CN1013196B - Benzoyl urea compounds producing process - Google Patents
Benzoyl urea compounds producing processInfo
- Publication number
- CN1013196B CN1013196B CN86101087A CN86101087A CN1013196B CN 1013196 B CN1013196 B CN 1013196B CN 86101087 A CN86101087 A CN 86101087A CN 86101087 A CN86101087 A CN 86101087A CN 1013196 B CN1013196 B CN 1013196B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- small white
- white mouse
- gram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The method of the preparation of a benzoyl urea compound having the formula (I) wherein A is a bromine atom or a chlorine atom.
Description
The invention relates to new benzoyl urea compound, their preparation method and by they anti-tumor compositions as effective constituent.
It is found that benzoyl urea compound in the past with following formula
(wherein X is halogen atom or nitro, Y and Z
2Respectively be hydrogen atom or halogen atom, Z
1Be halogen atom or trifluoromethyl, T for=CH-or=N-) can be used as antitumor drug.More precisely, people invent cancer cells in peritonaeum is inoculated into the small white mouse body, and such medicine also when peritonaeum gives small white mouse, can be obtained antineoplastic effect (Japanese Unexamined Patent Publication NO.109721/1982).
But these compounds are generally almost insoluble in water and organic solvent, therefore are difficult to by intestinal absorption.Because the method for administration difference, such medicine often is difficult to demonstrate antineoplastic activity, and as the purpose for the treatment of, has limited the method for such medicinal application peritoneal administration.Therefore, require further to improve so that by practical and easy medication, with practicality and simply formulation be used for the treatment of the purpose of cancer, make these compounds give play to good antitumor action, and do not produce any side effect.
The purpose of this invention is to provide new benzoyl urea compound, they can be included in the above-mentioned general expression IV, but above-mentioned patent discloses their method of preparation particularly and by they anti-tumor compositions as effective constituent.
At first, the invention provides benzoyl urea compounds with following formula:
Wherein A is bromine atoms or chlorine atom.
Secondly, the invention provides the method for the above-mentioned formula I compound of preparation, this method is to make the substituted-nitrobenzene compound with following formula
R wherein
1Be isocyanate group, amino or
Group,
With substituted pyrimidines compound reaction with following formula,
Wherein the definition of A is the same, R
2Be halogen atom, or
Group, wherein R
3Be isocyanate group or amino, but work as R
1When being isocyanate group or amino, R
2For
Group needs with R
3And R
1Inequality is condition, and works as R
1Be
During group, R so
2Be halogen atom.
In addition, the third aspect is to the invention provides by the anti-tumor compositions of formula I compound as effective constituent.
The present inventor has at first carried out extensive studies to the compound of general expression IV representative, and at length studied the relation between chemical structure and the anti-tumor activity, the present inventor finds as a result, following substituting group makes up in above-mentioned formula IV can obtain desirable antitumor action, wherein X is a nitro, Y is the chlorine atom, and T is=N-Z
1Be halogen atom and Z
2It is hydrogen atom.Can observe then, when cancer cells inoculation position and medicine-feeding part not simultaneously, in above-mentioned combination, because Z
1The halogen atom difference of representative, anti-tumor activity has significant difference.Be exactly at Z
1Situation and Z for chlorine atom or bromine atoms
1Be the situation of iodine atom, relatively both activity can be seen, though when the approach of inoculating cancer cells is identical with route of administration, both do not have marked difference by anti-tumor activity, work as above-mentioned approach not simultaneously, and the former activity obviously is better than the latter.The present invention is with the following basis that is found to be, and promptly the above-claimed cpd that does not disclose as yet in aforementioned patent is compared with the compound of specifically mentioning in aforementioned patent, and they have higher anti-tumor activity.
