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N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound, preparation method and application thereof

A technology of benzyl piperidine and ferulamide, applied in the field of medicinal chemistry, can solve problems such as deterioration, dementia, neuron loss, etc., and achieve the effects of low toxicity, improvement of memory reproduction dysfunction, and good clinical application prospects.

Inactive Publication Date: 2017-05-31
NANYANG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, according to the β-amyloid cascade hypothesis, the production and aggregation of oligomeric Aβ in the brain triggers pathogenesis, eventually leading to neuronal loss and dementia, and Aβ can enter mitochondria to induce oxidative stress, while oxidative stress Excited in the brain of AD patients, and promotes Aβ toxicity through the generation of free radicals, further aggravating the AD process (Proc.Natl.Acad.Sci.U.S.A.2005,102,17213-17218.J.Med.Chem.59(2016) 7683-7689.)

Method used

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  • N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound, preparation method and application thereof
  • N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound, preparation method and application thereof
  • N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] A kind of preparation method of N-(benzylpiperidinyl)-ferulamide-O-alkylamine compound, its chemical reaction equation is as follows:

[0046]

[0047] Including the following steps, specifically X, n and NR 1 R 2 See Table 1, and the specific parameters are shown in Table 2:

[0048] The first step: add ferulic acid 1 (150mg, 0.772mmol), EDCI (3.54g, 0.926mmol), HOBT (178mg, 0.926mmol) and dichloromethane into the reaction flask, stir well and add benzylpiperidine Compound 2 (0.926mmol) was added, stirred at room temperature overnight, and monitored by TLC; after the reaction, the solvent was evaporated under reduced pressure, water (40mL) was added to the residue, extracted with dichloromethane (40mL×2), and the organic layers were combined Afterwards, it was washed with saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was pu...

Embodiment 2-90

[0052] Embodiments 2-90 are all prepared according to the method of Example 1. The chemical structures of the target products in Table 1 have been verified. 1 H NMR, 13 Confirmed by C NMR and ESI-MS.

[0053] Table 1 N-(benzylpiperidinyl)-ferulamide-O-alkylamines of Examples 1-90 of the present invention

[0054]

[0055]

[0056]

[0057] Part target compound N-(benzylpiperidinyl)-ferulamide-O-alkylamine compound in table 1 prepared by the present invention 1 HNMR, 13 C NMR and ESI-MS data are as follows:

[0058] The preparation of the target compound I-8, the operation process is the same as in Example 1, and a light yellow oily substance is obtained, with a yield of 59.2%. 1 HNMR (400MHz, CDCl 3 )δ7.60(d, J=15.6Hz, 1H, C=CH), 7.33-7.17(m, 8H, 8×Ar-H), 7.13(d, J=7.6Hz, 2H, 2×Ar-H ),7.07(d,J=8.0Hz,1H,Ar-H),7.03(s,1H,Ar-H),6.86(d,J=8.4Hz,1H,Ar-H),6.76(d,J =15.2Hz, 1H, C=CH), 4.69(t, J=6.0Hz, 1H, 1 / 2phCH 2 ), 4.08(t, J=6.0Hz, 3H, 1 / 2phCH 2 +OCH 2 ),3.86(s,3H...

Embodiment 91-95

[0075] Examples 91-95 used the same method as Example 1 to prepare compound I-1 in Table 1, the difference being that the parameters used in the preparation method were different, specifically as shown in Table 2, wherein the first in Table 2 The mol ratio in the step is the molar feed ratio of ferulic acid, benzylpiperidine compound and condensation agent, the mol ratio in the second step is the molar feed ratio of intermediate compound, dibromoalkane and alkali, in the 3rd step The molar ratio is the molar feed ratio of bromine compound intermediate, secondary amine and alkali.

[0076] Table 2 embodiment 1 and embodiment 91-95 parameter data

[0077]

[0078]

[0079] As can be seen from Table 2, using different parameters to prepare the compound I-1 in Table 1, the yield of the product is 25-90%, and the yield of the target product prepared by the parameters in Example 91 is the highest, illustrating that the present invention is implemented The parameters in Exampl...

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Abstract

The invention discloses an N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound, a preparation method and application thereof. The preparation method comprises the following steps: 1, taking ferulic acid and a benzylpiperidine compound as initial raw materials, and condensing in the presence of solvent and condensing agent to obtain an intermediate compound; 2, reacting the intermediate compound and dibromoalkane in the presence of solvent under alkaline conditions to obtain a bromide intermediate compound; and 3, reacting the bromide intermediate compound and secondary amine in the presence of solvent under alkaline conditions to obtain the N-(benzylpiperidyl)-feruloylagmatine-O-alkylamine compound. The compound is a selective butyryl cholinesterase inhibitor, can inhibit Abeta aggregation, and also has an antioxidant effect and a nerve cell protection effect. Further in vivo experiments reflect that the compound has a favorable effect for treating the Alzheimer's disease, is low in toxicity and has good clinical application prospects.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an N-(benzylpiperidinyl)-ferulamide-O-alkylamine compound, a preparation method and an application thereof. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD, senile dementia) is a central nervous system degenerative disease mainly characterized by progressive cognitive impairment and memory impairment. With the rapid aging of the global population, the elderly population Health problems have become a major social problem that needs to be solved urgently. Alzheimer's disease is one of the diseases with the highest morbidity and mortality among the elderly. According to the "2015 Global Alzheimer's Report" released by Alzheimer's Disease International (ADI), more than 46 million people worldwide suffered from dementia in 2015, and it is predicted that by 2050, there will be There are 131.5 million people suffering from dementia, and the inc...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D211/16C07D401/14C07D211/18C07D211/22C07D211/26A61K31/4545A61K31/496A61K31/506A61K31/445A61K31/4725A61P25/28
CPCC07D211/16C07D211/18C07D211/22C07D211/26C07D401/12C07D401/14
Inventor 桑志培王柯人柳文敏潘万里张胜李亭
Owner NANYANG NORMAL UNIV
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