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3,4-methylenedioxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivatives and uses thereof

A phenyl, unsubstituted technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problem of terminating the disease process and single target

Active Publication Date: 2020-10-16
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have a single target and can only control or improve cognitive symptoms, but cannot fundamentally terminate the disease process

Method used

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  • 3,4-methylenedioxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivatives and uses thereof
  • 3,4-methylenedioxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivatives and uses thereof
  • 3,4-methylenedioxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivatives and uses thereof

Examples

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preparation example Construction

[0055] The preparation method of the compound of the present invention is not limited to the specific preparation method described in the present invention, and can optionally be combined with various synthetic methods described in this description or known in the art to make it conveniently. Such a combination can be obtained by It is easy for those skilled in the art to which the present invention pertains.

[0056] Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

[0057] The preparation method of the compound of the present invention may comprise the following steps:

[0058]

[0059] (1) In an inert solvent, carry out Pictet-Spengler reaction with piperonal and D-tryptophan methyl ester hydrochloride or L-tryptophan methyl ester hydrochloride, thereby forming the compou...

Embodiment 1

[0099] Example 1 Preparation of 3,4-methylenedioxybenzaldehyde

[0100]

[0101] Dissolve 1.521g (10mmol) of piperonyl alcohol in 20mL of dichloromethane, add 8.694g (100mmol) of active manganese dioxide, stir and react at room temperature for 16h, after the reaction is complete, filter with suction, and evaporate the solvent under reduced pressure to obtain a white solid 1.389 g, yield 93%.

[0102] 1 H NMR (400MHz, CDCl 3 )δ9.82(s,1H),7.42(dd,J=7.9,1.6Hz,1H),7.34(d,J=1.5Hz,1H),6.94(d,J=7.9Hz,1H),6.08( s,2H).

Embodiment 2

[0103] Example 2 (1R, 3R)-1-(3,4-methylenedioxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (intermediate II-1) Preparation

[0104]

[0105] Add 900mg (6mmol) of piperonal, 1.528g (6mmol) of D-tryptophan methyl ester hydrochloride, and 20mL of isopropanol into a round-bottomed flask, heat and reflux for 24 hours, spin off the solvent after the reaction, and add an appropriate amount of Adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, separate and purify the residue by silica gel column chromatography, ethyl acetate / petroleum Ether = 1 / 3 was eluted to obtain 1.581 g of a yellow solid with a yield of 75%.

[0106] 1 H NMR (400MHz, Acetone-d 6 )δ9.54(s,1H),7.49(d,J=7.4Hz,1H),7.25(d,J=7.5Hz,1H),7.08–6.97(m,2H),6.95(d,J=7.9 Hz,1H),6.86(s,1H),6.82(d,J=7.9Hz,1H),5.98(s,2H),5.23(s,1H),3.93(dd,J=...

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Abstract

The present invention relates to a 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof, and specifically discloses a compound represented by a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each group is defined in the specification. According to the present invention, the compound has dual inhibitory activity on acetylcholinesterase and phosphodiesterase 5, and has good blood-brain barrier permeability, such that the compound can be used for preparing drugs for treatment and / or prevention ofAlzheimer's diseases. The formula I is defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and in particular relates to a 3,4-methylenedioxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivative and its application. Background technique [0002] Alzheimer's disease (AD) is a complex central nervous system disease characterized by senile plaques, formation of neurofibrillary tangles, and loss of hippocampal neurons. Its main clinical manifestations are memory loss, cognitive dysfunction, etc., and even complete loss of independent living ability in severe cases (Goedert, M. Science, 2006, 314, 777-781). Every 7 seconds in the world, there is one AD patient. However, due to its complex pathogenesis, the medical community has not yet found an effective prevention and treatment method. [0003] According to the report "Global Impact of Alzheimer's Disease: 2013-2050", the number of Alzheimer's patients in the world will increase significantly i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14A61K31/4985A61P25/28
CPCC07D471/14
Inventor 李剑章海燕毛斐王欢倪炜王曼炯郑新羽凌大正龚琦
Owner EAST CHINA UNIV OF SCI & TECH
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