CN113493443B - Application of erlotinib derivative in preparation of medicines for treating esophageal cancer - Google Patents
Application of erlotinib derivative in preparation of medicines for treating esophageal cancer Download PDFInfo
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Abstract
The invention discloses an erlotinib derivative with killing performance on wild cells and a preparation method thereof, belonging to the technical field of drug synthesis. The technical scheme of the invention is as follows: the erlotinib derivative has a structure
Wherein n is 1 or 2, R 1 And R is 2 And R is 3 And R is 4 Are different substituents. According to the invention, 3, 4-bis (2-methoxyl ethyl benzoate) is taken as a raw material, and a series of erlotinib-1, 2, 3-triazole compounds with novel structures are obtained through six-step reaction; the compound has good inhibitory effect on IDO1, and the 1,2, 3-triazole structure can form stronger action effect with Fe ions in heme, so that the IDO1 enzyme activity is competitively inhibited; the compound has good inhibition effect on wild lung cancer tumor cells, and also has inhibition effect on mutant lung cancer tumor cells, and has remarkable universality of tumor cell inhibition activity compared with erlotinib.
Description
Technical Field
The invention belongs to the technical field of synthesis of anti-tumor active medicaments, and particularly relates to application of erlotinib derivatives in preparation of medicaments for treating esophageal cancer.
Background
Erlotinib (Erlotinib), also known as Tarceva (Tarceva), was co-developed by three companies Genetech, OSI, roche and was a selective inhibitor of the first epidermal growth factor tyrosine kinase produced by Roche pharmaceutical factories. The medicine is used in China, the United states and Europe in 4 months in 2006, 11 months in 2004 and 9 months in 2005 respectively
Through approval, the product is marketed. Meanwhile, the approval of erlotinib hydrochloride in combination with gemcitabine for the treatment of pancreatic cancer in 2005 is the first drug approved for advanced treatment of pancreatic cancer in recent years. At present, the traditional Chinese medicine composition is mainly suitable for the two-wire and three-wire treatment of metastatic non-small cell lung cancer or locally advanced lung cancer after two or more chemotherapy schemes fail; erlotinib contains a quinazoline backbone. Quinazoline derivatives exist in natural alkaloids, quinazoline frameworks are also important structures in pharmaceutical chemistry, and many compounds containing quinazoline structures show good anticancer, antibacterial, anti-inflammatory and other effects. The 1,2, 3-triazole is an important pesticide and medicine pharmacophore, and has good biocompatibility and aromaticity. For many years, 1,2, 3-triazole is generally used as an important pharmacophore, pharmacophore molecules of different substrates are linked together through click chemistry reaction, and the pharmacophore has a better effect through structural modification. Erlotinib has developed resistance and adverse reactions as an anticancer agent. Therefore, the development of a compound with a tumor capable of inhibiting drug resistance has good prospect, and the cooperation of the compound and the university of south China and the university of Henan also has been modified for erlotinib, and relevant activity tests are carried out.
Disclosure of Invention
The preparation method of the erlotinib derivative is characterized in that the erlotinib derivative has the following structure:
wherein n is 0,1 or 2, R 1 And R is 2 And R is 3 And R is 4 Are different substituents.
The preparation method of the erlotinib derivative is characterized by comprising the following steps of:
(1): dissolving a certain amount of ethyl 3, 4-bis (2-methoxyethoxy) benzoate in dichloroethane, stirring uniformly at room temperature, adding N-iodosuccinimide, reacting at room temperature until the raw materials are completely reacted, filtering the reaction solution, pouring the filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, regulating the pH value of the organic phase to be neutral by using a dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain ethyl 6-iodo-3, 4-bis (2-methoxyethoxy) benzoate; the feeding amount molar ratio of the 3, 4-bis (2-methoxyethoxy) ethyl benzoate to the N-iodosuccinimide is 1:1.1-2.
