CN108125960A - Isobutyryl amino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament - Google Patents
Isobutyryl amino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament Download PDFInfo
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Abstract
The invention discloses a kind of isobutyryl amino benzo [d] azepinesApplication of the base quinazoline compounds in prevention or treatment human lung cancer drug is prepared, a kind of quinazoline compounds novel, that there is good anticancer (especially human lung cancer) activity are provided, are expected in the drug for being applied to prepare prevention or treatment human lung cancer；Isobutyryl amino benzo [d] azepine provided by the invention
Description
(1) technical field
The present invention relates to a kind of isobutyryl amino benzo [d] azepinesBase quinazoline compounds are preparing prevention or treatment
Application in the drug of tumor disease.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for novel quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148；A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) invention content
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound-isobutyryl amino benzo [d] azepinesBase
Application of the quinazoline compounds in prevention or treatment human lung cancer drug is prepared, such compound is under doses to people's lung
Cancer cell line A-549 has 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：
The present invention provides isobutyryl amino benzo [d] azepine shown in a kind of formula (I)It is prepared by base quinazoline compounds
Application in prevention or treatment human lung cancer drug,
Further, preferably described drug is with the drug for inhibiting human lung cancer cell lines A-549 activity.
Isobutyryl amino benzo [d] azepine shown in formula (I)The preparation method of base quinazoline compounds is：
(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in the effect of basic catalyst B
Under, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：3 (v/v), preferably 40~
100 DEG C of 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified, compound shown in formula (IV) is made；It is described organic
Solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；It is described
Basic catalyst B be selected from it is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- dimethylamino pyrroles
Pyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N- dimethylanilines or 4- dimethylamino pyrroles
Pyridine)；Compound shown in the formula (III) is with the ratio between compound shown in formula (II), the amount for the substance that feeds intake of basic catalyst B
1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0, the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g；
(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 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 organic
Solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；When described
Reducing agent E when being iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) compound represented and the iron powder, dense in reducing agent E
The mass ratio that feeds intake of hydrochloric acid or acetic acid is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0；When the reducing agent E for palladium carbon/ammonium formate or
During palladium carbon/hydrazine hydrate, the mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in formula (IV) compound represented and reducing agent E
For 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0；The dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented~
50mL/g；In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid；In the applicable palladium carbon of the present invention
The mass loading amount of palladium is 2~10%, preferably 5%, and hydrazine hydrate mass concentration is 40~80%, preferably 80%；
(3) compound shown in formula (V) is mixed with isobutyryl chloride or isobutyric 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), reaction solution isolates and purifies, and formula (I) compound represented is made；The base catalysis
Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidinyls
Pyridine or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, second
Nitrile, toluene or benzene；Compound shown in the formula (V) and isobutyryl chloride or isobutyric anhydride, the substance that feeds intake of basic catalyst F
The ratio between amount be calculated as the dosage of 1 ﹕ 1.0~8.0 ﹕ 1.0~3.0, the organic solvent G with the quality of compound shown in formula (V)
11~100mL/g.
Further, the method that reaction solution isolates and purifies described in step (1) is：After the reaction was complete, reaction solution is evaporated off molten
Agent takes concentrate to be dissolved with organic solvent C, 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=1：3(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 (IV) compound represented；The organic solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or acetic acid
Ethyl ester；The organic solvent C dosages are with being capable of dissolution residual substance.
Specific recommendation step (3) of the invention carries out as follows：By compound, basic catalyst F shown in formula (V)
Adding in organic solvent G (can not also add in organic solvent G), and under the conditions of -10~10 DEG C, the organic molten of isobutyryl chloride is added dropwise
The organic solvent G solution of agent G solution or isobutyric anhydride, drop finish, and -10~50 DEG C are reacted 3~12 hours, and filtering, filtrate is evaporated off molten
Agent, concentrate column chromatography obtain compound shown in formula (I)；Dissolve the organic solvent volume dosage pair of isobutyryl chloride or isobutyric 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), has
The total dosages of solvent G refer to the organic solvent of compound shown in catalyst-solvent and formula (V) and dissolving isobutyryl chloride or isobutyric acid
The total volume of acid anhydride organic solvent.
