CN108125958B - Application of o-toluidine amino acetamido chloro benzazepine radical quinazoline compound in preparing medicament for treating leukemia - Google Patents

Application of o-toluidine amino acetamido chloro benzazepine radical quinazoline compound in preparing medicament for treating leukemia Download PDF

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CN108125958B
CN108125958B CN201810069792.6A CN201810069792A CN108125958B CN 108125958 B CN108125958 B CN 108125958B CN 201810069792 A CN201810069792 A CN 201810069792A CN 108125958 B CN108125958 B CN 108125958B
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petroleum ether
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饶国武
郑泉
胡成海
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses o-toluidine aminoacetamido chlorobenzazepine

Description

Application of o-toluidine amino acetamido chloro benzazepine radical quinazoline compound in preparing medicament for treating leukemia
(I) technical field
The invention relates to a quinazoline compound, in particular to o-toluidine aminoacetamido chloro-benzo-aza-benzene
Figure BDA0001557821590000012
Application of the fluoroquinazoline compound in preparing medicaments for preventing or treating human leukemia.
(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.vatte, l. gosense, p.depenux, j.chem.1204, d.m.1189, d.1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound, namely o-toluidine amino acetamido chloro-benzo-aza-benzathine
Figure BDA0001557821590000013
The application of the quinazoline compound has good inhibition effect on human promyelocytic leukemia cell line HL-60 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 o-toluidine amino acetamido chloro benzazepine shown as a formula (I)
Figure BDA0001557821590000023
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating tumors, in particular the application in preparing the medicaments for preventing or treating human leukemia:
Figure BDA0001557821590000021
preferably, the medicament is a medicament for inhibiting the activity of the human promyelocytic leukemia cell line HL-60.
Furthermore, the present invention provides an o-toluidinoacetamidochlorobenzazepine of formula (I)
Figure BDA0001557821590000024
The preparation method of the fluoroquinazoline compound 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-di-N-methyl-ethyl-pyridine)Toluidine or 4-dimethylaminopyridine);
Figure BDA0001557821590000022
Figure BDA0001557821590000031
(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 chloroacetyl chloride or chloroacetic anhydride, completely reacting at-10-50 ℃ in an organic solvent G under the action of an alkaline catalyst F (tracking and monitoring by TLC, wherein a developing agent is ethyl acetate/petroleum ether (1: 1(v/v), preferably reacting at-10-50 ℃ for 3-12 h), and carrying out aftertreatment A on a reaction solution to obtain a compound shown as a formula (VI); 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;
(4) mixing a compound shown as a formula (VI) with o-toluidine, reacting at 25-120 ℃ in an organic solvent J under the action of a basic catalyst K (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v), preferably 40-100 ℃ for 0.5-36 h), and after the reaction is completed, carrying out aftertreatment B on a reaction liquid to obtain a compound shown as a formula (I); the organic solvent J is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst K is selected from one of the following: pyridine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
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 charging 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 to 3.0: 0.2 to 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 represented by the formula (iv) to palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1 to 0.5: 1.0 to 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).
In the step (3), the ratio of the compound of the formula (v) to the amount of chloroacetyl chloride or chloroacetic anhydride and the basic catalyst F to be fed 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 specific recommended step (3) of the present invention is performed as follows: dropwise adding chloroacetyl chloride or chloroacetic anhydride organic solvent G solution into the compound shown in the formula (V) and the organic solvent G solution of the basic catalyst F at-10 ℃ or the compound shown in the formula (V) and the basic catalyst F, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction solution A to obtain the compound shown in the formula (VI); the volume consumption of the organic solvent for dissolving the chloroacetyl chloride or the chloroacetic anhydride does not influence the invention, and the total consumption 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 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 chloroacetyl chloride or chloroacetic anhydride is dissolved.
Further, the method for post-treating the reaction solution A 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 a compound shown in a formula (VI); 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.
Further, in the step (4), the ratio of the amount of the compound represented by the formula (vi) to the amounts of the o-toluidine and the basic catalyst K to be charged is 1.0: 0.8 to 8.0: 1.0 to 8.0.