(2): adding a certain amount of 6-iodo-3, 4-bis (2-methoxyethoxy) ethyl benzoate, cobalt tri (triphenylphosphine) chloride and 1, 8-diazabicyclo undec-7-ene and cesium carbonate into anhydrous toluene in a closed reaction bottle with a water separator, uniformly stirring, replacing three gases with nitrogen, slowly heating to reflux, cooling to room temperature after reflux stirring reaction for a period of time, slowly dropwise adding a toluene solution containing azido trimethylsilane and potassium iodide, heating to 70 ℃ after dropwise adding, keeping the temperature for a period of time, obviously observing the deepening of the color of the reaction solution, judging that iodine on a benzene ring is replaced, heating to reflux after the color of the reaction solution is fixed, adding an aqueous solution containing ammonium sulfamate into the water separator after the toluene reflux enters the water separator to be mixed with water, slowly dropwise adding a mixed solution into the reaction solution through the water separator, continuously circulating through a reflux system, continuously reacting for a period of time, cooling to room temperature after continuous reaction, dropwise adding pH to the filtrate at the temperature of 1 ℃ until the pH of the filtrate is gradually cooled to the pH of 2, gradually precipitating 2-methoxyethyl benzoate, and then slowly filtering to obtain a solid ethyl benzoate after the crystallization, and gradually cooling to obtain 2-ethoxyl hydrochloride, and gradually filtering the filtrate after the ethyl 2-ethyl benzoate after the crystallization is gradually cooled; the molar ratio of the 6-iodo-3, 4-di (2-methoxyethoxy) ethyl benzoate to azido trimethylsilane to the addition of potassium iodide to ammonium sulfamate is 1:1.2:0.1:1.5.
(3): adding a certain amount of 4, 5-bis (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride into formamide, stirring uniformly at room temperature, then adding formamide solution dissolved with ammonium formate, slowly heating to a certain temperature under nitrogen atmosphere, reacting until the raw materials react completely, cooling to room temperature, adding ethyl acetate into the reaction solution, stirring for a period of time, adding water, separating out an organic phase, and concentrating to obtain 6, 7-bis (2-methoxyethoxy) quinazoline-4-one; the feeding amount molar ratio of the 4, 5-di (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride to the ammonium formate is 1:3; the certain temperature is 130-160 ℃.
(4): adding a certain amount of 6, 7-bis (2-methoxyethoxy) quinazoline-4-ketone and N, N-dimethylformamide into thionyl chloride, slowly heating to reflux, evaporating unreacted thionyl chloride in vacuum after the reaction is finished, adding saturated sodium bicarbonate solution at 0-10 ℃, stirring, extracting for multiple times by using dichloromethane, combining organic phases, washing once by using saturated saline water, washing for multiple times by using water, drying by using anhydrous sodium sulfate, and concentrating to obtain 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine.
(5): adding a certain amount of 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine into isopropanol, stirring uniformly at room temperature, then adding m-aminophenylacetylene, stirring uniformly again, heating and refluxing, cooling to room temperature after reacting for a period of time, generating a large amount of solid, filtering, and drying to obtain erlotinib.
(6): adding a certain amount of erlotinib and an azide into a solution of tertiary butanol, water and tetrahydrofuran, adding a certain amount of cupric sulfate pentahydrate and sodium ascorbate, heating to 70 ℃ to react until the erlotinib is monitored to be completely reacted, adding methylene dichloride into the reaction solution, filtering the reaction solution, separating out an organic phase, and concentrating to obtain a product; the mass ratio of the erlotinib to the azide to the copper sulfate pentahydrate to the sodium ascorbate is 2:2:1:2.
The preparation method of the erlotinib derivative is characterized in that the reaction equation in the preparation process is as follows:
the erlotinib derivative of the invention is applied to preparation of medicines for treating or preventing lung cancer.
The invention has the technical advantages that:
1, a series of erlotinib-1, 2, 3-triazole compounds with novel structures are obtained;
2, the compound has good inhibitory effect on IDO1, and the 1,2, 3-triazole structure can form a stronger action effect with Fe ions in heme, so that the IDO1 enzyme activity is competitively inhibited, the release of T cells is further improved, and drug-resistant tumor cells can be killed;
3, the compound has good inhibition effect on wild lung cancer tumor cells, and also has inhibition effect on esophageal cancer cells, and has remarkable universality of tumor cell inhibition activity compared with erlotinib.
