CN108250185A - 6- (2- (adjacent toluidino) acetylamino) quinazoline compounds and preparation and application - Google Patents
6- (2- (adjacent toluidino) acetylamino) quinazoline compounds and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of 6 (2 (adjacent toluidino) acetylamino) quinazoline compounds and preparations and application.6 (2 (adjacent toluidino) acetylamino) quinazoline compounds provided by the invention are respectively provided with significant inhibitory activity to Breast cancer lines MCF 7, human lung carcinoma cell line A 549, people in loop strain HL 60, human cervical carcinoma cell lines Siha, are expected to be applied to prepare in the drug for preventing or treating human breast carcinoma, human lung cancer, human leukemia, human cervical carcinoma's drug.The present invention provides the preparation methods of 6 (2 (adjacent toluidino) acetylamino) quinazoline compounds, and the preparation method is simple, easily operated, and raw material is easy to get and production cost is relatively low, suitable for practicality.
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, more particularly to a kind of 6- (2- (adjacent toluidino) second
Acylamino-) quinazoline compounds and preparation method thereof and the compound be in the medicine for preparing prevention or treatment tumor disease
Application in object.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for novel quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148；A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) invention content
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound with active anticancer -6- (2- (adjacent first
Phenylamino) acetylamino) quinazoline compounds and its preparation method and application, such compound is under doses to people's lung
Cancer cell line A-549, MCF-7 cell strainHJ2mm, people in loop strain HL-60 or human cervical carcinoma cell lines
Siha has good inhibition；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and production cost
It is relatively low, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
In a first aspect, the present invention provides 6- (2- (adjacent toluidino) acetylamino) quinazolines shown in a kind of formula (I)
Class compound,
Second aspect, the present invention provide 6- (2- (adjacent toluidino) acetylamino) quinazoline ditosylate salt shown in a kind of formula (I)
The preparation method of compound, the method are：(1) compound shown in formula (II) is mixed with compound shown in formula (III),
In organic solvent A, under the action of basic catalyst B, 25~120 DEG C are reacted that (TLC tracking and monitorings, solvent are acetic acid
Ethyl ester/petroleum ether=1：3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified,
Compound shown in formula (IV) is made；The organic solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropyl
Alcohol, acetonitrile or N,N-dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline
Quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine,
NN- dimethylanilines or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented under reducing agent E effects, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 entirely：1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction), instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration；
The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine；The reducing agent E is one of following：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion；
(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effects, in
In organic solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v),
It is preferred that -10~50 DEG C of 3~12h of reaction), formula (VI) compound represented is made in the post-treated A of reaction solution；The alkalinity is urged
Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidines
Yl pyridines or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether,
Acetonitrile, toluene or benzene；
(4) compound shown in formula (VI) is mixed with ortho-aminotoluene, in organic solvent J, in the effect of basic catalyst K
Under, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：1 (v/v), preferably 40~
100 DEG C of 0.5~36h of reaction), after the reaction was complete, by the post-treated B of reaction solution, compound shown in formula (I) is made；It is described organic
Solvent J is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；It is described
Basic catalyst K be selected from it is one of following：Pyridine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N, N- dimethylanilines or 4-dimethylaminopyridine)；
Further, in step (1), compound shown in compound shown in the formula (III) and formula (II), basic catalyst B
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution isolates and purifies described in step (1) of the present invention is：After the reaction was complete, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate add in concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Column is filled, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target components
Efflux (preferably with ethyl acetate/petroleum ether=1：3 (v/v) are solvent tracing detection, collect target components, preferably receive
Collect the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (IV) compound represented；It is described to have
Solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosages are residual can dissolve
Stay object.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in the compound and reducing agent E shown is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.
In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid.
Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, formula (IV) institute
The compound shown in reducing agent E palladium carbon, ammonium formate or hydrazine hydrate feed intake mass ratio for 1.0 ﹕, 0.1~0.5 ﹕ 1.0~
3.0.The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in the present invention, hydrazine hydrate mass concentration for 40~
80%, preferably 80%.
Further, in step (2), the dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented
~50mL/g.
