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Pregabalin derivative and application thereof

A technology of pregabalin and derivatives, applied in new pregabalin derivatives and their application fields, can solve problems such as limitation and wide application of side effects, and achieve obvious selectivity and significant resistance to acetylcholinesterase and butyrylcholine Effect of Esterase Activity

Active Publication Date: 2013-08-28
INSTITUTE OF ANALYSIS GUANGDONG ACADEMY OF SCIENCES (CHINA NATIONAL ANALYTICAL CENTER GUANGZHOU)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Acetylcholinesterase inhibitors such as tacrine, physostigmine, galantamine, zidoperidine, and huperzine A can enhance the cognitive ability of AD patients, but most drugs are not used because of their central or peripheral side effects. Its wide application is limited

Method used

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  • Pregabalin derivative and application thereof
  • Pregabalin derivative and application thereof
  • Pregabalin derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment one: the synthesis of 4-(8-bromooctyloxy)benzaldehyde (1f)

[0023] First add 2.4g (20mmol) p-hydroxybenzaldehyde, 15ml 1.8-dibromooctane and 5.52g (40mmol) potassium carbonate (microwave activation) into a 100ml round bottom flask, add 40ml of anhydrous acetone, and stir under reflux 24 hours. TLC tracked until the reaction was complete. Filter and spin dry the solvent to obtain the initial product. The yellow solid powder 1f was separated by silica gel column chromatography, and the yield was 63%. That 1 HNMR (CDCl 3 , 300MHz) δ, ppm data are: 9.86(s, 1H, CHO), 7.82(d, J=8.8Hz, 2H, ArH), 6.99(d, J=8.7Hz, 2H, ArH), 4.04(t, J=6.5Hz, 2H, H1), 3.20(t, J=7.0Hz, 2H, H8), 1.88-1.78(m, 4H, H7, H2), 1.42-1.30(m, 8H, H3, H4, H5 , H6). The structure of the product was thus determined.

[0024] 1a, 1b, 1c, 1d, 1e were prepared by the same method as above.

Embodiment 2

[0025] Embodiment two: BOC protects the synthesis of pregabalin p-n-octyloxybenzaldehyde ester (2f)

[0026] Take 2mmol of 4-(8-bromooctyloxy)benzaldehyde (1e) and 20ml of dry acetone in a 50ml flask, add 1.2g (5mmol) of KI, and stir overnight at room temperature. Then 0.54g (2mmol) of BOC-protected pregabalin and 1g (7.5mmol) of microwave-activated K 2 CO 3 Add the reaction system, heat up to 60°C and reflux for 24 hours. After treatment, potassium carbonate was removed by filtration, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography (developing solvent: 1:9 ethyl acetate:petroleum ether-1:2 ethyl acetate:petroleum ether gradient elution) to obtain BOC Protection of pregabalin p-n-octyloxybenzaldehyde ester (2f). product structure 1 HNMR analysis data confirmed.

[0027] 1 H NMR (CDCl 3 , 300MHz) δ, ppm: 9.86(s, 1H, CHO), 7.82(d, J=8.6Hz, 2H, ArH), 6.99(d, J=8.6Hz, 2H, ArH), 3.92(t, J= 6.2Hz, 2H,...

Embodiment 3

[0029] Example 3: Synthesis of BOC-protected pregabalin p-ethoxybenzyldiethylamino ester (3a).

[0030] Take 1 mmol of BOC-protected pregabalin p-n-butoxybenzaldehyde ester (2a), dissolve it in 20 ml of dry 1,2-dichloroethane, add 0.1 ml (1 mmol) of secondary amine and stir for 5 minutes. Then 0.7 g of sodium triacetoxyborohydride was added and stirred overnight. After the reaction was complete as detected by TLC, a saturated sodium bicarbonate solution was added to terminate the reaction, and extracted three times with ethyl acetate. The combined organic phases were dried. After the solvent was spin-dried, the crude product was subjected to silica gel column chromatography (developing solvent: 1:50 methanol:dichloromethane) to obtain BOC-protected pregabalin p-n-butoxybenzyldiethylamino ester (3a) as yellow oil. product structure 1 HNMR analysis data confirmed.

[0031] 1 H NMR (CDCl 3 , 300MHz) δ, ppm: 7.22 (d, J=8.6Hz, 2H, ArH), 6.84 (d, J=8.6Hz, 2H, ArH), 4.42-4.35 (...

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Abstract

The invention relates to a pregabalin derivative shown in formula I and application thereof in medicine for resisting senile dementia. Acetylcholinesterase in vitro test model shows that the pregabalin derivative has remarkable acetylcholinesterase resistance activity so as to be used for preparing the medicine for resisting senile dementia. The pregabalin derivative has the chemical structural formula shown by the formula I, and R in the formula is defined by the specification. Formula I.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to new pregabalin derivatives and applications thereof. technical background [0002] With the aging of the world's population, Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) has become one of the main diseases that threaten the life of the elderly in their later years. AD is an irreversible progressive degenerative disease of the brain. The clinical manifestation is memory loss accompanied by other cognitive function impairments, which leads to the loss of the ability to synthesize visual, auditory, tactile, olfactory and other information in advanced patients, resulting in the inability of patients to live independently. The pathogenesis of AD is complex, and the etiology is not yet fully understood, so far there is no good cure or reverse the course of the drug. At present, there are mainly three theories about the etio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/08C07D295/096C07C227/20A61K31/222A61K31/40A61K31/4453A61K31/5375A61P25/28
Inventor 俞亮潘文龙宋化灿万一千宋森川陈智勇陈泳孙一峰
Owner INSTITUTE OF ANALYSIS GUANGDONG ACADEMY OF SCIENCES (CHINA NATIONAL ANALYTICAL CENTER GUANGZHOU)
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