CN108078994A - 6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament - Google Patents
6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament Download PDFInfo
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Abstract
The invention discloses a kind of application of 6 (2 morpholinyl acetylamino) quinazoline compounds in prevention or tumor is prepared, the application in prevention or treatment human lung cancer drug is particularly prepared, there is remarkable result to inhibiting 549 activity of human lung carcinoma cell line A.
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- morpholinyls acetylamino)
Application of the quinazoline compounds in prevention or treatment human lung cancer drug is prepared.
(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 new 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) content of the invention
It is an object of the invention to provide a kind of novel quinazoline quinoline class compound -6- (2- morpholinyls acetylamino) quinoline azoles
The application of quinoline class compound, such compound have good inhibition under doses to human lung cancer cell lines A-549；
And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and production cost is relatively low, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides 6- (the 2- morpholinyls acetylamino) quinazoline compounds shown in a kind of formula (I) to prepare in advance
Application in anti-or tumor, the particularly application in prevention or treatment human lung cancer drug is prepared：
Preferably, the drug is with the drug for inhibiting human lung cancer cell lines A-549 activity.
In addition, the present invention provides a kind of system of 6- (2- morpholinyls acetylamino) quinazoline compounds shown in formula (I)
Preparation Method, the method are：(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A
In, under the action of basic catalyst B, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/oil
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, formula is made
(IV) compound shown in；The organic solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile
Or N,N-dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N-
Dimethylaniline, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N- bis-
Toluidines 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 alkalescence 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 morpholine, in organic solvent J, under the action of basic catalyst K,
25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：1 (v/v), preferably 40~100 DEG C
React 0.5~36h), after the reaction was complete, by the post-treated B of reaction solution, compound shown in formula (I) is made；The organic solvent J
Selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；The alkali
Property catalyst K be selected from it is one of following：Pyridine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidinyls
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 so as to dissolving is residual
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 when -10~50 DEG C of reactions 3~12 are small, 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 that step (3) the of the present invention reaction solution isolates and purifies 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 so as to
Dissolution residual substance.
Further, in step (4), compound shown in the formula (VI) and the amount of morpholine, the substance that feeds intake of basic catalyst K
The ratio between 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 so as to dissolving residual
Object.
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：Provide a kind of new quinazoline compounds -6- (2- morpholines
Base acetylamino) application of the quinazoline compounds (I) in the drug for preparing prevention or treatment human lung cancer, the compound is to people
Lung cancer cell line A-549 has significant inhibitory activity.
(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)), be stirred to react 10 it is small when, close 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)), be stirred to react 2 it is small when, close 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)), be stirred to react 8 it is small when, close 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 concentrates, and 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)), when reaction 12 is small, reaction is closed,
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)), be stirred to react 0.5 it is small when, close
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)), be stirred to react 10 it is small when, close 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)), when reaction 12 is small, 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)), be stirred to react 0.5 it is small when, 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)), be stirred to react 8 it is small when, 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)), be stirred to react 3 it is small when, 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
React 12 it is small when, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate dissolved, 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 to wash
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)), when reaction 8 is small under the conditions of 10 DEG C, filtering, 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) when, reaction 6 is small under the conditions of 25 DEG C, filtering, 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 concentrates, and 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) when, reaction 3 is small, filtering, filtrate steaming removal solvent, concentrate 20 milliliters of tetrahydrochysene furans of addition
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) when, reaction 12 is small under the conditions of -10 DEG C, filtering, 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) when, reaction 8 is small under the conditions of 10 DEG C, filtering, 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- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 11 method of embodiment preparation and 0.598 gram
(6.86mmol) morpholine, 3.626 grams of (45.84mmol) pyridines, 32.5 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)), be stirred to react 10 it is small when, close reaction,
Solvent is evaporated off in reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
1.5 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：10 petrol ether/ethyl acetate mixed solution is eluant, eluent,
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) institute
The eluent (Rf values are 0.5) for the compound shown, collection liquid concentration, 50 DEG C of pale solid productions being dried to obtain shown in formula (I)
Object, yield 65.4%, 122~125 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:2.65-2.72(m,4H),3.19(s,2H),
3.30 (m, 1H), 3.54 (d, J=15.3Hz, 1H), 3.74 (s, 3H), 3.81-3.84 (m, 11H), 3.99-4.01 (m, 2H),
4.64 (dd, J=8.2.14.2Hz, 1H), 5.27 (t, J=8.6Hz, 1H), 6.67 (s, 1H), 6.87 (d, J=8.6Hz, 2H),
7.07 (d, J=8.6Hz, 2H), 7.40 (dd, J=2.0,8.9Hz, 1H), 7.81 (d, J=8.9Hz, 1H), 8.58 (s, 1H),
8.84(s,1H),9.29(s,1H)。HRMS-ESI m/z:618.2477[M+H]+。IR(KBr,cm-1)ν:2933,2833,