Further, in the step (4), the amount of the organic solvent J is 10-60 mL/g based on the mass of the compound represented by the formula (VI).
Further, the method for post-treating the reaction solution B in the step (4) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent M 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 M 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: 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 M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent M is used in an amount capable of dissolving the residue.
The organic solvents A, C, D, G, H, J and M 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, the catalyst F and the catalyst K are all catalysts, so that the catalysts used in different steps are named for convenience of distinguishing, and letters have no meanings; the post-treatment A and the post-treatment B are both post-treatments, so that the post-treatments used for distinguishing different steps are named for convenience, and the letters have no meanings.
The invention has the following beneficial effects: provides a novel quinazoline compound-o-toluidinoacetamido chloro benzazepine
Figure BDA0001557821590000061
The application of the quinazoline compound in preparing the medicament for preventing or treating the human leukemia has obvious inhibitory activity on a human promyelocytic leukemia cell line HL-60.
(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 10 mixed solution of petroleum ether and ethyl acetate as eluent, detecting by TLC (developing solvent of ethyl acetate/petroleum ether: 1: 3(v/v)),collecting eluent containing the compound shown in the formula (IV) according to TLC detection (the Rf value is 0.5), 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) :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) and 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 60ml 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 mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a 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)
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 60ml of ethanol are added in turn to a 100ml three-neck flask, heated to 60 ℃ and detected by TLC (developing solvent is ethyl acetate)Petroleum ether is 1: 3(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the chloroform 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 the dried concentrate and the silica gel, filling the mixture into a column, and then performing reaction in 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)
Adding 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 60ml of isopropanol into a 100ml three-neck flask, stirring at room temperature and 25 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v)), reacting for 12 hours, closing 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 4.0 g of column chromatography silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating 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 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)
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, 12 ml of N,adding N-dimethylformamide into a 50-milliliter reaction bottle, heating to 120 ℃, performing TLC (thin layer chromatography) tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for reacting for 0.5 hour, closing the reaction, evaporating a reaction solution to remove a solvent, adding 20 milliliters of tetrahydrofuran into the obtained concentrate to dissolve the tetrahydrofuran to obtain a dissolved solution, adding 5.0 grams of column chromatography silica gel (300-400 meshes of 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 TLC (thin layer chromatography) detection on the mixture in 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 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)
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 20 ml of propanol 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 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate 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 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 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 of (A), (B), (C) prepared by the process of example 10.77mmol) 6-nitroquinazoline (iv), 0.40 g (6.34mmol) ammonium formate, 0.04 g 5% Pd/C, 4.0 ml chloroform were added to the reaction flask, stirred at 25 ℃ at room temperature, monitored by TLC (developing solvent ethyl acetate/petroleum ether ═ 1: 1(v/v)), reacting for 12 hours, filtering, concentrating the filtrate, and drying in vacuum at 25 ℃ to obtain a light yellow solid product 6-aminoquinazoline (V), wherein the yield is 98.2%, and the melting point is 122-126 ℃.1H NMR(500MHz,CDCl3):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 chloroacetamidoquinazoline (VI)
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 0.497 g (4.40mmol) of chloroacetyl chloride under the condition of stirring at-10 ℃, after completing dropwise addition, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at-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 by using a volume ratio of 1: eluting with 10 mixed petroleum ether/ethyl acetate solution as eluent, tracking and detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluent (Rf value is 0.5) containing the compound shown in formula (VI) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain yellow chloroacetylamidoquinazoline solid shown in formula (VI), wherein the yield is 95.6%, and the melting point is 255-258 ℃.1H NMR(500MHz,CDCl3):3.26-3.33(m,1H),3.54(dt,J＝3.7,15.4Hz,1H), 3.74(s,3H),3.81-3.82(m,7H),3.95-4.05(m,2H),4.28(s,2H),4.64(dd,J＝8.2,14.4Hz, 1H),5.24(t,J＝8.8Hz,1H).6.64(s,1H),6.88(d,J＝8.8Hz,2H),7.07(d,J＝8.7Hz,2H), 7.53(dd,J＝2.3,9.0Hz,1H),7.83(d,J＝9.0Hz,1H),8.54(s,1H),8.60(s,1H),8.69(d, J＝2.2Hz,1H)。IR(KBr,cm-1)ν:3396,2998,2937,2835,1694,1557,1525,1510, 1489,1463,1349,1249,1179,1036,840。
