CN108324718B - Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug - Google Patents

Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug Download PDF

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CN108324718B
CN108324718B CN201810069181.1A CN201810069181A CN108324718B CN 108324718 B CN108324718 B CN 108324718B CN 201810069181 A CN201810069181 A CN 201810069181A CN 108324718 B CN108324718 B CN 108324718B
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ethyl acetate
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饶国武
徐暄博
孔月月
胡成海
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Zhejiang University of Technology ZJUT
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract

The invention discloses cyclohexyl methoxy formyl amino chloro benzo aza

Description

Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug
(I) technical field
The invention relates to a cyclohexyl methoxy formyl amino chloro benzo aza
Figure BDA0001557620260000013
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-cyclohexyl methoxy group with anticancer activityCarboxamido chlorobenzazepines
Figure BDA0001557620260000012
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 cyclohexyl methoxy formyl amino chloro benzazepine shown as a formula (I)
Figure BDA0001557620260000024
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 BDA0001557620260000021
preferably, the medicament is a medicament for inhibiting the activity of the human promyelocytic leukemia cell line HL-60.
Furthermore, the present invention provides a cyclohexylmethoxyformylaminochlorobenzazepine of the formula (I)
Figure BDA0001557620260000022
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, pyridine,Diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
Figure BDA0001557620260000023
(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 cyclohexyl methyl chloroformate, completely reacting in an organic solvent G at-10-50 ℃ under the action of an alkaline catalyst F (tracking and monitoring by TLC, 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 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 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).
Further, in the step (3), the ratio of the compound represented by the formula (V) to the charged materials of cyclohexylmethylchloroformate and the basic catalyst F 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 an organic solvent G solution of cyclohexyl methyl chloroformate into a compound shown in a formula (V) and an organic solvent G solution of a basic catalyst F or 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 a formula (I); the volume dosage of the organic solvent for dissolving the cyclohexyl methyl chloroformate 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 the cyclohexylmethylchloroformate 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 leukemia, and the compound 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 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):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 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 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)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III), 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 in sequence, 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 meshes of column layer) into the dissolved solution to obtain a solutionSilica gel separation), 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 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 60 ml 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 and 12 ml of N, N-dimethylformamide were added in this order to a 50ml reaction flask, the flask was heated to 120 ℃ and subjected to TLC tracing (ethyl acetate/petroleum ether: 1: 3(v/v)) with stirring for 0.5 hour, the reaction was stopped, the solvent was distilled off from the reaction solution, and the resulting concentrate was added with the solventDissolving 20 ml of tetrahydrofuran to obtain a dissolved solution, adding 5.0 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 with the silica gel 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 (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 were sequentially added to a reaction flask, stirred at room temperature of 25 ℃ and subjected to TLC (developing solvent ethyl acetate/petroleum ether-1: 1(v/v)) to react for 12 hoursFiltering, 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 were the same as in 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 ℃.1HNMR 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) prepared in example 4, 0.40 g of acetic acid, 1.20 g of iron powder and 20.0 ml of isopropanol were sequentially added to a 50ml reaction flask, heated to 80 ℃ and monitored by TLC (developing solvent ethyl acetate/petroleum ether-1: 1(v/v))) Stirring for reaction for 3 hours, cooling and filtering, concentrating the filtrate, and vacuum drying at 25 ℃ to obtain a light yellow solid product 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: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000101
Preparation of a quiazoline (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 0.777 g (4.40mmol) of cyclohexyl methyl chloroformate under the condition of stirring at-10 ℃, after finishing dropping, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at-10 ℃, filtering, evaporating the solvent from the filtrate, 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 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 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 a collected solution, and drying at 50 ℃ to obtain an off-white solid shown in the formula (I), wherein the yield is 62.4%, and the melting point is 156-157 ℃.1H NMR(500MHz,CDCl3):0.99-1.07(m,2H),1.18-1.32(m,4H),1.69-1.73(m,1H), 1.76-1.81(m,4H),3.24-3.31(m,1H),3.53(dt,J＝3.6,15.0Hz,1H),3.75-3.79(m,4H), 3.81(s,3H),3.82(s,3H),3.92-4.04(m,4H),4.63(dd,J＝8.1,14.4Hz,1H),5.26(t, J＝8.5Hz,1H),6.67(s,1H),6.87-6.89(m,3H),7.08(d,J＝8.7Hz,2H),7.39(dd,J＝2.2, 9.4Hz,1H),7.77(d,J＝8.9Hz,1H),8.42(broad,s,1H),8.57(s,1H)。HRMS-ESI m/z: 631.2681[M+H]+。IR(KBr,cm-1)ν:2927,2850,1723,1609,1557,1509,1461,1348, 1217,1040,839。
Example 12: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000111
