CN108078995B - Application of benzoylaminoquinazoline compound in preparation of drugs for treating lung cancer - Google Patents

Application of benzoylaminoquinazoline compound in preparation of drugs for treating lung cancer Download PDF

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CN108078995B
CN108078995B CN201810070306.2A CN201810070306A CN108078995B CN 108078995 B CN108078995 B CN 108078995B CN 201810070306 A CN201810070306 A CN 201810070306A CN 108078995 B CN108078995 B CN 108078995B
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ethyl acetate
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饶国武
林雯雯
陈泽麒
胡成海
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses application of a benzamidoquinazoline compound in preparing a medicament for preventing or treating tumors, in particular to application in preparing a medicament for preventing or treating human lung cancer, and the benzamidoquinazoline compound has a remarkable effect of inhibiting the activity of a human lung cancer cell strain A-549.

Description

Application of benzoylaminoquinazoline compound in preparation of drugs for treating lung cancer
(I) technical field
The invention relates to an application of a benzamidoquinazoline compound in preparing a medicament for preventing or treating human lung cancer.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -y. ke, h. -y. shiao, y. c. hsu, c. -y. chu, w. -c. wang, y. -c. lee, w. -h. lin, c. -h. chen, j. t. a. hsu, c. -w. chang, c. -w. lin, t. -k. yeh, y. -s. chao, m.s. coumar, h. -p. hsieh, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide application of a novel quinazoline compound, namely a benzamidoquinazoline compound, wherein the compound has a good inhibition effect on a human lung cancer cell strain A-549 under a certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an application of a benzamidoquinazoline compound shown in a formula (I) in preparing a medicament for preventing or treating tumors, in particular an application in preparing a medicament for preventing or treating human lung cancer:
Figure BDA0001557961630000021
furthermore, the medicament is preferably a medicament for inhibiting the activity of a human lung cancer cell strain A-549.
The invention also provides a preparation method of the benzamidoquinazoline compound shown in the formula (I), which comprises the following steps: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
Figure BDA0001557961630000022
(2) completely reacting a compound shown in a formula (IV) in an organic solvent D under the action of a reducing agent E at 25-100 ℃ (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), and preferably reacting for 0.5-12 h at 40-80 ℃), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain a compound shown in a formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing a compound shown as a formula (V) with benzoyl chloride or benzoic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether-1: 1(v/v), preferably reacting for 3-12 h at-10-50 ℃), and carrying out aftertreatment on a reaction solution to obtain a compound shown as a formula (I); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene;
further, in the step (1), the ratio of the amount of the compound represented by the formula (III) to the amount of the compound represented by the formula (II) and the amount of the substance charged as the basic catalyst B is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the step (1), the amount of the organic solvent A is 10-50 mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the step (1) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain a compound shown in a formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent C is used in an amount capable of dissolving the residue.
Further, in the step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the feeding mass ratio of the compound represented by the formula (IV) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0; in the invention, the mass concentration of the concentrated hydrochloric acid is 36-38%, and the acetic acid is glacial acetic acid.
Further, in the step (2), when the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, the feeding mass ratio of the compound shown in the formula (IV) to the palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1-0.5: 1.0-3.0; the mass loading amount of palladium in the palladium-carbon applicable to the invention is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%.
Further, in the step (2), the amount of the organic solvent D is 10-50 mL/g based on the mass of the compound represented by the formula (IV).
Further, in the step (3), the ratio of the compound represented by the formula (V) to the amounts of the benzoyl chloride or benzoic anhydride and the basic catalyst F to be charged is 1: 1.0 to 8.0: 1.0 to 3.0.
Further, in the step (3), the amount of the organic solvent G is 11 to 100mL/G based on the mass of the compound represented by the formula (V).
