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Berberine derivative as well as preparation method and application thereof

A derivative, berberine technology, applied in the field of medicinal chemistry, can solve the problems of limited application of berberine, low bioavailability of berberine, etc., and achieves increased ejection fraction and short-axis shortening rate, and the preparation route is feasible and reliable. Reasonable and increase the effect of short axis shortening rate

Active Publication Date: 2022-03-11
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low bioavailability of berberine, the application of berberine is limited

Method used

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  • Berberine derivative as well as preparation method and application thereof
  • Berberine derivative as well as preparation method and application thereof
  • Berberine derivative as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0100] The fifth aspect of the present invention also provides the preparation method of the berberine derivatives of formula I of the present invention, which comprises the following steps:

[0101]

[0102] Step 1: the compound of formula II reacts with the compound of formula III to generate the compound of formula IV;

[0103] Step 2: reacting the compound of formula IV with the compound of formula V to generate the berberine derivative of formula I;

[0104] Among them, X 1 -X 3 , R 1 -R 3 , L, Het, M - as defined herein;

[0105] T A , T B Independently represents a leaving group, preferably halogen, more preferably chlorine or bromine;

[0106] m 1 - represents an anion, which can be combined with M -Same as M - different. preferred, M 1 - from F - , Cl - 、Br - , I - 、CH 3 COO - .

[0107] When the berberine derivative of formula I is selected from compound 1, the preparation method is:

[0108]

[0109] The reaction of berberine with 1,3-di...

Embodiment 1

[0111] Embodiment 1: the preparation of compound 1 (bromide 9-O-thiazole carboxylate propyl berberine)

[0112] Add 1g of berberine, 0.421mg of potassium carbonate, 0.93g of sodium iodide, 15ml of DMF to the round-bottomed flask in sequence. After reflux at 80°C for 30min, add 850μl of 1,3-dibromopropanol dropwise, continue the reflux reaction for 6h, and spot the plate Monitor the reaction, after the end, add 40ml of ethyl acetate, let stand in ice water for 30min, crystallization precipitates out, filter, after obtaining the crude product, 15ml of DMF is dissolved, then add 30ml of ethyl acetate, secondary recrystallization, suction filtration, drying, to obtain 9-O-bromopropyl berberine bromide 1.31g, yield 90%. Repeat several times to obtain enough intermediates.

[0113] Take 2.019g of 9-O-bromopropyl berberine bromide, 1.356g of thiazole-4-carboxylic acid, 633mg of sodium iodide, 120ml of DMF, and 2.33ml of triethylamine. After reflux reaction at 90°C for 2 hours, th...

Embodiment 2

[0126] Embodiment 2: the cytotoxicity test of compound of the present invention

[0127] 1. Experimental materials

[0128] Experimental cells: primary neonatal mouse cardiomyocytes

[0129] Test substance: bromide 9-O-thiazole carboxylate propyl berberine (compound 1, prepared in Example 1)

[0130] 2. Experimental principle

[0131] The toxicity of the new compound 9-O-thiazolecarboxylate propyl berberine bromide to primary neonatal rat cardiomyocytes was detected by CCK-8 method. CCK-8 reagent contains WST-8: chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfone Acid phenyl)-2H-tetrazole monosodium salt, it is reduced to A highly water-soluble yellow formazan product (Formazan). The amount of formazan produced is directly proportional to the number of viable cells. The light absorption value measured at a wavelength of 450nm by an enzyme-linked immunosorbent assay can reflect the number of living cells, and the larger the value, the stronger th...

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Abstract

The invention relates to a berberine derivative as well as a preparation method and application thereof. The berberine derivative disclosed by the invention is remarkable in myocardial ischemia resisting effect, feasible and reasonable in preparation route, relatively low in cost, relatively low in toxic and harmful reagent consumption, free from environmental pollution and suitable for large-scale industrial production. According to the berberine derivative with heart protection activity and the preparation method of the berberine derivative, a basis can be effectively provided for developing a new heart protection medicine, the economic benefit in the future is huge, the wide social benefit can be generated, and the application prospect is wide.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to a berberine derivative and a preparation method thereof, and also relates to applications of the berberine derivative. Background technique [0002] With the aging of our population and the change of residents' lifestyle, cardiovascular disease has become a major public health problem that threatens the life and health of our people. The "Guidelines for the Primary Prevention of Cardiovascular Diseases in China" (2020) pointed out that the proportion of the mortality rate of ischemic heart disease in the total cardiovascular disease mortality rate increased from 40% in 1990 to 61% in 2016. The average death toll increased from 1 million to 2.4 million, and the prevention and control situation became increasingly severe. Myocardial infarction (MI) is myocardial ischemic necrosis, which is caused by decreased coronary blood supply or increased demand, secon...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P9/10
CPCC07D455/03A61P9/10C07B2200/13Y02A50/30C07D491/147C07D471/04
Inventor 张勇杨宝峰刘鑫韩维娜赵立敏
Owner HARBIN MEDICAL UNIVERSITY
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