前苏联专利SU1500156A3 Method of producing benzoyl urea derivatives

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权利要求

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优先权

专利摘要:
A benzoyl urea compound having the formula: wherein A is a bromine atom or a chlorine atom.
公开号:SU1500156A3
申请号:SU864023808
申请日:1986-02-19
公开日:1989-08-07
发明作者:Хага Такахиро；Ямада Нобутоси；Суги Хидео；Коянаги Тору；Кондо Нобуо；Накадзима Цунетака；Ватанабе Масахиро；Йокояма Казумаса
申请人:Исихара Сангио Кайся, Лтд (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of benzoylurea derivatives, new biologically active compounds that can be used in medicine.
The purpose of the invention is a method for producing new low-toxic benzoylurea derivatives having a higher antitumor activity.
Example 1. Synthesis of Compound 1: M- (2-nitrobenzoyl) -K (5-bromo-2-pyrimidinyloxy) -3-chlorophenyl urea.
1. 7.00 g of 5-brsm--2-chloropyrimidine, 5.19 g of 4-amino-2-chlorophenol, 9.98 g of potassium carbonate and 70 ml of dimethyl sulfoxide are placed in a flask and the reaction is carried out under nitrogen for 1.5 h with stirring. After completion of the reaction, the product is extracted into water and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography, whereby half an hour
S5

s
31500
6.80 g of oily 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline are added.
2. A solution obtained by dissolving 6.80 g of 4- - (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 30 ml of dioxane is placed in a flask, and a solution obtained by dissolving 5 76 g of 2-nitrobenzoate isocyanate in 30 ml of dioxane, and then the resulting mixture is reacted at room temperature for 9 hours. After completion of the reaction, the product is poured into water, filtered, and washed with hot water. The crystals thus obtained are placed in methanol and the solution is stirred, then it is filtered, 9.42 g of the expected product is obtained, having a melting point of 234-2364. Example 2. Synthesis of compound 2: N- (2-nitrobenzoyl) -N-3-chloro -4- - (5-chloro-2-pyrimidinyl sy) phenyl 3 urea.
1.The flask is placed 1.50 g of 2,5-dichloropyrimidine, 1.45 g of 4-amino--2-chlorophenol, 2.76 g of potassium carbonate and 15 ml of dimethyl sulfoxide and is reacted under nitrogen atmosphere for 1 , 5 hours with stirring. After completion of the reaction, the product is poured into water and extracted with diethyl ether. The extract is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate, and then the solvent is distilled off. The crude product thus obtained is purified and purified by silica gel column chromatography to give 2.20 g of 3-chloro-4- (5-chloro-2-pyrimidinloxy) aniline, having a melting point of 95-96 ° C. .
2. A solution obtained by dissolving 1.50 g of 2-nitrobenzoyl isocyanate, 5 ml of dioxane is placed in the flask, and a solution obtained by dissolving 1.00 g of 3-chloro-4- (5- chloro-2-β-pyrimidinyloxy) aniline, obtained in this stage, in 6.5 ml of dioxane, the mixture is kept at room temperature for 3 hours. After completion of the reaction, the product is taken up in water and the crystals are filtered off. The crystals are washed with water at about a temperature, dried and suspended in ethyl acetate.

