CN108324719A - Adjacent toluidino acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug - Google Patents
Adjacent toluidino acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug Download PDFInfo
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- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
The invention discloses a kind of adjacent toluidino acetylamino anisyl benzo-azas
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds, more particularly to a kind of adjacent toluidino acetylamino anisyl benzene
And azepineBase quinazoline compounds are preparing the application in preventing or treating human cervical carcinoma's drug.
(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 treating lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib), and the Lapatinib (Lapatinib) for treating breast cancer, they
Belong to quinazoline compounds.Novel quinazoline compounds and its bioactivity also common document report (refering to Y.-
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148；A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) invention content
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound-neighbour's toluidino acetylamino methoxy benzene
Base benzo-azaThe application of base quinazoline compounds, such compound is under doses to human cervical carcinoma cell lines Siha
There is 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, fits
In industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides adjacent toluidino acetylamino anisyl benzo-azas shown in a kind of formula (I)Base quinoline azoles
Application of the quinoline class compound in preparing prevention or tumor is especially preparing prevention or treatment human cervical carcinoma's drug
In application：
Preferably, the drug is with the inhibition active drugs of human cervical carcinoma cell lines Siha.
In addition, adjacent toluidino acetylamino anisyl benzo-aza shown in a kind of formula (I) of present invention offerBase
The preparation method of quinazoline compounds, the method are：(1) by compound shown in compound shown in formula (II) and formula (III)
Mixing, in organic solvent A, under the action of basic catalyst B, 25~120 DEG C are reacted (TLC tracking and monitorings, solvent
For ethyl acetate/petroleum ether=1：3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, by reaction solution point
From purifying, compound shown in formula (IV) is made；The organic solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, third
Alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, three
Ethamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine,
Triethylamine, N, N- dimethylanilines or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented under reducing agent E effects, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 entirely：1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction), instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration；
The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyls
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
It is mixed with acetic acid arbitrary proportion that 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 iron powder
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion；
(3) compound shown in formula (V) is mixed with chloracetyl chloride or chloroacetic anhydride, under basic catalyst F effects, in
In organic solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v),
It is preferred that -10~50 DEG C of 3~12h of reaction), formula (VI) compound represented is made in the post-treated A of reaction solution；The alkalinity is urged
Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidines
Yl pyridines or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether,
Acetonitrile, toluene or benzene；
(4) compound shown in formula (VI) is mixed with ortho-aminotoluene, in organic solvent J, in the effect of basic catalyst K
Under, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：1 (v/v), preferably 40~
100 DEG C of 0.5~36h of reaction), after the reaction was complete, by the post-treated B of reaction solution, compound shown in formula (I) is made；It is described organic
Solvent J is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；It is described
Basic catalyst K be selected from it is one of following：Pyridine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N, N- dimethylanilines or 4-dimethylaminopyridine)；
Further, in step (1), compound shown in the formula (III) and compound, basic catalyst B shown in formula (II)
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 be added 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 with volume ratio for 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, collects and 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 formula (IV) compound represented；It is described to have
Solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosages are residual can dissolve
Stay object.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in the compound and reducing agent E shown is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.
In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid.
Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, formula (IV) institute
The mass ratio that feeds intake of the compound shown and palladium carbon, ammonium formate or hydrazine hydrate in reducing agent E be 1.0 ﹕, 0.1~0.5 ﹕ 1.0~
3.0.In the present invention be applicable in palladium carbon in palladium mass loading amount be 2~10%, preferably 5%, hydrazine hydrate mass concentration be 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 of the present invention (3) carries out as follows：Under the conditions of -10~10 DEG C, toward formula
(V) in the organic solvent G solution of compound shown in and basic catalyst F or toward compound and base catalysis shown in formula (V)
The organic solvent G solution of chloracetyl chloride or chloroacetic anhydride is added dropwise in agent F, drop finishes, and -10~50 DEG C are reacted 3~12 hours, and gained is anti-
The post-treated A of liquid is answered to obtain compound shown in formula (VI)；Dissolve the organic solvent volume dosage pair of chloracetyl chloride or chloroacetic anhydride
The present invention does not influence, and total dosage of the organic solvent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).Have
Total dosage of solvent G refers to dissolving the organic solvent G of compound shown in basic catalyst F and formula (V) and dissolving chloracetyl chloride
Or the total volume of chloroacetic anhydride organic solvent G.
