula, X is as described above) The solvent used in the above reaction may be the same as that used in the above reaction (A).

The raw material aniline compound used in the reaction (A) (
■') is produced, for example, by the following method.

0.5 to 10 hours (in the formula, flal is a halogen atom, and X is as described above) The alkaline substances used include sodium hydroxide,
Potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, n-butyllithium, etc. are mentioned, and the solvents include aprotic solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, acetone, methyl ethyl ketone, etc. , ketones such as methyl isobutyl ketone, methylene chloride,
Examples include halogenated hydrocarbons such as chloroform. It is also desirable to carry out this condensation reaction in the presence of nitrogen gas.

Further, the isocyanate compound (m'') as a raw material used in the CB) reaction is produced, for example, by the following method.

(In the formula, Examples include methyl ethyl ketone.

Synthesis examples of the compounds of the present invention are shown below.

Synthesis Example I N-(2-nitrobenzoyl)-N-(
Synthesis of 4-(5-bromo-2-pyrimidinyloxy)-3-fluorophenyl]urea (compound 1) (1) 2.28 g of 5-bromo-2-chloropyrimidine.

A solution of 1.79 g of anhydrous potassium carbonate and 1.50 g of 4-amino-2-fluorophenol in 20 ml of dimethyl sulfoxide was reacted with stirring at 70 to 80°C under a nitrogen stream for 1 hour.

After the reaction was completed, the product was poured into water and extracted with methylene chloride. The extracted layer was washed with a 10% aqueous sodium hydroxide solution and further washed several times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 4-(
1.65 g of 5-bromo-2-pyrimidinyloxy)-3-fluoroaniline was obtained.

(2) 1.40 g of the aniline compound obtained in the above step il+ was dissolved in 10 ml of dioxane, and while stirring, 0.95 g of 2-nitropenzoyl mesocyanate dissolved in 1 Q ml of dioxane was gradually added dropwise.
The reaction was allowed to proceed for 7 hours.

After the reaction is complete, the product is poured into hot water, the resulting precipitate is filtered, an appropriate amount of ethyl acetate is added to the precipitate, stirred, and filtered again to obtain the desired product 2 with a melting point of 217-219°C. ．．
33 g was obtained.

Synthesis Example 2 N~'2-nitrobenzoyl)-N'-(
4-(5-chloro-2-pyrimidinyloxy)-3-fluorophenyltourea (synthesis of compound Hikari 2) (1+2.5-dichloropyrimidine 1.76 g, anhydrous potassium carbonate 1.79 g and 4-amino-2 - 1.50 g of fluorophenol and 20 m of dimethyl sulfoxide
1 solution was reacted under stirring at 80 to 90° C. for 2 hours under a nitrogen stream.

After the reaction was completed, the product was poured into water and extracted with diethyl ether. After washing the extracted layer with water, it was dried with anhydrous sodium sulfate.
The solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 4-
1.24 g of (5-chloro-2-pyrimidinyloxy)-3-fluoroaniline was obtained.

(2) Aniline compound obtained in step (1) 1.
10 g was dissolved in 10 ml of dioxane, this was added dropwise to 0.88 g of 2-nitropenzoyl isocyanate, and the mixture was reacted at room temperature for 17 hours.

After the reaction was completed, the product was poured into warm water, and the resulting precipitate was filtered and washed with warm water to obtain 1.90 g of the desired product having a melting point of 209-211°C.

Next, the anticancer activity, acute toxicity, dosage, and administration method of the N-benzoyl urea compound according to the present invention will be described.

(11 Anticancer activity test example 1 (intraperitoneal - intraperitoneal) 1 x 10 p-388 leukemia cells were injected into BDF+ mice.
The mice were intraperitoneally transplanted at a rate of 6 mice/mouse, and the test drug was intraperitoneally administered twice on the 1st and 4th day after the transplant.

The survival rate of each treatment group (rlLs%) was determined by observing the survival of the mice for 30 days and setting the number of survival days of the control group 5 mice administered with physiological saline as 0, and the results are shown in Table 1. The drug is added to the test compound with a small amount of surfactant (e.g. Tw
This is a suspension to which een-80) has been added.

Table 1 (Note) 0 Life extension rate (ILS, %)... Increase Life Span (Increase Life 5pan)
) and can be calculated using the following formula.

Life extension rate (ILS, %) = Number of days of survival in the test group (X100) -100 Number of days of survival in the 1-ton U-R group 96 Comparison compound @! I-Ki 1...Unexamined Japanese Patent Publication No. 57-10
The compound described in Japanese Patent No. 9721 is N-(2-nitrobenzoyl)-N'-(3-chloro-4-(5-iodo-2-pyrimidinyloxy)phenyl)urea.

Comparative compound description 2...Compound described in the above publication, N-(2-chlorobenzoyl)-N'-(3-chloro-4-(5-chloro-2-pyrimidinyloxy)phenyl)urea It is.

Test Example 2 (intraperitoneal-oral) BDF, mice were injected with p-388 white plate disease cells for 1 x 10 hours.
After transplantation, the test drug was orally administered twice on the 1st and 4th day. The life and death of the mice were observed for 30 days, and the number of survival days of the mice in the control group administered with physiological saline was set as 0, and the survival rate of each treatment group was calculated.
ILS, %) was calculated and the results are shown in Table 2.
The test drug and comparative drug were formulated in Formulation Example 4 described below.

