CN111808117A - Artemisinin-anilinoquinazoline D-type derivative, and pharmaceutical composition and application thereof - Google Patents

Artemisinin-anilinoquinazoline D-type derivative, and pharmaceutical composition and application thereof Download PDF

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CN111808117A
CN111808117A CN202010716766.5A CN202010716766A CN111808117A CN 111808117 A CN111808117 A CN 111808117A CN 202010716766 A CN202010716766 A CN 202010716766A CN 111808117 A CN111808117 A CN 111808117A
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artemisinin
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anilinoquinazoline
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左之利
汪亮亮
张树群
刘辉
李艳
张云琴
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Kunming Institute of Botany of CAS
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Abstract

The invention provides artemisinin-anilino quinazoline derivatives d-1, d-2 and d-3, optical isomers and polymorphs thereof, a pharmaceutical composition taking the artemisinin-anilino quinazoline derivatives as active ingredients, a preparation method thereof and application of the artemisinin-anilino quinazoline derivatives in preparation of drugs for treating tumors. Through in vitro antitumor cell activity experimental evaluation, the compounds d-1, d-2 and d-3 have good inhibitory action on human colon cancer cells (HCT116) and melanoma cells (WM-266-4), and can be used for preparing antitumor drugs.

Description

Artemisinin-anilinoquinazoline D-type derivative, and pharmaceutical composition and application thereof
The application is a divisional application of Chinese patent application 'artemisinin-anilino quinazoline derivatives, a preparation method and application thereof' (application number: 201810468703.5, application date: 2018.05.16).
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to artemisinin-anilinoquinazoline derivatives, optical isomers and polymorphs thereof, a preparation method of the artemisinin-anilinoquinazoline derivatives, a pharmaceutical composition using the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof as active ingredients, and application of the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof in preparation of antitumor drugs.
Background
Cancer is the leading cause of human death and has become a major public health concern worldwide.
In 1971, artemisinin is separated from leaf of Artemisia annua of Compositae by U-yo and U-yo of Chinese scientist for the first time, and is sesquiterpene lactone compound with a unique peroxy bridge structure is extracted. The main derivatives include Dihydroartemisinin (DHA), Artesunate (AS), Artemether (ATM), Arteether (ATE), and Artesunone (ATS). Artemisinin has been listed as a recommended antimalarial drug by the WHO because of its outstanding efficacy against chloroquine-resistant falciparum malaria and its low toxicity. Recent studies have shown that artemisinin and its derivatives have many other pharmacological activities in addition to antimalarial, such as antibacterial, anti-inflammatory, antiviral, antitumor, anti-cardiovascular, anti-fibrotic, immunomodulatory and anti-parasitic effects. Among them, artemisinin has received much attention for its antitumor activity. Since the research of Dendron, Shanghai medicament of Chinese academy of sciences in 1991, first discovered that artemisinin and its derivatives have significant inhibitory effect on leukemia P388 cells, a hot tide of research on antitumor activity and mechanism of artemisinin compounds by scholars at home and abroad was triggered. The research finds that the artemisinin and the derivatives thereof have selective inhibition effect on various cancer cells, including leukemia, brain glioma, lung cancer, gastric cancer, breast cancer, liver cancer, colon cancer, cervical cancer, gallbladder cancer, nasopharyngeal carcinoma, pancreatic cancer, ovarian cancer, melanoma and the like.
To date, there has been no report on the novel artemisinin-anilinoquinazoline derivatives and the activities thereof of the present invention.
