Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof

A technology of tacrine and quinoline, applied in the field of biomedicine, can solve the problems of irreversible or curable diseases, high liver toxicity, and low bioavailability

Inactive Publication Date: 2016-03-02
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because it only targets a single cause, it cannot reverse or cure the disease, and at the same time, it has defects of varying degrees such as high liver toxicity and low bioavailability.
[0006] Other target inhibitors include Aβ aggregation inhibitors, tau protein hyperphosphorylation inhibitors, metal ion chelators, etc. There are currently no drugs on the market, but they have received more and more attention. For diseases with complex etiologies, multi-target synergy Treatment is a better strategy, and currently targeting AD, the development of multi-target drug candidates is its main research direction

Method used

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  • Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof
  • Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof
  • Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of 2-[(4-(8-hydroxyquinoline)-2-methyl)piperidine]-N-(1,2,3,4-tetrahydroacridin-9-amino)acetamide 1

[0058] Weigh compound ID (0.5mmol) and compound In (0.5mmol, R=H) in a 25mL round bottom bottle, add NaBH(OAc) 3 (1.0mmol), DCE (dry, 5mL), heated to 50°C under the protection of argon to react, TLC monitored the reaction, cooled the reaction solution to room temperature, washed with water, extracted with DCM, concentrated to dryness and separated by silica gel column, the obtained product was added 37%HCl (2mL), heat to reflux for 1h, add water after cooling, K 2 CO 3 Adjusted to weakly alkaline, concentrated to dryness after extraction with DCM and separated by silica gel column to obtain the compound 1 , white solid, yield 66%.

[0059] 1 (400MHz, CDCl 3 )δ=9.22(s,1H),8.14(d, J =10.0Hz,1H),8.00(d, J =8.0Hz,1H),7.71(d, J =8.4Hz,1H),7.66–7.61(m,2H),7.48–7.41(m,2H),7.32(d, J =8.4Hz,1H),7.16(d, J =7.6Hz,1H),3.88(s,2H),3.33(s,2H),3.15(t, J =6.4...

Embodiment 2

[0061] Synthesis of 2-[(4-(5-chloro-8-hydroxyquinoline)-2-methyl)piperidine]-N-(1,2,3,4-tetrahydroacridin-9-amino)ethyl Amide 2

[0062] compound ID (0.5mmol) and compound In (0.5mmol, R=5-Cl) With reference to the operation process of Example 1, the compound was isolated 2 , white solid, yield 63%.

[0063] 1 (400MHz, CDCl 3 )δ=9.21(s,1H),8.49(d, J =8.8Hz,1H),8.00(d, J =8.4Hz,1H),7.76–7.70(m,2H),7.63(t, J =7.2Hz,1H),7.49–7.45(m,2H),7.09(d, J =8.8Hz,1H),3.89(s,2H),3.31(s,2H),3.15(t, J =6.4Hz,2H),2.85–2.80(m,6H),2.70(brs,4H),2.01–1.86ppm(m,4H); 13 CNMR (100MHz, CDCl 3 )δ=168.6,159.9,157.6151.2,146.9,138.1,137.9,133.9,128.9,128.8,127.1,126.0,125.5,123.7,122.5,121.8,120.4,110.2,64.3,61.30.8,552.3,75 ,22.5ppm;purity:99.6%,determined byHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH 3 CN(contain0.05%CF 3 CO 2 H) / H 2 O=95:5, flowrate=1.2mL / min], t R =1.37min;ESI-MSm / z:538.3[M+Na] + .

Embodiment 3

[0065] Synthesis of 2-[(4-(5-fluoro8-hydroxyquinoline)-2-methyl)piperidine]-N-(1,2,3,4-tetrahydroacridin-9-amino)acetamide 3

[0066] compound ID (0.5mmol) and compound In (0.5mmol, R=5-F) with reference to the operation process of Example 1, the compound was isolated 3 , white solid, yield 60%.

[0067] 1 (400MHz, CDCl 3 )δ=9.21(s,1H),8.38(d, J =8.8Hz,1H),8.00(d, J =8.4Hz,1H),7.74–7.70(m,2H),7.65–7.61(m,2H),7.63(t, J =7.6Hz,1H),7.47(t, J =7.6Hz,1H),7.13–7.03(m,2H),3.88(s,2H),3.33(s,2H),3.15(t, J =6.4Hz,2H),2.86–2.80(m,6H),2.71(brs,4H),2.01–1.97(m,2H),1.90–1.86ppm(m,2H); 13 CNMR (100MHz, CDCl3 )δ=168.6,159.9,158.0,150.7( J C-F =244.1Hz), 148.2( J C-F =2.7Hz),147.0,138.0,137.1,137.0,130.3( J C-F =3.1Hz), 129.0, 128.9, 127.1, 125.9, 123.7, 121.8, 121.8 ( J C-F =1.9Hz), 118.0( J C-F =18.7Hz), 110.4( J C-F =20.5Hz), 108.8( J C-F =7.1Hz),64.5,61.8,54.0,53.5,34.0,25.8,22.7,22.5ppm;purity:94.2%,determined byHPLCwithInertSustainC18column(5μm,4.6×150mm)at2...

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Abstract

The present invention relates a tacrine-8-hydroxyl(amine)quinoline derivative and applications thereof, and belongs to the technical field of biological medicines. The derivative comprises a compound of a formula I and a pharmaceutically acceptable salt thereof. A preparation method thereof comprises the step of: performing reductive amination and deprotection on the compounds Id and Ii and an intermediate In / In' to obtain a compound I, wherein the compound I can react in an alcohol solution to produce a salt. Pharmacological tests verify that the compound has the activity against Alzheimer's disease and can inhibit acetylcholinesterase and butyrylcholinesterase activity, and meanwhile can inhibit self-polymerization of the beta-amyloid protein, and has a certain chelating effect on metal ions, particularly Cu<2+> and Zn<2+>, so that the hydrolysis of the acetylcholinesterase and the self-polymerization of the beta-amyloid protein are retarded, the effect of the acetylcholinesterase on synapses is improved, and the metal ions in the brain is regulated, and therefore the compound is effective for treating Alzheimer's disease.

Description

technical field [0001] The invention relates to a tacrine-8-hydroxy(amino)quinoline derivative and its application, in particular to a tacrine-8-hydroxy(amino)quinoline derivative and its anti-Alzheimer The application in mutism drugs belongs to the technical field of biomedicine. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development. AD is characterized by a gradual decline in cognitive functions such as memory, thinking, comprehension, calculation, language, learning ability, and judgment. Dementia is diagnosed when it is reduced enough to affect the individual's daily life behavior. Those who develop before the age of 65 are called premature aging Dementia; those who develop after the age of 65 are called senile dementia, which is a disease caused by multiple factors. The exact cause is still not conclusively clarified. There is considerable evidence that several forms of AD have a heritable...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P25/28
CPCC07D401/12
Inventor 董长治王刚王荣黄江全霖阳
Owner GUANGDONG UNIV OF TECH
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