Drawings
FIG. 1 shows the nuclear magnetic resonance spectrum of the compound obtained in example 9
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
3, 4-bis (2-methoxyethoxy)) 3g of ethyl benzoate is dissolved in 30mL of dichloroethane, stirred for 30min at room temperature, then 2.5g of N-iodosuccinimide is added in batches, each batch is 5g of N-iodosuccinimide is added at intervals of 10min, the reaction is carried out for 2h at room temperature after the last batch of N-iodosuccinimide is added, TLC monitors that the raw materials are completely reacted, the reaction solution is filtered, the filtrate is poured into 30mL of ice water, 8mL of saturated sodium hydroxide solution is added, an organic phase is separated, the pH value of the organic phase is regulated to be neutral by dilute hydrochloric acid solution, the organic phase is separated again, and 2.9g of 6-iodo-3, 4-bis (2-methoxyethoxy) ethyl benzoate is obtained after being dried by anhydrous magnesium sulfate and concentrated; 1 H NMR (400Hz, DMSO-d 6 ): 7.26 (s, 1H), 7.11 (s, 1H), 4.15 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 4.11 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 3.82-3.77 (m, 2H), 3.74 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 3.59-3.55 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H), 1.28 (t, J 1 =4.0Hz, J 2 =4.0Hz, 3H); LC-MS(ESI)：425[M+H] +
example 2
3g of ethyl 3, 4-bis (2-methoxyethoxy) benzoate is dissolved in 30mL of dichloroethane, stirred for 30min at room temperature, 4.6g of N-iodosuccinimide is added in batches, each batch is 1.15g of N-iodosuccinimide is added for 10min at intervals, the reaction is carried out for 1h at room temperature after the last batch of N-iodosuccinimide is added, TLC monitors the complete reaction of the raw materials, the reaction solution is filtered, the filtrate is poured into 50mL of ice water, 10mL of saturated sodium hydroxide solution is added, an organic phase is separated, the pH value of the organic phase is adjusted to be neutral by using a dilute hydrochloric acid solution, the organic phase is separated again, and 3.7g of 6-iodo-3, 4-bis (2-methoxyethoxy) ethyl benzoate is obtained after being dried by anhydrous magnesium sulfate; 1 H NMR (400Hz, DMSO-d 6 ): 7.26 (s, 1H), 7.11 (s, 1H), 4.15 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 4.11 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 3.82-3.77 (m, 2H), 3.74 (t, J 1 =4.0Hz, J 2 =4.0Hz, 2H), 3.59-3.55 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H), 1.28 (t, J 1 =4.0Hz, J 2 =4.0Hz, 3H); LC-MS(ESI)：425[M+H] + 。
example 3
In a closed reaction bottle with a water separator, 4.5g of ethyl 6-iodo-3, 4-bis (2-methoxyethoxy) benzoate and 0.35g of cobalt tri (triphenylphosphine) chloride and 3.2g of 1, 8-diazabicycloundec-7-ene are added into 50mL of anhydrous toluene, after stirring uniformly, three times of gas is replaced by nitrogen into the reaction bottle, then the temperature is slowly raised to reflux, the reaction is carried out for 2h, then the temperature is reduced to room temperature, 1.4g of azido trimethylsilane and 10mL of toluene solution of 0.17g of potassium iodide are slowly dripped, the temperature is raised to 70 ℃ after the dripping, the reaction is maintained for 30min, the color of the reaction liquid can be obviously observed to deepen in the reaction process, so that iodine on a benzene ring can be judged to be replaced, the reaction liquid is heated to reflux after the color of the reaction liquid is observed to be fixed, then 1.8g of aqueous solution of ammonium sulfamate is added into the water separator, the toluene reflux is mixed with water, the water is slowly heated to reflux, the aqueous solution is slowly mixed with the water, the mixed solution of the aqueous solution is added into the solution of ethyl benzene hydrochloride until the solution is gradually cooled to the pH is continuously reduced to the temperature is reduced to 2h, the reaction is continuously cooled to the pH of 2.0, the filtrate is continuously cooled to the pH of the solution is continuously cooled to the ethyl 2, the solution is continuously cooled to the pH of the solution is continuously, the solution is continuously cooled to be filtered, and the pH of the solution is continuously cooled to be 1.0, the filtrate is continuously cooled to be filtered to be the filtrate until the pH is cooled to be 1, and the filtrate is gradually cooled to be diluted to the filtrate is the solution is cooled to the solution is 10.