Further, the method for step (3) the of the present invention reaction solution post-processing A is：After the reaction was complete, by reaction solution mistake
Filter, filtrate steaming removal solvent take concentrate to be dissolved with organic solvent H, obtain lysate, and concentration is then added 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 with volume ratio for 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, collects and contains mesh
The efflux of component is marked (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target components,
It is preferred that collecting the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (VI) compound represented；
The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosages are with can
Dissolution residual substance.
Further, in step (4), compound shown in the formula (VI) and ortho-aminotoluene, the substance that feeds intake of basic catalyst K
The ratio between amount be 1.0 ﹕, 0.8~8.0 ﹕ 1.0~8.0.
Further, in step (4), the dosage of the organic solvent J is calculated as 10 with the quality of compound shown in formula (VI)~
60mL/g。
Further, the method for the post-processing of reaction solution described in step (4) of the present invention B is：After the reaction was complete, reaction solution is steamed
Except solvent, concentrate is taken to be dissolved with organic solvent M, obtain lysate, then into lysate be added 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 with volume ratio for 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, collects and 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 formula (I) compound represented；It is described organic
Solvent M is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent M dosages are can dissolve residual
Object.
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 novel quinazoline compounds-neighbour's toluidino
Acetylamino anisyl benzo-azaBase quinazoline compounds are preparing answering in preventing or treating human cervical carcinoma's drug
With the compound has significant inhibitory activity to human cervical carcinoma cell lines Siha.
(4) specific implementation mode
The present invention is further described in conjunction with specific embodiments, and embodiment below illustrates the present invention, rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtains lysate, 3.0 grams of columns is added into lysate for agent
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 with volume ratio for 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected containing formula (IV) compound represented according to TLC detections
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
85.1%, 164~166 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.32-3.38 (m, 1H), 3.63 (dt, J=3.4,
15.5Hz, 1H), 3.75 (s, 3H), 3.82 (s, 6H), 3.91 (dd, J=8.1,14.3Hz, 1H), 4.03 (td, J=4.1,
11.7Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 4.72 (dd, J=8.3,14.2Hz, 1H), 5.14 (t, J=8.9Hz,
1H), 6.60 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.93 (d, J=9.1Hz, 1H),
8.48 (dd, J=2.4,9.2Hz, 1H), 8.71 (s, 1H), 8.96 (d, J=2.4Hz, 1H).IR(KBr,cm-1)ν:2917,
2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Embodiment 2：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate is obtained, 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
Mixture is filled column by object, then with volume ratio for 1：5 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 and contains formula (IV) compound represented
Eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), it is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
20 milliliters of chloroforms are added in obtained concentrate and are dissolved, obtains lysate, 2.5 grams of column layers is added into lysate for solvent
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 with volume ratio for 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, elution, TLC tracking inspections
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield 77.2%,
164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it reacts 12 hours, closes reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column by the mixture of glue, then with volume ratio for 5：1 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 containing shown in formula (IV) according to TLC detections
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid shown in formula (IV) and produce
Object, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate is obtained, 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, obtain dry dense
Mixture is filled column by the mixture of contracting object and silica gel, then with volume ratio for 1：1 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 is contained according to TLC detections
The eluent (Rf values be 0.5) of formula (IV) compound represented, collection liquid concentration, 50 DEG C be dried to obtain it is yellowish shown in formula (IV)
Color solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 6：The preparation of 6- nitro-quinazolines (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, obtains lysate, 3.5 grams of columns is added into lysate for agent
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 with volume ratio for 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)), it is collected containing formula (IV) compound represented according to TLC detections
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain faint yellow solid product shown in formula (IV), yield
78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 1 method of embodiment, 0.40 gram
(6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C of vacuum drying
Obtain faint yellow solid product 6- amido quinazolines (V), yield 98.2%, 122~126 DEG C of fusing point.1H NMR(500MHz,
CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H),4.45
(dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s, 1H), 6.90 (d, J=8.7Hz,
2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=8.9,2.5Hz, 1H), 7.69 (d, J
=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,2825,1628,1566,1512,1487,
1353,1248,1036,834。
Embodiment 8：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 2 method of embodiment, 1.20 grams
(19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, heating
To 100 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 0.5 hour, it is cooled
Filter, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 100.0%, fusing point
122~126 DEG C.1H NMR and IR is the same as embodiment 7.
