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Sulfydryl-containing tacrine derivative and preparation method and application thereof

A technology of tacrine and its derivatives, applied in medical preparations containing active ingredients, pharmaceutical formulas, drug combinations, etc., to achieve the effects of improving learning and memory, improving learning and memory ability, and overcoming liver toxicity

Inactive Publication Date: 2012-03-28
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] 20.8 ml (0.29 mol) of thioacetic acid was dissolved in 20 ml of tetrahydrofuran, slowly added dropwise to the tetrahydrofuran solution containing 16 ml (0.224 mol) of 3-bromopropionic acid, and 29.0 g of triethylamine was added as a catalyst. The temperature was controlled to 50°C and the reaction was stirred for 20 hours. Most of the tetrahydrofuran was removed by rotary evaporation, and the resulting colorless viscous liquid was allowed to stand for crystallization for 24 hours to obtain colorless needle-like crystals. Suction filtration, wash the filter cake with a small amount of tetrahydrofuran, and dry under reduced pressure to obtain 13.0 g of colorless bulk 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] Example 1-1: 2-(thioacetyl)propionic acid can be prepared in a similar manner to Example 1:

[0052] 2.28g (0.03mol) of thioacetic acid was dissolved in 10ml of tetrahydrofuran, slowly added dropwise to the 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 to 50°C and the reaction was stirred for 20 hours. The crystals precipitated in the reaction solution were removed by suction filtration, and most of the tetrahydrofuran was removed by rotary distillation 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, dissolve it in 10ml of dichloromethane, add 0.7g of HOBt, control the temperature at 20°C and stir for 10min, then add 1.0g of EDC·HCl, and then The temperature was controlled at 25° C. and stirred for 30 min, and then 0.84 g (0.0033 mol) of 9-(3-aminopropylamino)-5,6,7,8-tetrahydroacridine was added. The reaction was stopped after stirring at a temperature of 25 °C for 18 h, and saturated brine was added to the reaction system, and then the reaction solution was washed with 0.5 M dilute acid water, and then saturated NaHCO was used after separation. 3 The dichloromethane layer was washed with the solution, and the dichloromethane layer was washed with saturated brine again after separation. The obtained dichloromethane layer was purified by direct column chromatography with anhydrous magnes...

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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 mercaptacrine-containing derivatives and their synthesis methods. The mercaptacrine-containing derivatives of the present invention are mainly used for the treatment of Alzheimer's disease and similar diseases. Background technique [0002] Alzheimer’s disease (AD), also known as Alzheimer’s disease, is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and impairment of learning and memory. The main pathological characteristics are brain atrophy, Aβ aggregation to form senile plaques, and tau protein hyperphosphorylation to form neurofibrillary tangles. The clinical manifestations are progressive dementia, the cause of which is not yet clear. In recent years, the medical community has proposed a variety of etiological hypotheses, including the cholinergic function decline hypothesis, amyloid deposition hypothesis, oxidative damage hypothe...

Claims

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Application Information

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Patent Type & Authority Applications(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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