CN108117542A - Propionamido anisyl benzo [d] azepine * bases quinazoline compounds and preparation and application - Google Patents
Propionamido anisyl benzo [d] azepine * bases quinazoline compounds and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of propionamido anisyl benzo [d] azepinesBase quinazoline compounds and preparation and application.Propionamido anisyl benzo [d] azepine provided by the inventionBase quinazoline compounds are respectively provided with significant inhibitory activity to Breast cancer lines MCF 7, human lung carcinoma cell line A 549, people in loop strain HL 60, human cervical carcinoma cell lines Siha, be expected to be applied to prepare prevention or treatment human breast carcinoma, human lung cancer, human leukemia, human cervical carcinoma drug in.The present invention provides propionamido anisyl benzo [d] azepines
Description
(1) technical field
The present invention relates to a kind of quinazoline compounds and its application, more particularly to a kind of propionamido anisyl benzo
[d] azepineBase quinazoline compounds and preparation method thereof and the compound are preparing prevention or treatment tumor disease
Drug in application.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for new quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148;A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) content of the invention
It is an object of the invention to provide a kind of novel quinazoline quinoline class compound-propionamidos with antitumor activity
Anisyl benzo [d] azepineBase quinazoline compounds and its preparation method and application, such compound is in doses
Under to MCF-7 cell strainHJ2mm, human lung cancer cell lines A-549, people in loop strain HL-60, human cervical carcinoma
Cell line Siha is respectively provided with significant inhibiting rate;And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and raw
It is relatively low to produce cost, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that:
In a first aspect, the present invention provides propionamido anisyl benzo [d] azepines shown in a kind of formula (I)Base quinoline
Oxazoline compound,
Second aspect, the present invention provide propionamido anisyl benzo [d] azepine shown in a kind of formula (I)Base quinoline azoles
The preparation method of quinoline class compound, the method are:(1) compound shown in formula (II) is mixed with compound shown in formula (III)
It closes, in organic solvent A, under the action of basic catalyst B, 25~120 DEG C are reacted that (TLC tracking and monitorings, solvent are
Ethyl acetate/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
Compound shown in formula (IV) is made in purifying;The organic solvent A is selected from one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol,
Isopropanol, acetonitrile or N,N-dimethylformamide;The basic catalyst B is selected from one of following:Pyridine, diethylamine, three second
Amine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, three
Ethamine, N, N- dimethylanilines or 4-dimethylaminopyridine);
(2) formula (IV) compound represented obtained by step (1) is dissolved in organic solvent D, under reducing agent E effects,
The reaction was complete at 25~100 DEG C, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1:1 (v/v), preferably 40~80
DEG C 0.5~12h of reaction), reacting liquid filtering, the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration is made
Formula (V) compound represented;The organic solvent D is one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, second
Nitrile or N,N-dimethylformamide;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;Iron powder/the 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
With the mixing of acetic acid arbitrary proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, the palladium carbon/
Hydrazine hydrate is the mixture of palladium carbon and hydrazine hydrate arbitrary proportion;
(3) compound shown in formula (V) obtained by step (2) with propionyl chloride or propionic andydride is mixed, made in basic catalyst F
Under, 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), preferably -10~50 DEG C 3~12h of reaction), reaction solution is post-treated, and formula (I) compound represented is made;It is described organic
Solvent G is one of following:Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;The alkalescence
Catalyst F is one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate;
Further, in step (1), compound shown in compound shown in the formula (III) and formula (II), basic catalyst B
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution isolates and purifies described in step (1) of the present invention is:After the reaction was complete, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate add in concentrate 1.0~
The column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of 2.0 times of weight after mixing, is evaporated off molten
Agent, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1:0.1~10 petroleum ether
It is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1:3
(v/v) it is solvent tracing detection, collects target components, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, drying is (excellent
Select 50 DEG C of dryings), obtain formula (IV) compound represented;The organic solvent C is one of following:Ethyl alcohol, chloroform, tetrahydrofuran
Or ethyl acetate.The organic solvent C dosages are so as to dissolution residual substance.
Further, in step (2), the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, shown in formula (IV)
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in compound and reducing agent E is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.This hair
Concentrated hydrochloric acid mass concentration described in bright is 36%~38%, and the acetic acid is glacial acetic acid.