Embodiment 9：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 3 method of embodiment, 0.08 gram of concentrated hydrochloric acid
(mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb, are heated to 40 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 4 method of embodiment, 0.40 gram of acetic acid,
1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain
Faint yellow solid product 6- amido quinazolines (V), yield 97.5%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 11：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.13 gram
(1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.497 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) chloracetyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), under the conditions of -10 DEG C
Reaction 12 hours, filtering, filtrate steaming removal solvent, concentrate are added 10 milliliters of ethyl acetate and are dissolved, and obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column by the mixture of object and silica gel, then with volume ratio for 1：10 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 and contains formula
(VI) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain chloracetyl shown in formula (VI)
Amido quinazoline yellow solid, yield 95.6%, 255~258 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.26-3.33
(m, 1H), 3.54 (dt, J=3.7,15.4Hz, 1H), 3.74 (s, 3H), 3.81-3.82 (m, 7H), 3.95-4.05 (m, 2H),
4.28 (s, 2H), 4.64 (dd, J=8.2,14.4Hz, 1H), 5.24 (t, J=8.8Hz, 1H) .6.64 (s, 1H), 6.88 (d, J
=8.8Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 7.53 (dd, J=2.3,9.0Hz, 1H), 7.83 (d, J=9.0Hz, 1H),
8.54 (s, 1H), 8.60 (s, 1H), 8.69 (d, J=2.2Hz, 1H).IR(KBr,cm-1)ν:3396,2998,2937,2835,
1694,1557,1525,1510,1489,1463,1349,1249,1179,1036,840。
Embodiment 12：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 8 method of embodiment, 0.04 gram
(0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, and 0.07 gram is added dropwise under 10 DEG C of stirring conditions
(0.55mmol) chloracetyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of ethyl alcohol are added in concentrate 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 into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio for 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
It is dry to obtain chloro acetylamino quinazoline yellow solid 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 be ethyl acetate/
Petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of chloroforms are added in concentrate, 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 with volume ratio for 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)),
The eluent (Rf values be 0.5) containing formula (VI) compound represented is collected according to TLC detections, and collection liquid concentration, 50 DEG C dry
To chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 70.5%, 255~258 DEG C of fusing point.1H NMR and IR is same
Embodiment 11.
Embodiment 14：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 10 method of embodiment, 0.067 gram
(0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, are added dropwise under 5 DEG C of stirring conditions
The solution of 0.376 gram of (2.20mmol) chloroacetic anhydride and 7.0 milliliters of toluene, drop finish, and are heated to 50 DEG C, (the expansion of TLC tracing detections
Agent is ethyl acetate/petroleum ether=1：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, 20 milliliters of tetrahydrochysene furans are added in concentrate
It mutters and is 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 with volume ratio for 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 chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 85.3%, 255~258 DEG C of fusing point.1H NMR
With IR with embodiment 11.
Embodiment 15：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.213 gram
(1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, and 0.28 gram is added dropwise under -10 DEG C of stirring conditions
The solution of (2.19mmol) chloracetyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/petroleum ether to TLC tracing detections
=1：1) it, reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, 20 milliliters of tetrahydrofurans are added in concentrate, 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 with volume ratio for 1：1 petroleum ether/second
Acetoacetic ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), root
The eluent (Rf values are 0.5) containing formula (VI) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C are dried to obtain
Chloro acetylamino quinazoline yellow solid shown in formula (VI), yield 82.1%, 255~258 DEG C of fusing point.1H NMR and IR are the same as real
Apply example 11.
Embodiment 16：The preparation of chloro acetylamino quinazoline (VI)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.164 gram
(1.10mmol) 4- pyrollidinopyridines, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, 10 DEG C of stirring conditions
00.14 gram of (1.09mmol) chloracetyl chloride of lower dropwise addition and 5.0 milliliters of dichloromethane solutions, drop finish, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, 20 millis are added in concentrate
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 into lysate
Glue), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, is then with volume ratio
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 are dried to obtain chloro acetylamino quinazoline yellow solid, yield 90.2%, fusing point 255~258 shown in formula (VI)
℃。1H NMR and IR is the same as embodiment 11.