Further, the step (3) is carried out according to the following method: dropwise adding an organic solvent G solution of benzoyl chloride or benzoic anhydride into a compound shown in the formula (V) and an organic solvent G solution of a basic catalyst F or into the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction liquid to obtain a compound shown in the formula (I); the volume dosage of the organic solvent for dissolving benzoyl chloride or benzoic anhydride has no influence on the invention, and the total dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V). The total amount of the organic solvent G used is the total volume of the organic solvent G in which the basic catalyst F and the compound represented by the formula (V) are dissolved and the organic solvent G in which benzoyl chloride or benzoic anhydride is dissolved.
Further, the method for post-treating the reaction solution in the step (3) of the present invention comprises: after the reaction is completed, filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent H according to a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 1(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain the compound shown in the formula (I); the organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent H is used in an amount capable of dissolving the residue.
The organic solvents A, C, D, G and H are organic solvents, so that the organic solvents used for distinguishing different steps are named for convenience, and letters have no meanings; the catalyst B, the reducing agent E and the catalyst F are all catalysts, are named for the convenience of distinguishing the catalysts used in different steps, and have no meaning by letters per se.
The invention has the following beneficial effects: provides the application of a novel quinazoline compound in preparing a medicament for preventing or treating human lung cancer, and the compound has obvious inhibitory activity on a human lung cancer cell strain A-549.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way.
The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. Preparation of 4-chloro-6-nitroquinazoline (III) according to the method of Fernandes, C.et al bioorg.Med.chem.,2007,15(12), 3974-3980.
The palladium-carbon (Pd/C) model D5H5A used in the embodiment of the invention is purchased from Shaanxi Rui New Material Co., Ltd.
Example 1: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 12 ml of chloroform into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 10 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.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。
Example 2: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III), 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 60 ml of toluene into a 100ml three-neck flask, heating to 100 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethanol into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a dried productIs mixed with silica gel, the mixture is filled into a column, and then the mixture is mixed according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 72.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 3: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 60 ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 77.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 4: preparation of 6-nitroquinazoline (IV)
1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.20 g (6.32mmol) of compound (II), 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60 ml of isopropanol are sequentially added into a 100ml three-neck flask, stirred at room temperature of 25 ℃, subjected to TLC tracing detection (developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v)), reacted for 12 hours, the reaction solution is closed, the solvent is distilled off, 20 ml of tetrahydrofuran is added into the obtained concentrate to be dissolved, a dissolved solution is obtained, 4.0 g of column is added into the dissolved solutionCarrying out chromatography silica gel (300-400 mesh column chromatography silica gel), mixing uniformly, evaporating to remove the solvent to obtain a mixture of a dried concentrate and the silica gel, loading the mixture into a column, and then mixing the mixture with the volume ratio of 5: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 80.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 5: preparation of 6-nitroquinazoline (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 12 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 3(v/v)) and stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 89.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 6: preparation of 6-nitroquinazoline (IV)
1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 20 ml of propanol were sequentially added to a 50ml reaction flask, heated to 40 ℃, followed by TLC detection (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)), stirred for 10 hours, the reaction was stopped, the solvent was distilled off from the reaction solution, and the resulting concentrate was added toAdding 20 ml of ethyl acetate to dissolve the ethyl acetate to obtain a dissolved solution, adding 3.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture according to a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g (6.34mmol) of ammonium formate, 0.04 g of 5% Pd/C and 4.0 ml of chloroform prepared in the method of example 1 are sequentially added into a reaction bottle, stirred at the room temperature of 25 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacted for 12 hours, filtered, concentrated, and dried in vacuum at the temperature of 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 98.2% and the melting point of 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。
Example 8: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 1.20 g (19.18mmol) of 80 wt% hydrazine hydrate, 0.20 g of 5% Pd/C and 20.0 ml of toluene prepared by the method in example 2 are sequentially added into a 50ml reaction bottle, heated to 100 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 0.5 hour, cooled and filtered, the filtrate is concentrated, and vacuum-dried at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 100.0% and the melting point of 122-126 ℃.1H NMR and IR
Example 7.
