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(N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound, and preparation method and application thereof

A technology of tetrahydroisoquinolinyl and ferulamide, which is applied in the field of medicine, can solve problems such as dementia, neuron loss, and deterioration, and achieve good antioxidant activity, low toxicity, and the effect of inhibiting aggregation activity

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, 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 worsening the AD process (Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 17213-17218. J.Med. Chem. 7683-7689.)

Method used

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  • (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound, and preparation method and application thereof
  • (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound, and preparation method and application thereof
  • (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1-10

[0034] The preparation method of (N-1,2,3,4-tetrahydroisoquinolinyl)-ferulamide compound comprises the following steps:

[0035] ,

[0036] In the formula, Me represents a methyl group,

[0037] Add ferulic acid (1), condensing agent and solvent into the reaction flask, stir evenly, then add 1,2,3,4-tetrahydroisoquinoline (2), after the addition, stir and react at temperature T for n hours, TLC Monitoring; after the reaction, evaporate the solvent under reduced pressure, add water to the residue, extract with dichloromethane, wash the organic layers with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to remove the solvent under reduced pressure , and the residue was purified by silica gel column chromatography (eluent: petroleum ether / acetone=20 / 1) to obtain the target product (N-1,2,3,4-tetrahydroisoquinolinyl)-ferulamide ( I).

[0038](N-1,2,3,4-tetrahydroisoquinolinyl)-ferulamide (I) is a white solid wi...

Embodiment 1

[0044] (N-1,2,3,4-tetrahydroisoquinolinyl)-ferulamide (I) obtained in Example 1 of the present invention 1 H NMR, 13 C NMR and ESI-MS detection results are:

[0045] 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 15.2 Hz, 1H, C=CH), 7.24-7.12 (m, 5H, 5× Ar-H), 7.16 (d, J = 1.6 Hz, 1H, Ar-H), 6.93 (d, J = 8.0 Hz, 1H, Ar-H), 6.80 (d, J =15.2 Hz, 1H, C=CH), 6.04 (s, 1H, OH), 4.84 (s, 2H, phCH 2 N), 3.94 (s, 3H, OCH 3 ), 3.88 (s, 2H, phCH 2 ), 3.97-2.91 (m, 2H, NCH 2 ), 3.80-3.74 (m, 4H, 2 × NCH 2 ).

[0046] 13 C NMR (100 MHz, CDCl 3 ) 166.24, 147.42, 146.74, 143.06, 134.25, 133.70, 128.97, 128.26, 127.81, 126.76, 126.14, 121.90, 114.79 (2C), 110.02, 56.02, 43.60, 29.74.

[0047] MS (ESI) m / z: 310.1 [M + H] + .

[0048] The present invention also provides a pharmaceutical composition for treating neurodegenerative diseases, comprising an effective amount of the above-mentioned drug for treating neurodegenerative diseases or a pharmaceutically acceptable hydrate the...

Embodiment 11

[0051] (1) Acetylcholinesterase and butyrylcholinesterase inhibitory activity

[0052] To the 96-well plate, 30 μL of 1.0 mmol / L thioacetylcholine iodide or thiobutyrylcholine (both purchased from Sigma), 40 μL of PBS buffer solution with pH=8.0, and 20 μL of the test compound solution ( DMSO content is less than 1%) and 10 μL acetylcholinesterase ( Ee AChE) or butyrylcholinesterase (equine serum BuChE, eq BuChE) (0.045U, all purchased from Sigma Company), after adding and mixing, incubate at 37°C for 15 min, and add 0.2% 5,5'-dithio-bis(2- Nitro) benzoic acid (DTNB, purchased from Sigma company) solution 30 μ L was developed, and the optical density value (OD value) of each well at 405 nm was measured with a microplate reader, compared with the blank well without the sample to be tested, and the compound was calculated. Enzyme inhibition rate [enzyme inhibition rate=(1-sample group OD value / blank group OD value)×100%]; select five to six concentrations of the compound, me...

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Abstract

The invention belongs to the technical field of medicine, and relates to a (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound, and a preparation method and application thereof. The structure is as shown in a formula I (the formula I is as shown in the description). The (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine compound provided by the invention has excellent butyrylcholine esterase inhibiting activity, remarkable Abeta1-42 aggregation inhibiting activity, anti-oxidation activity and high neuroprotective activity on PC12 cell injury induced by hydrogen peroxide in in-vitro experiments; and the (N-1,2,3,4-tetrahydroisoquinolinyl)-feruloylagmatine (I) compound is a multi-target-point inhibitor, 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 medicine, and specifically relates to a (N-1,2,3,4-tetrahydroisoquinolyl)-ferulamide 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 inciden...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/06A61K31/472A61P25/28
CPCC07D217/06
Inventor 桑志培柳文敏王柯人潘万里陈长中于林涛赵一阳
Owner NANYANG NORMAL UNIV
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