Table 2 (Note) "Survival Prolongation Rate and 1 Comparative Compound Patient 1" is the result of intraperitoneal administration of Compounds No. 1 and 2 of the present invention formulated according to Formulation Example 4 using (2) acutely toxic ddy mice in Table 1 above. When the LD50 values were determined after intravenous administration, all were 200 q/k+r or higher. As an injection or oral administration agent, in the case of humans, as an injection agent such as vascular injection into a vein or artery or local administration, or as an oral administration agent, suppository administration agent, 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 should be determined as appropriate depending on the administration method, the condition of the patient or treated animal, such as age, weight, sex, irritability, 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-mentioned guidelines.

The anticancer agent of the present invention is formulated in the same manner as ordinary pharmaceuticals,
For example, it is most suitably formulated from the active ingredient and various pharmacologically acceptable adjuvants, such as inert diluents, and administered orally, intravenously injected, or as a suppository.

In addition, the content of the active ingredient in the anticancer composition of the present invention varies depending on various conditions and cannot be absolutely specified, and it is sufficient to contain the active ingredient in the same manner as in the case of a normal anticancer composition. For example, the active ingredient can be contained at least 0.001% or more.

Since the compound of the present invention has the property of being difficult to i86 in both water and organic solvents, it is preferably made into an aqueous suspension, which may contain phospholipids or an aqueous suspension that does not contain phospholipids. As a method for producing a suspension, for example, the active ingredient compound is pulverized in advance, and then the above-mentioned pulverized active ingredient compound is added to an aqueous solution containing a surfactant and, if necessary, an antifoaming agent, and subjected to wet pulverization. An example of this method is to reduce the particle size to 5 μm or less, for example 80% of the particles to 2 μm or less, and then add a thickener if necessary. Examples of surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sucrose ester, polyoxyethylene, polyoxypropylene,
Examples of antifoaming agents include dimethylpolysiloxane, methylphenylsiloxane, sorbitan fatty acid ester, polyoxyethylene/polyoxypropylene cetyl ether, silicone, etc., and examples of thickening agents include Examples include guar gum, alginic acid, gum arabic, pectin, starch, xanthan gum, gelatin, and the like. On the other hand, as a method for producing an aqueous suspension containing phospholipids, for example, instead of the surfactant in the above method, a phospholipid such as soybean phospholipid or egg yolk phospholipid is used, and instead of using a thickener, α
-Methods using antioxidants such as tocopherol can be mentioned.

Furthermore, these can be made into tablets, capsules, frost melts, powders, injection moldings, suppositories, etc. using conventional pharmaceutical methods.

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

Formulation Example 1 70 µm of the amorphous powder of Compound Magnetism 2 is thoroughly mixed with 30 µm of milk, and 100 µm each is filled into capsules to prepare oral capsules.

Formulation Example 2 85 parts by weight of the amorphous powder of Compound Magnetism 2 was uniformly mixed with 1 part by weight of glucose, 10 parts by weight of cornstarch, and 1.5 parts by weight of 5% cornstarch paste, and made into granules by a wet method. After that, 1 part by weight of magnesium stearate is added and the mixture is compressed into tablets for oral use.

Formulation Example 3 5 g of the compound Hatsuko 1 was added to 5 mf of dimethylacetamide.
After understanding, Yashin Yu 25m! , Pegnol HC
7 g of -17 (manufactured by Toho Chemical Co., Ltd.) and 6 g of HO-10M (manufactured by Toho Chemical Co., Ltd.) were added to form an emulsion. To this emulsion is added the same amount of anti-dental Wisteria water and subjected to ultrasonication for 20 to 30 seconds to form an oily suspension.

Formulation Example 4 Firstly, the compound of the present invention, Hatsuko 1, was pulverized using a centrifugal pulverizer, and on the other hand, 5 parts by weight of polyoxyethylene (6o) hydrogenated castor oil,
0.2 parts by weight of silicone and 0.3 parts by weight of polyoxyethylene polyoxypropylene pro, Kuvolimer are added to 79.5 parts by weight of physiological saline to make an aqueous solution, and the above-mentioned finely divided compound of the present invention is added thereto by weight. xanthan gum (2% liquid)
Add parts by weight to form an aqueous suspension.

Formulation Example 5 The compound of the present invention 2 was added to an aqueous solution prepared by dissolving 1.5 parts by weight of oxyethylated polyallylphenol phosphate and 0.2 parts by weight of silicone in 53.3 parts by weight of physiological saline.
After adding 40 parts by weight and wet milling with a sand mill using glass beads (90% particles having a particle size of 2 μm or less), 5 parts by weight of xanthan gum (2% liquid) was added to prepare an aqueous Q35 agent.

Formulation Example 6 The compound Hatsuko 1 of the present invention is pulverized in advance using a centrifugal pulverizer. To an aqueous solution in which 2 parts by weight of egg yolk phospholipids, 0.001 parts by weight of α-tocopherol, and 92.999 parts by weight of physiological saline were stirred and dispersed, 5 parts by weight of the finely powdered Hatsuko 1 of the present invention was added, and the mixture was mixed with glass peas. Wet-pulverize in a sand mill (80% particle size is 2 μm or less) to form an aqueous suspension.

Claims (1)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ An N-benzoyl urea compound represented by (in the formula, X is a bromine atom or a chlorine atom). 2. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ An anticancer agent characterized by containing an N-benzoyl urea compound represented by the following (in the formula, X is a bromine atom or a chlorine atom). 3. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is an isocyanate group or amino group) where, X is a bromine atom or a chlorine atom, and R_2 is R
By reacting _1 with a compound represented by a different amino group or isocyanate group, N- A method for producing an N-benzoyl urea compound, the method comprising producing a benzoyl urea compound.