Ligustrazine substituted benzoic acid derivative (LQC-A) with neuroprotective activity and application of ligustrazine substituted benzoic acid derivative

A technology of benzoic acid derivatives, applied in ligustrazine derivatives and its preparation, preparation method and its application in neuroprotection, ligustrazine substitution of benzoic acid derivatives field, can solve clinical application limitations, traditional Chinese medicine compound Unclear ingredients, insufficient understanding of mechanism of action, etc.

Active Publication Date: 2015-04-29
雷海民
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Traditional Chinese medicine compound has significant advantages in the treatment of the above chronic and complex diseases, but due to problems such as uncl

Method used

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  • Ligustrazine substituted benzoic acid derivative (LQC-A) with neuroprotective activity and application of ligustrazine substituted benzoic acid derivative
  • Ligustrazine substituted benzoic acid derivative (LQC-A) with neuroprotective activity and application of ligustrazine substituted benzoic acid derivative
  • Ligustrazine substituted benzoic acid derivative (LQC-A) with neuroprotective activity and application of ligustrazine substituted benzoic acid derivative

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Experimental program
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Effect test

Embodiment 1

[0050] (3,5,6-trimethylpyrazin-2-yl)methyl

[0051] 2-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (1a)

[0052] Weigh 10.14mmol of 2-bromomethyl-3,5,6-trimethylpyrazine and 5.07mmol of salicylic acid into a 50ml round bottom flask, add 30ml of DMF, and after the mixture dissolves, add 5mmol of potassium carbonate, Stir at 85°C for 2 hours, TLC monitors that the reaction raw materials basically disappear, stop the reaction, add a large amount of saturated NaCl solution to the reaction solution to disperse, extract twice with 300ml ethyl acetate, and wash the ethyl acetate layer with anhydrous NaCl 2 SO 4 Dry, concentrate under reduced pressure, add 4ml of chloroform to the residue to dissolve, add 3.8g of silica gel, evaporate to dryness under reduced pressure and mix the sample. The eluent is petroleum ether: acetone = 10:1, and 1.258g of white solid is obtained. M.P.: 76.2-76.9°C, yield 61.1%.

[0053] Structure Identification: 1 H-NMR (CDCl 3 )(ppm): 7.84(m, 1H, Ar-H...

Embodiment 2

[0055] 2-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoic acid (1b).

[0056] Weigh 0.8g (1.97mmol) of 1a solid into a 100ml reaction flask, add 20ml of absolute ethanol, stir at 60°C until the solid is completely dissolved, add dropwise 8ml of 20% KOH solution, and the reaction time is about 30min. After the reaction is over, add 50ml of saturated NaCl solution into the reaction bottle, then add 4mol / L HCl dropwise to the reaction solution to adjust the pH to 3-4, and let stand until no white precipitates are precipitated. The reaction solution was suction filtered to obtain a precipitate, washed with distilled water until neutral, and dried to obtain 0.456 g of a white solid. M.P.: 172.2-172.9°C, yield 85.1%.

[0057] 1 H-NMR (CDCl 3 )(ppm): 8.10(d, 1H, J=7.5Hz, Ar-H), 7.53(t, 1H, J=8.0Hz, Ar-H), 7.16(d, 1H, J=8.5Hz, Ar- H), 7.12(t, 1H, J=7.5Hz, Ar-H), 5.40(s, 2H, -CH 2 ), 2.53 (brs, 6H, -CH 3 ), 2.52(s, 3H, -CH 3 ). 13 C-NMR (CDCl 3 )(ppm): 166.2, 157.0, 151.6, 149.1,...

Embodiment 3

[0059] (3,5,6-trimethylpyrazin-2-yl)methyl2-hydroxybenzoate (1c).

[0060] Weigh 10.87mmol of 2-bromomethyl-3,5,6-trimethylpyrazine and 10.87mmol of salicylic acid into a 50ml round bottom flask, add 25ml of DMF, and after the mixture is dissolved, add 10.0mmol of bicarbonate Sodium, stirred at room temperature for 12 hours, TLC monitoring reaction raw materials disappeared, stop the reaction, the reaction solution was dispersed by adding a large amount of saturated NaCl solution, 400ml ethyl acetate was extracted twice, the ethyl acetate layer was washed with anhydrous NaCl 2 SO 4 Dry, concentrate under reduced pressure, add 5ml of chloroform to the residue to dissolve, add 4.4g of silica gel, evaporate to dryness under reduced pressure and mix the sample. The eluent is petroleum ether: acetone = 12:1, and 1.892g of white solid is obtained. M.P.: 84.4-85.1°C, yield 64.0%.

[0061] 1 H-NMR (CDCl 3 )(ppm): 10.66(s, lH, -OH), 7.85(dd, J=8, 1.5Hz, 1H, Ar-H), 7.47(td, J=8, 1.5...

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Abstract

The invention provides a ligustrazine substituted benzoic acid derivative with a general formula structure 1. The compound comprises a substituent group substituting a benzoic acid mother nucleus and containing a ligustrazine structure, the general structural formula is represented as the formula 1, wherein R1 is selected from any one of -H or 3,5,6-trimethyl ligustrazine-2-methylene; R2 is selected from any one of -H, -OH, 3,5,6-trimethyl ligustrazine-2-methyleneoxy or 3,5,6-trimethyl ligustrazine-2-formyloxy; R3 is selected from any one of -H, -OH, -OCH3, 3,5,6-trimethyl ligustrazine-2-methyleneoxy or 3,5,6-trimethyl ligustrazine-2-formyloxy; R4 is selected from any one of -H, -OH, 3,5,6-trimethyl ligustrazine-2-methyleneoxy or 3,5,6-trimethyl ligustrazine-2-formyloxy; at least one of R1-R4 is the substituent group containing the ligustrazine structure. The invention further provides a preparation method of the derivative and an application in preparation of drugs for treating brain nerve injury and sequelae of brain nerve injury.

Description

technical field [0001] The invention relates to a ligustrazine derivative and its preparation method and application, in particular to a ligustrazine substituted benzoic acid derivative, a preparation method and its application in neuroprotection, and belongs to the field of medicinal chemistry. Background technique [0002] At present, brain diseases such as stroke, Alzheimer's disease, Parkinson's disease, and traumatic brain injury seriously endanger human health. The occurrence and development of brain diseases are accompanied by different degrees of nerve cell damage. For example, when ischemic stroke occurs, the decrease in blood flow leads to changes in the function of normal cells, and the brain tissue is very sensitive to local ischemia. Even brief ischemia of neurons triggers a cascade of events that culminates in neuronal death. Therefore, neuroprotective agents are widely used as an important therapeutic drug in the first-line clinical treatment of the above-men...

Claims

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Application Information

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IPC IPC(8): C07D241/12C07D241/24A61P9/10A61P25/28A61P25/16A61P25/00
CPCC07D241/12C07D241/24
Inventor 雷海民王鹏龙刘伟张宇忠徐昕林锦璇
Owner 雷海民
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