CN108245520B - Application of acetamido quinazoline compound in preparation of drugs for treating lung cancer - Google Patents
Application of acetamido quinazoline compound in preparation of drugs for treating lung cancer Download PDFInfo
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Abstract
The invention discloses an application of an acetamido quinazoline compound in preparing a medicament for preventing or treating human lung cancer, provides a novel quinazoline compound with good anti-cancer (especially human lung cancer) activity, and is expected to be applied to preparing medicaments for preventing or treating human lung cancer; the preparation method of the acetamido quinazoline compound provided by the invention is simple and easy to operate, has the advantages of easily available raw materials and low production cost, and is suitable for practical use.
Description
(I) technical field
The invention relates to an application of an acetamido quinazoline compound in preparing a medicament for preventing or treating tumor diseases.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -y. ke, h. -y. shiao, y. c. hsu, c. -y. chu, w. -c. wang, y. -c. lee, w. -h. lin, c. -h. chen, j. t. a. hsu, c. -w. chang, c. -w. lin, t. -k. yeh, y. -s. chao, m.s. coumar, h. -p. hsieh, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide application of a novel quinazoline compound, namely an acetamido quinazoline compound in preparing a medicament for preventing or treating human lung cancer, wherein the compound has a remarkable inhibition rate on a human lung cancer cell strain A-549 under a certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
The technical scheme adopted by the invention is as follows:
the invention provides an application of an acetamido quinazoline compound shown in a formula (I) in preparing a medicament for preventing or treating human lung cancer,
further, the medicament is preferably a medicament for inhibiting the activity of a human lung cancer cell strain A-549.
The preparation method of the acetamido quinazoline compound shown in the formula (I) comprises the following steps: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine); the ratio of the compound represented by the formula (III) to the compound represented by the formula (II) to the amount of the basic catalyst B fed is 1.0: 0.8 to 1.2: 1.0 to 8.0, and the amount of the organic solvent A is 10 to 50mL/g based on the mass of the compound represented by the formula (III);
(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 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 organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the feeding mass ratio of the compound shown in the formula (IV) to the iron powder, the concentrated hydrochloric acid or the acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0; when the reducing agent E is palladium-carbon/ammonium formate or palladium-carbon/hydrazine hydrate, the feeding mass ratio of the compound shown in the formula (IV) to palladium-carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1-0.5: 1.0-3.0; the dosage of the organic solvent D is 10-50 mL/g based on the mass of the compound shown in the formula (IV); the mass concentration of concentrated hydrochloric acid is 36-38%, and glacial acetic acid is adopted as acetic acid; the mass loading amount of palladium in the palladium-carbon applicable to the method is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%;
(3) mixing a compound shown as a formula (V) with acetyl chloride or acetic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of a basic catalyst F (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v), preferably reacting at-10-50 ℃ for 3-12 h), and separating and purifying 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; the ratio of the amount of the compound represented by the formula (V) to the amount of the acetyl chloride or acetic anhydride and the basic catalyst F is 1: 1.0 to 8.0: 1.0 to 3.0, and 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 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 (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel 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.
The specific recommended step (3) of the invention is carried out according to the following method: dropwise adding acetyl chloride or acetic anhydride in an organic solvent G solution of a compound shown in the formula (V) and a basic catalyst F or in the compound shown in the formula (V) and the basic catalyst F at-10 ℃, reacting for 3-12 hours at-10-50 ℃, filtering, evaporating the filtrate to remove the solvent, and carrying out column chromatography on the concentrate to obtain a compound shown in the formula (I); the volume consumption of the organic solvent for dissolving acetyl chloride or acetic anhydride has no influence on the invention, 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), and the total consumption of the organic solvent G refers to the total volume of the organic solvent for dissolving the catalyst and the compound shown in the formula (V) and the organic solvent for dissolving acetyl chloride or acetic anhydride.
Further, the method for separating and purifying 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 (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) into the dissolved solution in an amount which is 1.0-2.0 times the weight of the concentrate, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel 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 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 acetamido quinazoline (I) has a remarkable inhibition rate on a human lung cancer cell strain MCF-7, and can be applied to preparation of a medicament for preventing or treating human lung cancer.
