CN108395410A - A kind of anilinoquinazoline compound and its application in antitumor drug - Google Patents
A kind of anilinoquinazoline compound and its application in antitumor drug Download PDFInfo
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
A kind of application the present invention provides anilinoquinazoline compound and its in antitumor drug, the anilinoquinazoline compound have following chemical structural formula：
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, the present invention relates to a kind of anilinoquinazoline compound and its
Application in antitumor drug, more particularly to colorectal cancer, cancer of pancreas, non-small cell lung cancer, thyroid cancer, starlike nerve cell are swollen
Tumor treats or prevents useful antineoplastic.
Background technology
Tumour refers to body under the effect of the various tumorigenesis factors, and local organization hyperplasia is formed by neoformation, because
This neoformation is in occupancy block-like protrusions, also referred to as neoplasm more.
Tumor epithelial cell is tumour cell, and tumour cell is the main component of tumour, has tissue-derived specificity, it is determined
The particularity of the Biological characteristics of tumour and each tumour.The group of various tumours is identified generally according to the substantive form of tumour
Source is knitted, carries out the classification, name and histodiagnosis of tumour, and determine according to its differentiation and maturation degree and atypia size
Good pernicious and tumour the grade malignancy of tumour.There are three significant essential characteristics for tumour cell：Immortality, migration and loses
Contact inhibition.In addition to this, there are many more the physiology, biochemistry and the morphological features that are different from normal cell for tumour cell.
Malignant epithelial cell tumour is also cancer, is a kind of disease for endangering human health most serious at present.In the U.S., dislike
The death rate of property tumour is only second to angiocardiopathy and occupies second.It is public according to China's Development of Health Service situation statistics in 2016
Report, urban area Residents death cause first are malignant tumour, are secondly cerebrovascular disease, heart disease.Most commonly seen and harmfulness is tight
The tumour of weight is lung cancer, nasopharyngeal carcinoma, the cancer of the esophagus, gastric cancer, colorectal cancer, liver cancer, breast cancer, cervical carcinoma and lymthoma etc..
Treating tumour, there are two types of viewpoints, one is the tumour cell whole removing of patient's body or at least elimination is enough
Amount, makes patient's tumour within life cycle no longer recur；The second is changing the characteristic of cancer cell, the course of disease is made to slow down or even stop completely
Only.The conventional method of oncotherapy has three kinds of operation, radiation and chemotherapy.The cure rate of ocal resection depends on tumour
Position, size and property, some tumours are grown can not touch in deep, or cannot then be treated with operation method positioned at critical position.
Radiotherapy is exactly to use radioactive ray（Such as X, gamma-rays）Tumour cell is killed, external exposure can be carried out to tumour cell, can also be placed in
Radioactive source carries out internal exposure, and radiotherapy can also kill and normally be proliferated faster cell, cause infection, bleeding, catarrh, alopecia
Deng.Chemotherapy mainly uses DNA synthetic inhibitors（Such as 5 FU 5 fluorouracil）Or cell division inhibitor（Such as vincristine, Japanese yew
Phenol）Etc cellulotoxic preparation's object inhibit tumour cell, equally there is lethal effect to all dividing cells, thus can also draw
Play above-mentioned side effect.
Antitumor drug also has an impact the normal cell of body, while killing tumour cell to itself
Body has stronger adverse effect, thus affects resistivity of the patient itself for infectious diseases so that patient is changing
During treatment than usual in the case of, be easy cause infectious diseases, with prodigious drug-associated infectious diseases generation wind
Danger.Serious infectious diseases entail dangers to patient vitals, so that patient is caused not die of tumour itself, and die of drug phase
The infectious diseases of closing property.
Anilinoquinazoline compound is a kind of epidermal growth factor recipient tyrosine kinase（EGFR-TK）Inhibitor, it is right
The inhibition of EGFR-TK can hinder the growth, transfer and angiogenesis of tumour, and increase the apoptosis of tumour cell.It is not only to evening
Phase non-small cell lung cancer is effective, and also has antitumor activity, including prostate cancer, breast cancer, neck to other solid tumors
Portion's tumour, gastric cancer, cancer of pancreas, thyroid cancer, colorectal cancer, starlike nerve cell tumour etc., through research, anilinoquinazoline compound
Not only antitumous effect is fabulous, and does not have toxic side effect.