Further, in step (3), compound shown in the formula (V) and chloracetyl chloride or chloroacetic anhydride, base catalysis
The ratio between amount for the substance that feeds intake of agent F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0.
Further, in step (3), the dosage of the organic solvent G is calculated as 11 with the quality of compound shown in formula (V)~
100mL/g。
Further, the specific recommendation step (3) of the present invention carries out as follows：Under the conditions of -10~10 DEG C, toward formula
(V) in the organic solvent G solution of compound shown in and basic catalyst F or toward compound and base catalysis shown in formula (V)
The organic solvent G solution of chloracetyl chloride or chloroacetic anhydride is added dropwise in agent F, drop finishes, and -10~50 DEG C are reacted 3~12 hours, and gained is anti-
The post-treated A of liquid is answered to obtain compound shown in formula (VI)；Dissolve the organic solvent volume dosage pair of chloracetyl chloride or chloroacetic anhydride
The present invention does not influence, and total dosage of the organic solvent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).Have
Total dosage of solvent G refers to dissolve the organic solvent G of compound shown in basic catalyst F and formula (V) and dissolving chloracetyl chloride
Or the total volume of chloroacetic anhydride organic solvent G.
Further, the method for step (3) the of the present invention reaction solution post processing A is：After the reaction was complete, by reaction solution mistake
Filter, filtrate steaming removal solvent take concentrate to be dissolved with organic solvent H, obtain lysate, and concentration is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight of object, dry, obtains the mixture of concentrate and silica gel, will
Mixture fills column, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing mesh
The efflux of component is marked (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target components,
It is preferred that collecting the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (VI) compound represented；
The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosages are with can
Dissolution residual substance.
Further, in step (4), compound shown in the formula (VI) and ortho-aminotoluene, the substance that feeds intake of basic catalyst K
The ratio between amount be 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0.
Further, in step (4), the dosage of the organic solvent J is calculated as 10 with the quality of compound shown in formula (VI)~
60mL/g。
Further, the method for the post processing of reaction solution described in step (4) of the present invention B is：After the reaction was complete, reaction solution is steamed
Except solvent, concentrate is taken to be dissolved with organic solvent M, obtain lysate, then into lysate add in concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Column is filled, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target components
Efflux (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target components, preferably receives
Collect the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented；It is described organic
Solvent M is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent M dosages are can dissolve residual
Object.
The third aspect, the invention further relates to 6- shown in formula (I) (2- (adjacent toluidino) acetylamino) quinazoline ditosylate salt chemical combination
Application of the object in prevention or tumor is prepared, particularly useful for making answering in prevention or treatment human breast carcinoma drug
With.
Preferably, the drug is with the drug for inhibiting MCF-7 cell strainHJ2mm activity.Provided by the inventionization
Close object (I) has preferable inhibition to MCF-7 cell strainHJ2mm.
6- shown in formula (I) of the present invention (2- (adjacent toluidino) acetylamino) quinazoline compounds are also to human lung cancer
Cell strain A-549, people in loop strain HL-60 or human cervical carcinoma cell lines Siha have significant inhibiting effect,
It can be applied to prepare prevention or treat in human lung cancer, human leukemia or the drug of human cervical carcinoma.
Organic solvent A of the present invention, C, D, G, H, J and M are organic solvent, for the ease of distinguishing used in different step
Organic solvent is different and names, and letter itself does not have meaning；The catalyst B, reducing agent E, catalyst F and catalyst K are
Catalyst is named for the ease of distinguishing different step used catalyst difference, and letter itself does not have meaning；The post processing A,
Post processing B is post processing, is named for the ease of distinguishing post processing difference used in different step, letter itself does not have meaning.