Example 4
In a reaction bottle, 3.5g of 4, 5-bis (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride is added into 20mL of formamide, stirring is carried out for 10min at room temperature, then 10mL of formamide solution dissolved with 2g of ammonium formate is added, the mixture is slowly heated to 130 ℃ under nitrogen atmosphere, the reaction is carried out for 6h, TLC monitors that the raw materials react completely, cooling is carried out to room temperature, 35mL of ethyl acetate is added into the reaction liquid, stirring is carried out for 30min, then 15mL of water is added, stirring is continued for 10min, an organic phase is separated, and 2.7g of 6, 7-bis (2-methoxyethoxy) quinazoline-4-one is obtained after concentration.
Example 5
In a reaction bottle, 3g of 6, 7-bis (2-methoxyethoxy) quinazoline-4-ketone and 1mL of N, N-dimethylformamide are added into 30mL of thionyl chloride, the temperature is slowly increased to reflux, unreacted thionyl chloride is distilled off in vacuum after the reaction is finished, then 20mL of saturated sodium bicarbonate solution is added at the temperature of 0-10 ℃ for stirring for 20min, 10mL of dichloromethane is used for extraction for many times, organic phases are combined, then the organic phases are washed once with saturated saline solution, and then washed for many times with water, and after anhydrous sodium sulfate is dried, the mixture is concentrated to obtain 2.4g of 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine.
Example 6
In a reaction bottle, adding 3g of 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine into 50mL of isopropanol, stirring uniformly at room temperature, then adding 1.3g of m-aminophenylacetylene, stirring uniformly again, heating and refluxing, reacting for 1.2h, slowly cooling to room temperature, generating a large amount of solid, continuously cooling to 0 ℃, stirring for 30min, filtering and drying to obtain 3.1g of erlotinib.
Example 7
Erlotinib 1g and 2-fluorobenzazide 1g were added to a solution of t-butanol 10mL, water 10mL and tetrahydrofuran 10mLAdding 0.5g of copper sulfate pentahydrate and 1g of sodium ascorbate, heating to 70 ℃ for reaction until TLC monitors complete erlotinib reaction, adding methylene dichloride into the reaction liquid, filtering the reaction liquid, separating out an organic phase, and concentrating to obtain 1.17g of a product; 1 H NMR (400Hz, DMSO-d 6 ): 9.62 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.95 (dd, J 1 =4.0Hz, J 2 =8.0Hz, 3H), 7.69-7.59 (m, 3H), 7.54-7.47 (m, 2H), 7.24 (s, 1H), 4.34-4.29 (m, 4H), 3.81-3.75 (m, 4H), 3.39 (s, 3H), 3.36 (s, 3H); 13 C NMR (101Hz, DMSO-d 6 ): 156.85, 154.07, 153.40, 153.12, 148.54, 147.47, 147.40, 140.64, 131.92, 130.76, 129.60, 126.53, 126.10, 123.37, 122.73, 121.07, 119.47, 117.77, 117.57, 109.45, 108.67, 103.69, 70.61, 70.54, 68.84, 68.50, 58.87, 58.81。
example 8
Adding 1g of erlotinib and 1g of 3-nitrophenylazide into a solution of 10mL of tertiary butanol, 10mL of water and 10mL of tetrahydrofuran, adding 0.5g of cupric sulfate pentahydrate and 10mL of sodium ascorbate, heating to 70 ℃ to react until TLC monitors complete erlotinib reaction, adding dichloromethane into the reaction solution, filtering the reaction solution, separating out an organic phase, and concentrating to obtain 1.07g of a product; LC-MS (ESI): 558[ M+H ]] + 。
Example 9