five
0 5 0

five
A small amount of n-hexane and precipitated crystals are added to the mixture. , tally collected by filtration, dried,. having obtained 1.05 g of the desired product having a melting point of 222-225 C.
Example 3. In a flask with a solution of 6.80 g. 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline, prepared according to Preparation Example 1.1., In 30 ml of chlorobenzene was added dropwise at solution 5, 76 g of 2-nitrobenzene or isocyanate in 30 ml of chlorobenzene and then the mixture is left to continue the reaction at 0 ° C for 24 hours. After completion of the reaction, the product is filtered. The crystals are dissolved in dimethyl sulfoxide and the solution is poured into water, followed by filtration. The crystals thus obtained are placed in methyl alcohol and stirred, and then again subjected to filtration, and 7.05 g of the desired product are obtained.
Example 4: 1.73 g of 2-nitrobenzoyl isocyanate are dissolved in 3 ml of 1,2-dichloroethane. Then a solution of 2.47 g of 4- (5-bromo-2-pyrimidinyloxy) -3-chloroaniline in 1,2-dichloroethane is added to it with dropwise.
After the addition is complete, the mixture is left to continue the reaction for 30 minutes under heating at reflux. Upon completion of the reaction, the reaction mixture is cooled and filtered. The crystals are then washed with 1,2-dichloroethane and 3.7 g of the title compound are obtained.
Examples 5-9. The starting materials and the solvent are mixed and reacted under the reaction conditions shown in Table 1. Upon completion of the reaction, the resulting product is cooled in case it is. necessary. Then 30 ml of methyl alcohol is added to the reaction mixture and filtered to obtain the desired product.
The results obtained with this are shown in Table. 1 together with the results obtained in examples 1-4.
Biological tests of benzoylurea derivatives obtained under the conditions of the proposed method were carried out. H- (2-nitrobenzoyl) -N - {3-chloro-4- (5-iodo-2-pyrimidinyloxy) phenyl urea was used as a comparison compound.
Example 1 (test). Inoculation of cancer cells and top5
The test substances are produced intraperitoneally (in the same part of the body). Mice of the BDF strain were inoculated intraperitoneally with P-388 leukemia cells in the number of 1tO cells / mouse The test compound was administered intraperitoneally twice, i.e. 1 and 4 days after inoculation. examined for 30 days for survival or death. The ratio of the average survival time of test and control animals is determined, and the number of days of survival of mice in the control group that received physiological saline is estimated to be 100. Compounds are administered as a dispersion obtained by adding a small amount of surfactant (e.g. Twin-80), supplied by the company Atlas Powder CO, to the test compound.
The effect of the subjects: the compounds on P-388 leukemia when administered intraperitoneally to the site affected by cancer cells is presented in Table. 2
Example 2 (test). P-388 leukemia cells are inoculated intraperitoneally, while test compounds are administered orally.
In mice of the BDF strain, P-388 leukemia cells were injected intraperitoneally in an amount of 1-10 cells / mouse. The test compound is orally administered twice, i.e. 1 and 4 days after inoculation. Mice are observed for 30 days. for survival or death and determine the ratio of the average survival time of the test
animals and control animals for
each treated group (10 animals per group), and the number of the bottom of the survival of mice in the control group in which physiological saline was administered was estimated at 100.
Test compounds are prepared according to Formulation Example 1.
The effect of the tested compounds on leukemia P-388 after oral administration is presented in Table. 3
Example 3 (test). P-388 inoculates the leukemia cells intraperitoneally, while the drug is administered orally.
The ratio of the average survival time of test and control animals is determined by test example 2, except for that.
Q d
c
five
0
0
0
five
0
five
1566
that the test compounds prepared according to prescription example 1 are prepared according to prescription example 2. The effects of the test compounds on P-388 leukemia when administered orally to a large background are presented in Table. four.
Example 4 (test). L-1210 leukemia cells are inoculated intraperitoneally, while test compounds are injected intravenously.
In mice of the BDF strain, 1-1210 leukemia cells in the amount of 1-10 cells / mouse are inoculated intraperitoneally. A test compound prepared according to Formula 2 was administered intravenously. Mice were observed for 30 days for survival or death, and the ratio of the average survival time of test and control animals for each treated group (10 animals per group) was determined; mice of the control group, which were given physiological saline, were rated as 100.
The effect of compound 1 on. leukemia P-388 when administered intravenously is presented in Table. five.
Example 5 (test), L-1210 leukemia cells are inoculated intraperitoneally, while the test compound is administered orally. L-1210 leukemia cells in the amount of 1-10 cells / mouse are inoculated intraperitoneally in the BDF strain. The test substance prepared according to the prescription example 1 is administered twice, i.e. 1 and 4 days after inoculation. Mice are monitored for 30 days for survival or death, and the ratio of the average survival time of test and control animals for each treated group (10 animals per group) is determined, with the number of days of survival of the control group given a physiological saline solution. estimated at 100. S.
