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Sulfydryl-containing tacrine derivative and preparation method and application thereof

A technology of tacrine and derivatives, which is used in medical preparations, pharmaceutical formulations, and drug combinations containing active ingredients to achieve the effects of improving learning and memory, improving learning and memory ability, and overcoming liver toxicity

Inactive Publication Date: 2014-04-09
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Enhancing or facilitating the production of hippocampal LTP can enhance the learning and memory ability of experimental animals, and blocking the production of hippocampal LTP will seriously affect the learning and memory ability

Method used

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  • Sulfydryl-containing tacrine derivative and preparation method and application thereof
  • Sulfydryl-containing tacrine derivative and preparation method and application thereof
  • Sulfydryl-containing tacrine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Preparation of 3-(thioacetyl)propionic acid

[0050] 20.8ml (0.29mol) of thioacetic acid was dissolved in 20ml of tetrahydrofuran, slowly added dropwise to the tetrahydrofuran solution containing 16ml (0.224mol) of 3-bromopropionic acid, and 29.0g of triethylamine was added as a catalyst. The temperature was controlled at 50°C and the reaction was stirred for 20 hours. Most of the tetrahydrofuran was removed by rotary evaporation, and the obtained colorless viscous liquid was left to stand for crystallization for 24 hours to obtain colorless needle-like crystals. Suction filter and wash the filter cake with a small amount of tetrahydrofuran, and dry under reduced pressure to obtain 13.0 g of colorless massive crystals with a yield of 39.2%. 1 H-NMR (DCCl 3 , 400MHz, δ / ppm): 11.0(s, 1H), 3.08(t, J=7.2Hz, 2H), 2.66(t, J=7.2Hz, 3H), 2.32(s, 3H).

Embodiment 1-1

[0051] Embodiment 1-1: 2-(thioacetyl) propionic acid can be prepared in a method similar to that of Example 1:

[0052] 2.28g (0.03mol) of thioacetic acid was dissolved in 10ml of tetrahydrofuran, slowly added dropwise to a solution containing 4.56g (0.03mol) of 2-bromopropionic acid in tetrahydrofuran, and 3.0g of triethylamine was added as a catalyst. The temperature was controlled at 50°C and the reaction was stirred for 20 hours. The precipitated crystals in the reaction solution were filtered off with suction, and most of the tetrahydrofuran was removed by rotary evaporation of the filtrate to obtain 2.4 g of a yellow liquid with a yield of 54%. 1 H-NMR (DCCl 3 , 400MHz, δ / ppm): 12.99(s, 1H), 4.02(q, J=7.2Hz, 1H), 2.32(s, 3H), 1.37(d, J=7.2Hz, 3H).ESI-MS: [M-1] - =146.8.

Embodiment 2

[0053] Example 2 Preparation of 3-thioacetyl-N-((5,6,7,8-tetrahydroacridinyl-9-amino)propylamino)propionamide

[0054]

[0055] Weigh 0.444g (0.003mol) of 3-(thioacetyl)propionic acid and dissolve it in 10ml of dichloromethane, add 0.7g of HOBt, stir at 20°C for 10min, then add 1.0g of EDC·HCl, and then The temperature was controlled at 25°C and stirred for 30 minutes, and then 0.84 g (0.0033 mol) of 9-(3-aminopropylamino)-5,6,7,8-tetrahydroacridine was added. Control the temperature at 25°C and stir for 18 hours to stop the reaction, add saturated brine to the reaction system, then wash the reaction solution with 0.5M dilute acid, separate the liquid and then wash it with saturated NaHCO 3 The dichloromethane layer was washed with the solution, the layers were separated and the dichloromethane layer was washed again with saturated brine. Separation of the obtained dichloromethane layer with anhydrous magnesium sulfate, direct column chromatography purification (dichlorome...

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Abstract

The invention provides a sulfydryl-containing tacrine compound or a dynamic isomer or a medicinal salt thereof. The compound or the dynamic isomer or the medicinal salt thereof have the functions of suppressing acetylcholine esterase, enhancing sea horse LTP (Long-Term Potentiation) and improving learning and memory, and can be used for treating, improving or preventing cognitive function decline-related neurous system diseases such as the Alzheimer's disease, vascular dementia, mild cognitive impairment and other oxidative stress participated dementia.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a mercaptotacrine derivative and a synthesis method thereof. The mercaptotacrine derivative of the invention is mainly used for the treatment of Alzheimer's disease and similar diseases. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and learning and memory impairment. The main pathological features are brain atrophy, Aβ aggregation to form senile plaques, and tau hyperphosphorylation to form neurofibrillary tangles. The clinical manifestation is progressive dementia, and its etiology is not yet clear. In recent years, the medical community has put forward a variety of etiological hypotheses, mainly including the hypothesis of cholinergic function decline, the hypothesis of amyloid protein deposition, the hypothesis of oxidative damage cau...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D219/12A61K31/473A61P25/28
Inventor 陈建国姜凤超王芳王悦关鑫磊吴鹏飞张俊琦
Owner HUAZHONG UNIV OF SCI & TECH
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