Adding 1g of erlotinib and 1g of 4-methylphenyl azide into a solution of 10mL of tertiary butanol, 10mL of water and 10mL of tetrahydrofuran, adding 0.5g of cupric sulfate pentahydrate and 1g of sodium ascorbate, heating to 70 ℃ to react until TLC monitors complete erlotinib reaction, adding dichloromethane into the reaction solution, filtering the reaction solution, separating out an organic phase, and concentrating to obtain 0.66g of product; 1 H NMR (400Hz, DMSO-d 6 ): 9.63 (s, 1H), 9.28 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.95 (d, J=4.0Hz, 2H), 7.87 (d, J=8.0Hz, 2H), 7.67 (d, J=4.0Hz, 1H), 7.52 (t, J 1 =8.0Hz, J 2 =4.0Hz, 1H), 7.45 (d, J=4.0Hz, 2H), 7.25 (s, 1H), 4.34-4.30 (m, 4H), 3.82-3.76 (m, 4H), 3.39 (s, 3H), 3.37 (s, 3H), 2.51 (s, 3H); 13 C NMR (101Hz, DMSO-d 6 ): 156.88, 154.09, 153.40, 148.58, 147.70, 147.40, 140.59, 138.83, 134.89, 131.06, 130.75, 129.57, 122.69, 121.02, 120.36, 120.02, 119.46, 109.43, 108.64, 103.69, 70.60, 70.54, 68.84, 68.52, 58.88, 58.82, 21.07。
example 10
0.5g of erlotinib and 0.5g of benzyl azide are added into a solution of 5mL of tertiary butanol, 5mL of water and 5mL of tetrahydrofuran, 0.25g of cupric sulfate pentahydrate and 0.5g of sodium ascorbate are added, then the mixture is heated to 70 ℃ to react until TLC monitoring erlotinib reaction is complete, methylene dichloride is added into the reaction solution, the reaction solution is filtered, an organic phase is separated out, and the product of 0.41g is obtained after concentration; 1 H NMR (400Hz, DMSO-d 6 ): 9.55 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 7.90 (d, J=12.0Hz, 2H), 7.56 (d, J=4.0Hz, 1H), 7.45 (t, J1=8.0Hz, J2=8.0Hz, 1H), 7.41-7.33 (m, 5H), 7.23 (s, 1H), 5.66 (s, 2H), 4.32-4.28 (m, 4H), 3.80-3.74 (m, 4H), 3.38 (s, 3H), 3.36 (s, 3H); 13 C NMR (101Hz, DMSO-d6): 156.83, 154.06, 153.39, 148.55, 147.44, 147.11, 140.52, 136.50, 131.39, 129.48, 129.29, 128.66, 128.42, 122.27, 122.12, 120.78, 119.23, 109.43, 108.67, 103.68, 70.60, 70.53, 68.82, 68.50, 58.87, 58.82, 53.52。
example 11
From CO 2 Taking out the human cervical cancer Hela cell culture dishes with activity from the incubator, and respectively performing the following operations: sterile operation is performed beside an alcohol lamp, a dish cover is opened, the culture solution is sucked out in a waste liquid jar, the culture solution in the culture bottle is washed twice by PBS of 2mL, and digestion is performed by trypsin of 0.25%Stopping digestion when the increase of cell gaps and the change of cells into a small circle shape are observed, blowing the bottom of a culture bottle by using a liquid-transferring gun to enable the cells to fall off, transferring the obtained cell suspension into a sterile centrifuge tube, setting a centrifuge to be 1000 r/min for 3 min, centrifuging, slowly pouring the supernatant in the centrifuge tube, adding 2-5 mL of culture solution, and performing cell counting under an inverted microscope. According to the counting result, human cervical cancer Hela cells with activity growing in logarithmic phase are spread in 96-well cell culture plates at 50000 cells per well, cultured for 5-6 hours with RPMI1640 containing 10% fetal bovine serum, 100 μl of test compound diluted with culture medium (0.2 mol/L,0.4 mol/L,0.8 mol/L,1.6 mol/L,3.2 mol/L,6.4 mol/L,12.8 mol/L,25.6 mol/L) and recombinant human interferon γ (final concentration 100 ng/mg) are added to activate IDO1 expression in Hela cells. After the completion of the operation, the 96-well cell culture plate was placed in a 37℃cell culture