Chalcone derivative and application thereof

A drug and compound technology, applied in the field of chalcone derivatives and their use as a drug for the treatment of neurodegenerative diseases, can solve the problems of inability to effectively metabolize dietary amines and low selectivity of MAO-B, and achieve the treatment of neurodegenerative diseases. , the effect of reducing side effects

Pending Publication Date: 2021-06-04
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the early MAO inhibitors used in the treatment of depression were irreversible inhibitors with low selectivity for MAO-B compared to MAO-A
This can be problematic because of side effects associated with irreversibly inhibited enzymes that are subsequently unable to efficiently metabolize dietary amines, which is associated with cardiovascular problems ("cheese effect"), and with Potential for drug-drug interactions with other drugs metabolized by MAO-B

Method used

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  • Chalcone derivative and application thereof
  • Chalcone derivative and application thereof
  • Chalcone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031] Step 1): Add 2-bromo-6-(bromomethyl)pyridine (25g, 0.1mol) and triethyl phosphite (30mL, 0.18mmol) into a 150mL three-necked round-bottomed flask, and react at 135°C for 13 hours ; After the reaction was completed, spin-dried under reduced pressure, separated and purified by column chromatography to obtain 26.2 g of intermediate 1 as light yellow oil.

[0032] 1HNMR (400MHz, CDCl3) δ (ppm) 7.49-7.51 (t, 1H), 7.25-7.32 (m, 2H), 4.12-4.06 (m, 4H), 3.39 (d, 2H), 1.22-1.28 (t, 6H).

[0033] Step 2): Intermediate 2 (4.62g, 15mmol), tetrahydro-2H-pyran (3.0g, 30mmol) and tetrahydrofuran (80mL) were added to a 200mL single-necked round bottom flask at 0°C, and sodium hydride ( 0.7g, 17.5mmol), stirred and reacted for 20 minutes, transferred to room temperature and continued to react for 6.5 hours; stopped the reaction, added water (150mL), extracted with dichloromethane (200mL×2), collected the organic phase, added anhydrous sulfuric acid Sodium-dried, filtered, ...

Embodiment 2

[0037] Example 2 The inhibitory activity of compound (I) to monoamine oxidase A and B

[0038] Use 100mM pH 7.4 potassium phosphate buffer to make recombinant human MAO-A into 12.5 μg / mL sample solution, and MAO-B into 75 μg / mL sample solution. Add 20 μL of the test compound solution and 80 μL of monoamine oxidase to a black 96-well plate, mix well, incubate at 37°C in a dark place for 15 minutes, add 200 μM Amplex Red reagent, 2U / mL horseradish peroxidase, 2mM p-hydroxyphenylethylamine (inhibit MAO-A) or 2mM benzylamine (inhibit MAO-B) to initiate the reaction, incubate at 37°C for 20min, measure the fluorescence emission intensity at 590nm on a multi-functional microplate reader with a fixed excitation wavelength of 545nm, buffer with potassium phosphate solution instead of MAO-A or MAO-B as blank; the formula for the inhibitory rate of monoamine oxidase inhibition by the compound is: 100-(IFi) / (IFc)*100, where IFi and IFc are the presence of inhibitors and no inhibitors res...

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PUM

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Abstract

The present invention relates to a chalcone derivative which can be used to inhibit monoamine oxidase (MAO), and in particular MAO-B, and to the use thereof. Meanwhile, the compound can be used for treating MAO-mediated diseases, especially MAO-B-mediated diseases; the disease is selected from neurodegenerative disorders, for example, brain injury, cerebral apoplexy, traumatic brain injury, anxiety, mood disorder, autism, vascular dementia, Alzheimer's disease, Parkinson's disease, trauma-dependent cognitive loss (associated with cerebrovascular disease, head injury, or brain trauma).

Description

technical field [0001] The present invention relates to a chalcone derivative and its use as a drug for treating neurodegenerative diseases. Background technique [0002] Oxidative stress is mediated by reactive oxygen species (Reactive oxygen species, ROS) free radicals, including superoxide anion, hydrogen peroxide and hydroxyl radicals. Under normal physiological conditions, the level of ROS production and the body's antioxidant capacity are in a state of dynamic balance. When the production of ROS exceeds the antioxidant capacity of cells, oxidative stress (Oxidative stress) occurs, and the brain is particularly sensitive to oxidative stress, which induces multiple a nervous system disease. Another study found that ischemic stroke, hemorrhagic stroke, and nerve damage caused by traumatic brain injury are also related to oxidative stress and neuroinflammation in the body. [0003] Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-dependent metabolic enzyme responsible for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06A61K31/4433A61P25/00A61P9/12A61P25/22A61P25/24A61P25/28A61P25/16
CPCC07D405/06A61P25/00A61P9/12A61P25/22A61P25/24A61P25/28A61P25/16
Inventor 谭回李维平
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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