Because Z
1The halogen atom difference of representative, and it is also not fully aware of to make anti-tumor activity the reason of difference occur.But can think, method according to administration, intestines are for the absorption of medicine, the concentration of medicine in blood can change with the different of halogen atom type with the characteristics of drug transport to target site, therefore the position of medicine arrival disease just has remarkable difference, and has produced significant difference aspect anti-tumor activity.So as if some ins and outs of The compounds of this invention often relevant with anti-tumor activity.According to the present invention, by the medicine indirect application is arrived disease location, promptly taking medicine makes it act on whole body, and the position of the interior disease of body is the position away from medication, for example medicine can be oral, intravenously administrable (intravenous injection), rectal suppository, intramuscular administration or percutaneous dosing, preferentially select oral, intravenously administrable or the administration of rectal suppository mode for use, preferably oral, can obtain fabulous antitumor action.According to the present invention, can simplify method, the minimizing dosage of taking medicine in addition, patient's pain in the time of can also alleviating administration, and can alleviate side reaction.
Benzoyl urine compounds of the present invention can following method prepare, for example
Wherein the definition of A is the same.
In above-mentioned reaction, the solvent of application can be octane, benzene,toluene,xylene, pyridine, diox, dimethyl sulfoxide (DMSO), mono chloro benzene or vinyl acetic monomer.
Wherein the definition of A is the same.
In above-mentioned reaction, solvent phase used in adaptable solvent and (A) reaction is same.
Wherein Hal is a halogen atom, and the definition of A is the same.
In above-mentioned reaction, adaptable alkaline matter has sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood.Adaptable solvent is that proton is had the inert polar solvent, as dimethyl sulfoxide (DMSO), dimethyl formamide, hexamethylphosphoramide and tetramethylene sulfone; Ketone is as acetone, methyl ethyl ketone and methyl iso-butyl ketone (MIBK); Halogenated hydrocarbon is as methylene dichloride or chloroform.
In above-mentioned each reaction, as the aniline compound of starting raw material, phenylcarbimide compounds or N-substituted-phenyl-N '-benzoyl urea compounds can be by following method preparations, for example
Wherein the definition of Hal and A is the same.
Adaptable alkaline matter is identical with reaction (C) with solvent.In addition, this condensation reaction is preferably in the nitrogen and carries out.
Wherein the definition of A is the same.
Adaptable solvent has pair phosgene to be the inert solvent, as toluene, dimethylbenzene, mono chloro benzene, vinyl acetic monomer Huo diox.
In the above-mentioned reaction in adaptable solvent and (A) reaction used solvent phase with.
Now, the present invention will be described in further detail with example, but be to be understood that the present invention never is subjected to the restriction of these specific exampless.
Synthetic example 1:
The N-(2-nitro benzoyl)-and N '-(4-(5-bromo-2-2-pyrimidinyl oxy)-3-chloro-phenyl-) urea (compound N is O.1) synthetic:
(1) 7.00 gram 5-bromo-2-chloropyrimide, 5.19 gram 4-amino-2-chlorophenols, 9.98 gram salt of wormwood and 70 milliliters of dimethyl sulfoxide (DMSO) are placed flask, under nitrogen gas stream,, reacted 1.5 hours in 120 ℃ of stirrings.After reaction finished, product injected water, uses ethyl acetate extraction.Extraction liquid water and saturated sodium-chloride water solution washing with anhydrous sodium sulfate drying, then through purification by silica gel column chromatography, get 6.80 gram 4-(5-bromo-2-2-pyrimidinyl oxies)-the 3-chloroaniline, be oily matter.
(2) 6.80 gram 4-(5-bromo-2-2-pyrimidinyl oxies that will obtain above)-the 3-chloroaniline is dissolved in 30 milliliters of solution in the diox and places flask; and 5.76 gram 2-nitro benzoyl isocyanic ester are dissolved in 30 milliliters of solution in the diox splash into, mixture at room temperature reacted 9 hours then.Reaction finishes the back product and injects water, filters, and uses hot wash.Methyl alcohol is put in the crystallization that obtains, and stirs, and filters once more, gets 9.42 gram desired products, 234～236 ℃ of fusing points.