Example 12: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.04 g (0.55mmol) of diethylamine and 10.0 ml of chloroform prepared in the method of example 8 into a 50ml reaction bottle, dropwise adding a mixed solution of 0.07 g (0.55mmol) of chloroacetyl chloride and 5.0 ml of chloroform under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), reacting for 8 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.26 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: and (3) eluting by using a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent (the Rf value is 0.5) containing the compound shown in the formula (VI) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 83.4%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate prepared in the method of example 9 into a 50ml reaction bottle, dropwise adding 0.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 6 hours at 25 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of chloroform into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.30 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 dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking and detecting by TLC (developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluate (Rf value is 0.5) containing compound shown in formula (VI) according to TLC detection, concentrating the collected solution, and drying at 50 deg.CDrying to obtain the chloracetyl amido quinazoline yellow solid shown in the formula (VI), wherein the yield is 70.5%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of chloroacetamidoquinazoline (VI)
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 0.376 g (2.20mmol) of chloroacetic 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 mixture reacts for 3 hours, the filtrate is filtered, the solvent is distilled off, the concentrate is dissolved by adding 20 ml of tetrahydrofuran 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 filled into a column, and then the volume ratio of the mixture is 5: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 85.3%, and the melting point is 255-258 ℃.1HNMR and IR were the same as in example 11.
Example 15: preparation of chloroacetamidoquinazoline (VI)
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 0.28 g (2.19mmol) of chloroacetyl chloride and 5.0 ml of benzene under the condition of stirring at-10 ℃, after dropwise adding, performing TLC tracking 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 dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: 1 ofEluting by using a petroleum ether/ethyl acetate mixed solution as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloracetyl amido quinazoline yellow solid shown in the formula (VI), wherein the yield is 82.1%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of chloroacetamidoquinazoline (VI)
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 in the method of example 7 into a 50ml reaction bottle, dropwise adding 00.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent, 1: 1), reacting for 8 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of silica gel (300-400 mesh silica gel) into the dissolved solution for column chromatography, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a 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 agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 90.2%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 17: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000141
Preparation of a quiazoline (I)
3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 11, 0.736 g (6.87mmol) of o-toluidine, 3.626 g (45.84mmol) of pyridine and 32.5 ml of methanol were added in succession to a 50ml reaction flask, heated to 40 ℃ and checked by TLC follow-up (developing solvent)Ethyl acetate/petroleum ether ═ 1: 1(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 10 ml of ethyl acetate into the obtained concentrate to dissolve the ethyl acetate to obtain a dissolved solution, adding 1.5 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 the dried concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture in 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: 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 the collected liquid, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 53.4%, and the melting point is 179-181 ℃.1H NMR(500MHz,CDCl3):2.32(s,3H),3.26-3.32(m,1H),3.55(dt,J＝3.5,15.3Hz, 1H),3.76(s,3H),3.81-3.82(m,7H),4.00-4.06(m,4H),4.33(t,J＝5.3Hz,1H),4.65(dd, J＝8.2,14.3Hz,1H),5.29(t,J＝8.8Hz,1H),6.62(d,J＝8.2Hz,1H),6.68(s,1H),6.84(t, J＝7.3Hz,1H),6.88(d,J＝8.7Hz,2H),7.09(d,J＝8.7Hz,2H),7.15-7.18(m,2H), 7.37(dd,J＝2.2,9.0Hz,1H),7.75(d,J＝8.9Hz,1H),8.57(s,1H),8.79(s,2H)。 HRMS-ESI m/z:638.2527[M+H]+。13C NMR(125MHz,CDCl3):17.6,28.8,49.7, 50.0,51.1,54.4,55.3,56.0,60.5,110.9,113.9,114.2,114.4,116.1,120.0,123.0, 125.3,127.6,128.0,128.1,128.7,128.8,130.7,133.6,135.0,137.5,144.0,145.0, 149.0,152.2,153.3,158.4,163.7,169.1。IR(KBr,cm-1)ν:2934,2831,1695,1562,1512,1487,1453,1349,1248,1036,837。
Example 18: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000151
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 12, 0.490 g (4.57mmol) of o-toluidine, 2.95 g (22.84mmol) of quinoline and 80 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: 1(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 mixture of dried concentrate and silica gel, loading the mixture into a column, and then mixing in a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 52.8%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 19: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000161