Further, in step (2), the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV)
The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.This
The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in invention, and hydrazine hydrate mass concentration is 40~80%, excellent
Select 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 propionyl chloride or propionic andydride, basic catalyst F
The ratio between the amount of substance of feeding intake 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, step (3) carries out as follows:Under the conditions of -10~10 DEG C, toward compound shown in formula (V) and
Be added dropwise in the organic solvent G solution of basic catalyst F or into compound shown in formula (V) and basic catalyst F propionyl chloride or
The organic solvent G solution of propionic andydride, drop finish, and when -10~50 DEG C of reactions 3~12 are small, gained reaction solution is post-treated to obtain formula (I)
Shown compound;Dissolving the organic solvent volume dosage of propionyl chloride or propionic andydride does not influence the present invention, the organic solvent G's
Total dosage is calculated as 11~100mL/g with the quality of compound shown in formula (V).Total dosage of organic solvent G refers to that dissolving alkalescence urges
The organic solvent G of compound shown in agent F and formula (V) and dissolving propionyl chloride or the total volume of propionic andydride organic solvent G.
Further, the post-processing approach of step (3) the of the present invention reaction solution is:By reacting liquid filtering, filtrate is evaporated off molten
Agent takes concentrate to be dissolved with organic solvent H, obtains lysate, and 1.0~2.0 times of concentrate is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of weight, does
It is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1:0.1~10 petroleum ether and second
Acetoacetic ester mixed solution is eluant, eluent, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1:1(v/v)
For solvent tracing detections, target components are collected, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, it is (preferably 50 DEG C dry
It is dry), obtain formula (I) compound represented;The organic solvent H is one of following:Ethyl alcohol, chloroform, tetrahydrofuran or acetic acid
Ethyl ester.The organic solvent H dosages are so as to dissolution residual substance.
Organic solvent A of the present invention, C, D, G and H are organic solvent, organic used in different step for the ease of distinguishing
Solvent is different and names, and letter itself does not have meaning;The catalyst B, reducing agent E and catalyst F are catalyst, in order to just
It is named in differentiation different step used catalyst difference, letter itself does not have meaning.
The third aspect, the present invention provides described propionamido anisyl benzo [d] azepinesBase quinazoline (I) exists
Prevention or the application for the treatment of tumor disease drug are prepared, particularly prepares the application in prevention or treatment human breast carcinoma drug.
Preferably, the drug is with the drug for inhibiting MCF-7 cell strainHJ2mm activity.Of the present invention third
Acylamino- anisyl benzo [d] azepineBase quinazoline has significant inhibitory action to MCF-7 cell strainHJ2mm.
Propionamido anisyl benzo [d] azepine of the present inventionBase quinazoline also to human lung cancer cell lines A-549,
People in loop strain HL-60 and human cervical carcinoma cell lines Siha has significant inhibitory action, can be applied to prepare
Prevention is treated in human lung cancer, human leukemia or the drug of human cervical carcinoma.
The beneficial effects are mainly as follows:(1) provide it is a kind of it is new, have well it is antitumor (especially
Human breast carcinoma, human lung cancer, human leukemia, human cervical carcinoma) activity quinazoline compounds, be expected to be applied to prepare prevention or
Treat human breast carcinoma, human lung cancer, human leukemia, human cervical carcinoma drug in;(2) propionamido anisyl provided by the invention
Benzo [d] azepineThe preparation method of base quinazoline compounds (I), simple easily operated, raw material is easy to get, and production cost compared with
It is low, suitable for practicality.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), be stirred to react 10 it is small when, close reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1:10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), receive
Rate 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:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), be stirred to react 2 it is small when, close reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object:5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), the eluent concentration of collection, 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:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection:3 (v/v)), be stirred to react 8 it is small when, close reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey:3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), the eluent concentration of collection, 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:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), when reaction 12 is small, reaction is closed,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the pale yellow colored solid shown in formula (IV)
Body product, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), be stirred to react 0.5 it is small when, close
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel:1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values are 0.5) of formula (IV) compound represented, the eluent concentration of collection, 50 DEG C are dried to obtain shown in formula (IV)
Faint 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:Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), be stirred to react 10 it is small when, close reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), receive
Rate 78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 1 method of embodimentBase quinazoline (IV),
0.40 gram of (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,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), when reaction 12 is small, filtering, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 98.2%, fusing point 122~
126℃。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:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 2 method of embodimentBase quinazoline (IV),
1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters of reaction bulb
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it is small to be stirred to react 0.5
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline
(V), yield 100.0%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 9:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 3 method of embodimentBase quinazoline (IV),
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,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), be stirred to react 8 it is small when, cooling
Filtering, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline (V) is received
Rate 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10:Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 4 method of embodimentBase quinazoline (IV),
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 tracking
(solvent is ethyl acetate/petroleum ether=1 for detection:1 (v/v)), be stirred to react 3 it is small when, cold filtration, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 97.5%, fusing point 122~
126℃。1H NMR and IR is the same as embodiment 7.
