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Compounds having anti-Alzheimer's disease effect, and preparation method and application thereof

A technology for compounds and nitrogen compounds, applied in the field of compounds, can solve the problems of lack of effective binding of PAS sites, limited anti-AD activity, etc., and achieve the effects of reasonable process design, high purity and few by-products

Active Publication Date: 2016-12-07
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its simple structure, tacrine can only occupy the CAS site, but lacks effective binding to the PAS site, which further limits the anti-AD activity of tacrine

Method used

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  • Compounds having anti-Alzheimer's disease effect, and preparation method and application thereof
  • Compounds having anti-Alzheimer's disease effect, and preparation method and application thereof
  • Compounds having anti-Alzheimer's disease effect, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of 9-chloro-1,2,3,4 tetrahydroacridine (compound 1)

[0030]

[0031] Add anthranilic acid (5g, 36.2mmol) and cyclohexanone (3.6g, 36.2mmol) into a di[neck flask, add phosphorus oxychloride (15ml in total) dropwise in an ice bath, and stir for 5 minutes in an ice bath , heated in an oil bath to 115°C. The reaction solution was refluxed for about 5 hours and cooled to room temperature. Dilute with 80ml of ice DCM, add 40ml of water to the ice bath, and adjust the pH to 9. The organic layer was separated, extracted three times with DCM, washed three times with brine, and dried over anhydrous sodium sulfate. Spin dry, and separate by column chromatography (developing solvent: PE / EA=8 / 1, v / v). A tan solid was finally obtained with a yield of 86%.

[0032] Synthesis of 9-(β-aminoethylenediamine)-1,2,3,4-tetrahydroacridine (compound 2)

[0033]

[0034] Add ethylenediamine (1.44g, 6mmol) and a catalytic amount of NaI into a 100ml two-necked flask, add 22m...

Embodiment 2

[0036] Example 2 (E)-N-(2-((9-(1,2,3,4-tetrahydroacridinyl)) amino) ethyl) synthesis of cinnamic acid amides (3)

[0037]

[0038] Trans-cinnamic acid (0.147g, 0.1mmol), PyBOP (0.56g, 1.08mmol), DIPEA (0.21g, 1.66mmol) were dissolved in 5ml of DCM and stirred at room temperature for 1 hour. Then compound 2 (0.2 g, 0.83 mmol) of Example 1 was added into the reaction flask, and stirred at room temperature overnight. The reaction was quenched with 15 ml of water, and the organic layer was separated and dried over anhydrous sodium sulfate. Spin to dry, and separate by column chromatography (developer: DCM / MeOH=30 / 1, v / v, add 1ml triethylamine per 1000ml developer). 0.21 g of the product was obtained with a yield of 68%. 1 H-NMR (CDCl 3 ):δ8.04-8.01(m,2H,arom),7.64-7.56(m,2H,arom),7.51-7.45(m,3H,arom),7.31-7.25(m,3H,arom,COCH=C H ), 6.34 (d, J=15Hz, 1H, COC H =CH),3.40-3.36(m,2H,NHC H 2 ),3.04(br,2H,C H 2 NHCO),2.87(m,2H,C4-H 2 ),2.67(m,2H,C1-H 2 ),1.81-1.74(m,4H,C2-H...

Embodiment 3

[0039] Example 3 (E)-3-(o-tolyl)-N-(2-((9-(1,2,3,4-tetrahydroacridinyl))amino)ethyl)acrylic acid (compound 4) Synthesis

[0040]

[0041] Referring to the synthesis method in Example 2, compound 4 was synthesized using 2-methyltrans-cinnamic acid (0.16 g, 0.1 mmol) as a raw material. Yield 80%. 1 H-NMR (CDCl 3 ):δ8.04-8.01(m,2H,arom),7.64-7.56(m,2H,arom),7.51-7.45(m,2H,arom),7.31-7.25(m,3H,arom,COCH=C H ), 6.34 (d, J=15Hz, 1H, COC H =CH),3.40-3.36(m,2H,NHC H 2 ),3.04(br,2H,C H 2 NHCO),2.87(m,2H,C4-H 2 ),2.67(m,2H,C1-H 2 ),2.22(s,3H,C H 3 ),1.81-1.74(m,4H,C2-H 2 ,C3-H 2 ).HRMS(ESI):calcd for C 25 h 27 N 3 O[M+H] + 385.50, found 385.5004.

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Abstract

The invention discloses a series of compounds having an anti-Alzheimer's disease effect; o-aminobenzoic acid as a raw material is subjected to a reaction with cyclohexanone to obtain 9-chloro-1,2,3,4-tetrahydro acridine, and then 9-chloro-1,2,3,4-tetrahydro acridine is subjected to a reaction with ethylenediamine to obtain 9-(beta-amino ethylenediamine)-1,2,3,4-tetrahydro acridine; then 9-(beta-amino ethylenediamine)-1,2,3,4-tetrahydro acridine is subjected to a reaction with cinnamic acid and derivatives thereof to prepare a series of compounds having the anti-Alzheimer's disease effect; the whole process has the advantages of reasonable design, high yield, fewer by-products, and low cost; the prepared compounds have the advantages of high purity and good anti-Alzheimer's disease effect, and can realize industrialized mass production.

Description

technical field [0001] The invention relates to a compound, in particular to a compound having an anti-Alzheimer's effect by inhibiting cholinesterase activity, a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD) is an extremely complex brain neurodegenerative syndrome, clinically manifested as central cognitive decline, mental and motor disorders, etc. With the increasing aging phenomenon in today's society, AD has become one of the major diseases that seriously threaten the health and life of the elderly. The pathological causes of AD are extremely complex, and no clear pathogenic factors have been found so far. Many targets and signaling pathways are involved in the pathological process. There is great controversy in the medical field about the pathogenic model of AD, which directly hinders the development of AD. Development of anti-AD drugs. There are two main problems in the current anti-AD drug research: one is that th...

Claims

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Application Information

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IPC IPC(8): C07D219/12C07D405/12A61K31/473A61P25/28
CPCC07D219/12C07D405/12
Inventor 陈瑶卞尧尧裴玉琼吴亮付廷明
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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