Synthetic example 2:
The N-(2-nitro benzoyl)-and N '-(3-chloro-4-(5-chloro-2-2-pyrimidinyl oxy) phenyl) urea (compound N is O.2) synthetic:
(1) with 1.50 grams 2,5-dichloro pyrimidine, 1.45 gram 4-amino-2-chlorophenols, 2.76 gram salt of wormwood and 15 milliliters of dimethyl sulfoxide (DMSO) place flask, in 100 ℃ of stirrings, react 1.5 hours under nitrogen gas stream.Reaction finishes the back product and injects water, and uses extracted with diethyl ether.Extraction liquid washs with saturated sodium-chloride water solution, with anhydrous sodium sulfate drying, boils off solvent then.The thick product that obtains through purification by silica gel column chromatography with separate, 2.20 gram 3-chloro-4-(5-chloro-2-2-pyrimidinyl oxies) aniline, 95～96 ℃ of fusing points.
(2) solution that 1.50 gram 2-nitro benzoyl isocyanic ester is dissolved in 6.5 milliliters of dioxs places flask; and the 1.00 gram 3-chloro-4-(5-chloro-2-2-pyrimidinyl oxies that will make above) aniline is dissolved in 6.5 milliliters of solution in the diox and splashes into, and mixture at room temperature reacted 3 hours.Reaction finishes the back product and injects water, filters and collects the crystallization of separating out.With about 50 ℃ water washing crystallization, drying, and be suspended in the vinyl acetic monomer.On a small quantity just add-hexane, filter and collect the crystallization of separating out, drying, 1.5 gram desired products, 222～225 ℃ of fusing points.
Synthetic example 3:
O.1 synthetic of compound N:
(1) solution of 0.02 moles of phosgene in 30 milliliters of vinyl acetic monomers is placed flask.With 3 gram 4-(5-bromo-2-2-pyrimidinyl oxies)-solution of 3-chloroaniline in 10 milliliters of vinyl acetic monomers splashes into.Mixture at room temperature stirs, and reacts 3 hours, and reheat refluxed 1 hour.Reaction finishes the back decompression and steams vinyl acetic monomer, and resistates vacuum-drying gets 3.10 gram 4-(5-bromo-2-2-pyrimidinyl oxies)-3-chloro-phenyl-isocyanic ester, 63～68 ℃ of fusing points.
(2) 1.22 gram 4-(5-bromo-2-2-pyrimidinyl oxies that will obtain above)-3-chloro-phenyl-isocyanic ester places flask, adds 20 milliliters of toluene.In addition, under agitation add 0.62 gram 2-nitrobenzamide again, mixture heating up refluxed 4 hours.Reaction is added to 5 ml methanol in the reaction product after finishing, and makes the mixture cooling.Filter and collect the crystallization of separating out, get 0.79 gram desired product.
Synthetic example 4:
O.2 synthetic of compound N:
(1) the 5.19 gram 4-amino-solution of 2-chlorophenol in 100 milliliters of dioxs is placed flask.The solution of 5.78 gram 2-nitro benzoyl isocyanic ester in 10 milliliters of dioxs is splashed under room temperature.Mixture at room temperature stirs, and reacts 12 hours.Reaction finishes the afterreaction product and injects water.Filter and collect the crystallization of separating out, use methanol wash, get 8.60 gram N-(2-nitro benzoyls)-N '-(3-chloro-4-hydroxy phenyl) urea, 237～239 ℃ of fusing points.
(2) 1 gram N-(2-nitro benzoyl that will obtain above)-and N '-(3-chloro-4-hydroxy phenyl) urea solution in 10 milliliters of dimethyl sulfoxide (DMSO) places flask, adds 0.14 gram potassium hydroxide, then 0.58 gram 5-bromo-2-chloropyrimide is added.Mixture was 50 ℃ of reactions 5 hours, and reaction is added to 20 ml methanol in this reaction product after finishing.Filter and collect the crystallization of separating out.Water and methanol wash crystallization get 0.81 gram desired product.