Invention content
For the existing above problem, one of the objects of the present invention is to provide a kind of anilinoquinazoline compounds.
An object of the present invention, which also resides in, provides a kind of preparation method of anilinoquinazoline compound.
An object of the present invention, which also resides in, provides a kind of anilinoquinazoline compound or its pharmaceutically acceptable salt, same
The pharmaceutical composition of enantiomers or solvate as active constituent.
An object of the present invention, which also resides in, provides a kind of anilinoquinazoline compound or its pharmaceutically acceptable salt, same
The application of enantiomers or solvate in antitumor drug.
To achieve the above object, the present invention provides a kind of anilinoquinazoline compound, the anilinoquinazoline compounds
With following chemical structural formula：
,
Wherein：
X is halogens, and X is located at at least one in phenyl ring residue binding site, and X is covalently attached with the carbon atom on phenyl ring；
R1For alkyl, R1It is covalently attached with oxygen atom by the carbon atom on alkyl；
R2Group after being replaced by alkyl for heterocycle, R2It is covalently attached with oxygen atom by the carbon atom on alkyl.
Further, X is fluorine（F）, chlorine（Cl）, bromine（Br）Or iodine（I）；
Further, the R1For C1-C6 alkyl；
Further, the R2Group after being replaced by C1-C4 alkyl for C2-C10 heterocycles.
The present invention also provides a kind of preparation method of anilinoquinazoline compound, which includes following synthesis road
Line：
；
The preparation method includes following synthesis step：
The first step, in a solvent, compound（A）Condensation reaction, vacuum distillation recycling are carried out under accelerating agent and catalyst action
Solvent obtains compound（B）, obtained compound（B）It need not be detached, be directly used in the reaction of following second step；
Reaction solution after condensation reaction in the first step is added solvent, formic acid and compound by second step（C）, temperature rising reflux is cold
But to room temperature, pH to 8-9 is adjusted with alkali nertralizer, there is solid precipitation；
Third walks, and the solid being precipitated in second step is continued to cool down, is filtered after stirred crystallization 1h, and ethyl acetate washing filter is used in combination
Cake；Methanol, acetone and pure water recrystallization, vacuum drying is used to obtain solid chemical compound successively again（D）.
Further, solvent is toluene in the synthesis step first step, and accelerating agent is n,N-Dimethylformamide diformazan
Acetal（DMF-DMA）, catalyst is formic acid, acetic acid, pyrovinic acid, sulfuric acid or phosphoric acid, preferably acetic acid.
Further, solvent is absolute ethyl alcohol in the synthesis step second step, and temperature is 110-130 DEG C after heating, is returned
The stream time is 6h, and alkali nertralizer is sodium hydroxide, potassium hydroxide, niter cake, potassium carbonate, ammonium hydroxide or triethylamine, preferably ammonium hydroxide.
Further, temperature is 2-6 DEG C after cooling down in synthesis step third step, vacuum drying at 40-50 DEG C into
Row.
The present invention also provides a kind of anilinoquinazoline compound or its pharmaceutically acceptable salt, isomers or molten
Pharmaceutical composition of the agent compound as active constituent.
Further, buffer salt, osmotic pressure regulator are also contained in pharmaceutical composition of the present invention.According to pharmaceutical composition
Dosage form, it is also optional in pharmaceutical composition to contain preservative, thickener.
Further, its pH range of pharmaceutical composition of the present invention is preferably maintained at 6.8-8.0.In order to maintain this hair
Bright pharmaceutical composition pH is maintained at 6.8-8.0, and adoptable buffer salt is selected from boric acid-borax, disodium hydrogen phosphate-biphosphate
Sodium, boric acid-sodium carbonate or boric acid-sodium acetate.
Further, in pharmaceutical composition of the present invention, its preferred osmotic pressure keeps 260-340mosm/L.