The effects of Compound 1 and Compound on L-1210 leukemia when administered orally are presented in
tab. 6. I - -:
Example 6 (test). B-16 melanoma cells inoculated
intraperitoneally, while test compounds are administered orally.
In mice, the BDF strain is intraperitoneally inoculated with 0.5 ml of the liquid obtained by dispersing 1 g of B-16 melanoma cells into 8 cm of physiological saline in the amount of 0.5 ml / ml. A test compound prepared according to Formulation Example 1 was administered orally three times, i.e. i, 7, and 14 days after inoculation. Mice are monitored for 60 days to determine survival or death, and the ratio of the average survival time of test and control animals for each treated group (10 animals per group) is determined, while the number of days of survival of mice of the control group that were administered physiological saline solution, estimated as 100.
The effect of Compound 1 and Compound-Comparison on lilololysis of B-16 after oral administration is presented in Table 25. 7
Example 7 (test). M-5074 cells of the ovarian sarcoma are inoculated intraperitoneally, while test compounds are orally administered jg.
In the BCF strain, intraperitoneal inoculation of N-5074 ovarian sarcoma cells in an amount of 1.10 cells / murine is carried out. The test compound prepared in accordance with Receptor Example 1 is administered orally three times, i.e. 1, 7 and 14 days after inoculation. Mice are monitored for 60 days for survival or death and the ratio of the average survival time of the test and control animals for each treated group (10 animals per) is determined, the number of days of survival of mice of the control group, 5 of which are given physiological saline the solution is estimated at 100.
The effect of the tested compounds on the sarcoma of the ovary M-5074 when administered orally is presented in Table. 8. 50
The data on acute toxicity, dosage and methods for administering benzoylurea derivatives obtained under the conditions of the described method are as follows .. 55 iI Acute toxicity. Compound 1 or 2 was prepared intravenously in the ctdy strain (10 animals), Prepared-.
according to prescription example 1, the amount of the compound was 100 mg / kg, after which none of the mice died. Thus, it has been established that the acute toxicity values (LDj-j) of compounds 1 and 2 are at least 100 mg / kg, i.e. they can be classified as low-toxic.
Dosages These compounds are administered continuously or intermittently in a certain range in which the full dosage does not exceed a certain level, taking into account the results of experiments on animals and various conditions. However, the dosage can be changed depending on the route of administration and on the condition of the patient or animal that is to be treated (e.g., age, body weight, sex, sensitivity, food, etc.), the intervals in which the medication is administered, the medications used in combination with the indicated compounds and on the degree of the disease. The optimal dosage and number of injections in some conditions can be determined by specialists.
Ways of introduction. Antitumor agents can be administered by the oral, intravenous, rectal, intramuscular, and subcutaneous routes, preferably by the oral, intravenous, or rectal routes, most preferably by the oral route.
The proposed compounds are poorly soluble in both water and organic solvents, therefore it is preferable to include them in the formulation in aqueous suspensions, which may additionally contain phospholipids.
In addition, these compounds can be formulated into tablets, capsules, intestinal agents, granules, powders, solutions for injection or in suppositories using known methods of preparation.
, Example 1 (ReCEPTURN), Connection 1 is pre-ground using centrifugal grinding. Take 5 ma.ch. Polymer-cured polyethylene (60) of castor oil, 0.2 wt.h. silicone and 0.3 pts polyoxy-ethylene-polyoxypropylene block polymer, is added to 79.5 May, of a physiological saline solution, in order to obtain an aqueous solution, to which is added 10 parts by weight. crushed compound 1. Dough grind
in a wet system using a sand mill, using glass beads (80% of particles have a particle size of no more than 2 microns). Then 5 ma.ch. Xanthan gum (2% solution) is added there to form an aqueous suspension.
Example 2 (prescription). Take Oh, 24 ma.ch. Compounds 1, 2.4 MW of purified yolk phospholipid and 0.0024. mas.h. and / -tocoferol solution in 48.7576 ma.ch. chloroform and then chloroform is distilled off by heating under reduced pressure using a rotary evaporator to obtain a thin layer of phospholipid containing compound 1. To this thin layer, 48.6 parts by weight are added. a physiological aqueous solution of sodium chloride and immediately vigorously shaken at room temperature, and then ultrasonic treatment is carried out for 1 hour with ice cooling using a Zonikator apparatus. Then centrifugal separation is carried out at room temperature, after which the residue of the bottom layer itself is collected and washed with a centrifuge several times with the indicated physiological aqueous solution of sodium chloride, and then filtered to remove bacteria, whereby an aqueous suspension is obtained. 0.2 - 2 microns.
The tests carried out show that the benzoylurea derivatives obtained by the proposed method are of low toxicity and show a higher antitumor activity against ovarian sarcoma M-5074, melano
we B-16, leukemia L-1210 and leukemia P-388 when orally administered in comparison with the known: K- (5-nitrobenzoyl) -N-3-chloro-4- (5-iodo-2-pyrimidinyl-CHJ phenyl urea