Particular compound of the present invention is listed as follows:
Compound N is O.1:
The N-(2-nitro benzoyl)-and N '-(3-chloro-4-(5-bromo-2-2-pyrimidinyl oxy) phenyl) urea, 234～236 ℃ of fusing points.
Compound N is O.2:
The N-(2-nitro benzoyl)-and N '-(3-chloro-4-(5-chloro-2-2-pyrimidinyl oxy) phenyl) urea, 222～225 ℃ of fusing points.
Concrete intermediate of the present invention is listed as follows:
4-(5-bromo-2-2-pyrimidinyl oxy)-and the 3-chloroaniline, 52～61.5 ℃ of fusing points.
3-chloro-4-(5-chloro-2-2-pyrimidinyl oxy) aniline, 95～96 ℃ of fusing points.
4-(5-bromo-2-2-pyrimidinyl oxy)-and 3-chloro-phenyl-isocyanic ester, 63～68 ℃ of fusing points.
N-(3-chloro-4-hydroxy phenyl)-and N '-(2-nitro benzoyl) urea, 237～239 ℃ of fusing points.
The compound name that is used for comparison below in the example is called:
Comparative compound NO.1:
The N-(2-nitro benzoyl)-and N '-(3-chloro-4-(5-iodo-2-2-pyrimidinyl oxy) phenyl) urea (open in Japanese Unexamined Patent Publication NO.109721/1982).
Now the distinctive anti-tumor activity of benzoyl urea compound of the present invention is described below.
For example with its title of comparative compound NO.1(and antitumous effect specifically narration in above-mentioned Japanese Patent) compare, under the situation of test examples 1 (wherein, the position of inoculation cancer cells is identical with medicine-feeding part), O.1, compound N of the present invention is not seen obvious raising with 2 anti-tumor activities, but under the situation of test examples 2 and 3 (wherein, above-mentioned two positions are different), O.1 compound N of the present invention shows fabulous anti-tumor activity with 2.
Test examples 1(adopts the mode of intraperitoneal inoculation cancer cells and administration as the situation of above-mentioned Japanese Patent test examples 1)
Give BDF
1Small white mouse intraperitoneal inoculation P-388 leukemia cell, inoculation quantity is 1 * 10
6Cell/small white mouse.Intraperitoneal is subjected to reagent thing secondary (promptly after inoculation the 1st day and the 4th day), sight is small white mouse survival and dead situation in 30 days, total fate with the control group small white mouse survival that only gives physiological saline, can obtain the ratio (%) of experimental animal and control animal mean survival time (MST), total fate of control group small white mouse survival is with 100 expressions.Add low quantity of surfactant (for example adding the tween-80 of making by Atlas Powder company) in test compound, used dispersion agent (table 1) in can obtaining testing.
Table 1
Compound number dosage (effective constituent, milligram/kg/day) test group MST/ control group MST(%)
1 25 168
12.5 173
2 25 210
12.5 150
Comparative compound 25 230
NO·1 12.5 171
Test examples 2(intraperitoneal inoculation P-388 leukemia cell, and medicine is oral)
Give BDF
1Small white mouse intraperitoneal inoculation P-388 leukemia cell, inoculation quantity is 1 * 10
6Cell/small white mouse.Oral test medicine secondary (promptly after inoculation the 1st day and the 4th day), observe small white mouse survival and dead situation in 30 days, according to total fate of each treatment group (every group has 10 animals) small white mouse survival with only give total fate that the control group small white mouse of physiological saline survives, can obtain the ratio (%) of experimental animal and control animal mean survival time, total fate of control group small white mouse survival is with 100 expressions.
Preparation example 1 test preparation medicine by the back.
Table 2
Compound number dosage (effective constituent, test group MST/ control group
Milligram/kg/day) MST(%)
1 100 173
50 157
2 50 178
25 139
Comparative compound 1,600 186
NO·1 800 143
400 116
Test examples 3(intraperitoneal inoculation P-388 leukemia cell, and medicine is oral)
The ratio of experimental animal and control animal mean survival time (%) records by test examples 2 same modes, and just the trial drug that obtains with preparation example 2 replaces preparing the trial drug (table 3) that example 1 obtains.