The beneficial effects are mainly as follows：(1) 6- (2- (adjacent toluidino) acetylamino) of the present invention
The active anticancer that quinazoline compounds (I) have had is expected in the drug for being applied to prepare prevention or treatment tumor disease, especially
It is the application in human breast carcinoma, human lung cancer, human leukemia or human cervical carcinoma's drug；(2) 6- (2- (adjacent first provided by the invention
Phenylamino) acetylamino) quinazoline compounds (I) preparation method, simple easily operated, raw material is easy to get, and production cost
It is relatively low, suitable for practicality.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
85.1%, 164~166 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.32-3.38 (m, 1H), 3.63 (dt, J=3.4,
15.5Hz, 1H), 3.75 (s, 3H), 3.82 (s, 6H), 3.91 (dd, J=8.1,14.3Hz, 1H), 4.03 (td, J=4.1,
11.7Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 4.72 (dd, J=8.3,14.2Hz, 1H), 5.14 (t, J=8.9Hz,
1H), 6.60 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.93 (d, J=9.1Hz, 1H),
8.48 (dd, J=2.4,9.2Hz, 1H), 8.71 (s, 1H), 8.96 (d, J=2.4Hz, 1H).IR(KBr,cm-1)ν:2917,
2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Embodiment 2：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object：5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), it is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield 77.2%,
164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it reacts 12 hours, closes reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C of faint yellow solids productions being dried to obtain shown in formula (IV)
Object, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel：1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values be 0.5) of formula (IV) compound represented, collection liquid concentration, 50 DEG C be dried to obtain it is yellowish shown in formula (IV)
Color solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 6：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 1 method of embodiment, 0.40 gram
(6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C of vacuum drying
Obtain faint yellow solid product 6- amido quinazolines (V), yield 98.2%, 122~126 DEG C of fusing point.1H NMR(500MHz,
CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H),4.45
(dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s, 1H), 6.90 (d, J=8.7Hz,
2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=8.9,2.5Hz, 1H), 7.69 (d, J
=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,2825,1628,1566,1512,1487,
1353,1248,1036,834。
Embodiment 8：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 2 method of embodiment, 1.20 grams
(19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, heating
To 100 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 0.5 hour, it is cooled
Filter, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 100.0%, fusing point
122~126 DEG C.1H NMR and IR is the same as embodiment 7.
Embodiment 9：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 3 method of embodiment, 0.08 gram of concentrated hydrochloric acid
(mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb, are heated to 40 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 4 method of embodiment, 0.40 gram of acetic acid,
1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain
Faint yellow solid product 6- amido quinazolines (V), yield 97.5%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 11：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.13 gram
(1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.497 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) chloracetyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), under the conditions of -10 DEG C
Reaction 12 hours, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate and are dissolved, and obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column, then using volume ratio as 1 by the mixture of object and silica gel：10 petrol ether/ethyl acetate mixed solution is washes
De- agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing formula
(VI) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the chloracetyl shown in formula (VI)
Amido quinazoline yellow solid, yield 95.6%, 255~258 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.26-3.33
(m, 1H), 3.54 (dt, J=3.7,15.4Hz, 1H), 3.74 (s, 3H), 3.81-3.82 (m, 7H), 3.95-4.05 (m, 2H),
4.28 (s, 2H), 4.64 (dd, J=8.2,14.4Hz, 1H), 5.24 (t, J=8.8Hz, 1H) .6.64 (s, 1H), 6.88 (d, J
=8.8Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 7.53 (dd, J=2.3,9.0Hz, 1H), 7.83 (d, J=9.0Hz, 1H),
8.54 (s, 1H), 8.60 (s, 1H), 8.69 (d, J=2.2Hz, 1H).IR(KBr,cm-1)ν:3396,2998,2937,2835,
1694,1557,1525,1510,1489,1463,1349,1249,1179,1036,840。
Embodiment 12：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 8 method of embodiment, 0.04 gram
(0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, and 0.07 gram is added dropwise under 10 DEG C of stirring conditions
(0.55mmol) chloracetyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of ethyl alcohol will
It is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added in into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：5 oil
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1(v/
V)), the eluent (Rf values are 0.5) containing formula (VI) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C dry
The dry chloro acetylamino quinazoline yellow solid obtained shown in formula (VI), yield 83.4%, 255~258 DEG C of fusing point.1H NMR and
IR is the same as embodiment 11.
