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Tacrine- nicotinic acid conjugate, preparation method and medical application thereof

A compound and medicinal salt technology, applied in tacrine-nicotinic acid conjugates, in the application field of Alzheimer's disease treatment, can solve the problems of high liver toxicity, cognitive function defects, and large dosage

Inactive Publication Date: 2014-06-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are two main problems with tacrine: (1) hepatotoxicity is relatively high, and patients need to undergo strict monitoring of transaminases while taking the drug; (2) compared with other AD treatment drugs such as donepezil, the dosage is relatively large, and 80 mg is required in the later stage of treatment / d
Green et al evaluated the therapeutic effect of nicotinamide in transgenic AD mice and found that nicotinamide can reverse the cognitive deficits of AD transgenic mice

Method used

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  • Tacrine- nicotinic acid conjugate, preparation method and medical application thereof
  • Tacrine- nicotinic acid conjugate, preparation method and medical application thereof
  • Tacrine- nicotinic acid conjugate, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of N-(6-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)hexyl)nicotinamide

[0054] (1) 9-Chloro-2,3-dihydro-1H-cyclopenta[b]quinoline

[0055]

[0056] Anthranilic acid (5.55g, 40.5mmol) and cyclopentanone (4.02ml, 45mmol) were placed in a 100ml three-necked flask, and 33.6ml of POCl was slowly added dropwise under an ice bath 3 , heated to reflux at 105°C for 3h, allowed to cool to room temperature, spin-dried under reduced pressure and vacuum, mixed solvent CH 2 Cl 2 .CH 3 Dissolve in OH (100ml, v:v=2:1), neutralize with saturated potassium carbonate, wash with saturated brine (200ml*5), dry the organic layer over anhydrous sodium sulfate, and separate by column chromatography (PE:EtOAc, v:v= 20:4) to obtain 5.76 g of 9-chloro-2,3-dihydro-1H-cyclopenta[b]quinoline with a yield of 70%. m.p.58-61℃. 1 H NMR (CDCl 3 , 500MHz): 8.17-8.15 (1H, d, J=8.35Hz), 8.05-8.03 (1H, d, J=8.35Hz), 7.69-7.66 (1H, t, J=8.2Hz), 7.58-7.55 ( 1H, t, J=8.05Hz), 3.26-3...

Embodiment 2

[0064] Preparation of N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)nicotinamide

[0065] (1) 9-chloro-1,2,3,4-tetrahydroacridine

[0066]

[0067] Anthranilic acid (5.55g, 40.5mmol) and cyclohexanone (4.02mL, 45.0mmol) were added to a 100ml three-necked flask, and 33.6ml of POCl was slowly added dropwise under an ice bath 3 , Reflux at 105°C for 3h, and let the reaction solution cool to room temperature. Spin dry under reduced pressure, mixed solvent CH 2 Cl 2 :CH 3Dissolve in OH (100ml, v:v=2:1), neutralize with saturated potassium carbonate, wash with saturated brine (200ml*5), dry the organic layer over anhydrous sodium sulfate, and separate by column chromatography (PE:EtOAc, v:v= 20:4), to obtain 4.8 g of solid 9-chloro-1,2,3,4-tetrahydroacridine. m.p.67-69℃, hydrogen spectrum data consistent with literature reports.

[0068] (2)N 1 -(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine

[0069]

[0070] 9-Chloro-1,2,3,4-tetrahydroacridine (2.17g, 1mmol) a...

Embodiment 3

[0075] Preparation of N-(7-(1,2,3,4-tetrahydroacridin-9-ylamino)heptyl)nicotinamide

[0076] (1)N 1 -(1,2,3,4-tetrahydroacridin-9-yl)heptane-1,7-diamine

[0077]

[0078] Reference Example 2, using 9-chloro-1,2,3,4-tetrahydroacridine and 1,7-heptanediamine as raw materials to synthesize viscous compound N 1 -(1,2,3,4-tetrahydroacridin-9-yl)heptane-1,7-diamine, yield: 75%. 1 H NMR (DMSO-d6, 300MHz): 8.20-8.17 (1H, d, J=8.76Hz), 7.69-7.66 (1H, d, J=8.16HZ), 7.54-7.49 (1H, t, J=6.90Hz ), 7.35-7.30(1H, t, J=7.92Hz), 3.51-3.50(2H, m), 3.24-3.23(2H, m), 3.03-3.01(2H, m), 2.89-2.84(2H, m ), 2.76-2.73 (4H, m), 2.09-2.00 (4H, m), 1.52 (6H, br); MS (m / z): 312.2 [M+H] + .

[0079] (2) N-(7-(1,2,3,4-tetrahydroacridin-9-ylamino)heptyl)nicotinamide

[0080]

[0081] Referring to Example 2, with N 1 Synthesis of N-(7-(1,2,3,4-tetrahydro Acridin-9-ylamino)heptyl)nicotinamide, yield 85%. 1 H NMR (CDCl 3 , 500MHz): 9.06-9.05 (d, 1H, J=1.65Hz), 8.68-8.66 (dd, 1H, J 1 = 4.8Hz,J ...

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Abstract

The invention relates to the medical field and in particular relates to tacrine- nicotinic acid conjugates. The invention further discloses a preparation method of the tacrine- nicotinic acid conjugates as well as medical salts, pharmaceutical compositions or pharmaceutical agents containing the compounds and application of the compounds in medicines, especially treating Alzheimer disease.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a class of tacrine-niacin conjugates. The present invention also discloses the preparation method of these tacrine-nicotinic acid conjugates and the pharmaceutically acceptable salts, pharmaceutical compositions or pharmaceutical preparations containing said compounds, and said compounds are used in medicine, especially in the treatment of Alzheimer's disease. application in disease. Background technique [0002] Alzheimer's disease (AD), commonly known as senile dementia, is a progressive and fatal neurodegenerative disease characterized by cognitive impairment and memory impairment. With the aging of the population, the prevalence of AD has also increased significantly. There are more than 6 million AD patients in my country, ranking first in the world, and it is the fourth leading killer of the elderly. The pathogenic mechanism of AD is not completely clear, and there are more than t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/473A61P25/28
CPCC07D401/12
Inventor 查晓明许常旭张莉莉康迪陈莉徐云根张陆勇
Owner CHINA PHARM UNIV
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