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Amide group substituted hesperetin derivatives, preparation method thereof and application of derivatives as anti-AD (anti-Alzheimer's disease) drugs

A technology of hesperetin and derivatives, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve problems such as no effective treatment

Active Publication Date: 2017-06-30
ANHUI MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is currently no effective treatment, termination or delay of the disease process, so effective methods are urgently needed to be discovered

Method used

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  • Amide group substituted hesperetin derivatives, preparation method thereof and application of derivatives as anti-AD (anti-Alzheimer's disease) drugs
  • Amide group substituted hesperetin derivatives, preparation method thereof and application of derivatives as anti-AD (anti-Alzheimer's disease) drugs
  • Amide group substituted hesperetin derivatives, preparation method thereof and application of derivatives as anti-AD (anti-Alzheimer's disease) drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment one: the synthesis of compound 3

[0029] compound 2, hesperetin (5.72 g, about 0.02 mol) was dissolved in 100 mL of anhydrous DMF, 1.5 times the molar amount of K2CO3 was added, followed by 2 times the amount of ethyl bromoacetate, and stirred at room temperature for 20 min. Terminate the reaction, extract with ethyl acetate, repeatedly extract with saturated brine, wash away DMF, dry, recover ethyl acetate under reduced pressure, concentrate to oil, add water, precipitate a yellow solid, recrystallize with methanol and dichloromethane successively, White crystals were obtained in 68% yield,

[0030] The chemical formula of compound 3 is as follows:

[0031]

Embodiment 2

[0032] Embodiment two: the synthesis of compound 5a

[0033] Compound 3 (3.72g, 10mmol), dissolved in ethanol, add 10% NaOH dropwise, adjust the pH to about 12 to 13, react for 2 hours, add dilute hydrochloric acid to adjust the pH to about 2 to 3, stop the reaction, add water to precipitate, and filter with suction The crude light yellow solid compound 4 was obtained. Take 0.33 g of the crude product of compound 4, dissolve it in chloroform, add 3 times the amount of benzylamine, add appropriate amount of HOBT and EDC hydrochloride, and stir overnight at room temperature. Stop the reaction, transfer the reaction solution to an extraction bottle, adjust the pH to a weak acid, wash with saturated brine (40mL×3), dry the organic phase with anhydrous calcium chloride, filter, and distill the filtrate under reduced pressure to obtain a light yellow oil. A white solid 5a was obtained by silica gel column chromatography [V (chloroform): V (petroleum ether) = 3: 1]. 1 H NMR (400MHz...

Embodiment 3

[0036] Embodiment three: the synthesis of compound 5b

[0037] The method was the same as in Example 2, except that p-chlorobenzylamine was used instead of benzylamine to obtain compound 5b as a white solid. 1 H NMR (400MHz, CDCl 3)δ11.98(s,5-OH),7.33–7.28(m,2H,Ar-H),7.25–7.20(m,2H,Ar-H),7.03(d,J=2.0Hz,1H,2 '-H),6.92(dd,J=8.4,1.9Hz,1H,5'-H),6.88(d,J=8.3Hz,1H,4'-H),6.74(t,J=5.7Hz, 1H,NH),6.07(d,J=2.4Hz,1H,8-H),6.04(d,J=2.4Hz,1H,6-H),5.34(dd,J=12.8,3.1Hz,1H, 2-H),4.53(s,2H,C=OCH 2 O), 4.50(d, J=6.1Hz, 2H, NCH 2 ),3.92(s,3H,OCH 3 ), 3.09(dd, J=17.2, 12.8Hz, 1H, 3-H), 2.82(dd, J=17.2, 3.1Hz, 1H, 3-H).TOF-HRMS m / z: 509.0977[M+Na ] + ,

[0038] The chemical formula of compound 5b is as follows:

[0039]

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Abstract

The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics and discloses amide group substituted hesperetin derivatives, a preparation method thereof and an application of the derivatives as AD (Alzheimer's disease) treatment drugs. Study proves that the amide group substituted hesperetin derivatives have strong inhibition property and good inhibition selectivity on acetylcholinesterase, and inhibition capacity of the derivatives on acetylcholinesterase is more than 500 times higher than inhibitory activity on butyrylcholinesterase. The study indicates that the compounds can be developed into the AD treatment drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and specifically relates to an amido-substituted hesperetin derivative, a preparation method thereof, and an application as an anti-Alzheimer's drug. Background technique [0002] Alzheimer's disease (AD) is an age-related neurodegenerative disease, and as the population ages, the incidence rate will increase significantly in the next decade. Worldwide, nearly 40 million people suffer from AD. AD is characterized by progressive memory loss, decline in language function, and other cognitive impairments. Although the mechanism of AD is not fully understood, common hallmarks like β-amyloid peptide (Aβ) deposition, tau protein aggregation and oxidative stress play an important role in the mechanism of the disease. Furthermore, in AD patients, selective loss of cholinergic neurons leads to a deficiency of acetylcholine in specific regions of the brain, which affects learni...

Claims

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Application Information

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IPC IPC(8): C07D311/32C07D405/12C07D407/12A61P25/28
CPCC07D311/32C07D405/12C07D407/12
Inventor 李俊张义龙黄成李增马陶陶孟晓明李波
Owner ANHUI MEDICAL UNIV
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