Method of producing derivatives of n-benzoyl-nъ-pyrimidinyloxyphenylcarbamide

专利摘要:
N-benzoyl-N'-pyrimidinyloxyphenyl urea compounds having the formula: wherein X represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group and Z represents a hydrogen atom or a halogen atom, are useful as active ingredients of antitumorous compositions.
公开号:SU1375131A3
申请号:SU853909801
申请日:1985-06-14
公开日:1988-02-15
发明作者:Хага Такахиро；Ямада Нобутоси；Суги Хидео；Коянаги Тору；Окада Хироси
申请人:Исихара Сангио Кайся,Лтд (Фирма)；
IPC主号:

专利说明:


O4
This invention relates to a process for the preparation of new derivatives of N-benzoyl-N-pyrimidinyl urea of general formula I
Usomno ZNX
where X is chlorine, bromine or nitro;
Z is chlorine or bromine, characterized in that the compound of general formula II
COR
No
where X has the indicated meanings;
R is isocyanate or amino group, is subjected to interaction with the compound of the formula III
j
R.
CF,
where Z has the indicated meanings;
R is an isocyanate or amino group, if R is an isocyanate group, then R is an amino group, if R is an amino group, then R is an isocyanate group at a temperature from 0 ° to boiling point, in an environment of a solvent such as benzene, toluene, xylene, pyridine, dioxane, dimethyl sulfoxide, monochlorobenzene, ethyl acetate, which can be used as biologically active substances.
The aim of the invention is to develop a process for the preparation of new derivatives of H-benzoyl-H-pyrimidinyl-oxyphenylureas, which have a higher antitumor activity compared to the known ones.
Example I, Preparation of N- (2-nit robenzoyl) -Y (5-bromo-2-pyrimidinyloxy) -3-trifluoromethylphenyl urea (compound I).
Step A. 50 ml of a dimethyl sulfoxide solution containing 4.18 g of 5-bromo-2-chloropyrimidine, .3.5 g of 2-trifluoromethylphenol and 5.96 g of potassium carbonate are introduced into a flask and stirred for 2 hours. The reaction mixture is then introduced into water and extracted with ethyl acetate. The extract is washed with water and dried in anhydrous sodium sulfate. Then the ethyl acetate is distilled off and the residue is purified at
0
five
0
five
0 5
0
five
Q g
using silica gel column chromatography, whereby 5.03 g of 5-bromo-2- (2-trifluoromethylphenoxy) pyrimidine are obtained, having a refractive index (p) of 1.5417.
Stage B, 5.0 g of the substituted pyrimidine obtained in this step A is introduced into a flask and dissolved in 25 ml of concentrated sulfuric acid. Then a mixed solution containing 1.2 ml of 60% nitric acid and 3 ml of concentrated sulfuric acid is gradually added dropwise at room temperature over 30 minutes and the mixture is subjected to reaction at room temperature over 20 minutes. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract is washed with water and dried on anhydrous sodium sulphate. Then, ethyl acetate is distilled off to obtain 4.8 g of 5-bromo-2- (2-trifluoromethyl-4-nitrophenoxy) pyrimidine, having a refractive index (p) equal to 1.5719.
Step B. A solution obtained by dissolving in 40 ml of glacial acetic acid, 4.8 g of the substituted pyrimidine obtained in stage B, is introduced into a flask and heated to. Then, 3.69 g of reduced iron was gradually added and the mixture was heated at reflux for 5 minutes, then cooled to room temperature. Acetone is added to the reaction mixture and the mixture is filtered. Under reduced pressure, the acetone is distilled off from the filtrate and ethyl acetate is added to the residue. The mixture is rinsed with water, then with sodium bicarbonate solution and additionally with water, and then dried on anhydrous sodium sulphate. The ethyl acetate is then distilled off and the residue is purified by silica gel column chromatography, whereby 3.42 g of 4- (5-bromo-2-pyrimidinyloxy) -3-trifluoromethylaniline are obtained, having a melting point of I40-145 ° C.
Step G. A solution obtained by dissolving 1.0 g of the substituted aniline obtained in Step B in 1 O ml of dioxane was introduced into a flask and a solution prepared by dissolving 0.89 g of 2-nitrobenzoyl isocyanate in 10 ml of dioxane was added thereto. The mixture is left at room temperature for 5 hours. After completion of the reaction, the product is introduced into hot water and the precipitate is filtered off. The crystals thus obtained were suspended in ethyl acetate and, after the addition of n-hexane, filtered off, washed with methanol and dried, to obtain 0.82 g of the title compound having a melting point of 196-197 C.
Found,%: C 43.1; H 2.0; N 13.1.
Calculated,%: C 43.4; H 2.1; N13.3.
EXAMPLE 2 Synthesis of N- (2-HHTpo-benzoyl) -N-4-5-chloro-2-pyrimidinyl-oxy) -3-trifluoromethane1 urea (compound No. 2).
Step A. 50 ml of a dimethyl sulfoxide solution containing 5.0 g of 2.5-dichloropyrimidine, 6.6, g of 2-trifrp-methylphenol and 9.4 g of potassium carbonate are introduced into a flask and stirred for 2 hours. The reaction mixture is then introduced into ice water and extracted with ethyl acetate. The extract is rinsed with water and dried on anhydrous sodium sulphate. Ethyl acetate is then distilled off and the residue is purified by silica gel column chromatography, whereby 7.7 g of 5-chloro-2- (2-trifluoromethylphenoxy) pyrimidine are obtained.
Stage B. 7.7 g of the substituted pyrimidine obtained in Step A are introduced into a flask and dissolved in 45 ml of concentrated sulfuric acid. Then a mixed solution containing 2.1 ml of nitric acid and 10 ml of concentrated sulfuric acid is added gradually dropwise at room temperature over 30 minutes and the mixture is stirred at room temperature for 20 minutes. After completion of the reaction, the reaction mixture was introduced into ice water and extracted with ethyl acetate. The extract is rinsed with water and dried on anhydrous sodium sulphate. The ethyl acetate is then distilled off and the residue is purified by silica gel column chromatography, after which 8.4 g of 5-chloro-2- (2-trifluoromethyl-4-nitrophenoxy) pyrimyl dine is obtained.