Disclosure of Invention
Based on the pharmacophore split principle, the invention introduces the corresponding structure of anilinoquinazoline with biological activity into the 10 th position of dihydroartemisinin, and takes an ether chain, an ester chain, an amide chain and the like as connecting bridges respectively to obtain the novel artemisinin-anilinoquinazoline derivative, thereby improving the antitumor activity. The artemisinin-anilino quinazoline compound in the formula (I), a preparation method thereof, a pharmaceutical composition taking the artemisinin-anilino quinazoline compound as an active ingredient, and application of the artemisinin-anilino quinazoline compound in preparation of antitumor drugs are provided.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
artemisinin-anilino quinazoline derivatives shown in the general formula (I), optical isomers and polymorphs thereof,
Figure BDA0002598452600000021
wherein R is one of the following groups:
Figure BDA0002598452600000022
Figure BDA0002598452600000031
according to the artemisinin-anilinoquinazoline derivative, the optical isomer and the polymorphic substance thereof, the derivative is as follows:
Figure BDA0002598452600000032
the pharmaceutical composition comprises the artemisinin-anilinoquinazoline derivative, the optical isomer and the polymorphic substance thereof and at least one pharmaceutically acceptable carrier.
The artemisinin-anilino quinazoline derivative, the optical isomer and the polymorphic substance thereof are applied to preparation of antitumor drugs.
The artemisinin-anilino quinazoline derivative, the optical isomer and the polymorphic substance thereof are applied to preparation of medicines for resisting colon cancer and melanoma.
The preparation method of the compounds d-1, d-2 and d-3 comprises the following steps:
Figure BDA0002598452600000041
dissolving an artemisinin compound and an anilinoquinazoline derivative in anhydrous N, N-dimethylformamide under the protection of argon, adding diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI and 4-dimethylaminopyridine DMAP at room temperature, reacting at room temperature overnight, monitoring the reaction process by TLC (thin layer chromatography), adding dichloromethane for dilution after the reaction is finished, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography, and obtaining a compound d-1, wherein petroleum ether/ethyl acetate is 1: 1;
preparation of Compound d-2, d-3:
Figure BDA0002598452600000042
dissolving dihydroartemisinin and anilinoquinazoline derivatives in anhydrous dichloromethane as shown in formula 4-2, protecting with argon, and slowly adding BF dropwise at 0 deg.C3·Et2And O, reacting the mixture in the reaction solution, then continuously reacting the system at 0 ℃ overnight, monitoring the reaction process by TLC, after the reaction is finished, adding dichloromethane for dilution, washing with saturated sodium bicarbonate water solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography, and obtaining two isomers of a compound d-2 and a compound d-3 respectively, wherein the ratio of petroleum ether to ethyl acetate is 3: 1.
The invention discovers and verifies that the artemisinin-anilinoquinazoline compound with the general formula (I) has good anti-tumor activity through anti-tumor activity tests of human colon cancer cells (HCT116) and melanoma cells (WM-266-4), and provides the preparation of the compound and new application of the compound with anti-tumor effect.
Detailed Description
The following examples are provided to further illustrate the essence of the present invention, but are not intended to limit the present invention.
Example 1:
the structures of the compounds a-1, a-2, a-3, a-4, a-5, a-6, a-7 and a-8 are respectively shown as follows:
Figure BDA0002598452600000051
preparation of Compound a-1/a-5:
Figure BDA0002598452600000061
as shown in the formula 1-1, dihydroartemisinin (1.2eq.) and anilinoquinazolol (1eq.) are dissolved in anhydrous dichloromethane, argon is used for protection, and BF is slowly dropped at 0 DEG C3·Et2O (2eq.) in the above reaction mixture. The system was then allowed to continue at 0 ℃ overnight. TLC (thin layer chromatography) was used to monitor the reaction process, after the reaction was completed, dichloromethane was added for dilution, the mixture was washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate: 3:1) to obtain two epimers, i.e., compound a-1(α) and a-5(β), with yields of 25% and 23%, respectively.
Preparation of Compound a-2/a-6, a-3/a-7, a-4/a-8:
Figure BDA0002598452600000062
as shown in formula 1-2, dihydroartemisinin and n are respectively prepared1Dissolving anilino quinazoline with different values in anhydrous dichloromethane, protecting with argon, and slowly dripping BF at 0 DEG C3·Et2O (2eq.) in the above reaction mixture. The system was then allowed to continue at 0 ℃ overnight. TLC monitoring reaction process, after the reaction is finished, adding dichloromethane for dilution, washing with saturated sodium bicarbonate aqueous solution, washing with saturated brine, and drying with anhydrous sodium sulfateFiltering, concentrating under reduced pressure, and purifying with silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain compounds a-2 (alpha) and a-6 (beta), respectively, with a yield of 31%, 27%; compounds a-3(α) and a-7(β) in 28% yield, 33%; compounds a-4 (. alpha.) and a-8 (. beta.) were obtained in 21%, 19% yield.
