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Tetrahydro-beta-carboline dimer as well as preparation method and application thereof

A carboline dimer, carboline technology, which is applied in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problem of incompletely clear pathogenesis, poor long-term efficacy, mental and economic burden, etc. question

Active Publication Date: 2020-09-18
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the pathogenesis of AD is not completely clear, the current treatment of AD has limitations, there is no fundamental treatment, and the long-term curative effect is poor. AD will inevitably affect the quality of life of the elderly population in our country, causing serious harm to patients, families and society. mental and financial burden

Method used

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  • Tetrahydro-beta-carboline dimer as well as preparation method and application thereof
  • Tetrahydro-beta-carboline dimer as well as preparation method and application thereof
  • Tetrahydro-beta-carboline dimer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] 1-Methyl-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carbaline

[0069] a, L-tryptophan methyl ester

[0070]

[0071] Add SOCl dropwise to 450 mL methanol solution in ice bath 2 (4ml, 55.1mmol), after the dropwise addition was completed, the ice bath was removed, and after stirring at room temperature for 1h, L-tryptophan (5g, 24.5mmol) was added, stirred at room temperature overnight, TLC detected that the reaction was complete, and the solvent was evaporated under reduced pressure to obtain Add a small amount of water to dissolve the white solid, repeat several times, then add a certain amount of water, slowly add ammonia water to adjust the pH=7-8, add dichloromethane to dissolve, extract 3 times, 30ml each time, combine the organic layer, After drying with anhydrous sodium sulfate and concentrating dichloromethane, 3.7 g of viscous solid was obtained, with a yield of 69.2%. ESI-MS m / z:219.1[M+H] + , The relative molecular mass is 218.

[0072] b, Preparation of 1...

Embodiment 2

[0076] Preparation of 1-phenyl-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carbaline (compound 31)

[0077]

[0078] L-tryptophan methyl ester (1.0g, 4.58mmol) was dissolved in 20ml of anhydrous DCM, and trifluoroacetic acid TFA (2ml, 26.8mmol) was added dropwise under ice-bath conditions. After the dropwise addition, the ice bath was removed. After stirring at room temperature for 0.5 h, benzaldehyde (2 ml, 19.6 mmol) was added and reacted at room temperature for 12 h. TLC detected the completion of the reaction, adjusted the pH to 8-9 with ammonia water, extracted the reaction solution with 40 mL of dichloromethane, washed 3 times with saturated brine, 20 mL each time, dried the organic layer with anhydrous sodium sulfate, and evaporated the solvent under reduced pressure. Separation and purification by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate (1:2), to obtain 0.68 g of a light brown solid with a yield of 48.4%. Identified as 1-phenyl-3-...

Embodiment 3

[0080] Preparation of 2-chloro-1-(1-methyl-1,2,3,4-tetrahydro-β-carbaline-3-carboxylic acid methyl ester)ethanone (compound 37)

[0081]

[0082] Dissolve compound 1 (200mg, 0.820mmol) in anhydrous CHCl 3 , add NaHCO 3 (82mg, 0.982mmol / L), after stirring for 30min, slowly added 2-chloroacetyl chloride (97μL, 1.23mmol) dissolved by an appropriate amount of chloroform, and reacted at room temperature for 6h under nitrogen dry conditions, after the reaction was detected by TLC, The reaction solution was filtered, the solvent was evaporated under reduced pressure, an appropriate amount of dichloromethane was added, and saturated NaHCO 3 Solution extraction, multiple extractions, combined organic layers, distilled off the solvent under reduced pressure to obtain a brown viscous substance, which was separated and purified by silica gel column chromatography, the eluent was dichloromethane:methanol (50:1), and 160 mg of light yellow powder was obtained. The yield was 60.9%. Ide...

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Abstract

The invention discloses an application of a tetrahydro-beta-carboline dimer derivative in the preparation of a medicine for preventing or treating Alzheimer's disease. The tetrahydro-beta-carboline dimer derivative is as shown in a structural formula I, which is described in the specification, L-tryptophan and tryptamine are used as raw materials; a tetrahydro-beta-carboline monomer is generated through a Picet-Spengler reaction and aldehyde cyclization, then a tetrahydro-beta-carboline dimer is generated through acyl chloride connection and a click chemical reaction, the synthesis steps are simple, the raw materials are easy to obtain, the yield is high, and the tetrahydro-beta-carboline dimer has remarkable inhibitory activity on butyrylcholine esterase and A[beta]1-42 aggregation. According to the neural protective effect under three AD models on cells, after the cells are independently treated by A[beta]1-42, H2O2 and OA, the survival rate of the cells is low, and apoptosis or necrosis of the cells occurs. The compounds 11, 12, 13, 17 and 19 are used for co-treatment, the compounds 11, 12, 13, 17 and 19 successfully block A[beta]1-42, H2O2 and OA induced cell death, and it is proved that the compounds 11, 12, 13, 17 and 19 have a remarkable neural protective effect.

Description

technical field [0001] The present invention relates to compounds and their preparation methods and uses, in particular to tetrahydro-β-carbaline dimers and their preparation methods, as well as their use in the preparation of neuroprotective drugs and drugs for treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Its main clinical manifestations are progressive memory loss, cognitive dysfunction, abnormal behavior and social impairment. The etiology and pathogenesis of Alzheimer's disease are not completely clear, but there are many hypotheses, including cholinergic damage hypothesis, Aβ toxicity hypothesis, Tau protein hypothesis, insulin hypothesis, free radical damage hypothesis and so on. The typical pathological changes in AD are senile plaques (senile plaques, SPs) formed by the deposition of β-amyloid protein and neurofibrillary tangles (neurofibrillary tangles, NFTs) in the nerve ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/496A61K31/437A61P25/28
CPCC07D519/00A61P25/28
Inventor 冯锋曲玮廖清宏柳文媛孙昊鹏赵依凡
Owner CHINA PHARM UNIV
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