Further, in order to maintain the osmotic pressure of pharmaceutical composition of the present invention, adoptable osmotic pressure regulator is selected from chlorine
Change sodium, potassium chloride, glycerine, glucose, propylene glycol or mannitol.
Further, the preservative suitable for pharmaceutical composition of the present invention is selected from ethyl hydroxy benzoate, gluconic acid chlorine
Oneself fixed, chlorhexidine hydrochloride, chlorhexidine acetate, cetrimonium bromide, benzalkonium chloride, benzalkonium bromide, Phenoxyethanol or anesin.
Further, the thickener suitable for pharmaceutical composition of the present invention is selected from sodium hyaluronate, polyvinyl alcohol, gathers
Tie up ketone or water soluble chitosan.
Contain reactive compound 0.8-15.0% in described pharmaceutical composition (by weight percentage).Work as pharmaceutical composition
In contain preservative or thickener when, preservative be 0.001-5% (by weight percentage), thickener be 0.01-3% (press
Weight percent meter).
The present invention also provides a kind of anilinoquinazoline compound or its pharmaceutically acceptable salt, isomers
Or application of the solvate in antitumor drug, for treating colorectal cancer, cancer of pancreas, non-small cell lung cancer, thyroid cancer, star
Shape nerve cell tumour.
Compared with the existing technology, the invention has the advantages that：
1, the present invention is anilinoquinazoline compound, is strong EGF-R ELISA（EGFG）Tyrosine kinase inhibition
Agent, EGF-R ELISA（EGFG）Served in the proliferation of tumour cell, growth, survival etc. it is extremely important,
And anilinoquinazoline compound of the present invention plays antagonism to the signal transduction pathway of the proliferation of tumour cell, growth, survival.
2, the present invention in preparation process reaction condition it is simply mild, using Gas chromatography compound as raw material, first and
N,N-dimethylformamide dimethylacetal（DMF-DMA）Reality while carrying out condensation reaction, then quinazoline ring is formed by formic acid
Now with the connection of amine benzene, to obtain target compound.
3, reaction step of the present invention is few, reacts and carries out preparing aniline quinazoline not over any chlorination reaction in overall process
Compound, therefore avoid having used toxic and environmental pollution chlorinating agent, for example, phosphorus oxychloride, phosphorus trichloride, thionyl chloride,
Sulfonic acid chloride etc., protects environment, is suitble to the requirement of industrialized production.
4, anilinoquinazoline compound is relatively simple for structure in the present invention, only carries R1R2Liang Zhong functional groups, and function unity
Structure is also simple, therefore using condensation and ring-closure reaction, improves the selectivity of condensation and ring-closure reaction, reduce impurity product
Occur, the synthesis and industrialization to anilinoquinazoline compound have more real meaning.
5, the present invention passes through by rat and beagle experiments have shown that anilinoquinazoline compound of the present invention has no toxic side effect
Test pancreas graft cancer cell line, colorectal cancer cell lines, stomach cancer cell line, it was demonstrated that anilinoquinazoline compound of the present invention is antitumor
Effect is very strong, has effects that extend the service life.
Now by following embodiment come the particular compound of the present invention is more fully described anilinoquinazoline compound
Reaction process and purposes.However, it should be noted that these embodiments are to provide by way of illustration and unrestricted.
Specific implementation mode
Present invention is further elaborated in following combination specific embodiment, and the embodiment is only for technical scheme of the present invention
It is explained, the present invention is not limited to following embodiments.
The present invention provides a kind of anilinoquinazoline compound, the anilinoquinazoline compound has following chemical constitution
Formula：
,
Wherein：
X is halogens, and X is located at at least one in phenyl ring residue binding site, and X is covalently attached with the carbon atom on phenyl ring；
R1For alkyl, R1It is covalently attached with oxygen atom by the carbon atom on alkyl；
R2Group after being replaced by alkyl for heterocycle, R2It is covalently attached with oxygen atom by the carbon atom on alkyl.
Further, X is fluorine（F）, chlorine（Cl）, bromine（Br）Or iodine（I）；
Further, the R1For C1-C6 alkyl；
Further, the R2Group after being replaced by C1-C4 alkyl for C2-C10 heterocycles.
