Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives

A multi-drug resistance, derivative technology, applied in the field of medicine, can solve the problems of unstable chemical and biological metabolism, low anti-tumor multi-drug resistance activity, etc.

Inactive Publication Date: 2012-07-25
OCEAN UNIV OF CHINA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention provides a chroman skeleton-containing catechin compounds and chromene-skeleton-containing flavonoids in the prior art, which have low anti-tumor multi-drug resistance activity and unstable chemical and biological metabolism. Man and chromene derivatives and a preparation method thereof, the chroman and chromene derivatives have the same skeleton structure as epigallocatechin gallate and flavone, but the chroman and chromene derivatives are low-toxic and have Better anti-tumor multidrug resistance activity

Method used

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  • Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives
  • Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives
  • Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. Example 1: Preparation of (2R,3R)-2-(3,4,5-trimethoxyphenyl)-3-(3,4,5-trimethoxybenzoyloxy)-5,7- Dimethoxychroman (compound 3 shown in the synthetic route structure diagram)

[0044] Add 2.0 g, 2.5 mmol, of peracetylated epigallocatechin gallate to 50 mL of saturated hydrogen chloride methanol solution, the solid slowly dissolves, and the solution appears pale yellow. The reaction was stirred at room temperature for 12 hours, the color of the solution gradually deepened, and finally turned into wine red, and the reaction was complete as detected by TLC. The reaction solution was rotary evaporated to remove methanol to obtain epigallocatechin gallate (EGCG). EGCG was not further purified, and 100 mL of ethylene glycol dimethyl ether-acetone mixed solvent was added to dissolve it completely, and then 7.5 g of potassium carbonate and 10 mL ...

Embodiment 2

[0046] Example 2: Preparation of (2R, 3R)-2-(3,4,5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxychroman (compound 4 shown in the synthetic route structure diagram )

[0047] (2R,3R)-2-(3,4,5-trimethoxyphenyl)-3-(3,4,5-trimethoxybenzoyloxy)-5,7 prepared in Example 1 -Dimethoxychroman (0.50g, 0.86mmol) was dissolved in a mixed solvent of 10mL methanol and 10mL ethylene glycol dimethyl ether, and then 0.2g K 2 CO 3, the reaction was stirred at room temperature, and the progress of the reaction was detected by TLC. After 1 h, the starting material disappeared. Evaporate to dryness to obtain a white solid, add 20 mL of ethyl acetate, filter off the insoluble matter, concentrate by rotary evaporation, and separate by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to obtain the product (2R, 3R)-2-( 3,4,5-trimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman 0.28g, yield: 87%.

[0048] mp 157-159°C; 1 H NMR (CDCl 3 , 500MHz) δ (ppm): 6.70 (s, 2H), 6.31 (d, J = 8.0...

Embodiment 3

[0049] Example 3: Preparation of (2R, 3R)-2-(3,4,5-trimethoxyphenyl)-3-(4-methoxybenzoyloxy)-5,7-dimethoxychrome Full (compound 5 shown in the synthetic route structure diagram)

[0050] Take 4-methoxybenzoic acid (0.18g, 1.18mmol) and (2R,3R)-2-(3,4,5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxychrome Full (200mg, 0.53mmol), then add p-dimethylaminopyridine (0.26g, 2.15mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.29g , 2.15mmol), under nitrogen protection, dissolved in 20ml of anhydrous dichloromethane, stirred at room temperature for 24h to complete the reaction. Washed three times with saturated sodium bicarbonate solution, collected the organic phase, dried over anhydrous magnesium sulfate for 4 h, and spin-dried to obtain the crude product, which was separated by column (petroleum ether / ethyl acetate=3 / 1v / v) to obtain pure product (2R, 3R )-2-(3,4,5-trimethoxyphenyl)-3-(4-methoxybenzoyloxy)-5,7-dimethoxychroman 0.18g, yield 68%. mp 67-69°C.

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Abstract

The invention provides chroman and chromene derivatives as tumor multidrug resistance inhibitors as well as a preparation method of the chroman and chromene derivatives. The chroman and chromene derivatives are represented by the following general formulae I and II respectively, wherein R is one or more of hydrogen, hydroxy, alkoxy, alkyl amino, alkyl acylamino, halogen, fluorine-containing alkyl or benzoyl; the benzoyl contains one or more of substituent groups of hydroxy, alkoxy, alkyl amino, alkyl acylamino, halogen or fluorine-containing alkyl; the alkyls in the alkoxy, the alkyl amino, the fluorine-containing alkyl and the alkyl acylamino are linear-chain or branch-chain alkyls with 1-10 carbon atoms; X is hydrogen or oxygen; and Y is oxygen or nitrogen. The chroman and chromene derivatives have low toxicity and good tumor multidrug resistance inhibiting activities, and can be used for preparing drugs for treating breast cancer, colon cancer, prostate cancer, leukemia, myeloma, pancreatic cancer and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a chroman and chromene derivative, a preparation method thereof and an application as an anti-tumor multi-drug resistance inhibitor. Background technique [0002] Chemotherapy is one of the main ways to treat tumors. Multidrug resistance (MDR) of tumor cells is the main reason for tumor chemotherapy failure and tumor recurrence and metastasis, which makes chemotherapy face serious challenges. P-gp is an ATP-dependent broad-spectrum antitumor drug efflux pump. [0003] Roughly three generations of P-gp inhibitors have been developed [Ramalingam, et al: Clin Lung Cancer 2005;7:773]. The first generation itself is a P-gp substrate, which inhibits drug uptake, but its ability to inhibit P-gp efflux is poor, and its toxic and side effects are severe, which seriously limits its clinical application. Representative drugs such as verapamil, it is found earlier multi-drug re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/04C07D311/30C07D311/62A61K31/353A61P35/00A61P35/02
Inventor 万升标周铭祥苑建黄丽琼江涛李学敏张晓瑜孙东魁
Owner OCEAN UNIV OF CHINA
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