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Benzofuran quinoline derivatives and their application in the preparation of medicines for treating Alzheimer's disease

A technology of benzofuran-quinoline and Alzheimer's disease, applied in antipyretics, drug combinations, nervous system diseases, etc., can solve problems such as inability to cure, achieve strong metal ion complexing ability, and inhibit nerves Inflammation, improved cognition and spatial memory effects

Inactive Publication Date: 2018-04-20
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs can only slow down the progress of the disease to a certain extent, and cannot play a role in curing

Method used

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  • Benzofuran quinoline derivatives and their application in the preparation of medicines for treating Alzheimer's disease
  • Benzofuran quinoline derivatives and their application in the preparation of medicines for treating Alzheimer's disease
  • Benzofuran quinoline derivatives and their application in the preparation of medicines for treating Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: 5-(5-hydroxybenzofuran-2-substituted)-8-hydroxyquinoline

[0036]

[0037] (1) Step 1: Synthesis of 5-chloromethyl-8-hydroxyquinoline hydrochloride

[0038]

[0039] Add 14.50g (100mmol) of 8-hydroxyquinoline, 16mL of concentrated hydrochloric acid, 16mL of 37% formaldehyde solution into a 100mL round-bottom bottle, pass hydrogen chloride gas under ice bath for 6h, stir at room temperature for 2h, filter with suction, wash with water, and dry in vacuo , 15.12 g of a yellow solid was obtained, and the yield was 78%.

[0040] (2) Step 2: Synthesis of 8-hydroxy-5-quinolinemethylphosphonodiethyl ester

[0041]

[0042]Add 13.55g (70mmol) 5-chloromethyl-8-hydroxyquinoline hydrochloride and 36mL triethyl phosphite to a 100mL round bottom bottle, react at 110°C for 6h, and distill off excess triethyl phosphite under reduced pressure The ester was separated by silica gel column chromatography and eluted with ethyl acetate to obtain 16.95 g of a light yello...

Embodiment 2

[0061] Example 2: 5-(5-hydroxybenzofuran-2-substituted)-7-chloro-8-hydroxyquinoline

[0062]

[0063] (1) Synthesis of 7-chloro-8-hydroxyl-5-quinolinemethylphosphonodiethyl ester

[0064]

[0065] Add 5 g of 8-hydroxy-5-quinolinemethylphosphonodiethyl ester and 30 mL of water into a 100 mL round bottom flask, add 1 NKOH (17 mL) solution, and add NaClO solution (15.3 mL, 7.5% excess) dropwise at room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 6.0, and suction filtered to obtain 4.6 g of a white solid with a yield of 84%. R f =0.33 (CH 2 Cl 2 / CH 3 OH=20 / 1). 1 H NMR (400MHz, CDCl 3 )δ8.81(dd, J=4.1,1.0Hz,1H),8.44(dd,J=8.6,1.2Hz,1H),7.51(dd,J=8.6,4.2Hz,1H),7.45(d,J =3.8Hz,1H),4.05–3.93(m,4H),3.50(s,1H),3.44(s,1H),1.21(t,J=7.1Hz,6H).LC / MS(ESI):330.1 [M+H] + .

[0066] (2) Synthesis of 7-chloro 8-methoxyl-5-quinolinemethylphosphonodiethyl ester

[0067]

[0068] Add 2g of 7-chloro-8-hydroxy-5-quinolinemethy...

Embodiment 3

[0081] Example 3: 5-(5-hydroxybenzofuran-2-substituted)-7-iodo-8-hydroxyquinoline

[0082]

[0083] (1) Synthesis of 7-iodo-8-hydroxyl-5-quinolinemethylphosphonodiethyl ester

[0084]

[0085] Add 5g of 8-hydroxy-5-quinolinemethylphosphonodiethyl ester and 30mL of water into a 100mL round bottom bottle, add 1NKOH (40mL) solution, add the equivalent iodine and potassium iodide mixture in batches at room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 6.0, and suction filtered to obtain a black solid, which was separated by silica gel column chromatography and eluted with ethyl acetate to obtain a brown solid. Yield 65%. R f =0.32 (CH 2 Cl 2 / CH 3 OH=20 / 1). 1 H NMR (400MHz, CDCl 3 )δ8.77(dd, J=4.2,1.2Hz,1H),8.43(dd,J=8.6,1.3Hz,1H),7.74(d,J=3.9Hz,1H),7.53(dd,J=8.6 ,4.2Hz,1H),4.10–3.90(m,4H),3.47(s,1H),3.42(s,1H),1.21(t,J=7.1Hz,6H).LC / MS(ESI):422.0 [M+H] + .

[0086] (2) Synthesis of 7-iodo8-methoxy-5-quinolinem...

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Abstract

The invention discloses a benzofuran quinolone derivative and application of the benzofuran quinolone derivative in preparation of a medicine for treating Alzheimer's disease. The benzofuran quinolone derivative is a multiple target point active molecule for resisting the Alzheimer's disease, has inhibitory activity of phosphodiesterase 4D and also has functions of resisting oxidation, inhibiting A beta aggregation and depolymerizing; animal experimental results show that the benzofuran quinolone derivative disclosed by the invention has efficacies of improving cognitive ability and spatial memory of rats with the Alzheimer's disease, protecting brain hippocampal neuronal cells of the rats with the Alzheimer's disease, and inhibiting the loss and necrosis of neuronal cells.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a benzofuran quinoline derivative and its application in the preparation of medicines for treating, improving and / or preventing Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system with memory loss and cognitive dysfunction as the main clinical manifestations. The incidence of AD increases rapidly with age . According to statistics, there are more than 30 million AD patients in the world, with 4.6 million new cases every year. It is estimated that by 2050, this number will exceed 100 million. Currently, clinical drugs for the treatment of Alzheimer's disease are mainly acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and huperzine A, etc. However, these drugs can only slow down the progress of the disease to a certain extent, but cannot cure them. [0003] The...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04A61K31/4709A61P25/28A61P29/00A61P39/06
CPCC07D405/04
Inventor 黎兴术王志仁黄玲陈新滋
Owner SUN YAT SEN UNIV
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