In one embodiment, it is fluorine that X is selected to the present invention（F）, chlorine（Cl）, R1Selected from methyl（-CH3）,R2Selected from morpholine quilt
Group after propane substitution（-CH3-CH3-CH3-C4H8ON）.
In one embodiment, it is fluorine that X is selected to the present invention（F）, bromine（Br）, R1Selected from ethyl（-CH2-CH3）,R2Selected from phonetic
Pyridine replaced by ethane after group（-CH3-CH3-C4H3N2）.
In one embodiment, it is fluorine that X is selected to the present invention（Br）, chlorine（Cl）, R1Selected from propyl（-CH3-CH3-CH3）,R2Choosing
From pyrroles replaced by ethane after group（-CH3-CH3- C4H4N）.
Anilinoquinazoline compound is selected from 4- to the present invention in one embodiment（The chloro- 4- fluoroanilinos of 3-）- 7- methoxyl groups-
6-（Morpholinyl propoxyl group）Quinazoline.
Anilinoquinazoline compound is selected from 4- to the present invention in one embodiment（The bromo- 4- fluoroanilinos of 3-）- 7- ethyoxyls-
6-（2- pyrimidine base oxethyls）Quinazoline.
Anilinoquinazoline compound is selected from 4- to the present invention in one embodiment（The bromo- 4- chloroanilinos of 3-）- 7- propoxyl group-
6-（2- pyrroles's base oxethyl）Quinazoline.
Embodiment 1
4-（The chloro- 4- fluoroanilinos of 3-）- 7- methoxyl groups -6-（Morpholinyl propoxyl group）The preparation of quinazoline.
Synthetic route is：
；
Synthesis step is：
In toluene（150ml）In, 2- itrile group -4- methoxyl groups -5-（Morpholinyl propoxyl group）Aniline（A）（12.0g）In N, N- bis-
Methylformamide dimethylacetal（DMF-DMA）（6.5g）With acetic acid（60ml）Effect is lower to carry out condensation reaction, vacuum distillation recycling
Toluene obtains 2- itrile group -4- methoxyl groups -5-（Morpholinyl propoxyl group）- N, N- dimethylamino cyanophenyl（B）, obtained 2- itrile groups-
4- methoxyl groups -5-（Morpholinyl propoxyl group）- N, N- dimethylamino cyanophenyl（B）It need not be detached, be directly used in following
The reaction of two steps；
Reaction solution after above-mentioned condensation reaction is added into absolute ethyl alcohol（120ml）, formic acid（40ml）With compound 3-chlorin -4- fluorine
Aniline（C）（7.2g）, 115 DEG C are warming up to, flow back 6h, is cooled to room temperature, and adjusts pH to 8 with 5% ammonium hydroxide, there is solid precipitation；
The solid of above-mentioned precipitation is continued to be cooled to 2.5 DEG C, is filtered after stirred crystallization 1h, ethyl acetate is used in combination to wash filter cake；Again
Methanol, acetone and pure water recrystallization are used successively, are dried in vacuo at 40 DEG C, obtain solid 4-（The chloro- 4- fluoroanilinos of 3-）-
7- methoxyl groups -6-（Morpholinyl propoxyl group）Quinazoline（D）（12.62g）, yield 82.6%.
Embodiment 2
4-（The bromo- 4- fluoroanilinos of 3-）- 7- ethyoxyls -6-（2- pyrimidine base oxethyls）The preparation of quinazoline.