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 13, 0.614 g (5.73mmol) of o-toluidine, 0.58 g (5.73mmol) of triethylamine and 80 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: 1(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, loading the mixture into a column, and then performing column chromatography on the mixture according to 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: 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 a yellow solid product shown in the formula (I), wherein the yield is 47.6%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 20: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000162
Preparation of a quiazoline (I)
3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared by the method of example 14, 2.456 g (22.92mmol) of o-toluidine, 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60ml of isopropanol are sequentially added into a 100ml three-neck flask, stirred at room temperature of 25 ℃, subjected to TLC tracing detection (ethyl acetate/petroleum ether ═ 1: 1(v/v)) and reacted for 36 hours, the reaction is stopped, the solvent is distilled off from the reaction solution, 20 ml of tetrahydrofuran is added into the obtained concentrate to be dissolved to obtain a dissolved solution, 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) is added into the dissolved solution, after uniform mixing, 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: the petroleum ether/ethyl acetate mixed solution of 1 is used as an eluent to elute, follow-up detection by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), eluent containing the compound shown in the formula (I) is collected according to TLC detection (the Rf value is 0.5), collected liquid is concentrated, and drying is carried out at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 62.2%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 21: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000171
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 15, 0.552 g (5.15mmol) of o-toluidine, 1.04 g (8.58mmol) of N, N-xylidine and 33 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 1(v/v)) and stirring for reaction for 0.5 hour, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, 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 at 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: 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 a yellow solid product shown in the formula (I), wherein the yield is 58.1%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 22: o-toluidinoacetamidochlorobenzazepine
Figure BDA0001557821590000172
Preparation of a quiazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 16, 4.912 g (45.84mmol) of o-toluidine, 3.626 g (45.84mmol) of pyridine and 195 ml of propanol into a 500 ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 6.0 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 dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using 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: 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 a yellow solid product shown in the formula (I), wherein the yield is 65.3%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 23: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to biological activity test of a human promyelocytic leukemia cell strain HL-60.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human promyelocytic leukemia cell line HL-60. 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 with 40. mu.L of LDMSO, 2. mu.L was diluted with 1000. mu.L of the 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 cultivation of 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 2 nd generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 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.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 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. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample 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 HL-60
Figure BDA0001557821590000191
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
Figure BDA0001557821590000192
the prepared quinazoline compounds (b) and (c) are subjected to a biological activity test of a human promyelocytic leukemia cell line HL-60 according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human promyelocytic leukemia cell line HL-60, and the anticancer activities of the compounds (b) and (c) on the human promyelocytic leukemia cell line HL-60 are far lower than that of the compound (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 HL-60
Figure BDA0001557821590000193
Figure BDA0001557821590000201
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 the human promyelocytic leukemia cell line HL-60. The compound (I) has obvious inhibition effect on the growth of human promyelocytic leukemia cell strain HL-60, and is obviously superior to the compounds (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized in the same manner as in example 17 except that o-toluidine was replaced with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, according to example 17, and the structures thereof were as follows:
Figure BDA0001557821590000202
the biological activity of the quinazoline compounds (d), (e) and (f) prepared by the method in a human promyelocytic leukemia cell line HL-60 test proves that the anticancer activity of the quinazoline compounds (d), (e) and (f) in the human promyelocytic leukemia cell line HL-60 is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line HL-60
Figure BDA0001557821590000203
Figure BDA0001557821590000211

Claims (2)

1. O-toluylamino-acetylamino-chlorobenzazepines of formula (I)
Figure FDA0001557821580000012
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating the human leukemia;
Figure FDA0001557821580000011
2. the use according to claim 1, wherein the medicament is a medicament having activity against the human promyelocytic leukemia cell line HL-60.
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