Embodiment 13：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 9 method of embodiment, 0.111 gram
(1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, and 0.14 is added dropwise under 0 DEG C of stirring condition
Gram (1.09mmol) chloracetyl chloride and 5.0 milliliters of ethyl acetate solutions, drop finish, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of chloroforms, and its is molten
Solution obtains lysate, 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, steams
Except solvent, the mixture of dry concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 10：1 petroleum ether/
Ethyl acetate mixture is eluant, eluent, elution, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)),
Eluent (Rf values be 0.5) containing formula (VI) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C dry
To the chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 70.5%, 255~258 DEG C of fusing point.1H NMR and IR is same
Embodiment 11.
Embodiment 14：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 10 method of embodiment, 0.067 gram
(0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, are added dropwise under 5 DEG C of stirring conditions
The solution of 0.376 gram of (2.20mmol) chloroacetic anhydride and 7.0 milliliters of toluene, drop finish, and are heated to 50 DEG C, (the expansion of TLC tracing detections
Agent is ethyl acetate/petroleum ether=1：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrochysene furans
It mutters and is dissolved, obtain lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate, mix
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 5：1 stone
Oily ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (VI) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain the chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 85.3%, 255~258 DEG C of fusing point.1H NMR
With IR with embodiment 11.
Embodiment 15：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.213 gram
(1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, and 0.28 gram is added dropwise under -10 DEG C of stirring conditions
The solution of (2.19mmol) chloracetyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/petroleum ether to TLC tracing detections
=1：1) it, reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans, and its is molten
Solution obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, steams
Except solvent, the mixture of dry concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：1 petroleum ether/second
Acetoacetic ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), root
The eluent (Rf values are 0.5) containing formula (VI) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C are dried to obtain
Chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 82.1%, 255~258 DEG C of fusing point.1H NMR and IR are the same as real
Apply example 11.
Embodiment 16：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.164 gram
(1.10mmol) 4- pyrollidinopyridines, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, 10 DEG C of stirring conditions
00.14 gram of (1.09mmol) chloracetyl chloride of lower dropwise addition and 5.0 milliliters of dichloromethane solutions, drop finish, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 millis
It rises ethyl alcohol to be dissolved, obtains lysate, 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography silicon is added in into lysate
Glue), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as
10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (VI) compound represented is collected according to TLC detections, collection liquid is dense
Contracting, 50 DEG C of chloro acetylamino quinazoline yellow solids being dried to obtain shown in formula (VI), yield 90.2%, fusing point 255~258
℃。1H NMR and IR is the same as embodiment 11.
Embodiment 17：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 11 method of embodiment preparation and 0.736 gram
(6.87mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 32.5 ml methanols are added in 50 milliliters of reaction bulb, are added
Heat is to 40 DEG C, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 10 hours, closes anti-
Should, solvent is evaporated off in reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate are obtained, to dissolving
1.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in liquid, after mixing, solvent is evaporated off, obtains dry concentrate
With the mixture of silica gel, mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C of yellow solid productions being dried to obtain shown in formula (I)
Object, yield 53.4%, 179~181 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:2.32(s,3H),3.26-3.32(m,1H),
3.55 (dt, J=3.5,15.3Hz, 1H), 3.76 (s, 3H), 3.81-3.82 (m, 7H), 4.00-4.06 (m, 4H), 4.33 (t, J
=5.3Hz, 1H), 4.65 (dd, J=8.2,14.3Hz, 1H), 5.29 (t, J=8.8Hz, 1H), 6.62 (d, J=8.2Hz,
1H), 6.68 (s, 1H), 6.84 (t, J=7.3Hz, 1H), 6.88 (d, J=8.7Hz, 2H), 7.09 (d, J=8.7Hz, 2H),
7.15-7.18 (m, 2H), 7.37 (dd, J=2.2,9.0Hz, 1H), 7.75 (d, J=8.9Hz, 1H), 8.57 (s, 1H), 8.79
(s,2H)。HRMS-ESI m/z:638.2527[M+H]+。13C NMR(125MHz,CDCl3)δ:17.6,28.8,49.7,50.0,
51.1,54.4,55.3,56.0,60.5,110.9,113.9,114.2,114.4,116.1,120.0,123.0,125.3,
127.6,128.0,128.1,128.7,128.8,130.7,133.6,135.0,137.5,144.0,145.0,149.0,
152.2,153.3,158.4,163.7,169.1。IR(KBr,cm-1)ν:2934,2831,1695,1562,1512,1487,
1453,1349,1248,1036,837。
Embodiment 18：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 12 method of embodiment preparation and 0.490 gram
(4.57mmol) ortho-aminotoluene, 2.95 grams of (22.84mmol) quinoline, 80 milliliters of toluene are added in 100 milliliters of three-necked flask, are added