incubator rich in 5% carbon dioxide for 18 hours, and the reaction was terminated with a certain amount of 3.05N trichloroacetic acid, followed by incubation at 50℃for 30 minutes. After the cell culture solution is precipitated, supernatant is taken, and after the supernatant is developed by (N, N-dimethyl) benzaldehyde, absorbance at 480 and nm is detected by a multifunctional enzyme-labeled instrument. The group treated with IFNγ medium alone without drug was taken as 100% (At), and the group treated with DMSO medium alone At 0.1% was taken as blank 0% (Ab); the absorbance at different conditions was calculated according to the following formula: absorbance% = (a-Ab)/(At-Ab), a: drug treatment +100 ng/mL IFNγ, ab: blank, at: no drug contained only 100 ng/mL ifnγ; generating a memory with IC according to using Graph Pad Prism 8.0 software 50 Inhibition curves of values. The target compound obtained in example 10 was 0.678. Mu. Mol/L; the objective compound obtained in example 9 was 0.342. Mu. Mol/L.
Example 12
From CO 2 The culture dishes of the tumor cells such as H460, H1975, H1299, A549 and the like are taken out of the incubator and respectively subjected to the following operations: sterile operation is carried out beside an alcohol lamp, a dish cover is opened, the culture solution is sucked out in a waste liquid jar, the culture solution in the culture bottle is washed twice by PBS (phosphate buffered saline) of 2mL, and is digested by trypsin of 0.25 percent, and the hair is observedWhen the cell gap is increased and the cells become small circles, stopping digestion, blowing the bottom of a culture bottle by using a pipetting gun to enable the cells to fall off, transferring the obtained cell suspension into a sterile centrifuge tube, setting the centrifuge to be 800 r/min for 3 min, centrifuging, slowly pouring the supernatant in the centrifuge tube, adding 2-5 mL of culture solution, and counting the cells under an inverted microscope. Based on the counting result, it was formulated to 1X 10 with the corresponding culture solution 5 The cell/mL single cell suspension was then seeded in 6-well plates with 2mL per well. Placing a 6-well plate at 37deg.C, 5% CO 2 Culture 24h in incubator.
Inoculating 100 mu L of tumor cell suspension into 96 holes in advance for 24 hours, wherein 1500-2000 cells/hole; the original medium was removed, 100. Mu.L of medium containing different test drugs (final concentration 1. Mu.M, 2. Mu.M, 4. Mu.M, 8. Mu.M or 16. Mu.M) was added, and culture was continued for 48 h, 3 wells per group, with 0.1% DMSO as a control; removing the culture medium containing the medicine, adding 100 mu L of 1X Cell Counting Kit-8 (CCK-8) reagent diluted by the complete culture medium, and placing a 96-well plate in an incubator for incubation for 1-4 hours; detecting the absorbance at 450 nm using a Synergy HTX multifunctional microplate reader; the inhibition rate was calculated using absorbance, the calculation formula was: inhibition ratio = [ (Ac-As)/(Ac-Ab)]X 100%; as, experimental wells (drug treatment); ac, control wells (0.1% dsmo treatment); ab, blank (without cells). Semi-inhibitory concentration of drug on cell growth was determined using Graph Pad Prism 8.0 software (IC 50 ）。
The target compounds obtained in example 9 were 3.77. Mu. Mol/L, 7.25. Mu. Mol/L, 4.97. Mu. Mol/L, 5.91. Mu. Mol/L and erlotinib 6.04. Mu. Mol/L, 12.67. Mu. Mol/L, 22.31. Mu. Mol/L and 10.20. Mu. Mol/L, respectively.