Step B. A solution prepared by dissolving in 70 ml of glacial acetic acid 8.4 g of the substituted pyrimidine obtained in Step B is introduced into a flask and heated to 100 ° C. Then, 7.4 g of reduction is gradually added.
0
five
0
five
0
five
0
five
iron and heat under reflux for 10 min. The reaction mixture is then cooled to room temperature, introduced into water and extracted with methylene chloride. The extract solution is washed with water and dried on anhydrous sodium sulphate. Then methylene chloride is distilled off and the residue is purified by silica gel column chromatography, whereby 6.0 g of 4- (5-chloro-2-pyrimidinyloxy) -3-trifluoromethylaniline, having a melting point of 154-155, is obtained.
Stage G. A solution obtained by dissolving 2.0 g of substituted aniline obtained in stage B in 15 ml of dioxane is introduced into a flask and a solution prepared by dissolving 1.62 g of 2-nitrobenzene 1 Isocyanate in 10 ml of dioxane is added thereto. The mixture is then reacted at room temperature for. 16 hours. After completion of the reaction, the product is introduced into hot water and the precipitates are filtered off. The crystals thus obtained were suspended in ethyl acetate and, after adding p-hexane, subjected to filtration and drying, 0.8 g of the title product was obtained, having a melting point of 201-205 C.
Found,%: C 47.3; H 2.3; N 14.2. .
Calculated,%: C 47.4; H 2.3; N14.5.
Other compounds were prepared similarly.
Connection number 3.
N- (2-nitrobenzoyl) -N (5-iodo-2-pyrimidinyloxy) -3 trifluoromethylphene1 urea.
Melting point 211-214 ° C.
Connection number 4.
N- (2-chlorobenzoyl) (5-chloro-2-pyrimidinyloxy) -3-trifluorme tilphenyl urea.
Found,% 48.7; H 2.6; N 11.9.
Calculated,%: C 48.4: H 2.3; N11.9.
Connection number 5.
K- (2-trifluoromethylbenzoyl) (5-chloro-2-pyrimidinoxioxy) -3-trifluoromethylphenyl urea.
Connection No. 6,
N- (2-bromobenzoyl) (5-chloro-2-pyrimidine-1-oxy) -3-trifluoromethylphenyl urea.
Found,%: C 44.6; H 2.2; N 10.8.
Calculated,%: C 44.3; H 2.2; N10.9;
Compound No. 7, Nr (2-nitrobenzosh1) -N - 4- (2-pyrimi
513
dinyloxy) -3-trifluoromethylphenyl urea.
Compound 8.
N-6eH3omi-N - A- (5-hlO-2-pyrimidiniloxio) -3-trifoptermethylphenyl urine.
The conditions for obtaining the desired products according to examples 1 and 2 are presented in Table 1.
EXAMPLE 3: A solution of 2.1 g of 4- (5-bromo-2-pyridinyl-oxy) -3-trifluoromethyl phenoethiocyanate in 40 ml of toluene was introduced into the flask and 0.97 g of 2- to this solution was added. nitrobenzamide. This mixture is then reacted at reflux for 4 hours. After completion of the reaction, the product is poured into 10 ml of methanol and the o-g precipitate is filtered off to give 1.63 g of the desired compound N- (2 nitrobenzoyl) -N (5 -bromo-2 pyridinesh1Oxy) -3- trifluoromethylphenyl urea.
The conditions for obtaining the desired products according to Example 3 are presented in Table 2.
PRI me R 4. This example illustrates the antitumor activity
Myopia BDF inoculate inside the abdominal but p-388 leukenia cells in an amount of 1–10 cells per minute. The test drug is administered intraperitoneally twice, i.e. one day and four days after vaccination. A younger one is observed for 30 days for survival or death. The ratio (%) of the average survival time of the test and control animals is obtained by means of the survival of a control group that was injected with saline for 100 days. The results are shown in table 1. Comparison is carried out with dispersions obtained by adding small amounts of surfactants (for example, Tween-80) to the comparative compounds:
N- (2-nitrobenzoyl) -N 3-chloro-4- (5-iodo-2-pyrimidinyloxy) -phenyl urine wine No. 1;
one
K- (2-chlorobenzosch1) -H-3-chloro-4- (5-chloro-2-pyrimidinyloxy) -phenyl urea No. 2;
N- (2-chlorobenzoyl) -N -S3-chloro-4- (5-iodo-2-pyrimrzdinyloxy) -phenyl urea No. 3.
o
50
five
about Q 5
five
0
five
31 6
N- (2-bromobenzoyl) -N - {3-chloro-4- (5-iodo-2-pyrimidinyloxy) -phenyl urea No. 4.
The results are presented in table 3.
Drugs based on the proposed compounds were obtained in accordance with the prescription example 6 that is given later in the description.
P r and m 6 p 5. (Intraperitoneal, oral) ..
BDF grafts intraperitoneally leukemia p-388 cells in an amount
1XI o cells per mouse. The test drug is administered orally twice, i.e. one day and four days after vaccination. Mice are observed for 30 days for survival or death. The ratio of the average survival time of the test and control animals is obtained by means of control mice received 100 times the number of days of survival, and saline is administered to them. The results are presented in table 4. The test and comparative compounds were molded according to Formulation Example 6.
PRI me R 6. The test compound is crushed using a centrifugal atomizer. Then, 5 parts by weight of polyoxyethylene (60) hydrogenated castor oil, 0.2 weight parts of siloxane, 0.3 weight parts of polyoxyethylene polyoxypropylene block polymer are taken and added to 79.5 g weight parts of physiological saline in order to obtain an aqueous solution, to the 10 weight parts of said ground compound are added to the solution. The mixture is ground in a wet system using a sand crusher using glass beads (80% of particles have a particle size of not more than
2 microns); Then 5 parts by weight of xanthan gum (2% solution) is added thereto to form an aqueous suspension.
As can be seen from the comparative data, the proposed compounds have a higher anti-tumor activity.
Example 7: Compounds Nos. 1 and 2, molded: in accordance with Example 6, are administered orally to young ddV (10 animals) in an amount of 12.5 mg / kg, after which no mice have died.
Thus, the LD of compounds No. 1 and 2 is 12.5 mg / kg.
When administered intraperitoneally to the same mice, the suspension prepared with the addition of a small amount of a surfactant (Tween 80) to compound No. 3 of the present invention amounts to 100 mg / kg.
LD is from 50