Table 3
Compound number dosage (effective constituent, test group MST/ control group
Milligram/kg/day) MST(%)
1 400 235
300 180
200 143
Comparative compound 3,200 183
NO·1 1600 141
Test examples 4(intraperitoneal inoculation L-1210 leukemia cell, and medicine is intravenous injection)
Give BDF
1Small white mouse intraperitoneal inoculation L-1210 leukemia cell, inoculation quantity is 1 * 10
5Cell/small white mouse, the trial drug that intravenous injection is obtained by preparation example 2, observe small white mouse survival and dead situation in 30 days, according to total fate of each treatment group (every group has 10 animals) small white mouse survival with only give total fate that the control group small white mouse of physiological saline survives, can obtain the ratio (%) of experimental animal and control animal mean survival time, total fate of control group small white mouse survival is with 100 expressions (table 4).
Table 4
Compound number dosage (effective constituent, test group MST/ control group
Milligram/kg/day) MST(%)
1 12.5 195
Test examples 5(intraperitoneal inoculation L-1210 leukemia cell, and medicine is oral)
Give BDF
1Small white mouse intraperitoneal inoculation L-1210 leukemia cell, inoculation quantity is 1 * 10
5Cell/small white mouse, the oral trial drug secondary that obtains by preparation example 1 (promptly the inoculation back is the 1st day and the 4th day), observe small white mouse survival and dead situation in 30 days, according to total fate of each treatment group (every group has 10 animals) small white mouse survival with only give total fate that the control group small white mouse of physiological saline survives, can obtain the ratio (%) of experimental animal and control animal mean survival time, total fate of control group small white mouse survival is with 100 expressions.
Table 5
Compound number dosage (effective constituent, test group MST/ control group
Milligram/kg/day) MST(%)
1 100 213
50 165
Test examples 6(intraperitoneal inoculation B-16 melanoma cells, and medicine is oral)
Give BDF
1The small white mouse intraperitoneal is inoculated 0.5 milliliters of liquid (1 gram B-16 melanoma is dispersed in 8 ml physiological salines and make), inoculum size is 0.5 a milliliter/small white mouse, oral by the trial drug that obtains of preparation example 1 three times (promptly after inoculation the 1st day, the 7th day and the 14th day), observe small white mouse survival and dead situation in 60 days, according to total fate of each treatment group (every group has 10 animals) small white mouse survival with only give total fate that the control group small white mouse of physiological saline survives, can obtain the ratio (%) of experimental animal and control animal mean survival time, total fate of control group small white mouse survival is with 100 expressions (table 6).
Table 6
(effective constituent, experimental animal MST/ contrast is moving for compound number dosage
Milligram/kg/day) thing MST(%)
1 100 139
Test examples 7(intraperitoneal inoculation M-5074 ovarian sarcoma cell, and medicine is oral)
Give BCF
1Small white mouse intraperitoneal inoculation M-5074 ovarian sarcoma cell, inoculation quantity is 1 * 10
6Cell/small white mouse.Oral by the trial drug that obtains of preparation example 1 three times (promptly after inoculation the 1st day, the 7th day and the 14th day), observe small white mouse survival and death condition in 60 days, according to total fate of each treatment group (every group of 10 animals) small white mouse survival with only give total fate that the control group small white mouse of physiological saline survives, can obtain the ratio (%) of experimental animal and control animal mean survival time, total fate of control group small white mouse survival is with 100 expressions (table 7).
Table 7
(effective constituent, experimental animal MST/ contrast is moving for compound number dosage
Milligram/kg/day) thing MST(%)
1 25 139
Narrate acute toxicity, dosage and the route of administration of benzoyl urea compound of the present invention below.
(1) acute toxicity:
Contain The compounds of this invention NO.1 and NO.2 for ddY small white mouse (10 animals) intravenous injection, and by the medicine of preparing example 1 preparation, the consumption of compound is 100 milligrams/kilogram, does not have mice dying subsequently.Therefore compound N O.1 with the acute toxicity value (LD of NO.2
50) be at least 100 milligrams/kilogram.