Synthetic route is：
；
Synthesis step is：
In toluene（240ml）In, 2- itrile group -4- ethyoxyls -5-（2- pyrimidine base oxethyls）Aniline（A）（14.5g）In N, N- bis-
Methylformamide dimethylacetal（DMF-DMA）（7.78g）With acetic acid（80ml）Effect is lower to carry out condensation reaction, vacuum distillation recycling
Toluene obtains 2- itrile group -4- ethyoxyls -5-（2- pyrimidine base oxethyls）- N, N- dimethylamino cyanophenyl（B）, obtained 2- itrile groups-
4- ethyoxyls -5-（2- pyrimidine base oxethyls）- N, N- dimethylamino cyanophenyl（B）It need not be detached, be directly used in following
The reaction of two steps；
Reaction solution after above-mentioned condensation reaction is added into absolute ethyl alcohol（150ml）, formic acid（60ml）With the bromo- 4- fluorine of compound 3-
Aniline（C）（9.2g）, 122 DEG C are warming up to, flow back 6h, is cooled to room temperature, and adjusts pH to 8.5 with 5% ammonium hydroxide, there is solid precipitation；
The solid of above-mentioned precipitation is continued to be cooled to 5 DEG C, is filtered after stirred crystallization 1h, ethyl acetate is used in combination to wash filter cake；Again according to
Secondary methanol, acetone and pure water recrystallization, are dried in vacuo at 45 DEG C, obtain solid 4-（The bromo- 4- fluoroanilinos of 3-）-7-
Ethyoxyl -6-（2- pyrimidine base oxethyls）Quinazoline（D）（15.21g）, yield 83.1%.
Embodiment 3
4-（The bromo- 4- chloroanilinos of 3-）- 7- propoxyl group -6-（2- pyrroles's base oxethyl）The preparation of quinazoline.
Synthetic route is：
；
Synthesis step is：
In toluene（300ml）In, 2- itrile group -4- propoxyl group -5-（2- pyrroles's base oxethyl）Aniline（A）（20g）In N, N- diformazans
Base formamide dimethylacetal（DMF-DMA）（11.2g）With pyrovinic acid（110ml）Effect is lower to carry out condensation reaction, vacuum distillation
Toluene is recycled, 2- itrile group -4- propoxyl group -5- is obtained（2- pyrroles's base oxethyl）- N, N- dimethylamino cyanophenyl（B）, obtained 2-
Itrile group -4- propoxyl group -5-（2- pyrroles's base oxethyl）- N, N- dimethylamino cyanophenyl（B）It need not be detached, be directly used in down
The reaction of face second step；
Reaction solution after above-mentioned condensation reaction is added into absolute ethyl alcohol（200ml）, formic acid（80ml）With the bromo- 4- chlorine of compound 3-
Aniline（C）（15.0g）, 130 DEG C are warming up to, flow back 6h, is cooled to room temperature, and adjusts pH to 9 with triethylamine, there is solid precipitation；
The solid of above-mentioned precipitation is continued to be cooled to 6 DEG C, is filtered after stirred crystallization 1h, ethyl acetate is used in combination to wash filter cake；Again according to
Secondary methanol, acetone and pure water recrystallization, are dried in vacuo at 50 DEG C, obtain solid 4-（The bromo- 4- chloroanilinos of 3-）-7-
Propoxyl group -6-（2- pyrroles's base oxethyl）Quinazoline（D）（20.61g）, yield 82.54%.
The final compound obtained to embodiment 1, embodiment 2 and embodiment 3 forms medicine group respectively as active constituent
Object is closed, pharmaceutical composition includes pharmaceutically acceptable salt, also any comprising being built from the compound by conventional method
Possible salt, isomer or solvate.
In the present invention, solvate refers to that one or more solvent molecules are formed by association with the compound of the present invention
Object.The solvent for forming solvate includes but is not limited to water, isopropanol, ethyl alcohol, ethyl acetate, acetic acid.
The present invention is specifically described below with embodiment 1-3, but the present invention is not limited to this.Aniline of the present invention
The antitumor action experiment of quinazoline compound is as follows：
Experiment 1
To Female nude mice subcutaneous transplantation 3 × 106/ mL human pancreas cancer cell strain.Reach 100mm in tumour capacity31 day after above
The pharmaceutical composition that 1 final compound prepared respectively with the embodiment 1-3 of 30mg/kg oral medication groups forms is (hereinafter referred to as
For pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C), continuous 21 days.Tumour is extracted in the next day being finally administered, is measured
Tumor weight.In addition, as comparative example, the group not to be administered orally equally measures tumor weight as a control group.Based on administration
Group and control group tumor weight measure inhibiting rate, pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C inhibiting rate be
92.68%、93.1%、92.45%.It can be seen that by giving pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C, significantly
Ground inhibits the proliferation of tumour.
