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Styrene pyridine compound, its preparation method and use

A technology of styrylpyridine and compound, which is applied in the field of styrylpyridine compound, its preparation and use, can solve the problems of many toxic and side effects, single action target, complex pathogenesis and the like

Active Publication Date: 2020-04-14
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] AD is a disease caused by many factors, and its pathogenesis is complex. Its pathogenesis has not been fully elucidated yet, but studies have shown that the decline of acetylcholine levels in the brain of patients, β -Excessive production and deposition of amyloid, metal ion metabolism disorder, Ca 2+ imbalance, tau - Neurofibrillary tangles caused by protein hyperphosphorylation, enhanced activity of monoamine oxidase B (MAO-B), hyperactivity of glutamate receptors, oxidative stress to generate a large number of reactive oxygen species (ROS) and free radicals, and neuroinflammation reactions, etc. Factors play an important role in the pathogenesis of AD
In response to the above-mentioned pathogenic factors, researchers adopted the traditional "one drug, one target" drug design strategy, and discovered a large number of drugs with high activity and high selectivity for a certain target, such as: cholinesterase inhibitors and N -methyl- D - Aspartate receptor antagonists, etc., but these drugs have problems such as a single target, more toxic and side effects in clinical use, and poor long-term curative effect on AD patients

Method used

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  • Styrene pyridine compound, its preparation method and use
  • Styrene pyridine compound, its preparation method and use
  • Styrene pyridine compound, its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] When Ar represents the structural unit (B), the general method for preparing styrene pyridine compound (I-1)

[0032] Add 4.0 mmol 5-(chloromethyl)-2,2,8-trimethyl-4 to the reaction flask H -[1,3] dioxane [4,5-c] pyridine (1) and 25.0 mmol of triethyl phosphite, heated and refluxed and stirred for 4.0 hours (reaction progress is tracked by TLC); after the reaction, the pressure is reduced The excess triethyl phosphite was evaporated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=1:1 v / v) to obtain 2,2,8-trimethyl-4 H -[1,3]dioxane[4,5-c]pyridine-5-methyl diethyl phosphate (2), the yield is 95.0%;

[0033] The 2,2,8-trimethyl-4 obtained in the previous step H -[1,3]Dioxane[4,5-c]pyridine-5-methyl diethyl phosphate (2) dissolved in 20 ml of tetrahydrofuran, cooled to 0~5℃, added 10.0 mmol of sodium hydride , Keep stirring and react for 30 minutes, then add benzaldehyde compound (R 1 R 2 PhCHO) 4.0 mmol, keep stirring at...

Embodiment 2

[0039] When Ar represents (A) structural unit, the general method for preparing styrene pyridine compound (I-2)

[0040] Add 4.0 mmol 5-(bromomethyl)-2,2,8-trimethyl-4 to the reaction flask H -[1,3]dioxane[4,5-c]pyridine (1), 10.0 mmol trimethyl phosphite and 25 ml chlorobenzene, heated and refluxed and stirred for 5.0 hours (reaction progress is tracked by TLC); After completion, the excess trimethyl phosphite and chlorobenzene were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate = 1:1 v / v) to obtain 2,2 ,8-Trimethyl-4 H -[1,3]Dioxane[4,5-c]pyridine-5-methyl dimethyl phosphate (2), the yield is 88.2%;

[0041] The 2,2,8-trimethyl-4 obtained in the previous step H -[1,3]Dioxane[4,5-c]pyridine-5-methyl dimethyl phosphate (2) dissolve in 20 ml of toluene, cool to 0~5℃, add 10.0 mmol sodium methoxide , The reaction was stirred at room temperature for 30 minutes, and then benzaldehyde compounds ...

Embodiment 3

[0045] Example 3 General method for preparing salt of styrene pyridine compound (I) and acid

[0046] Add 2.0 mmol of the styrene pyridine compound (I) obtained in the above example 1 or 2 and 50 ml of methanol into the reaction flask, stir evenly, add 6.0 mmol of the corresponding acid, heat and reflux and stir for 10 minutes, and cool after the reaction is complete At room temperature, the solvent was evaporated under reduced pressure, the residue was recrystallized with acetone, and the precipitated solid was filtered to obtain the salt of styrene pyridine compound (I). Its chemical structure was 1 Confirmed by H NMR and ESI-MS.

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Abstract

The invention discloses a novel stilbazole compound (I), and a pharmaceutically acceptable salt, a preparation method, and a pharmaceutical composition thereof, and also discloses applications of thestilbazole compound in preparation of drugs used for treating and / or preventing neurodegenerative diseases including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's Disease, HIV associated dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, and glaucoma.

Description

Technical field [0001] The present invention belongs to the field of medicinal chemistry, and relates to a new type of styrene pyridine compound (I) and pharmaceutically acceptable salts thereof, its preparation method, pharmaceutical composition and preparation of drugs for treating and / or preventing neurodegenerative diseases Uses in, including but not limited to vascular dementia, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, HIV-related dementia, multiple sclerosis, progressive lateral spinal sclerosis, neuropathic pain, glaucoma, etc. Neurodegenerative diseases. Background technique [0002] Alzheimer's disease (AD, Alzheimer's disease) is a degenerative disease of the central nervous system with progressive cognitive impairment and memory impairment. Its incidence is increasing year by year, becoming second only to the heart. The high incidence of vascular disease and cancer has risen to the fourth cause of death in developed countries such as Europe and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/056A61K31/436A61K31/4545A61K31/5377A61K31/496A61P25/28A61P25/16A61P25/14A61P25/00A61P27/06
CPCC07D491/056
Inventor 邓勇杨霞徐锐宋青张小玉刘红艳
Owner SICHUAN UNIV