Heat is to 100 DEG C, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 2 hours, closes anti-
Should, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 1 by the mixture of glue：5 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing shown in formula (I)
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain the yellow solid product shown in formula (I), receive
Rate 52.8%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 19：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 13 method of embodiment preparation and 0.614 gram
(5.73mmol) ortho-aminotoluene, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask,
60 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate are obtained, to lysate
2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) of middle addition, after mixing, are evaporated off solvent, obtain dry concentrate with
Mixture is filled column, then using volume ratio as 10 by the mixture of silica gel：1 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C of yellow solid productions being dried to obtain shown in formula (I)
Object, yield 47.6%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 20：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 14 method of embodiment preparation and 2.456 grams
(22.92mmol) ortho-aminotoluene, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols add in 100 milliliters
In three-necked flask, 25 DEG C of stirrings of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), reaction 36
Hour, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, are obtained molten
Liquid is solved, 3.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in into lysate, after mixing, solvent is evaporated off, obtains dry
Mixture is filled column, then using volume ratio as 5 by dry concentrate and the mixture of silica gel：1 petrol ether/ethyl acetate mixing
Solution is eluant, eluent, elution, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected, collection liquid concentration, 50 DEG C are dried to obtain shown in formula (I)
Yellow solid product, yield 62.2%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 21：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 15 method of embodiment preparation and 0.552 gram
(5.15mmol) ortho-aminotoluene, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of n,N-Dimethylformamide add in 50
In the reaction bulb of milliliter, 120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it stirs
Reaction 0.5 hour is mixed, closes reaction, solvent is evaporated off in reaction solution, 20 milliliters of tetrahydrofurans is added in obtained concentrate its is molten
Solution obtains lysate, 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, is evaporated off
Solvent obtains the mixture of dry concentrate and silica gel, mixture is filled column, then using volume ratio as 1：1 petroleum ether/acetic acid
Ethyl ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), according to
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected in TLC detections, and collection liquid concentration, 50 DEG C are dried to obtain formula
(I) yellow solid product shown in, yield 58.1%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 22：The preparation of 6- (2- (adjacent toluidino) acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 16 method of embodiment preparation and 4.912 grams
(45.84mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol are added in 500 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 10 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtain lysate, Xiang Rong
It solves and 6.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column, then using volume ratio as 1 by the mixture of object and silica gel：1 petrol ether/ethyl acetate mixed solution is washes
De- agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing formula
(I) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the yellow solid shown in formula (I)
Product, yield 65.3%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 23：Active anticancer testing in vitro
(1) compound obtained (I) MCF-7 cell strainHJ2mm biological activity test has been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：MCF-7 cell strainHJ2mm.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
10th generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6/ mL is added to 96 holes
In tissue culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, medium culture containing similary concentration DMSO cell as control, calculate IC of the sample to growth of tumour cell50。
The results are shown in Table 1 for test：
The inhibiting effect that 1. compound of table (I) grows cancer cell line MCF-7
(2) according to embodiment 11, chloracetyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl respectively
Chloro replaces, other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11：
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out Breast cancer lines
MCF-7 biological activity tests, test result show quinazoline compounds (a), and (b) and (c) is to MCF-7 cell strainHJ2mm
The equal unobvious of inhibition, compound (a), (b) and (c) can not show a candle to chemical combination to the active anticancer of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 2：
The inhibiting effect that 2. compound (a) of table, (b) and (c) grow cancer cell line MCF-7
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibiting effect of breast cancer cell line mcf-7 growth.Compound (I) grows MCF-7 cell strainHJ2mm
Inhibiting effect is notable, hence it is evident that better than compound (a), (b) and (c).