1692,1609,1523,1568,1523,1488,1461,1348,1248,1116,1035,838。
Embodiment 18：The preparation of 6- (2- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 12 method of embodiment preparation and 0.398 gram
(4.57mmol) morpholine, 2.95 grams of (22.84mmol) quinoline, 80 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：1 (v/v)), be stirred to react 2 it is small when, close reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate is obtained, is added in into lysate
After mixing, solvent is evaporated off in 2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel), obtains dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by mixture：5 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing the change shown in formula (I)
The eluent (Rf values are 0.5) of object is closed, collection liquid concentration, 50 DEG C are dried to obtain the product as off-white solid shown in formula (I), yield
61.6%, 122~125 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 19：The preparation of 6- (2- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 13 method of embodiment preparation and 0.499 gram
(5.73mmol) morpholine, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, heating
To 60 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), be stirred to react 8 it is small when, close reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate is obtained, is added in into lysate
After mixing, solvent is evaporated off in 2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel), obtains dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 10 by mixture：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing the change shown in formula (I)
The eluent (Rf values are 0.5) of object is closed, collection liquid concentration, 50 DEG C are dried to obtain the product as off-white solid shown in formula (I), yield
57.7%, 122~125 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 20：The preparation of 6- (2- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 14 method of embodiment preparation and 1.997 grams
(22.92mmol) morpholine, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols add in three mouthfuls of 100 milliliters
In 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 is small
When, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, are dissolved
Liquid adds in 3.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) into lysate, after mixing, solvent is evaporated off, obtains drying
Concentrate and silica gel mixture, mixture is filled into column, then using volume ratio as 5：1 petrol ether/ethyl acetate mixing is molten
Liquid is eluant, eluent, elution, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected and received according to TLC
Eluent (Rf value be 0.5) of the collection containing formula (I) compound represented, collection liquid concentration, 50 DEG C are dried to obtain the ash shown in formula (I)
White solid product, yield 71.3%, 122~125 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 21：The preparation of 6- (2- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 15 method of embodiment preparation and 0.449 gram
(5.15mmol) morpholine, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of n,N-Dimethylformamide add in 50 milliliters
Reaction bulb in, be heated to 120 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), stirring is anti-
Answer 0.5 it is small when, close reaction, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, are obtained
Lysate, 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in into lysate, after mixing, solvent is evaporated off,
Mixture is filled column, then using volume ratio as 1 by the concentrate and the mixture of silica gel that must be dried：1 petrol ether/ethyl acetate
Mixed solution is eluant, eluent, elution, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), according to TLC
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected in detection, and collection liquid concentration, 50 DEG C are dried to obtain formula (I) institute
The product as off-white solid shown, yield 55.2%, 122~125 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 22：The preparation of 6- (2- morpholinyls acetylamino) quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 16 method of embodiment preparation and 3.994 grams
(45.84mmol) morpholine, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol are added in 500 milliliters of reaction bulb, heating
To 40 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), be stirred to react 10 it is small when, close anti-
Should, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate are obtained, to dissolving
6.0 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 1：1 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 are dried to obtain the pale solid shown in formula (I)
Product, yield 75.7%, 122~125 DEG C of fusing point.1H NMR and IR is the same as embodiment 17.
Embodiment 23：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 line：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 storehouse.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ LDMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(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 inhibitory action of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and 1 × 10 is diluted to 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 results are shown in Table 1 for examination：
The inhibitory action that 1. 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 2 for body：
The inhibitory action that 2. 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 inhibitory action 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 morpholine respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or di-n-propylamine generation
It 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 3：
The inhibitory action that 3. 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 4：
The inhibitory action that 4. compound (g) of table grows cancer cell line A-549
Claims (2)
1. 6- (the 2- morpholinyls acetylamino) quinazoline compounds as shown in formula (I) are preparing prevention or treatment human lung cancer medicine
Application in object；
2. application as described in claim 1, it is characterised in that the drug is active with human lung cancer cell lines A-549 is inhibited
Drug.
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| CN111973601A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
| CN111973602A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of morpholinyl acetamido quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor |
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| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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| CN111973601A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
| CN111973602A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of morpholinyl acetamido quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor |
| CN111973601B (en) * | 2019-05-21 | 2022-02-11 | 浙江工业大学 | Application of cinnamyl amino quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor in preparation of medicines |
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