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N-(1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine-O-alkylamine compound and application

A technology based on tetrahydroisoquinolinyl and tetrahydroisoquinoline, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve the problems of neuron loss and deterioration, and achieve low toxicity and inhibition Aggregation activity, good effect in treating Alzheimer's disease

Inactive Publication Date: 2017-06-13
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, brain oligomer A β The production and aggregation of A β Can enter mitochondria to induce oxidative stress, while oxidative stress exists in the brain of AD patients, and promotes A through the generation of free radicals β Toxicity, further worsening AD process (Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 17213-17218.J. Med. Chem. 2016, 59, 7683-7689.)

Method used

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Experimental program
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Effect test

Embodiment 1-15

[0039] N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O -Alkylamine compound (I), obtained by the following preparation method:

[0040] ,

[0041] In the formula: n is 2~12, Y represents H, methoxy, C 1 ~C 12 Alkyl, halogen or dimethylamino, with substituents at any possible position on the benzene ring; NR 1 R 2 represents 1,2,3,4-tetrahydroisoquinoline, benzylpiperidine, benzylmethylamine or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;

[0042] Step (i): Add ferulic acid 1, condensing agent and solvent into the reaction flask, stir evenly, then add 1,2,3,4-tetrahydroisoquinoline compound 2, after the addition, the temperature T 1 under stirring reaction n 1 hours, TLC monitoring; after the reaction, the solvent was evaporated under reduced pressure, water was added to the residue, extracted with dichloromethane, the organic layers were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filt...

Embodiment 16

[0060] The specific process conditions are the same as in Example 1, the difference is: investigate different substituents, the specific substituents are shown in Table 4, and the obtained N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O - Alkylamine compound (I), the chemical structure of which is confirmed by 1H-NMR, 13C-NMR and ESI-MS.

[0061] Experimental results of different substituents N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O -Alkylamine compounds (I) are shown in Table 4.

[0062] Table 4 Experimental results of different substituents

[0063]

[0064] .

Embodiment 17

[0066] N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O -The preparation method of alkylamine compound (I) and acid salt formation, comprising the following steps:

[0067] In reaction bottle, add embodiment 1 gained N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O - Alkylamine compound (I) 2.5 mmol and acetone 50 mL, after stirring evenly, add 10.0 mmol of a suitable acid, heat and reflux and stir for 30 minutes, cool to room temperature after the reaction, evaporate the solvent under reduced pressure, and wash the residue with acetone Recrystallize, and filter the precipitated solid to obtain N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O - the salt of alkylamine compound (I), its chemical structure is verified 1 Confirmed by H NMR and ESI-MS.

[0068] Described acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C 1-6 Fatty carboxylic acids (such as: formic acid, acetic acid, propionic acid, etc.), oxalic ac...

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Abstract

The invention belongs to the technical field of medicinal chemistry and discloses a N-(1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine-O-alkylamine compound (I) and pharmaceutically acceptable salt, and a preparation method and application thereof. The structure is as shown in a formula I. The compound (I) provided by the invention has high butyrylcholine esterase inhibiting activity, anti-oxidation activity and Abeta1-42 aggregation inhibiting activity, and has remarkable neuroprotective function on PC12 cell injury induced by hydrogen peroxide, which indicates that the compound is a multi-target-point inhibitor. The compound further shows a good effect of treating alzheimer disease in in-vivo experiments, and has low toxicity and a good clinical application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a new class of N -(1,2,3,4-Tetrahydroisoquinolinyl)-ferulamide- O - Alkylamine compound (I) and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its application in the preparation of drugs for treating and / or preventing Alzheimer's disease. 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 (AD) is one of the diseases with the highest morbidity and mortality among the elderly. According to the "2015 Global Alzheimer's Report" issued by Alzheimer's Disease International (ADI), more than...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/06A61K31/472A61K31/4725A61P25/28
CPCC07D217/06
Inventor 桑志培王柯人柳文敏潘万里冷超粮徐茜
Owner NANYANG NORMAL UNIV
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