(3) according to embodiment 17, by ortho-aminotoluene respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or two positive third
Amine replaces, other operations have been respectively synthesized quinazoline compounds (d), (e) and (f), structure is as follows with embodiment 17：
Quinazoline compounds (d) obtained, (e) and (f) have been carried out by Breast cancer lines according to the above method
MCF-7 biological activity tests, the results showed that quinazoline compounds (d), (e) and (f) resist MCF-7 cell strainHJ2mm
Cancer activity can not show a candle to compound (I).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (d) of table, (e) and (f) grow cancer cell line MCF-7
(4) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
To 4- chloro-quinazolines, further according to embodiment 1, the chloro- 6- nitro-quinazolines of 4- are replaced with 4- chloro-quinazolines, other operations are the same as implementation
Example 1, has synthesized quinazoline compounds (g), and structure is as follows：
Quinazoline compounds (g) obtained have been carried out MCF-7 cell strainHJ2mm biology according to the above method to live
Property test, test result shows that quinazoline compounds (g) can not show a candle to chemical combination to the active anticancer of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 4：
The inhibiting effect that 4. compound (g) of table grows cancer cell line MCF-7
Embodiment 24：Active anticancer testing in vitro
(1) compound obtained (I), (IV) and (VI) human lung cancer cell lines A-549 biological activity test has been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human lung cancer cell lines A-549.Above-mentioned tumor cell line is thin purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Born of the same parents library.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into and is diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubator
It cultivates, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, add in DMSO, every hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 5 for test：
The inhibiting effect that 5. compound of table (I), (IV) and (VI) grows cancer cell line A-549
(2) according to embodiment 11, chloracetyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl respectively
Chloro replaces, other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11：
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out human lung cancer cell lines A-549
Biological activity test, test result show quinazoline compounds (a), and (b) and (c) inhibits to imitate to human lung cancer cell lines A-549
The equal unobvious of fruit, compound (a), (b) and (c) can not show a candle to the active anticancer of human lung cancer cell lines A-549 compound (I).Tool
The results are shown in Table 6 for body：
The inhibiting effect that 6. compound (a) of table, (b) and (c) grow cancer cell line A-549
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibiting effect of lung cancer cell line A-549 growths.The inhibition that compound (I) grows human lung cancer cell lines A-549
Effect is notable, hence it is evident that better than compound (a), (b) and (c).
(3) according to embodiment 17, by ortho-aminotoluene respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or two positive third
Amine replaces, other operations have been respectively synthesized quinazoline compounds (d), (e) and (f), structure is as follows with embodiment 17：
Quinazoline compounds (d) obtained, (e) and (f) have been carried out by human lung cancer cell lines A-549 according to the above method
Biological activity test, the results showed that quinazoline compounds (d), (e) are with (f) to the active anticancer of human lung cancer cell lines A-549
It can not show a candle to compound (I).Concrete outcome is as shown in table 7：
The inhibiting effect that 7. compound (d) of table, (e) and (f) grow cancer cell line A-549
(4) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
To 4- chloro-quinazolines, further according to embodiment 1, the chloro- 6- nitro-quinazolines of 4- are replaced with 4- chloro-quinazolines, other operations are the same as implementation
Example 1, has synthesized quinazoline compounds (g), and structure is as follows：
Quinazoline compounds (g) obtained have been carried out by human lung cancer cell lines A-549 bioactivity according to the above method
Test, test result show that quinazoline compounds (g) can not show a candle to compound to the active anticancer of human lung cancer cell lines A-549
(Ⅰ).Concrete outcome is as shown in table 8：
The inhibiting effect that 8. compound (g) of table grows cancer cell line A-549
Embodiment 25：Active anticancer testing in vitro
(1) compound obtained (I) people in loop strain HL-60 biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：People in loop strain HL-60.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai life
Academy of sciences's cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into and is diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubator
It cultivates, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, add in DMSO, every hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 9 for test：
The inhibiting effect that 9. compound of table (I) grows cancer cell line HL-60
(2) according to embodiment 11, chloracetyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other behaviour
Make with embodiment 11, be respectively synthesized quinazoline compounds (b) and (c), structure is as follows：
Quinazoline compounds (b) obtained and (c) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (b) and (c) to people in loop strain HL-