Next, the target compound obtained in example 8 and the inhibitory activity of KYSE70 against esophageal cancer cells, IC were examined by the same method 50 The inhibition effect of the target compound on esophageal cancer cells is better than that of erlotinib, wherein the erlotinib is 3.92 mu mol/L and the erlotinib is more than 20 mu mol/L.
While the basic principles, principal features and advantages of the present invention have been described in the foregoing examples, it will be appreciated by those skilled in the art that the present invention is not limited by the foregoing examples, but is merely illustrative of the principles of the invention, and various changes and modifications can be made without departing from the scope of the invention, which is defined by the appended claims.
Claims (8)
1. An application of erlotinib derivatives in preparing medicines for treating esophageal cancer is characterized in that the erlotinib derivatives have the following structures:
2. the use according to claim 1, wherein: the preparation method of the erlotinib derivative comprises the following specific preparation steps:
(1) Iodination reaction of ethyl 3, 4-di (2-methoxyethoxy) benzoate to obtain ethyl 6-iodo-3, 4-di (2-methoxyethoxy) benzoate;
(2) Amino substitution of 6-iodo-3, 4-bis (2-methoxyethoxy) benzoic acid ethyl ester to give 4, 5-bis (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride;
(3) The 4, 5-di (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride is cyclized to obtain 6, 7-di (2-methoxyethoxy) quinazoline-4-ketone;
(4) Chlorination of 6, 7-bis (2-methoxyethoxy) quinazolin-4-one to give 6, 7-bis (2-methoxyethoxy) quinazolin-4-chloro;
(5) 6, 7-di (2-methoxyethoxy) quinazoline-4-chloro substitution to obtain erlotinib;
(6) The erlotinib reacts with the azide compound to obtain a target compound; the azide compound is 3-nitrophenyl azide.
3. The use according to claim 2, wherein: the step (1) is as follows: dissolving a certain amount of ethyl 3, 4-bis (2-methoxyethoxy) benzoate in dichloroethane, stirring uniformly at room temperature, adding N-iodosuccinimide, reacting at room temperature until the raw materials are completely reacted, filtering the reaction solution, pouring the filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, regulating the pH value of the organic phase to be neutral by using a dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain ethyl 6-iodo-3, 4-bis (2-methoxyethoxy) benzoate; the feeding amount molar ratio of the 3, 4-bis (2-methoxyethoxy) ethyl benzoate to the N-iodosuccinimide is 1:1.1-2.
4. The use according to claim 2, wherein: the step (2) is as follows: adding a certain amount of 6-iodine-3, 4-bis (2-methoxyethoxy) ethyl benzoate, cobalt chloride tris (triphenylphosphine), 1, 8-diazabicyclo undec-7-ene and cesium carbonate into anhydrous toluene in a closed reaction bottle with a water separator, uniformly stirring, replacing three gases with nitrogen, slowly heating to reflux, cooling to room temperature after reflux stirring reaction for a period of time, slowly dropwise adding a toluene solution containing azido trimethylsilane and potassium iodide, heating to 70 ℃ after dropwise adding, keeping the temperature for a period of time, obviously observing the deepening of the color of the reaction solution, judging that iodine on a benzene ring is replaced, heating to reflux after the color of the reaction solution is fixed, adding an aqueous solution containing ammonium sulfamate into the water separator after the toluene reflux enters the water separator to be mixed with water, slowly dropwise adding a mixed solution into the reaction solution through the water separator, continuously circulating through a reflux system, continuously reacting for a period of time, cooling to room temperature after continuous reaction, dropwise adding pH to the filtrate at the temperature of 1 ℃ until the pH of the filtrate is gradually cooled to 10 ℃, slowly adding the filtrate to the pH of 2, and then slowly filtering to obtain a solid ethyl benzoate, and gradually filtering to obtain a filtrate after the ethyl 2-methoxysulfonate, and gradually filtering the ethyl acetate after the crystallization is subjected to 2-ethyl acetate, and the filtrate is gradually filtered to obtain 2-ethyl acetate after the filtrate is subjected to filtration; the molar ratio of the 6-iodo-3, 4-di (2-methoxyethoxy) ethyl benzoate to azido trimethylsilane to the addition of potassium iodide to ammonium sulfamate is 1:1.2:0.1:1.5.
