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Tacrine-phenothiazine isodiad compound and preparation method thereof

A phenothiazine and doublet technology, which is applied in the field of tacrine-phenothiazine heterodimer compounds, can solve the problems of unreported double inhibitory effects and the like

Active Publication Date: 2013-02-20
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Scholars at home and abroad have done a lot of research work on tacrine heterodimeric compounds, some of which not only have good AChE inhibitory activity, but also have Aβ aggregation inhibitory or antioxidant activity, but none of them have been reported to have AChE inhibitory activity. Compounds with dual inhibitory effects on Tau protein

Method used

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  • Tacrine-phenothiazine isodiad compound and preparation method thereof
  • Tacrine-phenothiazine isodiad compound and preparation method thereof
  • Tacrine-phenothiazine isodiad compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: Synthesis of Intermediate A—N-(1,2,3,4-tetrahydroacridine-9-)-pentane-1,5-diamine

[0094]

[0095] Weigh 6.5g of 9-chloro-1,2,3,4-tetrahydroacridine, 12.3g of 1.5-pentanediamine, 0.45g of sodium iodide and 11.3g of phenol, mix and react at 90°C for 4 hours, and the reaction ends After cooling to room temperature, add 10wt% NaOH solution to adjust the pH value to 9-10, extract twice with ethyl acetate, combine the two extracts, wash with water, wash with saturated NaCl, anhydrous Na 2 SO 4 Dry, separate and purify by silica gel column chromatography (eluent by volume: dichloromethane / methanol / ammonia = 9:1:0.1) and concentrate to obtain a brownish-yellow oily product which is the intermediate A—N—(1,2 , 3,4-tetrahydroacridine-9-)-pentane-1,5-diamine 5.9g, yield 70%.

[0096] 1 H NMR (CDCl 3 ,300MHz) 7.90-7.97(m,2H),7.52-7.58(m,1H),7.32-7.37(m,1H),4.01(br,1H),3.45-3.52(m,2H),3.07(m, 2H),2.66-2.72(m,4H),2.01(br,2H),1.91-1.95(m,4H),1.62-1.72(m,2H),1.32-1...

Embodiment 2

[0097] Example 2: Synthesis of Intermediate A - N-(1,2,3,4-tetrahydroacridine-6-chloro-9-)-butane-1,4-diamine

[0098]

[0099] Weigh 2.5g of 6-chloro-9-chloro-1,2,3,4-tetrahydroacridine, 3.5g of 1.4-butanediamine, 0.15g of sodium iodide and 3.8g of phenol, mix and heat at 90°C for reaction After 4 hours, cool to room temperature after the reaction, add 10wt% NaOH solution to adjust the pH value to 9-10, extract twice with ethyl acetate, combine the two extracts, wash with water, wash with saturated NaCl, anhydrous Na 2 SO 4 Drying, separation and purification by silica gel column chromatography (eluent by volume ratio: dichloromethane / methanol / ammonia water = 10:1:0.1) to obtain a brownish-yellow oily product which is the intermediate A—N—(1,2,3, 2.3 g of 4-tetrahydroacridine-6-chloro-9-)-butane-1,4-diamine, yield 75%.

[0100] 1 H NMR (CDCl 3 ,300MHz) 8.03-8.10(m,1H),7.82-7.86(m,1H),7.32-7.35(m,1H),4.08(br,1H),3.15-3.23(m,2H),2.97-3.02( m,2H),2.58-2.67(m,4H),2.01(br,2H...

Embodiment 3

[0101] Example 3: Synthesis of Intermediate B—10-(2-chloroacetyl)-10H-phenothiazine

[0102]

[0103] Take 10.1g of phenothiazine, 14.7g of chloroacetyl chloride and 5.2g of triethylamine and add them into 250ml of dichloromethane, stir and reflux for 2 hours, after TLC analysis, the phenothiazine is consumed, and the reaction solution is cooled to room temperature, followed by 10wt %Na 2 CO 3 aqueous solution, 10wt% HCl aqueous solution and water washing, and then anhydrous MgSO 4 Dry, filter, and concentrate under reduced pressure to obtain the crude product, which is pre-separated and purified with 60 mesh silica gel, and the eluent containing the product is collected and concentrated, and recrystallized and purified with petroleum ether / dichloromethane = 1:1 (V / V) to obtain a white The solid 7.6g is the intermediate B—10-(2-chloroacetyl)-10H-phenothiazine, and the yield is 55%.

[0104] 1 H NMR (CDCl 3 ,300MHz)7.60(d,2H),7.48(d,2H),7.33-7.38(m,2H),7.24-7.30(m,2H),4...

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Abstract

The invention discloses a tacrine-phenothiazine isodiad compound and a preparation method thereof, wherein the tacrine-phenothiazine isodiad compound has a structural formula shown by a general formula (I) and a general formula (II): the tacrine-phenothiazine isodiad compound is combined with tacrine and phenothiazine parent nucleuses which are used for effectively treating senile dementia, is added with a proper length of a linking group, has dual inhibition functions of Acetylcholinesterase (AchE) and tau protein hyperphosphorylation, is relatively lower in toxicity, and can be used for prevention and treatment of Alzheimer's Dieses (AD).

Description

1. Technical field [0001] The invention relates to a novel tacrine-phenothiazine heterodimer compound, which can be used as an AChE inhibitor or a dual-target drug of AChE and Tau protein, and thus is expected to be applied to the prevention and treatment of AD. 2. Background technology [0002] Alzheimer's disease (AD) is the most important neurodegenerative disease. The prevalence rate among people over 60 years old is 5.1%, and among those over 85 years old is 30%. At present, the clinical first-line drugs for the treatment of AD are mainly acetylcholinesterase inhibitors (Acetylcholinesterase Inhibitors, AChEI, such as tacrine, donepezil, huperzine A) and N-methyl-D-aspartic acid (N-methyl-D-aspartic acid). D-aspartate, NMDA) receptor antagonists (such as memantine). Tacrine (1,2,3,4-tetrahydro-9-aminoacridine, Tacrine) is the first clinical drug approved by the US FDA for the treatment of AD. It can effectively inhibit acetylcholinesterase (AChE), and has a certain t...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D417/14A61P25/28
Inventor 惠爱玲潘见甘昌胜
Owner HEFEI UNIV OF TECH
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