Example 9: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol which are prepared by the method in example 3 are sequentially added into a 50ml reaction bottle, heated to 40 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred and reacted for 8 hours, cooled and filtered, and the filtrate is concentrated and dried in vacuum at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), the yield is 94.1% and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 10: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g of acetic acid, 1.20 g of iron powder and 20.0 ml of isopropanol prepared in the method of example 4 are sequentially added into a 50ml reaction bottle, heated to 80 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for reaction for 3 hours, cooled and filtered, and concentrated and dried in vacuum at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), wherein the yield is 97.5% and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 11: preparation of benzoylaminoquinazolines (I)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran prepared in the method of example 7 into a reaction bottle, dropwise adding 0.618 g (4.40mmol) of benzoyl chloride under the stirring condition of-10 ℃, completing dropwise detection, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours under the condition of-10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 10 ml of ethyl acetate into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.60 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture in a volume ratio of 1: eluting with 10 mixed solution of petroleum ether and ethyl acetate as eluent, and detecting by TLC (developing solvent is ethyl acetate/petroleum)Ether 1: 1(v/v)), collecting eluent containing the compound shown in the formula (I) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain the benzoylaminoquinazoline shown in the formula (I) as an off-white solid, wherein the yield is 55.4%, and the melting point is 152-153 ℃.1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)δ:3.28-3.34(m,1H),3.56(dt,J＝3.6,15.4Hz,1H),3.74(s,3H),3.81-3.84(m,7H),4.00-4.10(m,2H),4.68(dd,J＝8.3,14.4Hz,1H),5.31(t,J＝8.7Hz,1H),6.70(s,1H),6.88(d,J＝8.7Hz,2H),7.10(d,J＝8.7Hz,2H),7.54-7.63(m,4H),7.85(d,J＝8.9Hz,1H),7.95(d,J＝7.3Hz,2H),8.13(s,1H),8.60(s,1H),8.86(s,1H)。HRMS-ESI m/z:595.2107[M+H]+。IR(KBr,cm-1)ν:2996,2935,2825,1668,1599,1550,1523,1488,1463,1349,1249,1108,1037,837。
Example 12: preparation of benzoylaminoquinazolines (I)
0.27 g (0.55mmol) of 6-aminoquinazoline (v), 0.04 g (0.55mmol) of diethylamine and 10.0 ml of chloroform prepared in example 8 were sequentially added to a 50ml reaction flask, a mixed solution of 0.077 g (0.55mmol) of benzoyl chloride and 5.0 ml of chloroform was added dropwise under stirring at 10 ℃, after completion of the dropwise addition, TLC tracking detection (developing solvent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), and reaction was carried out at 10 ℃ for 8 hours, filtration was carried out, the solvent was distilled off from the filtrate, the concentrate was dissolved by adding 20 ml of ethanol to obtain a dissolved solution, 0.26 g of silica gel (300 to 400 mesh column chromatography silica gel) was added to the dissolved solution, after the uniform mixing, the solvent was distilled off to obtain a mixture of dried concentrate and silica gel, the mixture was packed into a column, and then the volume ratio of the mixture was 1: eluting by using a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (a developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain the benzoylaminoquinazoline shown in the formula (I) as an off-white solid, wherein the yield is 53.8%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of benzoylaminoquinazolines (I)
0.27 g (0.55mmol) of 6-Adding aminoquinazoline (V), 0.111 g (1.10mmol) triethylamine and 10.0 ml ethyl acetate into a 50ml reaction bottle, dropwise adding 0.155 g (1.10mmol) benzoyl chloride and 5.0 ml ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent), reacting for 6 hours at 25 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml chloroform into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.30 g column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using the volume ratio of 10: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain the benzoylaminoquinazoline shown in the formula (I) as an off-white solid, wherein the yield is 64.8%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of benzoylaminoquinazolines (I)