Preparation of a quiazoline (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 0.097 g (0.55mmol) of cyclohexylmethylchloroformate and 5.0 ml of chloroform was added dropwise under stirring at 10 ℃, followed by TLC (ethyl acetate/petroleum ether as a developing solvent: 1(v/v)), and reacted at 10 ℃ for 8 hours, followed by filtration, 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 (300-400 mesh column chromatography silica gel) was added to the dissolved solution, and after 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 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: 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 an off-white solid shown in the formula (I), wherein the yield is 61.5%, and the melting point is 156-157 ℃.1H NMR and IR were the same as in example 11.
Example 13: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000112
Preparation of a quiazoline (I)
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 0.194 g (1.10mmol) of cyclohexyl methyl chloroformate and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 6 hours at 25 ℃, filtering, evaporating the solvent from the filtrate, 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 column chromatography silica gel) into the dissolved solution, uniformly mixing, and evaporating the solvent to obtain a dried concentrated solutionMixture of the substance and silica gel, loading the mixture into a column, and then mixing the mixture 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: 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 an off-white solid shown in the formula (I), wherein the yield is 77.2%, and the melting point is 156-157 ℃.1H NMR and IR were the same as in example 11.
Example 14: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000121
Preparation of a quiazoline (I)
Adding 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 the method of example 10 into a 50ml reaction bottle, dropwise adding a solution of 0.389 g (2.20mmol) of cyclohexylmethyl chloroformate and 7.0 ml of toluene under the condition of stirring at 5 ℃, heating to 50 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 3 hours, filtering, evaporating the solvent from the filtrate, 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 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 filling the mixture into the column at 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: 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 an off-white solid shown in the formula (I), wherein the yield is 59.0%, and the melting point is 156-157 ℃.1H NMR and IR were the same as in example 11.
Example 15: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000122
Preparation of a quiazoline (I)
Example in turnAdding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared by the method 7 into a 50ml reaction bottle, dropwise adding a solution of 0.389 g (2.20mmol) of cyclohexylmethylchloroformate and 5.0 ml of benzene under stirring at-10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 1), reacting at-10 ℃ for 12 hours, filtering, evaporating the solvent from the filtrate, adding 20 ml of tetrahydrofuran into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.40 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 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 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 an off-white solid shown in the formula (I), wherein the yield is 73.8%, and the melting point is 156-157 ℃.1H NMR and IR were the same as in example 11.
Example 16: cyclohexylmethoxycarboxamido chlorobenzazepines
Figure BDA0001557620260000131
Preparation of a quiazoline (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 in the method of example 7 into a 50ml reaction bottle, dropwise adding 0.194 g (1.10mmol) of cyclohexyl methyl chloroformate and 5.0 ml of dichloromethane solution 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 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 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 10: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, and detecting by TLC (developing solvent is ethyl acetate/petroleum)Ether 1: 1(v/v)), collecting the eluate containing the compound represented by the formula (I) (Rf value of 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 ℃ to obtain an off-white solid represented by the formula (I), wherein the yield is 50.9%, and the melting point is 156-157 ℃.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 example was subjected to bioactivity test on a human lung cancer cell line A-549, a human promyelocytic leukemia cell line HL-60 and a human cervical cancer cell line Siha.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549, human promyelocytic leukemia cell strain HL-60 and human cervical cancer cell strain Siha. 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 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 10 th 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.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% CO2Culturing in an incubator, adding 5mg/mL MTT into cell culture wells after 72h, incubating at 37 deg.C for 3h with 10 μ L MTT per well, adding DMSO into the wells with 150 μ L DMSO per well,the formazan was fully solubilized by shaking with an oscillator 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 tests are shown in tables 1, 2 and 3:
TABLE 1 inhibitory Effect of Compound (I) on the growth of cancer cell line A-549
Figure BDA0001557620260000141
TABLE 2 inhibitory Effect of Compound (I) on the growth of cancer cell line HL-60
Figure BDA0001557620260000151
TABLE 3 inhibitory Effect of Compound (I) on growth of cancer cell line Siha
Figure BDA0001557620260000152
(2) Using the same procedure as in example 11 except that cyclohexylmethylchloroformate was replaced with 3-methoxybenzoyl chloride or cinnamoyl chloride according to example 11, quinazoline compounds (b) and (c) were synthesized, respectively, and their structures are shown below:
Figure BDA0001557620260000153
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).
Specific results are shown in table 4:
TABLE 4 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line HL-60
Figure BDA0001557620260000161

Claims (2)

1. Cyclohexyl methoxy formyl amino chloro benzazepine shown as formula (I)
Figure FDA0001557620250000012
The application of the fluoroquinazoline compound in preparing the medicaments for preventing or treating the human leukemia;
Figure FDA0001557620250000011
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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