Embodiment 11:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.13 gram of (1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.407 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) propionyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1) it is, anti-under the conditions of -10 DEG C
Answer 12 it is small when, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate dissolved, obtain lysate, to dissolving
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 concentrate
With the mixture of silica gel, mixture is filled into column, then using volume ratio as 1:10 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections:1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the propionamido first shown in formula (I)
Oxygen phenyl benzo [d] azepineBase quinazoline pale solid, yield 63.2%, 125~129 DEG C of fusing point.1H NMR
(500MHz,CDCl3)δ:1.30 (t, J=7.6Hz, 3H), 2.44-2.53 (m, 2H), 3.26-3.32 (m, 1H), 3.57-3.49
(m, 1H), 3.75 (s, 3H), 3.76-3.82 (m, 7H), 3.95-4.06 (m, 2H), 4.64 (dd, J=8.2,14.3Hz, 1H),
5.27 (t, J=8.6Hz, 1H), 6.69 (s, 1H), 6.88 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.44-
7.48 (m, 2H), 7.78 (d, J=8.9Hz, 1H), 8.57 (s, 1H), 8.72 (s, 1H).HRMS-ESI m/z:547.2107[M+
H]+。IR(KBr,cm-1)ν:2936,2831,1690,1557,1523,1511,1460,1351,1247,1037,840。
Embodiment 12:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 8 method of embodimentBase quinazoline (V),
0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are added dropwise under 10 DEG C of stirring conditions
0.051 gram of (0.55mmol) propionyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid second to TLC tracing detections
Ester/petroleum ether=1:1 (v/v)), when reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of second
Alcohol is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate, is mixed
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 1:5 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 (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain propionamido anisyl benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
62.0%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 13:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.111 gram of (1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, under 0 DEG C of stirring condition
0.102 gram of (1.10mmol) propionyl chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is second to TLC tracing detections
Acetoacetic ester/petroleum ether=1:1) when, reaction 6 is small under the conditions of 25 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of chlorine
It is imitative to be dissolved, lysate is obtained, 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate, is mixed
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 10:1
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)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain propionamido anisyl benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
58.8%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 14:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.286 gram of (2.20mmol) propionic andydride and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection:1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, concentrate addition 20
Milliliter tetrahydrofuran is dissolved, and obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column layer is added in into lysate
Analyse silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume
Than for 5:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1:1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid are collected according to TLC detections
Concentration, 50 DEG C of propionamido anisyl benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid,
Yield 54.5%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 15:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are added dropwise under -10 DEG C of stirring conditions
The solution of 0.204 gram of (2.20mmol) propionyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1:1) when, reaction 12 is small under the conditions of -10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans will
It is dissolved, and obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added in into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1:1 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 (I) compound represented, collection liquid concentration, 50 DEG C of dryings are collected according to TLC detections
Obtain propionamido anisyl benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 72.1% melt
125~129 DEG C of point.1H NMR and IR is the same as embodiment 11.
Embodiment 16:Propionamido anisyl benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.164 gram of (1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, and 10 DEG C are stirred
0.102 gram of (1.10mmol) propionyl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, (the exhibition of TLC tracing detections
Agent is opened as ethyl acetate/petroleum ether=1:1) when, reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in
20 milliliters of ethyl alcohol are dissolved, and obtain lysate, and 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography is added in into lysate
Silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio
For 10:1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1:1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid are collected according to TLC detections
Concentration, 50 DEG C of propionamido anisyl benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid,
Yield 57.8%, 125~129 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 17:Active anticancer testing in vitro
(1) compound obtained (I) MCF-7 cell strainHJ2mm biological activity test has been subjected to.
