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Pyridine phenyl coupling compound and pharmaceutical composition and application thereof

A technology of pyridine phenyl di- and compound, which is applied in the fields of drug combination, active ingredient of heterocyclic compound, organic chemistry, etc.

Inactive Publication Date: 2016-10-05
YANTAI YENEPHARMA BIOMEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there is no drug that is a PSD-95 / nNOs uncoupler successfully on the market. Therefore, it is of great significance to develop such drugs

Method used

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  • Pyridine phenyl coupling compound and pharmaceutical composition and application thereof
  • Pyridine phenyl coupling compound and pharmaceutical composition and application thereof
  • Pyridine phenyl coupling compound and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Embodiment 1: the synthesis of compound S1

[0097] synthetic route:

[0098]

[0099] Dissolve 0.4g of 2-amino-4,6-dichlorophenol in 20ml of acetonitrile, stir in an ice bath, add 10ml of formaldehyde aqueous solution and NaBH 3 CN 0.7g, acetic acid 2ml, react at room temperature for 12 hours. Evaporate acetonitrile under reduced pressure, add ethyl acetate to disperse, wash with saturated aqueous sodium bicarbonate solution, dry the organic layer, perform column chromatography, petroleum ether:ethyl acetate=25:1~20:1, and obtain the product 2-dimethylamino- 257 mg of 4,6-dichlorophenol, yield 55.16%.

[0100] Compound 2-dimethylamino-4,6-dichlorophenol 70mg, 5-hydroxyethyl-2-cyanopyridine 50mg and PPh 3 Dissolve 98mg in 5ml of anhydrous tetrahydrofuran, add 0.65ml of DEAD dropwise under ice bath, stir overnight at 0°C, detect the reaction by TLC, the reaction is complete, add ethyl acetate, wash with saturated NaCl aqueous solution, dry, column chromatography, p...

Embodiment 2

[0102] Embodiment 2: the synthesis of compound S2

[0103] synthetic route:

[0104]

[0105] Dissolve 1g (1.0eq) of 2-chloro-5-cyanomethylpyridine in 15ml of anhydrous tetrahydrofuran, stir and add BH dropwise at 0°C 3 19.74ml (3.0eq) of tetrahydrofuran solution was heated to reflux for 2 hours, cooled, evaporated to remove the solvent and dried to obtain the product, which was directly carried out to the next reaction.

[0106] Add 240mg of the above product and 273mg of 2-hydroxy-3,5-dichlorobenzaldehyde into 20ml of methanol and stir to disperse. Slowly add NaBH to the system under ice bath 4 150 mg, heated and refluxed for 3 hours, TLC detected the completion of the reaction, stopped the reaction, cooled, and now added 1N hydrochloric acid solution to the system to adjust the pH to 1~2, refluxed for 1 hour, cooled and filtered, evaporated the solvent, added ethyl acetate to disperse, and the organic layer was decomposed with carbonic acid Washing with sodium hydrogen...

Embodiment 3

[0107] Embodiment 3: the synthesis of compound S3

[0108] synthetic route:

[0109]

[0110] Dissolve 1.0g (1.0eq) of 2,4-dichlorophenol in 20ml of ethanol, add 350mg of dimethylamine, add a healthy aqueous solution (containing 233mg of formaldehyde) under ice cooling, heat up to room temperature and stir for 4 hours, and evaporate the reaction solution to dryness After that, ethyl acetate was added to dissolve, washed with saturated NaCl aqueous solution, the organic layer was dried, concentrated, and subjected to column chromatography, petroleum ether: ethyl acetate = 10:1-2:1, and 158 mg of the product was obtained with a yield of 12.05%.

[0111] The above phenol compound 74mg, 5-hydroxyethyl-2-cyanopyridine 50mg and PPh 3 Dissolve 98mg in 5ml of anhydrous tetrahydrofuran, add 0.65ml of DEAD dropwise under ice bath, stir overnight at 0°C, detect the reaction by TLC, the reaction is complete, add ethyl acetate, wash with saturated NaCl aqueous solution, dry, column chr...

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Abstract

The invention discloses a pyridine phenyl coupling compound and a pharmaceutical composition and application thereof. The pyridine phenyl coupling compound is a PSD-95-nNOs uncoupling agent, can selectively inhibit combination between PSD-95 and nNOs to achieve the pharmaceutical effect, has the important potential treatment effect and has wide application in preparation of drugs for treating stroke, neuropathic pain and an alzheimer disease or vascular dementia.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of pyridine phenyl coupling compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compound or pharmaceutically acceptable salts thereof, to such compounds or pharmaceutically acceptable salts thereof Acceptable salts and pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are used as PSD-95 / nNOs uncoupling agents, especially in the preparation and treatment of neuropathic pain, stroke, and Alzheimer's disease Or use in vascular dementia medicine. Background technique [0002] Neuropathic pain is "pain that results directly from damage or disease affecting the somatosensory system." The etiology of neuropathic pain is complex, and conventional analgesics such as opioids and non-steroidal anti-inflammatory drugs have no obvious effect. It is a disease that is difficult to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81C07D213/61C07D413/12A61K31/44A61K31/4439A61P25/04A61P25/00A61P25/28
Inventor 王磊王鹏陈荣
Owner YANTAI YENEPHARMA BIOMEDICAL
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