4-methoxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof

An unsubstituted, alkoxy-based technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of terminating the disease process and single target

Active Publication Date: 2018-08-17
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 improve the cogn...

Method used

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  • 4-methoxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof
  • 4-methoxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof
  • 4-methoxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof

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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 4-methoxybenzaldehyde and D-tryptophan methyl ester hydrochloride or L-tryptophan methyl ester hydrochloride, thereby formin...

Embodiment 1

[0096] Example 1 (1R,3R)-1-(4-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (intermediate II-1) preparation of

[0097]

[0098] Add 817mg (6mmol) of 4-methoxybenzaldehyde, 1.528g (6mmol) of D-tryptophan methyl ester hydrochloride, and 20mL of isopropanol into a round-bottomed flask, and heat to reflux for 24 hours. After the reaction, spin off As a solvent, add an appropriate amount of saturated sodium bicarbonate solution to adjust the pH to 7-8, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and the residue is separated and purified by silica gel column chromatography. Eluted with ethyl acetate / petroleum ether=1 / 3, 876 mg of yellow solid was obtained with a yield of 43%.

[0099] 1 H NMR (400MHz, CDCl 3 )δ7.53(d, J=7.6Hz, 1H), 7.47(s, 1H), 7.29(d, J=8.5Hz, 2H), 7.21(d, J=6.9Hz, 1H), 7.18–7.08( m,2H),6.89(d,J=8.6Hz,2H),5.20(s,1H),3.97(dd,...

Embodiment 2

[0100] Example 2 (1S,3R)-1-(4-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (intermediate II-2) preparation of

[0101]

[0102] The specific implementation steps are the same as in Example 1, the solvent isopropanol is replaced by ethanol, the silica gel column chromatography is separated and purified, the eluent is ethyl acetate / petroleum ether=1 / 3-1 / 1, and 667 mg of white solid is obtained, and the yield is 33 %.

[0103] 1 H NMR (400MHz, CDCl 3 )δ7.55(d,J=6.6Hz,2H),7.17(ddd,J=22.0,13.9,6.0Hz,5H),6.86(d,J=8.5Hz,2H),5.41(s,1H), 3.99(t, J=6.0Hz, 1H), 3.79(s, 3H), 3.72(s, 3H), 3.28(dd, J=15.3, 5.3Hz, 1H), 3.15(dd, J=15.5, 6.5Hz ,1H).

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Abstract

The invention relates to a 4-methoxyphenyl 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 onacetylcholinesterase 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 of Alzheimer'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 4-methoxyphenyl substituted tetrahydro-β-carboline piperazine diketone derivative and application thereof. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease characterized by senile plaques, neurofibrillary tangle formation, and loss of hippocampal neurons. The main clinical manifestations are memory loss, cognitive dysfunction, aphasia, behavioral abnormalities, and social impairments, etc., and the condition usually worsens progressively until the complete loss of independent living ability, accompanied by a series of psychiatric symptoms (Goedert, M. Science, 2006, 314, 777-781). Due to its complex pathogenesis, so far, the medical community has not yet found effective prevention and treatment methods. [0003] AD is becoming a more common cause of death among older adults in the U.S. and other count...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/4985A61P25/28
CPCC07B2200/07C07D471/14
Inventor 李剑章海燕倪炜王欢毛斐王曼炯郑新羽龚琦
Owner EAST CHINA UNIV OF SCI & TECH
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