5. The use according to claim 2, wherein: the step (3) is as follows: adding a certain amount of 4, 5-bis (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride into formamide, stirring uniformly at room temperature, then adding formamide solution dissolved with ammonium formate, slowly heating to a certain temperature under nitrogen atmosphere, reacting until the raw materials react completely, cooling to room temperature, adding ethyl acetate into the reaction solution, stirring for a period of time, adding water, separating out an organic phase, and concentrating to obtain 6, 7-bis (2-methoxyethoxy) quinazoline-4-one; the feeding amount molar ratio of the 4, 5-di (2-methoxyethoxy) -2-aminobenzoic acid ethyl ester hydrochloride to the ammonium formate is 1:3; the certain temperature is 130-160 ℃.
6. The use according to claim 2, wherein: the step (4) is as follows: adding a certain amount of 6, 7-bis (2-methoxyethoxy) quinazoline-4-ketone and N, N-dimethylformamide into thionyl chloride, slowly heating to reflux, evaporating unreacted thionyl chloride in vacuum after the reaction is finished, adding saturated sodium bicarbonate solution at 0-10 ℃, stirring, extracting for multiple times by using dichloromethane, combining organic phases, washing once by using saturated saline water, washing for multiple times by using water, drying by using anhydrous sodium sulfate, and concentrating to obtain 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine.
7. The use according to claim 2, wherein: the step (5) is as follows: adding a certain amount of 6, 7-bis (2-methoxyethoxy) quinazoline-4-chlorine into isopropanol, stirring uniformly at room temperature, then adding m-aminophenylacetylene, stirring uniformly again, heating and refluxing, cooling to room temperature after reacting for a period of time, generating a large amount of solid, filtering, and drying to obtain erlotinib.
8. The use according to claim 2, wherein: the step (6) is as follows: adding a certain amount of erlotinib and an azide into a solution of tertiary butanol, water and tetrahydrofuran, adding a certain amount of cupric sulfate pentahydrate and sodium ascorbate, heating to 70 ℃ to react until the erlotinib is monitored to be completely reacted, adding methylene dichloride into the reaction solution, filtering the reaction solution, separating out an organic phase, and concentrating to obtain a product; the mass ratio of the erlotinib to the azide to the copper sulfate pentahydrate to the sodium ascorbate is 2:2:1:2.
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| CN202110219257.6A Active CN113149965B (en) | 2020-04-21 | 2021-02-26 | Erlotinib derivative and application thereof in preparation of IDO1 activity inhibition drugs and antitumor drugs |
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| CN103694227A (en) * | 2013-12-20 | 2014-04-02 | 浙江树人大学 | Erlotinib derivative, and preparation method and application thereof |
| CN106632271A (en) * | 2016-11-18 | 2017-05-10 | 河南师范大学 | Erlotinib derivative with antitumor activity, and preparation method and application thereof |
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| CN112176418A (en) * | 2019-07-05 | 2021-01-05 | 中国科学院上海有机化学研究所 | High-flux compound library construction and screening method and reaction device |
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| CN106632271A (en) * | 2016-11-18 | 2017-05-10 | 河南师范大学 | Erlotinib derivative with antitumor activity, and preparation method and application thereof |
| CN107245072A (en) * | 2016-11-18 | 2017-10-13 | 河南师范大学 | A kind of preparation method of the triazole compound of Tarceva 1,2,3 |
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| CN113493443A (en) | 2021-10-12 |
| CN113149965B (en) | 2022-09-27 |
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