(2) dosage:
About dosage, take above-claimed cpd continuously or intermittently, because animal experiment and various condition, total dose is no more than certain level.Certainly according to route of administration, need the patient of treatment and animal situation (as make in year, body weight, sex, susceptibility, food etc.), time of administration at interval, the medicine that is used in combination with this compound and the degree of disease suitably change dosage.Shi Yi dosage and administration total amount should be determined by the medical expert under certain condition.
(3) route of administration:
Antitumor drug of the present invention can through port, vein, rectum, muscle and subcutaneous route administration, preferentially selects through port, vein or rectum administration for use, the approach of handy oral administration.In this case, The compounds of this invention can be used pharmaceutically acceptable various carrier as common drug, as inert diluent or form the carrier of food, preferentially selects the mode of oral, intravenous injection or suppository administration for use, the most handy oral administration.
The almost both water insoluble organic solvent that also is insoluble to of compound of the present invention.Therefore preferably they are mixed with the water suspension that contains phosphatide.Preparation does not contain the method for the aqeous suspension of phosphatide, be that active compound tentatively is ground into fine powder, then the fine powder of active compound is added to and contains tensio-active agent (if necessary, also can contain defoamer) the aqueous solution in, in the wet type device, mixture is pulverized, particle up to 80% is no more than 5 microns, preferably is no more than 2 microns, also can add thickening material if desired.The example of concrete tensio-active agent has the nonionic phosphoric acid ester, and polyoxyethylene solidifies Viscotrol C, Vykamol Sorbitol 8B, sugar ester, polyox-yethylene-polyoxypropylene block copolymer etc.The object lesson of defoamer has dimethyl polysiloxane, methylphenyl siloxane, fatty acid esters of sorbitan, polyoxyethylene-polyoxypropylene cetyl ether, siloxanes etc.The object lesson of thickening material has pawl ear glue, gum arabic, pectin, starch, xanthane glue, gelatin etc.
On the other hand, preparation contains the method for the aqeous suspension of phosphatide, can replace tensio-active agent above-mentioned with phosphatide (as soybean phospholipid or egg phospholipids), and can use antioxidant (as alpha-tocopherol) to replace thickening material.
In addition, also have another preparation to contain the method for phosphatide aqeous suspension.Phosphatide and compound of the present invention are dissolved in the organic solvent (as chloroform), can add antioxidant if desired.Under reduced pressure steam solvent then, the result adheres to the phosphatide of skim at container inner wall, has obtained containing the phosphatide thin layer of The compounds of this invention.Again the acceptable aqueous solution on the physiology is added on the thin layer of formation, jolting or stirring, to destroy thin layer, the suspension that obtains like this stands ultrasonication, and centrifugation, tell the most of resistates of lower floor, and with the aqueous solution centrifuge washing that contains phosphatide (granular size: 5 microns at the most, for example from 0.2～2 micron).
In addition, these compounds can be mixed with tablet with the method for ordinary preparation, capsule, intestines inner absorbent, granule, pulvis, injection solution or suppository.
Narrate concrete preparation example below.
The compounds of this invention NO.1 tentatively pulverizes by centrifugal mill.On the other hand, the polyoxyethylene of 5 parts of weight (60) solidifies the siloxanes of Viscotrol C, 0.2 part of weight and the polyox-yethylene-polyoxypropylene block copolymer of 0.3 part of weight is added in the physiological saline of 79.5 parts of weight, obtain an aqueous solution, the above-mentioned The compounds of this invention NO.1 through pulverizing of 10 parts of weight is added in this aqueous solution.Use granulated glass sphere,, in the wet type device, mixture is pulverized (80% particle is no more than 2 microns) by sand mill.Then, add the xanthane glue (2% solution) of 5 parts of weight, obtain aqeous suspension.
