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Dimer of rivastigmine, caffeic acid and ferulic acid, preparation method and pharmaceutical composition thereof

A technology for preparing medicines and compositions, applied in the field of derivatives of Ming, can solve problems such as unclear central action

Active Publication Date: 2017-06-27
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional view is that because BuchE is mainly distributed in the periphery, its central role is not clear, and inhibition of BuchE may bring certain peripheral side effects, so this enzyme is not suitable as a target for AD drugs

Method used

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  • Dimer of rivastigmine, caffeic acid and ferulic acid, preparation method and pharmaceutical composition thereof
  • Dimer of rivastigmine, caffeic acid and ferulic acid, preparation method and pharmaceutical composition thereof
  • Dimer of rivastigmine, caffeic acid and ferulic acid, preparation method and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] (2E)-3-(3,4-dihydroxyphenyl)-N-(3-{[ethyl(methyl)carbamoyl]amino}phenyl)-2-acrylamide

[0040] Reagents: caffeic acid (109 mg, 0.53 mmol), 3-(3-aminophenyl)-1-ethyl-1-methylurea (111 mg, 0.53 mmol).

[0041] Purification: CHCl3 / MeOH (9.5:0.5). Silica gel column chromatography using CHCl3 / MeOH (9.5:0.5). Yellow solid, yield: 81 mg (43%).

[0042] mp 110-112°C;

[0043] 1 H NMR (CD 3 OD) δ: 1.17(t, 3H, J=7.2Hz, CH 3 ), 3.01 (s, 3H, CH 3 ), 3.43(q, 1H, J=7.2Hz, CH 2 ), 6.55(d, 1H, J=15.4Hz, CH=), 6.78(d, 1H, J=8.0Hz, Ar), 6.95(dd, 1H, J=1.6, 8.0Hz, Ar), 7.05(d , 1H, J=1.6Hz, Ar), 7.11(d, 1H, J=8.0Hz, Ar), 7.22(t, 1H, J=8.0Hz, Ar), 7.34(d, 1H, J=8.0Hz, Ar), 7.51(d, 1H, J=15.4Hz, CH=), 7.70(s, 1H, Ar) ppm;

[0044] 13 C NMR (Acetone-d 6 ( 19 h 21 N 3 o 4 ) Calc %: C 64.21, H 5.96, N 11.82; Trov %: C 64.47, H 6.08, N 11.69.

Embodiment 2

[0046]

[0047] (2E)-N-(3-{[Ethyl(methyl)carbamoyl]amino}phenyl)-3-(4-hydroxy-3-methoxyphenyl)-2-acrylamide

[0048] Reagents: ferulic acid (92 mg, 0.48 mmol), 3-(3-aminophenyl)-1-ethyl-1-methylurea (100 mg, 0.48 mmol).

[0049] Purification: silica gel column chromatography using CHCl 3 / MeOH (9.8:0.2). Yellow solid, yield: 71 mg (40%). mp112-115℃;

[0050] 1 H NMR (CD 3 OD) δ: 1.18(t, 3H, J=7.2Hz, CH 3 ), 3.02(s, 3H, CH 3 ), 3.44(q, 1H, J=7.2Hz, CH 2 ), 3.91 (s, 3H, OCH 3 ), 6.55(d, 1H, J=15.6Hz, CH=), 6.82(d, 1H, J=8.2Hz, Ar), 7.09(dd, 1H, J=1.8, 8.2Hz, Ar), 7.12(d , 1H, J=8.0Hz, Ar), 7.17(d, 1H, J=1.8Hz, Ar), 7.22(t, 1H, J=8.0Hz, Ar), 7.35(d, 1H, J=8.0Hz, Ar), 7.57(d, 1H, J=15.6Hz, CH=), 7.70(s, 1H, Ar) ppm;

[0051] 13 C NMR (Acetone-d 6 ( 20 h 23 N 3 o 4 ) Calc %: C 65.03, H 6.28, N 11.37; Trov %: C 65.32, H 6.44, N 11.53.

Embodiment 3

[0053]

[0054] 3-{[(2E)-3-(3,4-dihydroxyphenyl)-2-acryloyl]amino}phenylethyl(methyl)carbamate

[0055] Reagents: caffeic acid (167 mg, 0.93 mmol), 3-aminophenylethyl (methyl) carbamic acid (180 mg, 0.93 mmol).

[0056] Purification: silica gel column chromatography using CHCl 3 / MeOH (9.5:0.5) was used as the eluent, followed by precipitation from ethyl acetate / n-hexane. Yellow solid, yield: 278 mg (84%).

[0057] mp 193-195°C;

[0058] 1 H NMR (Acetone-d 6 )δ: 1.15(t, 1.5H, J=7.0Hz, CH 3 rotamer), 1.24(t, 1.5H, J=7.0Hz, CH 3 rotamer), 2.95(s, 1.5H, CH 3 rotamer), 3.08(s, 1.5H, CH 3 rotamer), 3.37(q, 1H, J=7.0Hz, CH 2 rotamer), 3.49 (q, 1H, J=7.0Hz, CH 2 rotamer), 6.59 (d, 1H, J=15.4Hz, CH=), 6.81-6.84 (m, 1H, Ar), 6.87 (d, 1H, J=8.0Hz, Ar), 6.99 (dd, 1H, J =8.0, 2.1Hz, Ar), 7.10(d, 1H, J=2.1Hz, Ar), 7.28(dd, 1H, J=8.4, 8.0Hz, Ar), 7.47(d, 1H, J=8.4Hz, Ar), 7.54 (d, 1H, J=15.4Hz, CH=), 7.73 (s, 1H, Ar) ppm;

[0059] 13 C NMR (Acetone-d 6 )δ: 164.18, 153.83, ...

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Abstract

The present invention relates to synthesis of a series of rivastigmine derivatives, wherein the structural formula is represented by a formula (I). According to the present invention, with the substituent changing, the inhibition of acetylcholine / butyrylcholine esterase by adjusting the rivastigmine derivatives, the inhibition of glutamic acid-induced oxidative stress, the reduction of damage of H2O2 and other ROS on HT22 cells, the inhibition of beta-amyloid protein self-aggregation, and the clearing of DPPH free radicals, the rivastigmine derivatives can simultaneously act on multiple targets. The rivastigmine derivatives can be made into the suitable pharmaceutical dosage form for Alzheimer's disease treatment.

Description

[0001] field of invention [0002] The present invention relates to the synthesis of a series of derivatives of rivastigmine, the structural formula of which is shown in formula (I). By changing substituents, it can be adjusted to inhibit ethyl / butyrylcholinesterase, inhibit glutamate-induced oxidative stress, and reduce H 2 o 2 The ability of ROS to damage HT22 cells, inhibit the self-aggregation of β-amyloid protein and scavenge DPPH free radicals enables it to act on multiple targets at the same time. They can be made into appropriate pharmaceutical dosage forms for treating Alzheimer's disease. [0003] Background of the invention [0004] The disease was first reported by German psychiatrist Eros Alzheimer in 1907, hence the name Alzheimer's disease (AD). Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. It is manifested as short-term memory loss in the early stage. With the development of the di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/44C07C269/06C07C275/40C07C273/18A61K31/17A61K31/27A61K9/00A61P25/28
Inventor 皮荣标杨晓红西蒙娜·拉波塞利陈紫薇王胜男褚佳琪涂亚林刘培庆玛丽亚·迪伽默马尔科·马基亚
Owner SUN YAT SEN UNIV
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