权利要求:
Claims (3)
[1]
Invention Formula
3, Method for the preparation of N-Benzoyl-N-pyrimidinyloxyphenylmobranyl compounds of general formula I,
.
SGS
v-CONHCONH- X
N
where X is chlorine, bromine or nitro;
Z is chlorine or bromine, characterized in that the compound of the general FO1X4ula II
where X has the indicated meanings;
R is isocyanate or amino group, is reacted with a compound of general formula III
Z
h
It has
CF indicated
0
value;
five
0
five
0
rhe
R is an isocyanate or amino group, while if R is an isocyanate group, then R is an amino group; if R is an amino group, then R is an isioate group, at a temperature from 0 to boiling point, in an environment of a solvent such as benzene, toluene, xylene, pyridine, dioxane, dimethyl sulfoxide, monochlorobenzene, ethyl acetate.
[2]
2. Method POP.1, which is different from the fact that if R is an isocyanate group and R is an amino group, then the process is carried out at a temperature from 0 to 120 ° C in an environment of benzene, toluene, xylene, pyridine, dioxane , dimethyl sulfoxide.
[3]
3. Method 1, which differs from the fact that if R is an amino group and an isocyanate group, then the process is carried out at a temperature from to the boiling point in toluene, xylene, monochlorobenzene, ethyl acetate or dioxane.
Priority featured:
15.06.84 when X is chlorine or bromine;
04/02/85 when X is a nitro group.
Table 1
C1
X x
Vg
N0
X N0 "

Dioxane Dioxane
Dimethyl sulfoxide
Pyridine Benzene Toluene Xylene
X no
i
2 4
X - N0,
X "C1
X Br
X NOf
table 2
Vg
C1 C1
01
Toluene
Xylene
Monochlorobenzene
Ethyl acetate
Z cr
Dioxane
eleven
note MST is the ratio of the average survival time of the sprayed and control animals.
1375131
12 Continuation of table 2
12
four
6
Comparative compound 1
183 167 178 201 185 143 116

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AU594098B2|1985-12-11|1990-03-01|Ishihara Sangyo Kaisha Ltd.|N-benzoyl urea compounds, antitumorous compositions containing them, and process for their preparation|US4727077A|1985-02-20|1988-02-23|Ishihara Sangyo Kaisha Ltd.|Benzoyl urea compounds, process for their production, and antitumorous compositions containing them|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP59123399A|JPS611670A|1984-06-15|1984-06-15|N-benzoyl-n'-pyrimidinylurea and anticancer containing the same|

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JP6942685A|JPH0578547B2|1985-04-02|1985-04-02|

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