Further, the method that step (3) the of the present invention reaction solution isolates and purifies is：After the reaction was complete, by reaction solution mistake
Filter, filtrate steaming removal solvent take concentrate to be dissolved with organic solvent H, obtain lysate, and concentration is then added in into lysate
The column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of 1.0~2.0 times of weight of object, after mixing,
Solvent is evaporated off, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：0.1~10
Petroleum ether is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether
=1：1 (v/v) is solvent tracing detection, collects target components, preferably collects the component that Rf values are 0.5), it is concentrated under reduced pressure, does
Dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented；The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrochysene
Furans or ethyl acetate；The organic solvent H dosages are with being capable of 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.
Isobutyryl amino benzo [d] azepine of the present inventionBase quinazoline (I) has human lung cancer cell lines A-549
Significant inhibiting rate can be applied to the drug for preparing prevention or treatment human lung cancer.
The beneficial effects are mainly as follows：(1) novel quinazoline compounds are provided, are had to human lung cancer
Significant inhibiting effect is expected in the drug for being applied to prepare prevention or treatment human lung cancer；(2) isobutyrimide provided by the invention
Base benzo [d] azepineThe preparation method of base quinazoline compounds (I), simple easily operated, raw material is easy to get, and production cost
It is relatively low, suitable for practicality.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1：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)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), 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)), it is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object：5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), 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)), it is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), 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)), it reacts 12 hours, closes reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), 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)), it is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel：1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values 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)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), 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)), it reacts 12 hours, 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)), it is stirred to react 8 hours, cools down
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)), it is stirred to react 3 hours, 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：Isobutyryl amino 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 0.469 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) isobutyryl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), under the conditions of -10 DEG C
Reaction 12 hours, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate and are dissolved, and obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column, then using volume ratio as 1 by the mixture of object and silica gel：10 petrol ether/ethyl acetate mixed solution is washes
De- agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing formula
(I) eluent (Rf values be 0.5) of compound represented, the eluent concentration of collection, 50 DEG C be dried to obtain it is different shown in formula (I)
Butyrylamino benzo [d] azepineBase quinazoline white solid, yield 57.6%, 159~162 DEG C of fusing point.1H NMR
(500MHz,CDCl3)δ:1.29 (d, J=6.9Hz, 3H), 1.32 (d, J=6.9Hz, 3H), 2.57-2.62 (m, 1H), 3.25-
3.32 (m, 1H), 3.52 (dt, J=15.2,3.7Hz, 1H), 3.75 (s, 3H), 3.76-3.82 (m, 7H), 3.94-4.05 (m,
2H), 4.63 (dd, J=8.2,14.3Hz, 1H), 5.29 (t, J=8.7Hz, 1H), 6.69 (s, 1H), 6.88 (d, J=8.7Hz,
2H), 7.09 (d, J=8.6Hz, 2H), 7.45 (dd, J=2.2,8.9Hz, 1H), 7.60 (s, 1H), 7.76 (d, J=8.9Hz,
1H), 8.57 (s, 1H), 8.75 (d, J=1.7Hz, 1H).IR(KBr,cm-1)ν:2966,2926,2867,1688,1554,
1507,1463,1348,1248,1037,838。
Embodiment 12：Isobutyryl amino 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
0.059 gram of (0.55mmol) isobutyryl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid to TLC tracing detections
Ethyl ester/petroleum ether=1：1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Ethyl 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,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：5
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, the eluent of collection is dense
Contracting, 50 DEG C of isobutyryl amino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline white solid, yield 79.4%,
159~162 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 13：Isobutyryl amino 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
0.117 gram of (1.10mmol) isobutyryl chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is TLC tracing detections
Ethyl acetate/petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Chloroform is dissolved, and obtains lysate, and 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 10：1
Petrol ether/ethyl acetate mixed solution for eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/petroleum ether=
1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented, the eluent of collection are collected according to TLC detections
Concentration, 50 DEG C of isobutyryl amino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline white solid, yield