The equal unobvious of 60 inhibitions, compound (b) and (c) can not show a candle to the active anticancer of people in loop strain HL-60
Compound (I).Concrete outcome is as shown in table 10：
The inhibiting effect that 10. compound (b) of table and (c) grow cancer cell line HL-60
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are early young to people
The equal unobvious of inhibiting effect of grain leukemia cell line HL-60 growth.Compound (I) is to people in loop strain HL-
The inhibiting effect of 60 growths is notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 17, by ortho-aminotoluene respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or two positive third
Amine replaces, other operations have been respectively synthesized quinazoline compounds (d), (e) and (f), structure is as follows with embodiment 17：
It is thin that quinazoline compounds (d) obtained, (e) and (f) have been carried out by human promyelocytic leukemia according to the above method
Born of the same parents' strain HL-60 biological activity tests, the results showed that quinazoline compounds (d), (e) are with (f) to people in loop
The active anticancer of strain HL-60 can not show a candle to compound (I).Concrete outcome is as shown in table 11：
The inhibiting effect that 11. compound (d) of table, (e) and (f) grow cancer cell line HL-60
Embodiment 26：Active anticancer testing in vitro
(1) compound obtained (I) human cervical carcinoma cell lines Siha biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into and is diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubator
It cultivates, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, add in DMSO, every hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50.It surveys
The result of examination is as shown in table 12：
The inhibiting effect that 12. compound of table (I) grows cancer cell line Siha
(2) according to embodiment 11, chloracetyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other behaviour
Make with embodiment 11, be respectively synthesized quinazoline compounds (b) and (c), structure is as follows：
Quinazoline compounds (b) obtained and (c) have been carried out by human cervical carcinoma cell lines Siha lifes according to the above method
Object active testing, test result show quinazoline compounds (b) and (c) to human cervical carcinoma cell lines Siha inhibitions not
Significantly, compound (b) and (c) can not show a candle to the active anticancer of human cervical carcinoma cell lines Siha compound (I).Concrete outcome such as table
Shown in 13：
The inhibiting effect that 13. compound (b) of table and (c) grow cancer cell line Siha
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are to people's uterine neck
The equal unobvious of inhibiting effect of cancer cell line Siha growths.Compound (I) makees the inhibition that human cervical carcinoma cell lines Siha is grown
With notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 17, by ortho-aminotoluene respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or two positive third
Amine replaces, other operations have been respectively synthesized quinazoline compounds (d), (e) and (f), structure is as follows with embodiment 17：
Quinazoline compounds (d) obtained, (e) and (f) have been carried out by human cervical carcinoma cell lines according to the above method
Siha biological activity tests, the results showed that quinazoline compounds (d), (e) are with (f) to the anticancer of human cervical carcinoma cell lines Siha
Activity can not show a candle to compound (I).Concrete outcome is as shown in table 14：
The inhibiting effect that 14. compound (d) of table, (e) and (f) grow cancer cell line Siha
Claims (10)
1. a kind of 6- (2- (adjacent toluidino) acetylamino) quinazoline compounds shown in formula (I)：
2. a kind of 6- (2- (adjacent toluidino) acetylamino) quinazoline ditosylate salt chemical combination shown in formula as described in claim 1 (I)
The preparation method of object, it is characterised in that the method is：
(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's
Under effect, 25~120 DEG C are reacted, and after the reaction was complete, reaction solution is isolated and purified, and compound shown in formula (IV) is made；Institute
Organic solvent A is stated selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- diformazans
Aminopyridine, 4- pyrollidinopyridines or sodium carbonate；
(2) formula (IV) compound represented is in organic solvent D, and under reducing agent E effects, at 25~100 DEG C, the reaction was complete, instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration；
The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine；The reducing agent E is one of following：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion；
(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effects, in organic
In solvent G, -10~50 DEG C the reaction was complete, the post-treated A of reaction solution, and formula (VI) compound represented is made；The alkalinity is urged
Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidines
Yl pyridines or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether,
Acetonitrile, toluene or benzene；
(4) compound shown in formula (VI) is mixed with ortho-aminotoluene, in organic solvent J, under the action of basic catalyst K,
25~120 DEG C are reacted, and after the reaction was complete, by the post-treated B of reaction solution, compound shown in formula (I) is made；It is described organic molten
Agent J is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；Described
Basic catalyst K is selected from one of following：Pyridine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidines
Yl pyridines or sodium carbonate.