Test method:Tetrazolium reduction method (mtt assay).
Cell line:MCF-7 cell strainHJ2mm.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Cell bank.
Experimental procedure is as follows:
(a) preparation of sample:For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell:By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibitory action of growth of tumour cell
10th 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%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570 nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of medium culture containing similary concentration DMSO calculate 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) grows cancer cell line MCF-7
(2) according to embodiment 11, propionyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl chloride respectively
Instead of other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11:
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out Breast cancer lines
MCF-7 biological activity tests, test result show quinazoline compounds (a), and (b) and (c) is to MCF-7 cell strainHJ2mm
The equal unobvious of inhibition, compound (a), (b) and (c) can not show a candle to chemical combination to the active anticancer of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 2:
The inhibitory action that 2. compound (a) of table, (b) and (c) grow cancer cell line MCF-7
Above-mentioned active anticancer testing in vitro experiment shows:The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibitory action of breast cancer cell line mcf-7 growth.Compound (I) grows MCF-7 cell strainHJ2mm
Inhibitory action is notable, hence it is evident that better than compound (a), (b) and (c).
(3) 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 (d), and structure is as follows:
Quinazoline compounds (d) obtained have been carried out MCF-7 cell strainHJ2mm biology according to the above method to live
Property test, test result shows that quinazoline compounds (d) can not show a candle to chemical combination to the active anticancer of MCF-7 cell strainHJ2mm
Object (I).Concrete outcome is as shown in table 3:
The inhibitory action that 3. compound (d) of table grows cancer cell line MCF-7
(4) according to embodiment 11, propionyl chloride is replaced respectively with chlorobenzoyl chloride or butyl chloride, other operate same embodiment
11, quinazoline compounds (e) and (f) are respectively synthesized, structure is as follows:
Quinazoline compounds (e) obtained and (f) have been carried out by MCF-7 cell strainHJ2mm life according to the above method
Object active testing, test result show the active anticancer of quinazoline compounds (e) and (f) to MCF-7 cell strainHJ2mm
It can not show a candle to compound (I).Concrete outcome is as shown in table 4:
The inhibitory action that 4. compound (e) of table and (f) grow cancer cell line MCF-7
18 active anticancer testing in vitro of embodiment
(1) compound obtained (I) and (IV) 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 dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell:By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibitory action of growth of tumour cell
10th 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%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 5 for test:
The inhibitory action that 5. compound of table (I) and (IV) grow cancer cell line A-549
(2) according to embodiment 11, propionyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl chloride respectively
Instead of other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11:
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out human lung cancer cell lines A-549
Biological activity test, test result show quinazoline compounds (a), and (b) and (c) inhibits to imitate to human lung cancer cell lines A-549
The equal unobvious of fruit, compound (a), (b) and (c) can not show a candle to the active anticancer of human lung cancer cell lines A-549 compound (I).Tool
The results are shown in Table 6 for body:
The inhibitory action that 6. compound (a) of table, (b) and (c) grow cancer cell line A-549
Above-mentioned active anticancer testing in vitro experiment shows:The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibitory action of lung cancer cell line A-549 growths.The inhibition that compound (I) grows human lung cancer cell lines A-549
Effect is notable, hence it is evident that better than compound (a), (b) and (c).
(3) 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 (d), and structure is as follows:
Quinazoline compounds (d) obtained have been carried out by human lung cancer cell lines A-549 bioactivity according to the above method
Test, test result show that quinazoline compounds (d) 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 7:
The inhibitory action that 7. compound (d) of table grows cancer cell line A-549
(4) according to embodiment 11, propionyl chloride is replaced respectively with chlorobenzoyl chloride, chloracetyl chloride or isobutyryl chloride, other behaviour
Make with embodiment 11, be respectively synthesized quinazoline compounds (e), (g) and (h), structure is as follows:
Quinazoline compounds (e) obtained, (g) and (h) have been carried out by human lung cancer cell lines A-549 according to the above method
Biological activity test, test result show the anticancer of quinazoline compounds (e), (g) with (h) to human lung cancer cell lines A-549
Activity is not so good as compound (I).Concrete outcome is as shown in table 8:
The inhibitory action that 8. compound (e) of table, (g) and (h) grow cancer cell line A-549
Embodiment 19:Active anticancer testing in vitro
(1) compound obtained (I) people in loop strain HL-60 biological activity tests have been subjected to.