82.1%, 159~162 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 14：Isobutyryl amino 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 0.348 gram of (2.20mmol) isobutyric anhydride and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate adds in
20 milliliters of tetrahydrofurans are dissolved, and obtain lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column is added in into lysate
Chromatographic silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with body
Product is than being 5：1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Eluent concentration, 50 DEG C of isobutyryl amino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline white solid,
Yield 75.4%, 159~162 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 15：Isobutyryl amino 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), 0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are dripped under -10 DEG C of stirring conditions
Add the solution of 0.234 gram of (2.20mmol) isobutyryl chloride and 5.0 milliliters of benzene, drop finishes, and (solvent is acetic acid second to TLC tracing detections
Ester/petroleum ether=1：1) it, reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrochysenes
Furans is dissolved, and obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：1
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, the eluent of collection is dense
Contracting, 50 DEG C of isobutyryl amino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline white solid, yield 61.8%,
159~162 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 16：Isobutyryl amino 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),
0.164 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
0.117 gram of (1.10mmol) isobutyryl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, TLC tracing detections
(solvent is ethyl acetate/petroleum ether=1：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds
Enter 20 milliliters of ethyl alcohol to be dissolved, obtain lysate, 0.50 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 being 10：1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Eluent concentration, 50 DEG C of isobutyryl amino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline white solid,
Yield 52.3%, 159~162 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) and (IV) are subjected to human lung cancer biological activity test.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human lung cancer cell lines A-549, purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in DMEM culture mediums (Gibco) per 1000mL
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
10th generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6/ mL is added to 96 holes
In tissue culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, addition culture medium is diluted
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2It is trained in incubator
It supports, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, DMSO is added in, per 150 μ of hole
L is vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of sample under similarity condition,
The cell of medium culture containing similary concentration DMSO calculates IC of the sample to growth of tumour cell as control50。
The results are shown in Table 1 for test：
The inhibiting effect that 1. compound of table (I) and (IV) grow cancer cell line A-549
(2) according to embodiment 11, isobutyryl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl respectively
Chloro replaces, other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11：
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out human lung cancer cell lines A-549
Biological activity test, test result show quinazoline compounds (a), and (b) and (c) inhibits to imitate to human lung cancer cell lines A-549
The equal unobvious of fruit, compound (a), (b) and (c) can not show a candle to the active anticancer of human lung cancer cell lines A-549 compound (I).Tool
The results are shown in Table 2 for body：
The inhibiting effect that 2. compound (a) of table, (b) and (c) grow cancer cell line A-549
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibiting effect of lung cancer cell line A-549 growths.The inhibition that compound (I) grows human lung cancer cell lines A-549
Effect is notable, hence it is evident that better than compound (a), (b) and (c).
(3) 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 3：
The inhibiting effect that 3. compound (d) of table grows cancer cell line A-549
(4) according to embodiment 11, isobutyryl chloride is replaced respectively with chlorobenzoyl chloride or chloracetyl chloride, other operations are the same as implementation
Example 11, has been respectively synthesized quinazoline compounds (e) and (h), and structure is as follows：
Quinazoline compounds (e) obtained and (h) have been carried out by human lung cancer cell lines A-549 biology according to the above method
Active testing, test result show that quinazoline compounds (e) and (h) are not so good as the active anticancer of human lung cancer cell lines A-549
Compound (I).Concrete outcome is as shown in table 4：
The inhibiting effect that 4. compound (e) of table and (h) grow cancer cell line A-549
Claims (2)
1. a kind of isobutyryl amino benzo [d] azepine shown in formula (I)Base quinazoline compounds are preparing prevention or treatment
Application in human lung cancer drug,
2. application as described in claim 1, it is characterised in that the drug is with inhibition human lung cancer cell lines A-549 activity
Drug.
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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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| 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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