Example 2:
the structures of the compounds b-1, b-2, b-3, b-4, b-5 and b-6 are respectively shown as follows:
Figure BDA0002598452600000071
preparation of Compound b-1, b-2, b-3:
Figure BDA0002598452600000072
as shown in formula 2-1, respectively adding n2Artemisinin compounds (1.2eq.) and anilinoquinazolol (1eq.) with different values were dissolved in anhydrous dichloromethane under argon protection, followed by the sequential addition of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2eq.) and 4-dimethylaminopyridine (0.5eq.) and stirring at room temperature for 6 h. After the reaction is finished, adding a saturated sodium bicarbonate aqueous solution for washing, extracting by ethyl acetate, washing by a saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate is 3:1) to respectively obtain a compound b-1 with a yield of 77%; b-2, yield 69%. (ii) a b-3, yield 63%.
Preparation of Compound b-4, b-5, b-6:
Figure BDA0002598452600000081
as shown in formulas 2-2, respectively adding n2Artemisinin compounds (1.2eq.) and acetyl-substituted anilinoquinazolinol (1eq.) were dissolved in anhydrous dichloromethane under argon protection, followed by addition of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2eq.) and 4-dimethylaminopyridine (0.5eq.) in that order and stirring at room temperature for 6 h. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution for washingWashing, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying with silica gel column chromatography (petroleum ether/ethyl acetate: 3:1) to obtain compound b-4 with a yield of 68%; compound b-5, 74% yield; compound b-6 was obtained with a yield of 71%.
Example 3:
the structures of the compounds c-1, c-2, c-3, c-4, c-5 and c-6 are respectively shown as follows:
Figure BDA0002598452600000082
preparation of Compound c-1, c-2, c-3:
Figure BDA0002598452600000091
as shown in formula 3-1, respectively adding n2Artemisinin compounds (1.2eq.) and anilinoquinazolol (1eq.) with different values were dissolved in anhydrous dichloromethane under argon protection, followed by the sequential addition of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2eq.) and 4-dimethylaminopyridine (0.5eq.) and stirring at room temperature for 6 h. After the reaction is finished, adding saturated sodium bicarbonate water solution for washing, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate is 3:1) to respectively obtain a compound c-1 with a yield of 64%; compound c-2, 67% yield; compound c-3, 58% yield.
Preparation of Compound c-4, c-5, c-6:
Figure BDA0002598452600000092
as shown in formulas 3-2, respectively adding n2Artemisinin compounds (1.2eq.) and acetyl-substituted anilinoquinazolinol (1eq.) were dissolved in anhydrous dichloromethane under argon protection, followed by addition of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2eq.) and 4-dimethylaminopyridine (0.5eq.) in that order and stirring at room temperature for 6 h. After the reaction is finished, adding saturated sodium bicarbonate for dissolving in waterWashing, extracting with ethyl acetate, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying with silica gel column chromatography (petroleum ether/ethyl acetate: 3:1) to obtain compound c-4 with a yield of 53%; compound c-5, yield 63%; compound c-6, 58% yield.
Example 4:
the structures of the compounds d-1, d-2 and d-3 are respectively shown as follows:
Figure BDA0002598452600000101
preparation of Compound d-1:
Figure BDA0002598452600000102
according to the formula 4-1, an artemisinin compound (1.2eq.) and an anilinoquinazoline derivative (1eq.) are dissolved in anhydrous N, N-dimethylformamide, under the protection of argon, diisopropylethylamine (2eq.), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (1.5eq.) and 4-Dimethylaminopyridine (DMAP) (1eq.) are added at room temperature, and the mixture is reacted at room temperature overnight. TLC monitored the reaction, after completion of the reaction, diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 1:1) to give compound d-1 in 8.36% yield.