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining benzoylurea derivatives of the general formula
OVCONHCONHNOi
l gX-0- 0 -A
M N-Cl
where A is bromine or chlorine, characterized in that the nitrobenzene compound of the formula
20
ten
CONGO
ten
N0
subjected to interaction with the pyrimidine derivative of general formula
ten
thirty
ten
35
where A has the indicated values, in the presence of an organic solvent, such as octane, keilol, pyridine, dimethyl sulphoxide, ethyl acetate, diokean, chlorobenzene or 1,2-dichloroztan, at 0-120 ° C.
Priority featured:
02.20.85 08.03.85
A - A bromine; bromine, chlorine.
2 3
5.76 Вг 6.80
1.50 5.76
C1 Br
1.00 6.80
Diocean 30 + 30 Rooms - 9h 9,42 for temperature
Diokean 6.5 + 6.5 Same 3 h 1.05
Chlorine- 30 + 30 O 24 h 7.05 benzene
Table 1
Example
Raw materials
Quantity (d)
Solvent (type)
Vg
2.47
-W-il
1,2-di- 3 + 4 chloro-ethane
1.73 1.73
Vg Vg
2.47 2.47
n-octane xylene
Same II
71.73 Вг 2.47 Pyridine 10 Same 5 h 3.2
81.73 W. 2.47 DMSO 10 5h 2.5
91.73 Wg 2.47 Etilacv-10-5-5h2.8
tat
. , p --- g 2
Compound Dose. Active Ingre- Ratio of the average medication, mg / kg / day of the survival time of the test / control,%
125168
112,5173
225210 12.5150
Compare- 25230
body 12,5171
Table3
Compound Dose of Active Ingre-Average Dienta Ratio, mg / kg / day of time and survival
test / control,%
1100173
50 .157
2-50178
25139
Compare - 1600186
full body 800143
400116
Time
Product yield, g
Kip hours from borat, decks. (83.5 ° C)
120
Room temperature
Same II
0.5 h
10 min 5 h
3.7
3.5 3.6
The same 5h 3,2
5h 2,5
Compound Dose of active ingredient; Ratio of average dienta, mg / kg / day of test / control survival time,%
1400235
300180
200143
Compare- 3200183
telny 1600141
Table 5
Compound Dose of active ingredient; Ratio of medium fluid, mg / kg / day of the survival rate of test / control,%
1 .12,5195
Table 6
Compound Dose of active ingredient; Average diente ratio, mg / kg / day survival time
test / control nsh,%
1100213
50165
2100212 Comparative 200 124
Table
Compound Dose of active ingredient; Ratio of average fluid, mg / kg / day of the survival rate of the test / control,%
150165 100 213
2200156 Comparative 200124
Table 8
Compound Dose of active ingredient Average ratio
enta, mg / kg / day test / control survival time,%
- ---------------. ---. ------. -.-.- Д ™ .-. .U .. -.-. ---.-.-.-.-..-.-.-.-..-. “.-..-.
125139
250138 Comparative40098
Table A

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同族专利:

公开号 | 公开日

EP0192235A1|1986-08-27|

CA1260396A|1989-09-26|

FR2577551B1|1988-04-15|

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FR2577551A1|1986-08-22|

EP0192263B1|1992-07-29|

GB2171695B|1989-01-05|

AU593233B2|1990-02-08|

US4849425A|1989-07-18|

AU5328586A|1986-09-11|

CA1266473A|1990-03-06|

EP0192263A3|1987-02-04|

GB8602792D0|1986-03-12|

EP0192263A2|1986-08-27|

GB2171695A|1986-09-03|

EP0192235B1|1989-11-23|

US4727077A|1988-02-23|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP60032365A|JPS61191623A|1985-02-20|1985-02-20|Easily absorbable medicinal composition|

JP4473785A|JPH0156065B2|1985-03-08|1985-03-08|

BR8603945A|BR8603945A|1985-02-20|1986-08-19|PROCESS FOR THE PRODUCTION OF A UREA BENZOIL COMPOUND|

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