Experiment 2
In the intra-abdominal transplantation 1.5 × 10 of male nude mouse6The Human Large Intestine Carcinoma Cells strain (C170MH2) of a/mL.After transplanting, 1 day 1
The medicine group that the final compound that the secondary embodiment 1-3 with 3mg/kg or 30mg/kg continuous oral administration groups is prepared respectively forms
Close object (hereinafter referred to as pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C).As positive control drug, 1 time 25mg/kg is quiet
5-fluor-uracil (hereinafter referred to as 5-FU) and folinic acid (after tumour is administered 1,4,7,10 day) are given in arteries and veins.By C170MH2 tumours
After being implanted into intraperitoneal 40 days, the tumor weight for being transferred to liver is measured.By giving pharmaceutical composition A, drug with 3mg/kg
Composition B, pharmaceutical composition C, can will be to the metastasis suppressor 86%, 86.7%, 85.92% of liver.By being given with 30mg/kg
Pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C, can by the metastasis suppressor 94.2% of liver, 94.38%,
94.15%。
On the other hand, the inhibiting rate after 5-FU and folinic acid are administered is 52%.From above result it is found that pharmaceutical composition
A, pharmaceutical composition B, pharmaceutical composition C have more preferably antitumous effect.
Experiment 3
In the intra-abdominal transplantation 5 × 10 of Female SCID mice5The human stomach cancer cell line (MGLVA1) of a/mL.After transplanting, 1 day 1 time
Pharmaceutical composition (the hereinafter referred to as medicine group formed with the 30mg/kg continuous oral embodiments 1-3 final compounds prepared respectively
Close object A, pharmaceutical composition B, pharmaceutical composition C).The model is the lethality model of MGLVA1 tumours, with prolonging for life span
The long effect for being used as drug is evaluated.Control group intra-abdominal transplantation 5 × 105The human stomach cancer cell line of a/mL
(MGLVA1) without administration after.After administration starts 16 days, the survival rate of control group is 6.7%, and administration group survival rate reaches
53.8%.From above result it is found that pharmaceutical composition A, pharmaceutical composition B, pharmaceutical composition C have the life after tumour transplatation
Deposit the effect of time lengthening.
The present invention is specifically described below with embodiment 1-3, but the present invention is not limited to this.Aniline of the present invention
Quinazoline compound is as follows to the toxicity test of rat and beagle：
Experiment 1
With 30mg/kg, 100mg/kg, 300mg/kg and 1000mg/kg to the male and female SD systems rat mouth repeatedly of 6 week old in 28 days
Take the pharmaceutical composition for the final compound composition that embodiment 1-3 is prepared respectively.Any group all has dead example without discovery, in body
It is showed no exception in weight, intake, eye examination, urine examination, organ weight, dissection inspection and histopathological examination.
Experiment 2
In 28 days 8 months big male and female beagles mouth repeatedly is given with 30mg/kg, 100mg/kg, 300mg/kg and 1000mg/kg
Take the pharmaceutical composition for the final compound composition that embodiment 1-3 is prepared respectively.Any group all has dead example without discovery, in body
Weight, intake, eye examination, electrocardiogram, blood pressure, urine examination, hematological examination, blood biochemistry checking, organ weight and solution dissect
Exception is showed no in looking into.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than above description limit, it is intended that all changes that will be fallen within the meaning and scope of the equivalent requirements of the claims
Change is included within the present invention.Any label in claim should not be considered as and be limited the claims involved.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Claims (8)
1. a kind of anilinoquinazoline compound, which is characterized in that the anilinoquinazoline compound has following chemical structural formula：
,
Wherein：
X is halogens, and X is located at at least one in phenyl ring residue binding site, and X is covalently attached with the carbon atom on phenyl ring；
R1For alkyl, R1It is covalently attached with oxygen atom by the carbon atom on alkyl；
R2Group after being replaced by alkyl for heterocycle, R2It is covalently attached with oxygen atom by the carbon atom on alkyl.