The invention has the following beneficial effects: (1) provides a novel quinazoline compound which has obvious inhibitory activity on human lung cancer and is expected to be used for preparing medicaments for preventing or treating human lung cancer; (2) the preparation method of the acetamido quinazoline compound (I) is simple and easy to operate, has easily obtained raw materials and lower production cost, and is suitable for practical use.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
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)
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 were sequentially added to a 50ml reaction flask, heated to 40 ℃, followed by TLC detection (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)), stirred for 10 hours, the reaction was stopped, and the solvent was distilled off from the reaction solution to obtain a reaction productAdding 10 ml of ethyl acetate into the 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 to remove 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 with the silica gel 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: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to the TLC detection, concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.1H NMR(500MHz,CDCl3)δ:3.32-3.38(m,1H),3.63(dt,J＝3.4,15.5Hz,1H),3.75(s,3H),3.82(s,6H),3.91(dd,J＝8.1,14.3Hz,1H),4.03(td,J＝4.1,11.7Hz,1H),4.15(d,J＝11.5Hz,1H),4.72(dd,J＝8.3,14.2Hz,1H),5.14(t,J＝8.9Hz,1H),6.60(s,1H),6.90(d,J＝8.7Hz,2H),7.08(d,J＝8.6Hz,2H),7.93(d,J＝9.1Hz,1H),8.48(dd,J＝2.4,9.2Hz,1H),8.71(s,1H),8.96(d,J＝2.4Hz,1H)。IR(KBr,cm-1)ν:2917,2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Example 2: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) 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 petroleum ether/ethyl acetate mixed solution of 5 as eluent, tracking by TLC (ethyl acetate/petroleum ether as developing solvent: 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5) according to TLC detection, concentrating the collected eluate, and drying at 50 deg.C to obtain light yellow solid product shown in formula (IV) with yield of 72.6%The melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 3: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 60 ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, 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 petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5) according to TLC detection,concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 80.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 5: preparation of 6-nitroquinazoline (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 12 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 3(v/v)) and stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected eluent, 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 petroleum ether/ethyl acetate mixed solution of 1 as eluent, and detecting by TLC (developing agent is ethyl acetate)Ester/petroleum ether ═ 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) according to TLC detection (the Rf value is 0.5), concentrating the collected eluent, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g (6.34mmol) of ammonium formate, 0.04 g of 5% Pd/C and 4.0 ml of chloroform prepared in the method of example 1 are sequentially added into a reaction bottle, stirred at the room temperature of 25 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacted for 12 hours, filtered, concentrated, and dried in vacuum at the temperature of 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 98.2% and the melting point of 122-126 ℃.1H NMR(500MHz,CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),3.87-3.98(m,5H),4.45(dd,J＝6.3,13.8Hz,1H),4.95(dd,J＝6.5,9.2Hz,1H),6.47(s,1H),6.90(d,J＝8.7Hz,2H),6.95(d,J＝2.5Hz,1H),7.11(d,J＝8.6Hz,2H),7.15(dd,J＝8.9,2.5Hz,1H),7.69(d,J＝8.9Hz,1H),8.50(s,1H)。IR(KBr,cm-1)ν:3368,3215,2932,2825,1628,1566,1512,1487,1353,1248,1036,834。
Example 8: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 1.20 g (19.18mmol) of 80 wt% hydrazine hydrate, 0.20 g of 5% Pd/C and 20.0 ml of toluene prepared by the method in example 2 are sequentially added into a 50ml reaction bottle, heated to 100 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 0.5 hour, cooled and filtered, the filtrate is concentrated, and vacuum-dried at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 100.0% and the melting point of 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV) prepared in the method of example 3, 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol are added into a 50ml reaction bottle in sequence,heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring to react for 8 hours, cooling, filtering, concentrating the filtrate, and performing vacuum drying at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), wherein 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
Example 7.