Embodiment 17：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 11 method of embodiment preparation and 0.736 gram
(6.87mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 32.5 ml methanols are added in 50 milliliters of reaction bulb, add
Heat is to 40 DEG C, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 10 hours, closes anti-
It answers, solvent is evaporated off in reaction solution, and 10 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate are obtained, to dissolving
1.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in liquid, after mixing, solvent is evaporated off, obtains dry concentrate
With the mixture of silica gel, mixture is filled into column, then with volume ratio for 1：10 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain yellow solid shown in formula (I) and produce
Object, yield 53.4%, 179~181 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:2.32(s,3H),3.26-3.32(m,1H),
3.55 (dt, J=3.5,15.3Hz, 1H), 3.76 (s, 3H), 3.81-3.82 (m, 7H), 4.00-4.06 (m, 4H), 4.33 (t, J
=5.3Hz, 1H), 4.65 (dd, J=8.2,14.3Hz, 1H), 5.29 (t, J=8.8Hz, 1H), 6.62 (d, J=8.2Hz,
1H), 6.68 (s, 1H), 6.84 (t, J=7.3Hz, 1H), 6.88 (d, J=8.7Hz, 2H), 7.09 (d, J=8.7Hz, 2H),
7.15-7.18 (m, 2H), 7.37 (dd, J=2.2,9.0Hz, 1H), 7.75 (d, J=8.9Hz, 1H), 8.57 (s, 1H), 8.79
(s,2H)。HRMS-ESI m/z:638.2527[M+H]+。13C NMR(125MHz,CDCl3)δ:17.6,28.8,49.7,50.0,
51.1,54.4,55.3,56.0,60.5,110.9,113.9,114.2,114.4,116.1,120.0,123.0,125.3,
127.6,128.0,128.1,128.7,128.8,130.7,133.6,135.0,137.5,144.0,145.0,149.0,
152.2,153.3,158.4,163.7,169.1。IR(KBr,cm-1)ν:2934,2831,1695,1562,1512,1487,
1453,1349,1248,1036,837。
Embodiment 18：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 12 method of embodiment preparation and 0.490 gram
(4.57mmol) ortho-aminotoluene, 2.95 grams of (22.84mmol) quinoline, 80 milliliters of toluene are added in 100 milliliters of three-necked flask, add
Heat is to 100 DEG C, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 2 hours, closes anti-
It answers, solvent is evaporated off in reaction solution, and 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column by the mixture of glue, then with volume ratio for 1：5 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected containing shown in formula (I) according to TLC detections
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain yellow solid product shown in formula (I), receive
Rate 52.8%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 19：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 13 method of embodiment preparation and 0.614 gram
(5.73mmol) ortho-aminotoluene, 0.58 gram of (5.73mmol) triethylamine, 80 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask,
60 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of chloroforms are added in obtained concentrate and are dissolved, lysate are obtained, to lysate
After mixing, solvent is evaporated off in 2.5 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) of middle addition, obtain dry concentrate with
Mixture is filled column by the mixture of silica gel, then with volume ratio for 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)), 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 yellow solid shown in formula (I) and produce
Object, yield 47.6%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 20：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 14 method of embodiment preparation and 2.456 grams
(22.92mmol) ortho-aminotoluene, 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added 100 milliliters
In three-necked flask, 25 DEG C of stirrings of room temperature, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), reaction 36
Hour, reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain molten
Liquid is solved, 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, obtains dry
Mixture is filled column by the mixture of dry concentrate and silica gel, then with volume ratio for 5：1 petrol ether/ethyl acetate mixing
Solution is eluant, eluent, elution, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected, collection liquid concentration, 50 DEG C are dried to obtain shown in formula (I)
Yellow solid product, yield 62.2%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 21：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 15 method of embodiment preparation and 0.552 gram
(5.15mmol) ortho-aminotoluene, 1.04 grams of (8.58mmol) N, N- dimethylanilines, 33 milliliters of n,N-Dimethylformamide are added 50
In the reaction bulb of milliliter, 120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it stirs
Reaction 0.5 hour is mixed, reaction is closed, solvent is evaporated off in reaction solution, 20 milliliters of tetrahydrofurans is added in obtained concentrate its is molten
Solution obtains lysate, 4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, is evaporated off
