Beta site amyloid protein precursor (APP)-cleaving enzyme (BACE1) inhibitor containing pyridine ring

A technology of amyloid protein and inhibitors, which is applied in the fields of nervous system diseases, organic chemistry, drug combination, etc., and can solve the problems of compound 1, such as strong fat solubility and little medicinal value

Inactive Publication Date: 2015-04-15
LESHAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, during the test, it was found that the fat solubility of compound 1 was too strong to dissolve in the test solvent used in the test such as dimethyl sulfoxide, and the test was a mixed solution, while Non-solution
Therefore, compound 1 has little medicinal value

Method used

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  • Beta site amyloid protein precursor (APP)-cleaving enzyme (BACE1) inhibitor containing pyridine ring
  • Beta site amyloid protein precursor (APP)-cleaving enzyme (BACE1) inhibitor containing pyridine ring
  • Beta site amyloid protein precursor (APP)-cleaving enzyme (BACE1) inhibitor containing pyridine ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 6,7-dichloro-5,8-quinoline diquinone (compound 6 ) preparation

[0022] First 1.5 grams of 8-hydroxyquinoline were dissolved in 60 milliliters of concentrated hydrochloric acid, and kept stirring, then slowly added 5.3 grams of sodium chlorate to this concentrated hydrochloric acid solution containing 8-hydroxyquinoline. After the reaction mixture was stirred at 50-60° C. for 2 hours, 200 ml of distilled water was added for dilution. The yellow solid formed was removed by filtration. The filtrate was extracted three times with 50 ml of dichloromethane (3×50 mL), the organic phase was washed once with water, and the dichloromethane was distilled off. The crude product was recrystallized in methanol to give pure bright yellow crystals of 6,7-dichloro-5,8-quinoline diquinone (compound 6 ) 0.95 g. 1 HNMR (Varian HFT-80) (Me 2 SO-d 6 ) δ(ppm) 9.05 (dd, J 2,3 = 4.8 Hz, J 2,4 = 1.6 Hz, 1 H), 8.46 (dd, J 3,4 = 8.0 Hz, J 2,4 = 1.6 Hz, 1 H), 7.88 (dd, J 3,4 = 8.0...

Embodiment 2

[0024] 6-Chloro-7-oxa-1,12-diaza-benzo(h)anthracen-5-one (compound 2 ) and 6-chloro-7-oxa-4,12-diaza-benzo(h)anthracen-5-one (compound 2’ ) preparation

[0025] To a flask containing 20 ml of absolute ethanol, add 1.15 g of 6,7-dichloro-5,8-quinoline diquinone, 0.54 g of o-hydroxyaniline, and 0.98 g of potassium acetate, respectively, and keep stirring. The reaction mixture was refluxed for 3 hours under continuous stirring. After the reaction, cool down, add ice water, stir, and filter. The obtained dark brown solid was first washed with cold water, washed with cold ethanol, and dried to obtain 0.95 g of 6-chloro-7-oxa-1,12-diaza-benzo(h)anthracene-5 - Keto (compound 2 ) and 6-chloro-7-oxa-4,12-diaza-benzo(h)anthracen-5-one (compound 2’ )mixture. ESI-MS m / z: 282.01 (C 15 h 7 ClN 2 o 2 Calculated value 282.02).

Embodiment 3

[0027]6-Chloro-7-oxa-4,12-diaza-benzo(h)anthracene-5-one (compound 3 ) preparation

[0028] Under constant stirring, 2.27 grams of 2,3-dichloro-1,4-naphthalene diquinone, 1.10 grams of 2-amino-3-hydroxypyridine, and 1.96 grams of acetic acid were added to a flask containing 50 milliliters of absolute ethanol. potassium. The reaction mixture was refluxed for 2 hours under continuous stirring, cooled, added with ice water, stirred, and filtered. The resulting dark brown solid was washed several times with cold water and ethanol, and dried to obtain 2.12 g of 6-chloro-7-oxa-11,12-diaza-benzo(h)anthracene-5-one (compound 3 ). 1 HNMR (Bruker DX400) (CDCl 3 )δ (ppm) 7.61 (m, 3H), 7.85 (m, 3H), 8.4 (m, 1H), 8.75 (m, 1H), 8.91 (m, 2H). ESI-MS m / z: 282.01; Calcd. C 15 h 7 ClN 2 o 2 282.02.

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PUM

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Abstract

The invention relates to synthesis of the following five compounds and application thereof as a BACE1 inhibitor for treating and preventing the Alzheimer's disease (senile dementia). The five compounds are 6-chloro-7-oxa-1,12-diaza-benzanthracene-5-one (compound 2), 6-chloro-7-oxa-4,12-diaza-benzanthracene-5-one (compound 2'), 6-chloro-7-oxa-11,12-diaza-benzanthracene-5-one (compound 3), 6-chloro-7-oxa-1,11,12-triaza-benzanthracene-5-one (compound 4), and 6-chloro-7-oxa-1,4,12-triaza-benzanthracene-5-one (compound 4').

Description

[0001] Technical field [0002] The present invention involves the discovery and synthesis of the pre -lyropramidine starch protein.This inhibitor can be used to treat and prevent Alzheimer's disease (early old dementia). [0003] Background technique [0004] Alzheimer's disease, also known as Alzheimer's Alzheimer, is a common disease that threatens human life.They mainly affect the cognition and behavior of the elderly over 60 years old, and there are currently no effective healing methods.At present, the basic causes of Alzheimer's disease have not been fully understood, but a large amount of data confirms that it is related to the production and accumulation of β-starch protein that causes toxic damage to neurotramid.β-starch-like protein is formed by the activity of several enzymes, which includes an enzyme called an enzyme 1 (BACE1) before starch protein.Researchers found that BACE1 not only helped generate β-starch-like proteins, it also regulated another cell process to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07D498/14A61P25/28
CPCC07D498/04C07D498/14
Inventor 罗云
Owner LESHAN NORMAL UNIV
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