Example 11: preparation of acetamidoquinazoline (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 0.345 g (4.39mmol) of acetyl chloride under the stirring condition at-10 ℃, completing dropwise, 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 reaction 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 eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 67.6%, and the melting point is 190-194 ℃.1H NMR(500MHz,CDCl3)δ:2.27(s,3H),3.26-3.33(m,1H),3.52(dt,J＝15.3,3.6Hz,1H),3.75(s,3H),3.79-3.84(m,7H),3.95-4.07(m,2H),4.65(dd,J＝7.9,14.1Hz,1H),5.24(t,J＝8.7Hz,1H),6.65(s,1H),6.88(d,J＝8.7Hz,2H),7.08(d,J＝8.7Hz,2H),7.48(d,J＝8.9Hz,1H),7.65(s,1H),7.81(d,J＝8.9Hz,1H),8.57(s,1H),8.70(s,1H)。IR(KBr,cm-1)ν:3274,2936,1682,1562,1525,1509,1450,1350,1245,1034,837。
Example 12: preparation of acetamidoquinazoline (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 0.043 g (0.55mmol) of acetyl chloride and 5.0 ml of chloroform was added dropwise under stirring at 10 ℃, after completion of the addition, TLC tracking detection (developing agent ethyl acetate/petroleum ether ═ 1: 1(v/v)) was performed, reaction was performed at 10 ℃ for 8 hours, filtration was performed, the solvent was distilled off from the filtrate, the concentrate was dissolved by adding 20 ml of ethanol to obtain a dissolved solution, 0.26 g of silica gel (300 to 400 mesh column chromatography silica gel) was added to the dissolved solution, after the uniform mixing, the solvent was distilled off to obtain a mixture of dried concentrate and silica gel, the mixture was packed into a column, and then the volume ratio of the mixture was 1: eluting 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 82.3%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of acetamidoquinazoline (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 in sequence, dropwise adding 0.086 g (1.10mmol) of acetyl chloride 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 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 column chromatography silica gel (300-400 meshes of column chromatography silica gel) into the dissolved solution, mixing, and performing column chromatography to obtain column chromatography silica gelAfter homogenization, the solvent is evaporated off to give a mixture of dry concentrate and silica gel, the mixture is packed into a column and then mixed 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 88.7%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of acetamidoquinazoline (I)
0.27 g (0.55mmol) of 6-aminoquinazoline (v), 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene prepared in example 10 are sequentially added to a 50ml reaction flask, a solution of 0.224 g (2.19mmol) of acetic anhydride and 7.0 ml of toluene is added dropwise under stirring at 5 ℃, the mixture is heated to 50 ℃, the mixture is reacted for 3 hours under TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), 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 column chromatography 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 loaded on a column, and then the volume ratio of the mixture is 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 74.2%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 15: preparation of acetamidoquinazoline (I)
0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared in example 10 were added in sequence to a 50ml reaction flask, and a solution of 0.173 g (2.20mmol) of acetyl chloride and 5.0 ml of benzene was added dropwise with stirring at-10 ℃ and TLC follow-up (developing solvent is ethyl acetate/petroleum ether)1: 1) reacting at the temperature of-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 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 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 62.5%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of acetamidoquinazoline (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 9 into a 50ml reaction bottle, dropwise adding 0.086 g (1.10mmol) of acetyl chloride 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, loading the mixture into a column, and then loading the mixture into the column at 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 the collected eluent, and drying at 50 ℃ to obtain an acetamidoquinazoline white solid shown in the formula (I), wherein the yield is 79.8%, and the melting point is 190-194 ℃.1H NMR and IR were the same as in example 11.
Example 17: in vitro test for anti-cancer Activity
(1) And (3) carrying out human lung cancer bioactivity test on the prepared compounds (I) and (IV).
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell line A-549, purchased from cell bank 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 culturing cells: inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-pancreatin and diluted to 1X 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. 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 Compounds (I) and (IV) on the growth of Lung cancer cell line A-549
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting acetyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride and cinnamoyl chloride, respectively, and following the following structures:
the prepared quinazoline compounds (a), (b) and (c) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human lung cancer cell strain A-549, and the compounds (a), (b) and (c) have far lower anti-cancer activity on the human lung cancer cell strain A-549 than acetamido quinazoline (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line A-549
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human lung cancer cell strain A-549. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549, and is obviously superior to the compounds (a), (b) and (c).
(3) 4-chloroquinazoline was prepared according to the method of the reference (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the quinazoline compound (d) was synthesized according to the same procedure as in example 1, and the structure thereof is as follows:
the prepared quinazoline compound (d) is subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and a test result shows that the anticancer activity of the quinazoline compound (d) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compound (d) on the growth of cancer cell line A-549
(4) Quinazoline compounds (e), (f), (g) and (h) were synthesized according to example 11 by substituting acetyl chloride with benzoyl chloride, butyryl chloride, propionyl chloride or chloroacetyl chloride, respectively, and following the same procedure as in example 11, respectively, and have the following structures:
the prepared quinazoline compounds (e), (f), (g) and (h) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and the test result shows that the quinazoline compounds (e), (f), (g) and (h) have inferior anticancer activity to the human lung cancer cell strain A-549 to the anticancer activity of the compound (I). Specific results are shown in table 4:
TABLE 4 inhibitory Effect of Compounds (e), (f), (g) and (h) on the growth of cancer cell line A-549
Claims (2)
1. An application of an acetamido quinazoline compound shown in a formula (I) in preparing a medicament for preventing or treating human lung cancer,
2. the use according to claim 1, wherein the medicament is a medicament having activity of inhibiting human lung cancer cell line a-549.
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