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2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative as well as preparation and application

A technology of tacrine and its derivatives, applied in the field of tacrine-8-aminoquinoline derivatives and their preparation and application, can solve the problems of high liver toxicity, urgency, low bioavailability, etc. Delayed Aggregation and Effective Treatment of Alzheimer's Disease

Active Publication Date: 2019-07-23
GUANGDONG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, there are different degrees of defects such as high liver toxicity and low bioavailability
[0005] Since memantine was approved by the FDA in 2003, no new drug has been marketed so far, so research and development of effective new drugs for the treatment of AD has become urgent

Method used

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  • 2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative as well as preparation and application
  • 2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative as well as preparation and application
  • 2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative as well as preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] (1) Synthetic compound Ia 1,4-dibenzylpiperazine-2-carboxylic acid ethyl ester

[0062] Weigh N,N'-dibenzylethylenediamine (50g, 208.04mmol) into a 1000mL round-bottomed flask containing 300mL of toluene, then add triethylamine (72mL, 520.1mmol) and keep stirring, 2, Ethyl 3-dibromopropionate (54.08g, 208.04mmol) was dissolved in 50mL of toluene, and then slowly poured into a flask. After the reaction system was stirred and reacted at 25°C for 30min, the toluene was removed by concentration under reduced pressure, and water and di Extract and separate the organic phase with methyl chloride, wash the organic phase with water once, then dry with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure; the crude product is separated and purified by silica gel column chromatography to obtain compound Ia 1,4-dibenzylpiperene in yellow oil Ethylazine-2-carboxylate, 85% yield.

[0063] 1 H NMR (400MHz, CDCl3): δ=7.31–7.29(m,2H),7.26–7.20(m,6H),7.19–7.15(m...

Embodiment 2

[0071] (1) Synthetic compound Id 6-fluoro-2-methylquinolin-8-alcohol (X=O, R=F)

[0072] 2-amino-5-fluorophenol (20g, 157.3mmol) and acetaldehyde (27.7g, 629.3mmol) in concentrated hydrochloric acid (140mL), 80 ℃ condensation cyclization reaction 2.5h; The product Id6-fluoro-2-methylquinolin-8-ol (X=O, R=F) was isolated as a black oil in 9% yield.

[0073] 1 H NMR (400MHz, CDCl3): δ = 7.95 (d, J = 8.4Hz, 1H), 7.31 (d, J = 8.4Hz, 1H), 6.94-6.88 (m, 2H), 2.69 (s, 3H); ESI-MSm / z:178.1[M+H] +

[0074] (2) Synthetic compound Id 6-fluoro-2-methylquinolin-8-amine (X=NH, R=F)

[0075] 4-Fluoro-2-nitroaniline (2g, 12.8mmol) and acetaldehyde (1.8g, 25.6mmol) were cyclized by condensation in hydrochloric acid (6M, 50mL) and toluene (20mL) at 80°C for 3h, separated by silica gel column The purified product (3g, 14.5mmol) was reacted with reduced iron powder (2.4g, 43.6mmol) in a mixed solution of acetic acid (30mL) and ethanol (50mL) for 2h under reflux; after the reaction was monito...

Embodiment 3

[0078] (1) Synthetic compound Ie 8-benzyloxy-2-methylquinoline (R=H)

[0079] Weigh compound Id 2-methylquinolin-8-ol (X=O, R=H, direct purchase) (5g, 31.4mmol) and potassium carbonate (6.5g, 47.1mmol) in a round bottom flask (50mL) Add benzyl bromide (3.8mL, 31.4mmol) and N,N-dimethylformamide (20mL) sequentially, heat the reaction system to 80°C and stir for 10h; after the reaction system is cooled, add water and ethyl acetate Extracted 3 times, the organic phase was washed again with water, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure; the crude product was separated and purified by silica gel column chromatography to obtain a white solid Ie8-benzyloxy-2-methylquinoline (R = H), the yield is 98%.

[0080] 1 H NMR (400MHz, CDCl3): δ = 8.00 (d, J = 8.4Hz, 1H), 7.52 (d, J = 7.2Hz, 2H), 7.40–7.27 (m, 6H), 7.01 (dd, J = 7.6 Hz,1.6Hz,1H),5.46(s,2H),2.81(s,3H); ESI-MSm / z:251.1[M+H] + .

[0081] (2) Synthetic compound Ie 8-benzyloxy...

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Abstract

The invention relates to the technical field of chemical synthesis, and specifically relates to a 2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative as well as preparation andapplication. The 2-carboxyl piperazine linked tacrine-8-amino(hydroxyl) quinoline derivative is a chemical compound shown in a formula I (the formula I is shown in the description) or a pharmaceutically acceptable salt thereof, and a solvent chemical compound, an enantiomer, a diastereoisomer, a tautomer or a mixture in any proportion of the chemical compound shown in the formula I or the pharmaceutically acceptable salt thereof, and includes a racemic mixture. Confirmed by a pharmacological test, the kind of chemical compound has an inhibiting effect on the activity of acetylcholinesterase(AChE) and butyrylcholinesterase(BuChE), and belongs to a cholinesterase inhibitor; the chemical compound also has an inhibiting effect on self-aggregation of beta-amyloid protein, and has delayed action on hydrolysis of acetylcholine and self-aggregation of the beta-amyloid protein, thereby improving the effect of the acetylcholine on a synapse, and finally realizing the purpose of effectively treating alzheimer's disease (AD).

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a 2-carboxypiperazine-linked tacrine-8-amino (hydroxyl) quinoline derivative and its preparation and application. Background technique [0002] Alzheimer's disease (AD) is also known as senile dementia. Clinically, the main symptoms of AD include: cognitive impairment, aphasia, executive and memory decline gradually, and eventually lead to death. Its pathogenic mechanism is not yet clear, and its onset is very insidious, age-related, and its prevalence increases with age. [0003] The pathogenic mechanism of AD has not yet been determined, but it is generally recognized that extracellular β-amyloid protein aggregates to form toxic oligomers, intracellular tau protein hyperphosphorylation forms neurofibrillary tangles, and cholinergic neurons Damage, leading to decreased cholinergic activity and so on. [0004] There are many pathogenic factors of AD and it is difficu...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/496A61P25/28
CPCC07D401/14A61P25/28
Inventor 董长治陈光银王静杜志云
Owner GUANGDONG UNIV OF TECH
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