Solvent obtains the mixture of dry concentrate and silica gel, and mixture is filled column, then with volume ratio for 1：1 petroleum ether/acetic acid
Ethyl ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), according to
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected in TLC detections, and collection liquid concentration, 50 DEG C are dried to obtain formula
(I) yellow solid product shown in, yield 58.1%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 22：Adjacent toluidino acetylamino anisyl benzo-azaThe preparation of base quinazoline (I)
Successively by 3.25 grams of (5.73mmol) chloro acetylamino quinazolines (VI) of 16 method of embodiment preparation and 4.912 grams
(45.84mmol) ortho-aminotoluene, 3.626 grams of (45.84mmol) pyridines, 195 milliliters of propyl alcohol are added in 500 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 10 hours, closes
Solvent is evaporated off in reaction, reaction solution, and 20 milliliters of ethyl acetate are added in obtained concentrate and are dissolved, lysate, Xiang Rong are obtained
It solves and 6.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column by the mixture of object and silica gel, then with volume ratio for 1：1 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 and contains formula
(I) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain yellow solid shown in formula (I)
Product, yield 65.3%, 179~181 DEG C of fusing point.Characterization is the same as embodiment 17.
Embodiment 23：Active anticancer testing in vitro
(1) compound obtained (I) human cervical carcinoma cell lines Siha biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, per 1mg with 40 μ LDMSO dissolvings, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium: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 set, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juices are digested, culture medium is used in combination to be diluted to 1 × 106It 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 set, 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, sets 37 DEG C, 5%CO2In incubator
It cultivates, the MTT of 5mg/mL is added after 72h in cell culture well, per 10 μ L of hole, set 37 DEG C of incubation 3h, DMSO, every hole is added
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 same concentration DMSO as a contrast, calculate IC of the sample to growth of tumour cell50.It surveys
The results are shown in Table 1 for examination：
The inhibiting effect that 1. compound of table (I) grows cancer cell line Siha
(2) according to embodiment 11, chloracetyl chloride is replaced with 3- methoxy benzoyl chlorides or cinnamoyl chloride respectively, other behaviour
Make, with embodiment 11, to be respectively synthesized quinazoline compounds (b) and (c), structure is as follows：
Quinazoline compounds (b) obtained and (c) human cervical carcinoma cell lines Siha lifes have been subjected to according to the above method
Object active testing, test result show quinazoline compounds (b) and (c) to human cervical carcinoma cell lines Siha inhibitions not
Obviously, compound (b) and (c) can not show a candle to compound (I) to the active anticancer of human cervical carcinoma cell lines Siha.Concrete outcome such as table
Shown in 2：
The inhibiting effect that 2. compound (b) of table and (c) grow cancer cell line Siha
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are to people's uterine neck
The equal unobvious of inhibiting effect of cancer cell line Siha growths.Compound (I) makees the inhibition that human cervical carcinoma cell lines Siha is grown
With notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 17, by ortho-aminotoluene respectively with 3,4- dimethylanilines, 3,4- dimethoxyanilines or two positive third
Amine replaces, other operations have been respectively synthesized quinazoline compounds (d), (e) and (f) with embodiment 17, and structure is as follows：
Quinazoline compounds (d) obtained, (e) and (f) human cervical carcinoma cell lines have been subjected to according to the above method
Siha biological activity tests, the results showed that quinazoline compounds (d), (e) are with (f) to the anticancer of human cervical carcinoma cell lines Siha
Activity can not show a candle to compound (I).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (d) of table, (e) and (f) grow cancer cell line Siha
。
Claims (2)
1. the adjacent toluidino acetylamino anisyl benzo-aza as shown in formula (I)It is prepared by base quinazoline compounds
Prevent or treat the application in human cervical carcinoma's drug；
2. application as described in claim 1, it is characterised in that the drug is to live with inhibition human cervical carcinoma cell lines Siha
The drug of property.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| 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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