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Tacrine heterocomplex, preparation method and use in medicines for curing neurodegenerative diseases thereof

A technology of tacrine and hybrids, applied in the field of medicine and chemical industry, to achieve the effects of high inhibition, high changes in the aggregation properties of β-amyloid protein, and strong inhibitory activity

Inactive Publication Date: 2011-11-02
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the curative effect of tacrine on senile dementia is certain, especially it has a strong inhibitory activity on cholinesterase, so the research on tacrine derivatives has not stopped.

Method used

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  • Tacrine heterocomplex, preparation method and use in medicines for curing neurodegenerative diseases thereof
  • Tacrine heterocomplex, preparation method and use in medicines for curing neurodegenerative diseases thereof
  • Tacrine heterocomplex, preparation method and use in medicines for curing neurodegenerative diseases thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] N-(1,2,3,4-tetrahydroacridin-9-amino)octyl-isonicotinamide.

[0043] N 1 -(1,2,3,4-tetrahydroacridine-9-amino)butyl-1,8-octanediamine (1.0 mmol) was dissolved in anhydrous dichloromethane, and pyridine-4-carboxylic acid was added under stirring (1.0 mmol), N , N '-Isopropylcarbodiimide (DIC, 1.1 mmol) and 4-dimethylaminopyridine (DMAP, 0.5 mmol), stirred overnight at room temperature. Wash with water, take the organic layer, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate the residue by column chromatography. The eluent is chloroform:methanol:ammonia=40:1:0.5%. A white solid was obtained.

[0044] Yield: 50%, m.p. 90-92℃, 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 3.85 (s, 1H), 3.47 (t, J = 7.2 Hz, 2H), 3.38 (dd, J = 13.8, 6.6 Hz, 2H), 3.00 (s, 2H), 2.67 (s, 2H), 1.87 (t, J = 3.0 Hz, 4H),...

Embodiment 2

[0046]

[0047] N 1 -(pyridine-4-methylene)-N 8 -(1,2,3,4-Tetrahydroacridin-9-amino)octyl-1,8-octanediamine.

[0048] N 1 -(1, 2, 3, 4-tetrahydroacridine-9-amino)butyl-1,8-octanediamine (1.0mmol) was dissolved in anhydrous methanol, and pyridine-4-carboxaldehyde (1.0 mmol), after stirring overnight at room temperature, sodium borohydride (6.0 mmol) was added under cooling in an ice bath, and the reaction was allowed to rise to room temperature naturally for 8 hours. After concentration, add water, extract with ethyl acetate, dry, concentrate, and separate by column chromatography. The eluent uses chloroform:methanol:ammonia=35:1:0.5%. A pale yellow oily liquid was obtained.

[0049] Yield: 52%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J = 6.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.34 – 7.29 (m, 1H), 7.23 (d, J = 5.9 Hz, 2H), 3.76 (s, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.05 (s, 2H), 2.67 (s, 2H), 2.57 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 3.2 Hz, 4H), 1.71 – 1.57 (m,...

Embodiment 3

[0051]

[0052] 4-{6-(1,2,3,4-tetrahydroacridin-9-amino)hexylamino-methylene}phenol.

[0053] Method is the same as embodiment two, and difference is to use N 1 -(1,2,3,4-tetrahydroacridin-9-amino)hexyl-1,6-hexanediamine instead of N 1 -(1, 2, 3, 4-tetrahydroacridine-9-amino)octyl-1,8-octanediamine, p-hydroxybenzaldehyde instead of pyridine-4-carbaldehyde, and finally a light yellow oily liquid was obtained.

[0054] Yield: 33%, 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (t, J = 9.1 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 5.98 (s, 1H), 4.09 (s, 1H), 3.66 (s, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.04 (s, 2H), 2.72 – 2.51 (m, 4H), 1.86 (d, J = 2.8 Hz, 4H), 1.69 – 1.56 (m, 2H), 1.57 – 1.45 (m, 2H), 1.32 (dd, J = 6.3, 3.2 Hz, 4H). 13 C NMR (100 MHz, CDCl 3) δ 157.98, 157.20, 151.33, 146.64, 129.66, 129.26, 128.70, 127.66, 123.70, 123.01, 119.84, 115.89, 115.30, 53.21, 49.28, 48.72, 33.11, 31.62,...

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Abstract

The invention belongs to the field of medicines and chemical industries, and discloses a method for preparing a series of tacrine heterocomplexes and use in medicines for curing neurodegenerative diseases. The invention further relates to use of the tacrine heterocomplex for preparing medicines for curing the neurodegenerative diseases independently or with other medicines. The structural formula of the tacrine heterocomplex is as follows: FORMULA, wherein when X is O or CH2 and Y is N, R1, R2 and R3 are H; n is 2, 3, 4, 5, 6, 8, 9, 10, 11 or 12; when X is O or CH2 and Y is C, R1 is H, OH or OCH3; R2 is H, OH or OCH3; R3 is H, OH or OCH3; R4 is H, OH or OCH3; and n is2, 3, 4, 5, 6, 8, 9, 10, 11 or 12. The tacrine heterocomplex disclosed by the invention has strong inhibitory activity to acetylcholinesterase (AChE) and butyrylcholine esterase (BuChE), which are effectively used for curing the neurodegenerative diseases, such as Alzheimer's diseases.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and discloses a series of preparation methods of tacrine hybrids and their application in the preparation of medicines for treating neurodegenerative diseases. The present invention also relates to the application of the tacrine hybrid alone or in combination with other drugs in the preparation of drugs for treating neurodegenerative diseases. Background technique [0002] Alzheimer's disease (Alzheimer disease, AD) is a neurodegenerative disease discovered by German neuropathologist Alois Alzheimer in 1907. The pathological features of senile plaques appear outside. Clinically, patients gradually develop memory loss, cognitive dysfunction, behavioral abnormalities, and social barriers. Usually, the condition is progressively aggravated until they completely lose the ability to live independently. [0003] Alzheimer's disease is a very common neurodegenerative disease among the eld...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D219/12C07D405/12A61K31/473A61P25/28A61P25/16A61P9/10
Inventor 黄志纾古练权罗稳谭嘉恒黄世亮贺彦
Owner SUN YAT SEN UNIV
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