2. a kind of anilinoquinazoline compound according to claim 1, which is characterized in that the X is fluorine（F）, chlorine（Cl）、
Bromine（Br）Or iodine（I）；The R1For C1-C6 alkyl；The R2Group after being replaced by C1-C4 alkyl for C2-C10 heterocycles.
3. a kind of preparation method of anilinoquinazoline compound, which is characterized in that the preparation method includes following synthetic route：
；
The preparation method includes following synthesis step：
The first step, in a solvent, compound（A）Condensation reaction, vacuum distillation recycling are carried out under accelerating agent and catalyst action
Solvent obtains compound（B）, obtained compound（B）It need not be detached, be directly used in the reaction of following second step；
Reaction solution after condensation reaction in the first step is added solvent, formic acid and compound by second step（C）, temperature rising reflux is cold
But to room temperature, pH to 8-9 is adjusted with alkali nertralizer, there is solid precipitation；
Third walks, and the solid being precipitated in second step is continued to cool down, is filtered after stirred crystallization 1h, and ethyl acetate washing filter is used in combination
Cake；Methanol, acetone and pure water recrystallization, vacuum drying is used to obtain solid chemical compound successively again（D）.
4. a kind of preparation method of anilinoquinazoline compound according to claim 3, which is characterized in that the synthesis step
Solvent is toluene in the rapid first step, and accelerating agent is n,N-Dimethylformamide dimethylacetal（DMF-DMA）, catalyst be formic acid,
Acetic acid, pyrovinic acid, sulfuric acid or phosphoric acid, preferably acetic acid.
5. a kind of preparation method of anilinoquinazoline compound according to claim 3, which is characterized in that the synthesis step
Solvent is absolute ethyl alcohol in rapid second step, and temperature is 110-130 DEG C after heating, and return time 6h, alkali nertralizer is hydroxide
Sodium, potassium hydroxide, niter cake, potassium carbonate, ammonium hydroxide or triethylamine, preferably ammonium hydroxide.
6. a kind of preparation method of anilinoquinazoline compound according to claim 3, which is characterized in that the synthesis step
Temperature is 2-6 DEG C after cooling down in rapid third step, and vacuum drying carries out at 40-50 DEG C.
7. a kind of anilinoquinazoline compound or its pharmaceutically acceptable salt, isomer or solvate as activity at
The pharmaceutical composition divided.
8. pharmaceutical composition according to claim 7, which is characterized in that the anilinoquinazoline compound or its pharmaceutically
The application of acceptable salt, isomer or solvate in antitumor drug, for treating colorectal cancer, cancer of pancreas, non-
Small Cell Lung Cancer, thyroid cancer, starlike nerve cell tumour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810439836.XA CN108395410A (en) | 2018-05-09 | 2018-05-09 | A kind of anilinoquinazoline compound and its application in antitumor drug |
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| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2003045395A1 (en) * | 2001-11-23 | 2003-06-05 | Astrazeneca Ab | Quinazoline derivatives for the treatment of t cell mediated diseases |
| CN101102776A (en) * | 2005-01-19 | 2008-01-09 | 善利亚新药工业股份有限公司 | Antitumor agent |
| CN102659716A (en) * | 2012-05-02 | 2012-09-12 | 北京国联诚辉医药技术有限公司 | Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib |
| CN103570633A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Preparation method of gefitinib |
| CN103755648A (en) * | 2013-12-20 | 2014-04-30 | 南京优科生物医药研究有限公司 | New impurity of gefitinib and preparation method thereof |
| CN104072426A (en) * | 2013-03-28 | 2014-10-01 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparing method of anticancer medicine |
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| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2003045395A1 (en) * | 2001-11-23 | 2003-06-05 | Astrazeneca Ab | Quinazoline derivatives for the treatment of t cell mediated diseases |
| CN101102776A (en) * | 2005-01-19 | 2008-01-09 | 善利亚新药工业股份有限公司 | Antitumor agent |
| CN102659716A (en) * | 2012-05-02 | 2012-09-12 | 北京国联诚辉医药技术有限公司 | Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib |
| CN103570633A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Preparation method of gefitinib |
| CN104072426A (en) * | 2013-03-28 | 2014-10-01 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparing method of anticancer medicine |
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Application publication date: 20180814 |