Preparation of Compound d-2, d-3:
Figure BDA0002598452600000111
as shown in formula 4-2, dihydroartemisinin (1.5eq.) and anilinoquinazoline derivative (1eq.) are dissolved in anhydrous dichloromethane, argon is used for protection, and BF is slowly dropped at 0 DEG C3·Et2O (2eq.) in the above reaction mixture. The system was then allowed to continue at 0 ℃ overnight. TLC monitoring reaction process, after reaction, adding dichloromethane for dilution, washing with saturated sodium bicarbonate water solution, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure,purification by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate) gave compounds d-2 and d-3 as two isomers, respectively, in 37.65% and 25.86% yields.
Example 5:
evaluation of the in vitro antitumor Activity of the Compounds of the invention.
In order to evaluate the inhibition effect of the compound on human colon cancer cells (HCT116) and melanoma cells (WM-266-4), the invention adopts an MTS method to detect the cell proliferation, and uses cisplatin and paclitaxel as positive controls. IC of the Compound50The values were determined by concentration effect generation curve calculation.
Principle of MTS method for detecting cell proliferation
The MTS method is used for detecting the cell proliferation principle: CellTiter
Figure BDA0002598452600000112
The Aqueous One Solution cell promotion Assay (a) is a reagent for detecting the number of viable cells in cell proliferation and cytotoxicity experiments by colorimetry. The reagent contains a novel tetrazole compound (3- (4, 5-dimethylthiozol-2-yl) -5- (3-carboxymethyloxyphenyl) -2- (4-sulfopheny) -2H-tetrazolium, MTS) and an electron coupling agent (PES). PES has enhanced chemical stability which allows it to be mixed with MTS to form a stable solution. MTS is biologically reduced into a colored formazan product by cells under the action of NADPH or NADH generated by dehydrogenase in cells with active metabolism, the colored formazan product can be directly dissolved in a culture medium, and the amount of the formazan product detected at 490nm is in direct proportion to the number of live cells in the culture medium.
2. Experimental methods
1) Pancreatin digestion of tumor cells in logarithmic growth phase, adjustment of the suspension concentration of individual cells to 5X 10 with a culture medium containing 10% fetal calf serum4Adding 100 mu L of cell suspension into a 96-well plate by using a multi-channel sample applicator, wherein 5000 cells are added into each well, and only adding the culture solution with the same volume into a blank control;
2) test compounds were prepared as 10mM stock solutions in DMSO and the test compounds were diluted in culture. The highest concentrations were 80. mu.M, 16. mu.M, 3.2. mu.M, 0.64. mu.M and 0.128. mu.M;
3) 100 μ L of the diluted test compound was added to a final volume of 200 μ L per well, and three duplicate wells were set. Adding DMSO (the concentration is less than 2 per thousand) with the same amount as that of the compound to be detected into a control hole, and adding a fresh culture solution with the same volume into a blank control hole;
4) the plates were placed in a 37 ℃ environment (containing CO)2) After 48h incubation, the culture was terminated, the culture medium was removed from all wells and 100. mu.L of fresh medium containing 20. mu.L MTS was added;
5) placing the culture plate added with MTS at 37 ℃ for incubation for 1-4 h, then oscillating at low speed for 5min in an oscillator, measuring the absorbance of each hole at 490nm of an enzyme linked immunosorbent assay (ELISA) detector, then calculating the proliferation inhibition rate of the compound to be detected on various tumor cell lines according to the detection result and calculating the IC of the compound to be detected50。
3. Results of the experiment
The IC of 23 artemisinin-anilino quinazoline compounds of the invention on two cell lines of human colorectal cancer cells (HCT116) and melanoma cells (WM-266-4)50The activity is shown in the following table.