3. method as claimed in claim 2, it is characterised in that：Compound shown in formula (III) described in step (1) and formula (II)
The ratio between shown compound, amount for the substance that feeds intake of basic catalyst B are 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0；The organic solvent A
Dosage 10~50mL/g is calculated as with the quality of compound shown in formula (III)..
4. method as claimed in claim 2, it is characterised in that：The method that reaction solution isolates and purifies described in step (1) is：Instead
After answering completely, solvent is evaporated off in reaction solution, concentrate is taken to be dissolved with organic solvent C, lysate is obtained, then to lysate
The middle column chromatography silica gel for adding in 1.0~2.0 times of weight of concentrate, after mixing, is evaporated off solvent, dry, obtains concentrate and silica gel
Mixture, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether is elution with ethyl acetate mixture
The efflux containing target components is collected in agent, is concentrated under reduced pressure, dry, obtains formula (IV) compound represented；The organic solvent C
It is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
5. method as claimed in claim 2, it is characterised in that：In step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid
Or iron powder/acetic acid, formula (IV) compound represented are with iron powder, the mass ratio that feeds intake of concentrated hydrochloric acid or acetic acid in reducing agent E
1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；When the reducing agent E be palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV)
The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.
6. method as claimed in claim 2, it is characterised in that：Compound and chloroethene shown in formula (V) described in step (3)
Acyl chlorides or chloroacetic anhydride, basic catalyst F the ratio between the amount for the substance that feeds intake be 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0；It is described organic molten
The dosage of agent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).
7. method as claimed in claim 2, it is characterised in that：The method of step (3) reaction solution post processing A is：It will be anti-
Liquid is answered to filter, filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, then adds into lysate
Enter the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, after mixing, solvent is evaporated off, it is dry, obtain the mixed of concentrate and silica gel
Object is closed, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture,
The efflux containing target components is collected, is concentrated under reduced pressure, it is dry, obtain formula (I) compound represented；Under the organic solvent H is
One of row：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
8. method as claimed in claim 2, it is characterised in that：In step (4), compound shown in the formula (VI) and adjacent toluene
Amine, basic catalyst K the ratio between the amount for the substance that feeds intake be 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0；The dosage of the organic solvent J with
The quality of compound is calculated as 10~60mL/g shown in formula (VI)；
The method of reaction solution post processing B is：After the reaction was complete, solvent is evaporated off in reaction solution, takes concentrate organic solvent M
It is dissolved, obtains lysate, the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, mixing are then added in into lysate
Afterwards, solvent is evaporated off, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：0.1~
10 petroleum ether is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components, is concentrated under reduced pressure, dry, is obtained
Obtain formula (I) compound represented；The organic solvent M is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
9. 6- (2- (adjacent toluidino) acetylamino) quinazoline compounds shown in formula (I) as described in claim 1 exist
Prepare the application in prevention or treatment human breast carcinoma drug.
10. application as claimed in claim 9, it is characterised in that the drug is with inhibition MCF-7 cell strainHJ2mm
The drug of activity.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| US6015814A (en) * | 1995-04-27 | 2000-01-18 | Zeneca Limited | Quinazoline derivative |
| CN101678019A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
-
2018
- 2018-01-24 CN CN201810069794.5A patent/CN108250185B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| US6015814A (en) * | 1995-04-27 | 2000-01-18 | Zeneca Limited | Quinazoline derivative |
| CN101678019A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 于艳红: "新型4-取代胺基喹唑啉类化合物的合成及其抗肿瘤活性研究", 《浙江工业大学硕士学位论文》 * |
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