Preparation example 2
0.24 The compounds of this invention NO.1, the purifying egg phospholipids of 2.4 parts of weight and the alpha-tocopherol of 0.0024 part of weight of part weight are dissolved in the chloroform of 48.7576 parts of weight, heating under reduced pressure then, use rotatory evaporator and steam chloroform, form the phosphatide thin layer that contains The compounds of this invention NO.1.The physiological sodium chloride aqueous solution of 48.6 parts of weight is added on this thin layer, and jolting intensely at room temperature immediately, carried out ultrasonication 1 hour with ultrasonoscope down ice-cooled then.At room temperature carry out centrifugation in addition, tell lower floor's resistates subsequently, with above-mentioned physiological sodium chloride aqueous solution centrifuge washing for several times, remove by filter bacterium, obtain containing the aqeous suspension of phosphatide (granular size: 0.2～2 micron).
Preparation example 3
With the aqeous suspension lyophilize that obtains in the preparation example 2, obtain containing the drying composition of phosphatide.
As the front in detail as described in, even when the position of taking medicine during away from disease sites, compound provided by the invention still demonstrates fabulous anti-tumor activity.In addition, can simplify according to the present invention dispensing, and dosage can reduce, can alleviate patient's pain during administration, side effect also can alleviate.
Preparation example 4
The The compounds of this invention NO.2 that 40 parts of weight are pulverized through centrifugal mill is added in the aqueous solution, this aqueous solution by the polyene propyl phenoxy phosphoric acid ester of 1.5 parts of weight oxyethylations of dissolving and 0.2 part of weight siloxane in 53.3 parts of weight physiological saline and make.Mixture is pulverized (90% particle should greater than 2 microns) with granulated glass sphere in the sand mill of wet type device.Add the xanthane glue (2% solution) of 5 parts of weight then, obtain aqeous suspension.
Preparation example 5
The compounds of this invention NO.1 tentatively pulverizes with centrifugal mill.The The compounds of this invention NO.1 of 5 parts of weight through pulverizing is added to by stirring and disperseing in the resulting aqueous solution of physiological saline of the alpha-tocopherol of the egg phospholipids of 2 parts of weight, 0.001 part of weight and 92.999 parts of weight.In the sand mill of wet type device, mixture is pulverized (80% particle should be not more than 2 microns) then, obtain aqeous suspension with granulated glass sphere.
Claims (1)
1, preparation has the method for the benzoyl urea compounds of formula I
A is bromine atoms or chlorine atom in the formula,
This method comprises: (A) in the presence of organic solvent in 0～120 ℃ of substituted mirbane oil compound that will have formula II
R in the formula
1' be isocyanate group
With substituted pyrimidines compounds reaction with formula III
A is bromine atoms or chlorine atom in the formula, R
3Be amino;
(B) in the presence of organic solvent, will have the substituted mirbane oil compound of formula II in 50 ℃～reflux temperature
R in the formula
1' be amino,
With substituted pyrimidines compounds reaction with formula III
A is bromine atoms or chlorine atom in the formula, R
3It is isocyanate group;
(C) in the presence of inorganic base substance and organic solvent, N-(2-nitro benzoyl)-N '-(3-chloro-4-hydroxy phenyl) urea substituted mirbane oil compound and the substituted pyrimidines compounds with following formula are reacted in 0 ℃～reflux temperature
A is bromine atoms or chlorine atom in the formula, and Hal is a halogen atom.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60032365A JPS61191623A (en) | 1985-02-20 | 1985-02-20 | Easily absorbable medicinal composition |
| JP32365/85 | 1985-02-20 | ||