TABLE 1 IC of the Compounds of the invention on human colorectal cancer cells (HCT116) and melanoma cells (WM-266-4)50Value of
Figure BDA0002598452600000121
Figure BDA0002598452600000131
From the activity data in table 1, it can be found that the artemisinin-anilinoquinazoline derivatives of the present invention show different degrees of inhibitory activity on two cells. The inhibition of human colorectal cancer (HCT116) by most compounds is significantly greater than that of melanoma cells (WM-266-4). Compared with Dihydroartemisinin (DHA), the activity of most compounds is improved and is greater than that of a cisplatin (DDP) positive control.
In conclusion, the compound disclosed by the invention has good in-vitro anti-tumor activity and good potential medicinal value, and can be used for preparing various anti-tumor medicaments.
Example 6:
preparation of tablets:
the artemisinin-anilino quinazoline derivatives, the optical isomers and the polymorphs thereof are prepared according to the methods of the examples 1 to 4, and the excipients are added according to the weight ratio of the artemisinin-anilino quinazoline derivatives to the excipients of 1:5 to 1:10, and then the mixture is granulated and tableted.
Example 7:
preparation of oral liquid preparation:
the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof are prepared according to the methods of examples 1 to 4, and the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs are prepared into oral liquid according to a conventional oral liquid preparation method.
Example 8:
preparation of capsules, granules or medicinal granules:
the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof are prepared according to the methods of the examples 1 to 4, and the excipients are added according to the weight ratio of 5:1 to the excipients to prepare capsules, granules or granules.

Claims (6)

1. Artemisinin-anilino quinazoline derivatives shown in the general formula (I), optical isomers and polymorphs thereof,
Figure FDA0002598452590000011
wherein R is one of the following groups:
Figure FDA0002598452590000012
2. the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof according to claim 1, characterized in that the derivatives are:
Figure FDA0002598452590000021
3. a pharmaceutical composition comprising the artemisinin-anilinoquinazoline derivatives of claim 1 or 2, optical isomers, polymorphs thereof and at least one pharmaceutically acceptable carrier.
4. The use of artemisinin-anilinoquinazoline derivatives, optical isomers and polymorphs thereof as claimed in claim 1 or 2 in the preparation of antitumor drugs.
5. The use of the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof as claimed in claim 1 or 2 in the preparation of anti-colon cancer and anti-melanoma drugs.
6. A process for the preparation of compounds d-1, d-2, d-3 of the structural formula in claim 2, which comprises:
Figure FDA0002598452590000022
dissolving an artemisinin compound and an anilinoquinazoline derivative in anhydrous N, N-dimethylformamide under the protection of argon, adding diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI and 4-dimethylaminopyridine DMAP at room temperature, reacting at room temperature overnight, monitoring the reaction process by TLC (thin layer chromatography), adding dichloromethane for dilution after the reaction is finished, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography, and obtaining a compound d-1, wherein petroleum ether/ethyl acetate is 1: 1;
preparation of Compound d-2, d-3:
Figure FDA0002598452590000031
dissolving dihydroartemisinin and anilinoquinazoline derivative in anhydrous dichloromethane as shown in formula 4-2, protecting with argon gas, and cooling to 0 deg.CSlowly dropping BF3·Et2And O, reacting the mixture in the reaction solution, then continuously reacting the system at 0 ℃ overnight, monitoring the reaction process by TLC, after the reaction is finished, adding dichloromethane for dilution, washing with saturated sodium bicarbonate water solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography, and obtaining two isomers of a compound d-2 and a compound d-3 respectively, wherein the ratio of petroleum ether to ethyl acetate is 3: 1.
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CN112707917A (en) * 2020-12-24 2021-04-27 石家庄学院 Benzisoselenazolone dihydroartemisinin derivative and preparation method and application thereof
CN113480559A (en) * 2021-07-13 2021-10-08 北京大学深圳医院 Artemether derivative with high anti-cancer biological activity and preparation method and application thereof
CN113480559B (en) * 2021-07-13 2022-06-03 北京大学深圳医院 Artemether derivative and preparation method and application thereof

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