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Tacrine-beta-carboline conjoined multifunction cholinesterase inhibitor

A technology of tacrine and carboline, applied in the field of medicinal chemistry, can solve problems such as liver toxicity and side effects

Active Publication Date: 2014-08-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tacrine is the earliest FDA-approved drug for the treatment of AD. It can effectively inhibit cholinesterase, and its in vitro activity reaches nanomolar levels. However, due to its severe liver toxicity and side effects, it has withdrawn from clinical application in recent years.

Method used

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  • Tacrine-beta-carboline conjoined multifunction cholinesterase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of intermediate 3S-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (Ⅳ-2-a)

[0049] Add 10.2g (50mmol) of L-tryptophan (50mmol), 2.05g (55mmol) of sodium hydroxide solid, and 100mL of water into a 250mL single-necked bottle, stir until all the solids are dissolved, add acetaldehyde aqueous solution (6mL) at room temperature, and the reaction solution Stir at room temperature for 3 h, then heat to reflux for 3 h, and TLC detects that the starting material disappears (developing solvent: methanol / chloroform=1:1). Pour the reaction solution into ice water (100 mL), adjust the pH to 6 with glacial acetic acid, a large amount of white solids precipitated, cooled, filtered with suction, washed the filter cake with water, recrystallized from methanol to obtain 9.0 g of pale white solids, yield 83.5% . 1 H NMR (500MHz, DMSO): δ11.92(s, 1H), 10.97(s, 1H), 9.17(s, 1H), 7.42(d, J=7.5Hz, 1H), 7.29(t, J=8.0 Hz, 1H), 7.10(t, J=8.0Hz, 1H), 7.00(t, J=7.5Hz, 1H),...

Embodiment 2

[0051] Preparation of intermediate 3S-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (Ⅳ-3-a)

[0052] Intermediate IV-2-a (25 g, 116 mmol) and 580 mL of anhydrous methanol were added to a 1000 mL three-necked flask, and thionyl chloride (23 mL, 315 mmol) was slowly added dropwise with stirring at room temperature. After the dropwise addition, the temperature was raised to reflux, and the reaction was carried out for 6h. Cool the reaction liquid to room temperature, evaporate the solvent under reduced pressure, and recrystallize the obtained solid from methanol-ethyl acetate to obtain 29.6 g of a yellow solid, with a yield of 95.5%.

Embodiment 3

[0054] Preparation of intermediate β-carboline-3-carboxylic acid methyl ester (Ⅳ-4-a)

[0055] Intermediate IV-3-a (6.9g, 30mmol) was placed in a 100ml single-necked bottle, anhydrous DMF was added under ice-bath cooling and potassium permanganate (5.0g, 32mmol) was added in batches, and the reaction solution was overnight , the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to form a reddish-brown solid, which was recrystallized from ethyl acetate to obtain 3.3 g of a light yellow solid, with a yield of 67.4%.

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Abstract

The invention relates to the field of medicinal chemistry, and particularly relates to tacrine-beta-carboline conjoined compounds (I, II and III). The pharmacodynamic test proves that the compound disclosed by the invention can be used as a multifunction cholinesterase inhibitor, and can be clinically applied to treatment of an alzheimer disease.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of tacrine-beta-carboline heterobilinker compounds, which can be used as multifunctional cholinesterase inhibitors. Background technique [0002] Alzheimer's disease is referred to as AD. AD is a heterogeneous disease with multiple pathogenesis. Its causes are not only related to the decrease of choline level in the brain, but also related to the aggregation of Aβ, the disorder of metal ion metabolism, the disorder of calcium balance, the increase of free radicals and the occurrence of inflammation. and other factors are closely related. For the above etiology, the therapeutic targets of AD mainly include: acetylcholinesterase (AChE), metal ions, β-amyloid peptide (Aβ), monoamine oxidase (MAO), free radicals, tau protein, N-methyl-D-day Aspartate (NMDA) receptors and other related targets. At present, most of the drugs used to treat AD clinically belong to the single...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D401/12A61K31/473A61P25/28
CPCC07D401/12C07D471/04
Inventor 孔令义王小兵兰金帅
Owner CHINA PHARM UNIV
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