| JP60044737A JPS61205257A (en) | 1985-03-08 | 1985-03-08 | Benzoylurea compound, production thereof, and anticancer drug containing same |
| JP44737/85 | 1985-03-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86101087A CN86101087A (en) | 1987-02-25 |
| CN1013196B true CN1013196B (en) | 1991-07-17 |
Family
ID=26370920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86101087A Expired CN1013196B (en) | 1985-02-20 | 1986-02-19 | Benzoyl urea compounds producing process |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR930004676B1 (en) |
| CN (1) | CN1013196B (en) |
| AR (1) | AR240557A1 (en) |
| DE (2) | DE3667055D1 (en) |
| DK (1) | DK163124C (en) |
| ES (1) | ES8707506A1 (en) |
| NZ (1) | NZ214953A (en) |
-
1986
- 1986-01-28 NZ NZ214953A patent/NZ214953A/en unknown
- 1986-02-17 AR AR30315286A patent/AR240557A1/en active
- 1986-02-18 DE DE8686102063T patent/DE3667055D1/en not_active Expired
- 1986-02-19 ES ES552191A patent/ES8707506A1/en not_active Expired
- 1986-02-19 KR KR1019860001154A patent/KR930004676B1/en not_active IP Right Cessation
- 1986-02-19 CN CN86101087A patent/CN1013196B/en not_active Expired
- 1986-02-20 DE DE8686102217T patent/DE3686177T2/en not_active Expired - Fee Related
- 1986-02-20 DK DK080286A patent/DK163124C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES552191A0 (en) | 1987-08-01 |
| DE3667055D1 (en) | 1989-12-28 |
| ES8707506A1 (en) | 1987-08-01 |
| DE3686177D1 (en) | 1992-09-03 |
| DK163124B (en) | 1992-01-20 |
| NZ214953A (en) | 1988-08-30 |
| KR930004676B1 (en) | 1993-06-03 |
| CN86101087A (en) | 1987-02-25 |
| DK80286D0 (en) | 1986-02-20 |
| DK80286A (en) | 1986-08-21 |
| KR860006447A (en) | 1986-09-11 |
| DK163124C (en) | 1992-06-09 |
| AR240557A1 (en) | 1990-05-31 |
| DE3686177T2 (en) | 1993-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1500156A3 (en) | Method of producing benzoyl urea derivatives | |
| CN1105111C (en) | Pyrazine compounds | |
| CN1301260A (en) | Fumagillol derivatives and processes for preparing the same | |
| CN86100411A (en) | Produce the method for thiazolidinedione | |
| CN1319088A (en) | Arylsulfonanilide ureas | |
| CN1036389C (en) | Acetamide derivatives | |
| CN1074764C (en) | Benzoxazinone dopamine D4 receptor antagonists | |
| CN87105516A (en) | Phenyl crotonamide compound that replaces and preparation method thereof | |
| CN1028528C (en) | Salts of optically active 4-hydroxy-8-(3-lower alkoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a]-1,3,5-triazines | |
| CN1148362C (en) | Polycyclic 2-aimino-thiazole systems, method for prodn. thereof and medicament contg. said compounds | |
| CN1161120C (en) | Utilization of polycyclic 2-amino-thiazole systems in the production of medicaments for prophylaxis treatment of obesity | |
| CN1019911C (en) | Benzoxazine derivative and processes for preparing same | |
| CN1094930C (en) | Quinoxaline and preparation method and application thereof | |
| CN1727332A (en) | Compound in category of aryl methylamino dithio formic ether, preparation method and application | |
| CN1009826B (en) | The method for preparing quinoline compound | |
| CN1313766A (en) | DNA-cleaving antitumor agents | |
| CN1141940C (en) | Use of polycyclic thiazole systems for producing medicaments for preventing of treating obesity | |
| CN1042935C (en) | Chemical compounds | |
| CN1013196B (en) | Benzoyl urea compounds producing process | |
| CN1083476A (en) | The fumarate of quinoline | |
| CN1149205C (en) | Polycyclic thiazole systems and their utilization as anorectics | |
| CN1198330A (en) | Method for treating protozoal infections | |
| CN1052305A (en) | New pyridine derivate, contain their pharmaceutical composition and preparation method thereof | |
| CN1152026C (en) | Polycyclic 2-amino-dihydrothiazole systems, process for the production thereof and their utilization as medicament | |
| CN1931869A (en) | Derivative of 5-deoxy-5-fluoro cytidine and its prepn process and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |