CN108014112A - Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament - Google Patents
Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament Download PDFInfo
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Abstract
The invention discloses a kind of adjacent toluidino acetylamino benzo [d] azepine
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds, more particularly to a kind of adjacent toluidino acetylamino benzo [d] nitrogen
It is miscellaneousApplication of the base quinazoline compounds in prevention or treatment human lung cancer medicine 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 obvious 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 (Lapatinib) of breast cancer, 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-neighbour's toluidino acetylamino benzo [d]
AzepineThe application of base quinazoline compounds, such compound have very human lung cancer cell lines A-549 under doses
Good inhibition；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 work
Industry application.
For achieving the above object, the present invention adopts the following technical scheme that：
Adjacent toluidino acetylamino benzo [d] azepine shown in the present invention provides a kind of formula (I)Base quinazoline ditosylate salt
Application of the compound in preparation prevention or tumor, particularly answering in prevention or treatment human lung cancer medicine is prepared
With：
Preferably, the medicine is with the medicine for suppressing human lung cancer cell lines A-549 activity.
In addition, the present invention provides adjacent toluidino acetylamino benzo [d] azepine shown in a kind of formula (I)Base quinazoline
The preparation method of class 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 second
Acetoacetic 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 separated pure
Change, compound shown in formula (IV) is made；The organic solvent A is selected from one of following：It is chloroform, toluene, methanol, ethanol, propyl alcohol, different
Propyl alcohol, acetonitrile or N,N-dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine,
Quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, three second
Amine, N, N- dimethylanilines or 4-dimethylaminopyridine)；
(2) compound shown in formula (IV) 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, the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration, is made the compound shown in formula (V)；
The organic solvent D is one of following：Chloroform, toluene, methanol, ethanol, 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
Close, 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), the post-treated A of reaction solution, is made the compound shown in formula (VI)；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 ortho-aminotoluene, in organic solvent J, in the effect of basic catalyst K
Under, 25~120 DEG C are reacted that (TLC tracking and monitorings, solvent are 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, ethanol, 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 material 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, takes concentrate to be dissolved with organic solvent C, obtain lysate, then into lysate add concentrate 1.0~
The column chromatography silica gel of 2.0 times of weight, after mixing, is evaporated off solvent, 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 and ethyl acetate mixture are eluant, eluent, and collection contains 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 the compound shown in formula (IV)；It is described to have
Solvent C is one of following：Ethanol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosages are so as to dissolving is residual
Stay thing.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The compound shown and the mass ratio that feeds intake of the iron powder in reducing agent E, concentrated hydrochloric acid or acetic acid are 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 and the palladium carbon in reducing agent E, 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 the compound shown in formula (IV)
~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 material 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 cumulative 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, takes concentrate to be dissolved with organic solvent H, obtains lysate, and concentration is then added into lysate
The column chromatography silica gel of 1.0~2.0 times of weight of thing, after mixing, is evaporated off solvent, dry, obtains the mixture of concentrate and silica gel, will
Mixture fills column, then using volume ratio as 1：0.1~10 petroleum ether and ethyl acetate mixture are eluant, eluent, and collection contains
The efflux of target components is (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target group
Point, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings), obtain the chemical combination shown in formula (VI)
Thing；The organic solvent H is one of following：Ethanol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosages are with energy
Enough dissolution residual substances.
Further, in step (4), compound shown in the formula (VI) and ortho-aminotoluene, the material 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, take concentrate to be dissolved with organic solvent M, obtain lysate, then into lysate add concentrate 1.0~
The column chromatography silica gel of 2.0 times of weight, after mixing, is evaporated off solvent, 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 and ethyl acetate mixture are eluant, eluent, and collection contains 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 the compound shown in formula (I)；It is described organic
Solvent M is one of following：Ethanol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent M dosages are so as to dissolving residual
Thing.
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 implication；The catalyst B, reducing agent E, catalyst F and catalyst K are
Catalyst, is named, letter itself does not have implication for the ease of distinguishing different step used catalyst difference；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 implication.
The beneficial effects are mainly as follows：Provide a kind of new quinazoline compounds-neighbour's toluidino
Acetylamino benzo [d] azepineApplication of the base quinazoline compounds in the medicine for preparing prevention or treatment human lung cancer, should
Compound has significant inhibitory activity to human lung cancer cell lines A-549.
(4) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment is to 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)), when stirring reaction 10 is small, reaction is closed, reaction solution is evaporated off molten
Agent, 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate is obtained, 3.0 grams of columns is added 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, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), collected according to TLC detections containing the compound shown in formula (IV)
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
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)), when stirring reaction 2 is small, close reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethanol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added 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
Thing, fills column, then using volume ratio as 1 by mixture：5 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), collected according to TLC detections containing the chemical combination shown in formula (IV)
The eluent (Rf values are 0.5) of thing, 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 ethanol 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)), when stirring reaction 8 is small, reaction is closed, reaction solution is evaporated off
Solvent, 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate is obtained, 2.5 grams of column layers is added 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, will
Mixture fills column, then using volume ratio as 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), collected according to TLC detections containing the compound shown in formula (IV)
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
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
25 DEG C of stirrings of temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), when reaction 12 is small, close anti-
Should, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, to dissolving
4.0 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 5：1 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), collected according to TLC detections and contain formula
(IV) eluent (Rf values be 0.5) of the compound shown in, collection liquid concentration, 50 DEG C be dried to obtain it is faint yellow shown in formula (IV)
Solid product, 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)), when stirring reaction 0.5 is small, 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
The mixture of contracting thing and silica gel, fills column, then using volume ratio as 1 by mixture：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)), collection is detected according to TLC and is contained
The eluent (Rf values be 0.5) of compound shown in formula (IV), collection liquid concentration, 50 DEG C be dried to obtain it is light shown in formula (IV)
Yellow 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)), when stirring reaction 10 is small, reaction is closed, reaction solution is evaporated off molten
Agent, 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate is obtained, 3.5 grams of columns is added 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, elution, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), collected according to TLC detections containing the compound shown in formula (IV)
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, the stirring of 25 DEG C of room temperature, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：1 (v/v)), when reaction 12 is small, filtering, filtrate concentration, 25 DEG C of vacuum
It is dried to 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)), when stirring reaction 0.5 is small, cooling
Filtering, 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 same
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)), when stirring reaction 8 is small, 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)), when stirring reaction 3 is small, cold filtration, filtrate concentrates, and 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 10 milliliters of ethyl acetate dissolved, obtain lysate, to
0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in lysate, after mixing, solvent is evaporated off, obtains dry
The mixture of concentrate and silica gel, fills column, then using volume ratio as 1 by mixture：10 petrol ether/ethyl acetate mixed solution
For eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), detected and collected according to TLC
Eluent (Rf values are 0.5) containing the compound shown in formula (VI), collection liquid concentration, 50 DEG C are dried to obtain the chlorine shown in formula (VI)
Acetylamino 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 20 milliliters of ethanol will
It is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added into lysate, is mixed
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 the compound shown in formula (VI) 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 20 milliliters of chloroforms, and its is molten
Solution, obtains lysate, and 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added 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, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections： 1(v/
V)), the eluent (Rf values are 0.5) containing the compound shown in formula (VI) 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 70.5%, 255~258 DEG C of fusing point.1H NMR
With IR with 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
Mutter and dissolved, obtain lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added 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 the compound shown in formula (VI), is collected according to TLC detections, collection liquid concentrates, and 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 and IR is the same as 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 20 milliliters of tetrahydrofurans, and its is molten
Solution, obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added 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)),
Eluent (Rf values are 0.5) containing the compound shown in formula (VI) 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 82.1%, 255~258 DEG C of fusing point.1H NMR and IR
With embodiment 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 20 millis
Rise ethanol to be dissolved, obtain lysate, 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography silicon is added 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 the compound shown in formula (VI), collection liquid are collected according to TLC detections
Concentration, 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：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 0.736 successively prepared by 11 method of embodiment
Gram (6.87mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 32.5 ml methanols are added in 50 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 10 is small, close
Solvent is evaporated off in reaction, reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtain lysate, Xiang Rong
Solve and 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 concentration
The mixture of thing and silica gel, fills column, then using volume ratio as 1 by mixture：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)), collected according to TLC detections and contain formula
(I) eluent (Rf values are 0.5) of the compound shown in, collection liquid concentration, 50 DEG C of yellow being dried to obtain shown in formula (I) are consolidated
Body product, 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：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 0.490 successively prepared by 12 method of embodiment
Gram (4.57mmol) ortho-aminotoluene, 2.95 grams of (22.84mmol) quinoline, 80 milliliters of toluene add 100 milliliters of three-necked flask
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 2 is small,
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of ethanol are added in obtained concentrate and are dissolved, obtain lysate, Xiang Rong
Solve and 2.5 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 concentration
The mixture of thing and silica gel, fills column, then using volume ratio as 1 by mixture：5 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)), collected according to TLC detections and contain formula
(I) eluent (Rf values are 0.5) of the compound shown in, collection liquid concentration, 50 DEG C are dried to obtain the yellow solid shown in formula (I)
Product, yield 52.8%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 19：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 0.614 successively prepared by 13 method of embodiment
Gram (5.73mmol) ortho-aminotoluene, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethanol add 100 milliliters of three-necked flask
In, 60 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 8 is small, close
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate are obtained, to dissolving
2.5 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 10：1 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), collected according to TLC detections and contain formula
(I) eluent (Rf values are 0.5) of the compound shown in, collection liquid concentration, 50 DEG C are dried to obtain the yellow solid shown in formula (I)
Product, yield 47.6%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 20：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 2.456 successively prepared by 14 method of embodiment
Gram (22.92mmol) ortho-aminotoluene, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols add 100 milliliters
Three-necked flask in, the stirring of 25 DEG C of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), reaction
36 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, 3.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off,
The concentrate and the mixture of silica gel that must be dried, fill column, then using volume ratio as 5 by mixture：1 petrol ether/ethyl acetate
Mixed solution is eluant, eluent, and elution, (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 the compound shown in formula (I) is collected in detection, and collection liquid concentration, 50 DEG C are dried to obtain formula (I) institute
The yellow solid product shown, yield 62.2%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 21：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 0.552 successively prepared by 15 method of embodiment
Gram (5.15mmol) ortho-aminotoluene, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of n,N-Dimethylformamide add
In 50 milliliters of reaction bulb, 120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)),
When stirring reaction 0.5 is small, close reaction, solvent is evaporated off in reaction solution, added in obtained concentrate 20 milliliters of tetrahydrofurans by its
Dissolving, obtains lysate, and 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added 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 the compound shown in formula (I) is collected according to TLC detections, 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：Adjacent toluidino acetylamino benzo [d] azepineThe preparation of base quinazoline (I)
3.25 grams of (5.73mmol) the chloro acetylamino quinazolines (VI) and 4.912 successively prepared by 16 method of embodiment
Gram (45.84mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol add 500 milliliters of reaction bulb
In, 40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when stirring reaction 10 is small,
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtain lysate,
6.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off, obtains dry
The mixture of concentrate and silica gel, fills column, then using volume ratio as 1 by mixture：1 petrol ether/ethyl acetate mixed solution
For eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), detected and collected according to TLC
Eluent (Rf values are 0.5) containing the compound shown in formula (I), collection liquid concentration, 50 DEG C are dried to obtain the Huang shown in formula (I)
Color solid 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) obtained compound (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 L DMSO, take 2 μ L with 1000 μ L culture mediums
Dilution, it is 100 μ g/mL to make concentration, then with nutrient solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Contain 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%CO2Cultivated 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 medium6/ mL, is added to 96 holes
In Tissue Culture Plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2Cultivated in incubator.After being inoculated with 24h, 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, the MTT of 5mg/mL is added after 72h in cell culture well, per 10 μ L of hole, is put 37 DEG C of incubation 3h, is added DMSO, often
150 μ L of hole, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.With under similarity condition not
Containing sample, the cell of the medium culture containing same concentration DMSO calculates IC of the sample to growth of tumour cell as control50。
The results are shown in Table 1 for test：
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：
Obtained quinazoline compounds (a), (b) and (c) have been carried out by human lung carcinoma cell line A- according to the above method
549 biological activity tests, test result show quinazoline compounds (a), and (b) and (c) suppresses human lung cancer cell lines A-549
The equal unobvious of effect, compound (a), (b) and (c) can not show a candle to the active anticancer of human lung cancer cell lines A-549 compound (I).
Concrete outcome is as shown in table 2：
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 suppression 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：
Obtained quinazoline compounds (d), (e) and (f) have been carried out by human lung carcinoma cell line A- according to the above method
549 biological activity tests, the results showed that the anticancer of quinazoline compounds (d), (e) with (f) to human lung cancer cell lines A-549
Activity 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：
Obtained quinazoline compounds (g) 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. adjacent toluidino acetylamino benzo [d] azepine as shown in formula (I)Base quinazoline compounds are preparing prevention
Or the application in treatment human lung cancer medicine；
2. application as claimed in claim 1, it is characterised in that the medicine is active with human lung cancer cell lines A-549 is suppressed
Medicine.
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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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| 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 |
| 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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