阅读说明：本技术 青蒿素-苯胺基喹唑啉类d类衍生物及其药物组合物和应用 (Artemisinin-anilinoquinazoline D-type derivative, and pharmaceutical composition and application thereof ) 是由 左之利 汪亮亮 张树群 刘辉 李艳 张云琴 于 2018-05-16 设计创作，主要内容包括：本发明提供一类青蒿素-苯胺基喹唑啉类衍生物d-1、d-2、d-3、其光学异构体、多晶型物,以其为活性成分的药物组合物,其制备方法,以及其在制备治疗肿瘤的药物中的应用。经体外抗肿瘤细胞活性实验评价,本发明化合物d-1、d-2、d-3对人结肠癌细胞(HCT116)和黑色素瘤细胞(WM-266-4)具有良好的抑制作用,能用于抗肿瘤药物的制备。(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.)

1. Artemisinin-anilino quinazoline derivatives shown in the general formula (I), optical isomers and polymorphs thereof,

wherein R is one of the following groups:

2. the artemisinin-anilinoquinazoline derivatives, the optical isomers and the polymorphs thereof according to claim 1, characterized in that the derivatives are:

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:

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:

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.

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,

wherein R is one of the following groups:

according to the artemisinin-anilinoquinazoline derivative, the optical isomer and the polymorphic substance thereof, the derivative is as follows:

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:

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:

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.