O-aryl glycoside derivative, pharmaceutical composition and application thereof

A drug and compound technology, applied in O-aryl glycoside derivatives, its pharmaceutical composition and application fields, can solve the problems of limited time window, poor effect, aggravated nerve damage, etc.

Active Publication Date: 2018-05-11
海口凯宝实业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The time window of thrombolytic therapy has been strictly limited for a long time, only 3-4.5 hours after stroke, only about 5% of stroke patients benefit, because thrombolytic drug treatment beyond this time window will aggravate nerve damage
In contrast, more than 120 clinical trials of neuroprotective agents have failed, and most approved neuroprotective drugs have shown poor clinical efficacy

Method used

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  • O-aryl glycoside derivative, pharmaceutical composition and application thereof
  • O-aryl glycoside derivative, pharmaceutical composition and application thereof
  • O-aryl glycoside derivative, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Embodiment 1: the synthesis of compound 1-1

[0112]

[0113] Step 1: Synthesis of Compound 1.1

[0114] Under ice bath, orcinol (10g, 82.6mmol) and imidazole (6.03g, 80.6mmol) were dissolved in dichloromethane (250mL), and tert-butyldimethylsilyl chloride (12.1g, 80.6mmol) was added dropwise . The reaction was then stirred overnight at room temperature. TLC monitoring showed that after the raw materials were reacted, the reaction solution was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1.1 (8.8 g, yield 46%) as a colorless oil.

[0115] Step 2: Synthesis of Compound 1.2

[0116] Under ice-cooling, ferulic acid (3 g, 15.5 mmol) was dissolved in pyridine (5 mL), and acetic anhydride (4.5 mL) was added dropwise. After the dropwise addition, the reaction system was stirred at room temperature for 3 hours. Th...

Embodiment 2

[0125] Embodiment 2: the synthesis of compound 1-2

[0126]

[0127] Step 1: Synthesis of Compound 2.1

[0128] Compound 1.3 (1 g, 1.76 mmol) and sodium methoxide (95 mg, 1.76 mmol) were dissolved in methanol (50 mL), and the reaction system was stirred at room temperature for 2 hours. The reaction solution was acidified to pH=6 with acetic acid and spin-dried. The crude product was purified by flash column chromatography (dichloromethane:methanol=15:1) to obtain compound 2.1 (600 mg, yield 89%) as a white solid.

[0129] Step 2: Synthesis of compound 2.2

[0130] To a solution of compound 1.2 (440 mg, 1.0 mmol) in pyridine (10 mL) was added dropwise a solution of compound 2.1 in toluene (256 mg, 1.0 mmol, 30 mL). The reaction system was stirred overnight at room temperature and concentrated directly. The residue was purified by flash column chromatography (dichloromethane:methanol=15:1) to obtain compound 2.2 (230 mg, yield 37%) as a white solid.

[0131] Step 3: Synth...

Embodiment 3

[0135] Embodiment 3: the synthesis of compound 1-3

[0136]

[0137] Step 1: Synthesis of Compound 3.1

[0138] Potassium carbonate (33 g, 0.24 mol) and benzyl bromide (15.4 g, 0.09 mol) were added to orcinol (10 g, 0.08 mol) in acetonitrile (250 mL), and the reaction system was stirred at 80° C. overnight. The reaction system was filtered, and the filtrate was spin-dried. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 3.1 (6.5 g, yield: 38%) as a yellow oil.

[0139] Step 2: Synthesis of compound 3.2

[0140] To a solution of D-glucose pentaacetate (11.7 g, 0.03 mmol) and compound 3.1 (6.5 g, 0.03 mol) in dichloromethane (50 mL) was added boron trifluoride diethyl ether (4.3 g, 0.03 mol) dropwise. The reaction was stirred overnight at room temperature. The reaction solution was adjusted to pH=6 with aqueous sodium hydroxide solution (1M) and concentrated. The crude product was purified by flash c...

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PUM

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Abstract

The invention relates to an O-aryl glycoside derivative, a preparation method and application thereof in preparation of drugs or pharmaceutical compositions. The O-aryl glycoside derivative (I), its isomer, prodrug, solvate or pharmaceutically acceptable salt has a structure shown as the specification. The O-aryl glycoside derivative provided by the invention has good efficacy of treating ischemicnerve injury, especially has no strict time window limit in treatment of ischemic nerve injury after stroke molding, and can achieve continuous multiple dosing within 7 days to generate better efficacy.

Description

technical field [0001] The present invention relates to an O-aryl glycoside derivative, its isomer, prodrug, solvate and pharmaceutically acceptable salt, as well as its pharmaceutical composition and application. Background technique [0002] Stroke is a kind of disease in which the rupture or blockage of cerebral blood vessels leads to nerve damage, and it is one of the three major causes of human death. There are about 15 million new strokes every year, about 80% of which are ischemic strokes, and there are more silent strokes or cavity strokes without significant clinical symptoms. Diabetes, high blood pressure, coronary heart disease, middle-aged and elderly people are high-risk groups of stroke. Stroke survivors present with various physical disabilities and commonly suffer from post-stroke depression and cognitive impairment, which have caused heavy social and economic burdens. [0003] Current drug treatments for stroke focus on improving cerebral blood circulation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/203A61K31/7034A61K31/7036A61P9/10A61P25/28A61P29/00A61P3/10A61P9/12
CPCC07H15/203
Inventor 徐林高大新裴钢刘凤涛谢宁周启心王朦乐
Owner 海口凯宝实业有限公司
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