Test method:Tetrazolium reduction method (mtt assay).
Cell line:People in loop strain HL-60.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai life
Academy of sciences's cell bank.
Experimental procedure is as follows:
(a) preparation of sample:For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell:By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibitory action of growth of tumour cell
10th 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%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 9 for test:
The inhibitory action that 9. compound of table (I) grows cancer cell line HL-60
(2) according to embodiment 11, propionyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other operations
With embodiment 11, quinazoline compounds (b) and (c) are respectively synthesized, structure is as follows:
Quinazoline compounds (b) obtained and (c) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (b) and (c) to people in loop strain HL-
The equal unobvious of 60 inhibitions, compound (b) and (c) can not show a candle to the active anticancer of people in loop strain HL-60
Compound (I).Concrete outcome is as shown in table 10:
The inhibitory action that 10. compound (b) of table and (c) grow cancer cell line HL-60
Above-mentioned active anticancer testing in vitro experiment shows:The similar compound (b) of other 2 structures and (c) are to the early children of people
The equal unobvious of inhibitory action of grain leukemia cell line HL-60 growth.Compound (I) is to people in loop strain HL-
The inhibitory action of 60 growths is notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 11, propionyl chloride is replaced with cyclohexyl methyl chloro-formate, other are operated with embodiment 11,
Quinazoline compounds (k) are synthesized, structure is as follows:
Quinazoline compounds (k) obtained have been carried out by people in loop strain HL-60 according to the above method
Biological activity test, test result show that compound (k) can not show a candle to the active anticancer of people in loop strain HL-60
Compound (I).Concrete outcome is as shown in table 11:
The inhibitory action that 11. compound (k) of table grows cancer cell line HL-60
Embodiment 20: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 line:Human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Cell bank.
Experimental procedure is as follows:
(a) preparation of sample:For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell:By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibitory action of growth of tumour cell
10th 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%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50.It surveys
The result of examination is as shown in table 12:
The inhibitory action that 12. compound of table (I) grows cancer cell line Siha
(2) according to embodiment 11, propionyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other operations
With embodiment 11, quinazoline compounds (b) and (c) are respectively synthesized, structure is as follows:
Quinazoline compounds (b) obtained and (c) have been carried out by human cervical carcinoma cell lines Siha lifes according to the above method
Object active testing, test result show quinazoline compounds (b) and (c) to human cervical carcinoma cell lines Siha inhibitions not
Substantially, compound (b) and (c) can not show a candle to the active anticancer of human cervical carcinoma cell lines Siha compound (I).Concrete outcome such as table
Shown in 13:
The inhibitory action that 13. compound (b) of table and (c) grow cancer cell line Siha
Above-mentioned active anticancer testing in vitro experiment shows:The similar compound (b) of other 2 structures and (c) are to people's uterine neck
The equal unobvious of inhibitory action 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 11, propionyl chloride is replaced with butyl chloride, other operations have synthesized quinazoline with embodiment 11
Class compound (f), structure are as follows:
Quinazoline compounds (f) obtained have been carried out by human cervical carcinoma cell lines Siha bioactivity according to the above method
Test, test result show that quinazoline compounds (f) can not show a candle to compound to the active anticancer of human cervical carcinoma cell lines Siha
(Ⅰ).Concrete outcome is as shown in table 14:
The inhibitory action that 14. compound (f) of table grows cancer cell line Siha
Claims (10)
1. a kind of propionamido anisyl benzo [d] azepine shown in formula (I)Base quinazoline compounds:
2. a kind of propionamido anisyl benzo [d] azepine shown in formula as described in claim 1 (I)Base quinazoline ditosylate salt
The preparation method of compound, it is characterised in that the method is:
(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's
Under effect, 25~120 DEG C are reacted, and after the reaction was complete, reaction solution is isolated and purified, and compound shown in formula (IV) is made;Institute
Organic solvent A is stated selected from one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine;The basic catalyst B is selected from one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- diformazans
Aminopyridine, 4- pyrollidinopyridines or sodium carbonate;
(2) formula (IV) compound represented obtained by step (1) is dissolved in organic solvent D, under reducing agent E effects, 25
~100 DEG C the reaction was complete, reacting liquid filtering, and formula (V) compound represented is made in the concentrate drying after filtrate decompression concentration;
The organic solvent D is one of following:Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine;The reducing agent E is one of following:Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate;It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion;
(3) compound shown in formula (V) obtained by step (2) is mixed with propionyl chloride or propionic andydride, under basic catalyst F effects,
In organic solvent G, -10~50 DEG C the reaction was complete, and reaction solution is post-treated, and formula (I) compound represented is made;It is described organic
Solvent G is one of following:Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene;The alkalescence
Catalyst F is one of following:Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate;
3. method as claimed in claim 2, it is characterised in that:Compound shown in formula (III) described in step (1) and formula (II)
The ratio between shown compound, amount for the substance that feeds intake of basic catalyst B be 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0, the organic solvent A
Dosage 10~50mL/g is calculated as with the quality of compound shown in formula (III).