0.27 g (0.55mmol) of 6-aminoquinazoline (v), 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene prepared in example 10 are sequentially added to a 50ml reaction flask, a solution of 0.498 g (2.20mmol) of benzoic anhydride and 7.0 ml of toluene is added dropwise under stirring at 5 ℃, the mixture is heated to 50 ℃, TLC tracking detection is carried out (the developing agent is ethyl acetate/petroleum ether is 1: 1), the reaction is carried out for 3 hours, the filtrate is filtered, the solvent is distilled off, 20 ml of tetrahydrofuran is added to the concentrate to be dissolved to obtain a dissolved solution, 0.40 g of silica gel (300-400 mesh column chromatography silica gel) is added to the dissolved solution, the mixture is uniformly mixed, the solvent is distilled off to obtain a mixture of dried concentrate and silica gel, the mixture is packed into a column, and then the volume ratio of the mixture is 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (ethyl acetate/petroleum ether is 1: 1(v/v)) to collect eluate containing compound shown in formula (I) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain benzoylaminoquinazoline shown in formula (I) as off-white solid with yield of 45.2%The melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 15: preparation of benzoylaminoquinazolines (I)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared in the method of example 7 into a 50ml reaction bottle, dropwise adding a solution of 0.309 g (2.20mmol) of benzoyl chloride and 5.0 ml of benzene under stirring at-10 ℃, after dropwise adding, performing TLC tracing detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting at-10 ℃ for 12 hours, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 g of silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating to remove the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain the benzoylaminoquinazoline shown in the formula (I) as an off-white solid, wherein the yield is 63.7%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of benzoylaminoquinazolines (I)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.164 g (1.10mmol) of 4-pyrrolidinylpyridine and 15.0 ml of dichloromethane prepared by the method of example 7 into a 50ml reaction bottle, dropwise adding 0.155 g (1.10mmol) of benzoyl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 8 hours at 10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 10: 1, eluting with petroleum ether/ethyl acetate mixed solution as eluent, and detecting by TLC (thin-layer chromatography)The opener is ethyl acetate/petroleum ether ═ 1: 1(v/v)), collecting eluent containing the compound shown in the formula (I) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain the benzoylaminoquinazoline shown in the formula (I) as an off-white solid, wherein the yield is 66.1%, and the melting point is 152-153 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) The compound (i) prepared in the examples was tested for human lung cancer bioactivity.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② culturing cells: inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-pancreatin and diluted to 1X 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Under the same conditionsCells cultured in medium without sample and with the same concentration of DMSO were used as controls, and IC of the samples on tumor cell growth was calculated50。
The results of the test are shown in table 1:
TABLE 1 inhibitory Effect of Compound (I) on the growth of cancer cell line A-549
Figure BDA0001557961630000141
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting benzoyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following the same procedure as in example 11, respectively, and have the following structures:
Figure BDA0001557961630000151
the prepared quinazoline compounds (b) and (c) are subjected to a human lung cancer cell strain A-549 bioactivity test according to the method, and the results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human lung cancer cell strain A-549, and the anticancer activity of the quinazoline compounds (b) and (c) is far lower than that of benzoylaminoquinazoline (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line A-549
Figure BDA0001557961630000152
The anti-cancer activity in vitro test experiment shows that: the other 2 compounds (b) and (c) with similar structures have no obvious inhibition effect on the growth of a human lung cancer cell strain A-549. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549, and is obviously superior to the compounds (b) and (c).

Claims (2)

1. The application of the benzoylaminoquinazoline compound shown as the formula (I) in preparing the medicaments for preventing or treating the lung cancer of the human body;
Figure FDA0001557961620000011
2. the use according to claim 1, wherein the medicament is a medicament having activity of inhibiting human lung cancer cell line a-549.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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ES2074867T3 (en) * 1990-11-06 1995-09-16 Pfizer QUINAZOLINE DERIVATIVES TO PROMOTE ANTITUMORAL ACTIVITY.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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