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Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof

A technology of dihydroartemisinin and bromoalkyldihydroartemisinin, which is applied in the field of medicinal chemistry, can solve the problems of lack of therapeutic drugs, etc., and achieve the effect of simple preparation process and excellent curative effect

Active Publication Date: 2016-07-06
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The incidence of Alzheimer's disease is increasing year by year, but there is still a lack of ideal therapeutic drugs. The research on the pathogenesis of AD and the development of new therapeutic drugs still need to be further studied

Method used

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  • Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof
  • Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof
  • Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of 12-beta-12-O-(2-memantine amino) ethyl dihydroartemisinin (ZLT-1) comprises the following three steps:

[0047] (1) Preparation of dihydroartemisinin: Dissolve artemisinin (565mg, 2.0mmol) in 50mL methanol, pre-cool in ice bath for 5min, then add NaBH in batches 4 (151mg, 4.0mmol), the reaction was continued for 3h under ice-bath conditions. After the reaction, neutralize excess NaBH with 50% AcOH / MeOH under ice-bath condition 4 , adjust the pH value to 6-7 until no more bubbles are produced. Remove methanol, add cold water, stir for 15 minutes, filter with suction, and wash the filter cake with water. The product was dissolved in DCM and dried over anhydrous sodium sulfate to obtain 482 mg of flocculent white solid with a yield of 85%.

[0048]The analytical data of the product are as follows: 1 HNMR (300MHz, CDCl 3 )δ:0.91-0.95(m,12H),1.22-1.25(m,1H),1.25-1.29(m,2H),1.29-1.32(m,1H),1.41(d,J=3.0Hz,6H) ,1.45-1.52(m,3H),1.63-1.68(m,2H),1.68-1.91(m,...

Embodiment 2

[0055] The synthesis of 12-β-12-O-(4-memantine amino) n-butyldihydroartemisinin (ZLT-2) comprises the following four steps:

[0056] (1) Preparation of dihydroartemisinin: steps are the same as step (1) in Example 1;

[0057] (2) Preparation of 4-bromobutanol: Dissolve 1,4-butanediol (1.8g, 20mmol) in 60mL of benzene, add HBr (2.4mL, 20mmol), and reflux for 2h. After the reaction, the benzene in the benzene layer was removed by rotary evaporation. The resulting substance was subjected to column chromatography [V (petroleum ether): V (ethyl acetate) = 5:1] to obtain 0.3 g of a colorless oil. Yield 10%.

[0058] The analytical data of the product are as follows: 1 HNMR (CDCl 3 ,300MHz)δ:1.56-1.68(m,2H),1.80-1.92(m,2H),3.37(t,J=6.9Hz,2H),3.57(t,J=6.6Hz,2H),3.98(s ,1H). The above data prove that this compound is 4-bromobutanol;

[0059] (3) Preparation of 12-β-O-(4-bromo-n-butyl)dihydroartemisinin: the steps are the same as step (2) in Example 1 to obtain a colorless oily l...

Embodiment 3

[0065] The synthesis of 12-β-12-O-(5-memantine amino) n-pentyldihydroartemisinin (ZLT-3) comprises the following four steps:

[0066] (1) Preparation of dihydroartemisinin: the steps are the same as step (1) in Example 1.

[0067] (2) Preparation of 5-bromo-n-pentanol: Dissolve (300mg, 2mmol) 1,5-pentanediol in 10mL of toluene, add HBr (0.3mL, 2.4mmol), and reflux for 36h. Spin-dry the toluene layer to obtain Colorless oily liquid.

[0068] The analytical data of the product are as follows: 1 HNMR (CDCl 3 ,300MHz)δ:1.32-1.50(m,4H),1.69-1.81(m,2H),3.30(t,J=6.6Hz,2H),3.48(t,J=6.3Hz,2H),4.21(s ,1H). The above data prove that the compound is 5-bromo-n-pentanol.

[0069] (3) Preparation of 12-β-O-(5-bromo-n-pentyl)dihydroartemisinin: the steps are the same as step (2) in Example 1 to obtain a colorless oily liquid.

[0070] The analytical data of the product are as follows: 1 HNMR (CDCl 3 ,300MHz)δ:0.82(d,J=7.2Hz,3H),0.88(d,J=6.0Hz,3H),1.07-1.21(m,2H),1.22-1.29(m,1H),1.33-1.3...

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Abstract

The invention discloses dihydroarteannuin-memantine diad compounds, and a synthesis method and application thereof. The structure of the compounds is disclosed as Formula I. The synthesis method comprises the following steps: reducing arteannuin to obtain dihydroarteannuin, carrying out acetalation reaction on the dihydroarteannuin and 2-bromoethanol under the catalytic action of Lewis acid, and carrying out reaction on the acetalation reaction product and memantine hydrochloride to obtain the dihydroarteannuin-memantine diad compounds. The compounds are reported for the first time, have an therapeutic effect on neurodegenerative diseases, and can be used for preparing drugs for treating neurodegenerative diseases. Compared with other prior arts, the compounds disclosed by the invention have the advantages of simple preparation technique and better curative effect than memantine.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a dihydroartemisinin-memantine double compound compound, a synthesis method thereof, and an application in the preparation of drugs for treating neurodegenerative diseases. Background technique [0002] Neurodegenerative diseases are a group of diseases that cause brain loss or physical dysfunction by destroying neurons that maintain normal brain function. Clinically, there are mainly Alzheimer's disease (Alzheimer's disease, AD), amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy Syndrome, multiple sclerosis, Parkinson's disease (Parkinson's disease, PD), primary lateral sclerosis and spinal muscular atrophy, among which AD and PD are the most common and most frequent. The patients of neurodegenerative diseases are mainly the elderly. As the population ages, th...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/357A61P25/28A61P25/24A61P25/00
CPCC07D493/20
Inventor 陈河如张来涛彭丽芝
Owner JINAN UNIVERSITY
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