4. method as claimed in claim 2, it is characterised in that:The method isolated and purified of reaction solution is in step (1):It will be anti-
It answers liquid that solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, concentrate is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight, dry, obtains the mixture of concentrate and silica gel, will be mixed
Object dress column is closed, then using volume ratio as 1:0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target
The efflux of component, is concentrated under reduced pressure, dry, obtains formula (IV) compound represented;The organic solvent C is one of following:Second
Alcohol, chloroform, tetrahydrofuran or ethyl acetate.
5. method as claimed in claim 2, it is characterised in that:In step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid
Or iron powder/acetic acid, formula (IV) compound represented are with iron powder, the mass ratio that feeds intake of concentrated hydrochloric acid or acetic acid in reducing agent E
1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0;When the reducing agent E be palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV)
The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0;Institute
It states the dosage of organic solvent D and 10~50mL/g is calculated as with the quality of formula (IV) compound represented.
6. method as claimed in claim 2, it is characterised in that:Step (3) carries out as follows:In -10~10 DEG C of items
Under part, into the organic solvent G solution of compound shown in formula (V) and basic catalyst F or toward compound shown in formula (V) and
The organic solvent G solution of propionyl chloride or propionic andydride is added dropwise in basic catalyst F, drop finishes, when -10~50 DEG C of reactions 3~12 are small, institute
Reaction solution is post-treated obtains compound shown in formula (I);Total dosage of the organic solvent G is with chemical combination shown in formula (V)
The quality of object is calculated as 11~100mL/g.
7. the method as described in claim 2 or 6, it is characterised in that:Compound and third shown in formula (V) described in step (3)
Acyl chlorides or propionic andydride, the ratio between the amount for the substance that feeds intake of basic catalyst F are 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0;The organic solvent G
Dosage 11~100mL/g is calculated as with the quality of compound shown in formula (V).
8. the method as described in claim 2 or 6, it is characterised in that:The post-processing approach of reaction solution is in step (3):It will be anti-
Liquid is answered to filter, filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, then adds into lysate
Enter the column chromatography silica gel of 1.0~2.0 times of weight of concentrate, after mixing, solvent is evaporated off, it is dry, obtain the mixed of concentrate and silica gel
Object is closed, mixture is filled into column, then using volume ratio as 1:0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture,
The efflux containing target components is collected, is concentrated under reduced pressure, it is dry, obtain formula (I) compound represented;Under the organic solvent H is
One of row:Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.
9. propionamido anisyl benzo [d] azepine shown in formula (I) as described in claim 1Base quinazoline ditosylate salt chemical combination
Application of the object in prevention or treatment human breast carcinoma drug is prepared.
10. application as claimed in claim 9, it is characterised in that the drug is with inhibition MCF-7 cell strainHJ2mm
The drug of activity.
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CN111973602A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of morpholinyl acetamido quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor |
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CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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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 |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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CN111973602A (en) * | 2019-05-21 | 2020-11-24 | 浙江工业大学 | Application of morpholinyl acetamido quinazoline compound as EGFR (epidermal growth factor receptor) inhibitor |
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