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3-cyanophenoxyalkyl aryl piperazine derivative and applications in the preparation of drugs

A technology of cyanophenoxyalkylaryl and derivatives, which is applied in the field of 3-cyanophenoxyalkylarylpiperazine derivatives, can solve the problems of difficult treatment and high muscle tension, and achieve significant curative effect

Active Publication Date: 2019-01-29
NHWA PHARMA CORPORATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The compounds disclosed in WO2014112729 act on catechol-O-methyltransferase (COMT) and dopamine system D 1 or D 2 receptor, which inevitably brings about the imbalance of dopamine (dopamine, DA) function, causing more serious side effects (EPS) of the extrapyramidal system, such as side effects such as inability to move, hypertonia, tremor, and autonomic dysfunction
Due to these obvious toxic and side effects, it is difficult to treat and apply to various indications, which is also the most difficult defect of this type of drug

Method used

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  • 3-cyanophenoxyalkyl aryl piperazine derivative and applications in the preparation of drugs
  • 3-cyanophenoxyalkyl aryl piperazine derivative and applications in the preparation of drugs
  • 3-cyanophenoxyalkyl aryl piperazine derivative and applications in the preparation of drugs

Examples

Experimental program
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Effect test

Embodiment 1

[0093] Preparation of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)benzonitrile (Ⅲ-1) hydrochloride and hydrobromide

[0094] 0.95g (8.0mmol, 1.0eq) of m-cyanophenol, 2.46g (8.0mmol, 1.0eq) of 1-(3-chloropropyl)-4-(2,3-dichlorophenyl)piperazine, K 2 CO 3 4.42g (32mmol, 4.0eq), 1.33g (8.0mmol, 1.0eq) of potassium iodide was dissolved in 50ml of acetonitrile, heated to reflux, stirred and reacted for 5h, stopped heating, distilled off the solvent under reduced pressure, added 50ml each of water and ethyl acetate, and stood Separate the layers, extract the aqueous phase with 20ml ethyl acetate for 3 times, combine the organic phases, wash with saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by column chromatography to obtain a light yellow oil Add 30ml of ethyl acetate to dissolve, add dropwise 5M HCl / EtOAc to adjust pH<3, solid precipitates, filter, and vacuum dry to obtain 2.6g of w...

Embodiment 2

[0101] Preparation of 3-(3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propoxy)benzonitrile (Ⅲ-2) hydrochloride

[0102] 0.95g (8.0mmol, 1.0eq) of m-cyanophenol, 2.13g (8.0mmol, 1.0eq) of 1-(3-chloropropyl)-4-(2,3-dimethylphenyl)piperazine, K 2 CO 3 4.42g (32mmol, 4.0eq), 1.33g (8.0mmol, 1.0eq) of potassium iodide was dissolved in 50ml of acetonitrile, heated to reflux, and stirred for 5h. Remove the solvent by distillation under reduced pressure, add 50ml each of water and ethyl acetate, let stand to separate layers, extract the water phase with 20ml ethyl acetate three times, combine the organic phases, wash with saturated brine, separate the liquids, and use anhydrous sodium sulfate for the organic phase Dry, filter, concentrate the filtrate, and purify by column chromatography to obtain a pale yellow oil, add 30ml of ethyl acetate to dissolve, add dropwise 5M HCl / EtOAc to adjust pH<3, solid precipitates out, filter, and dry in vacuo to obtain 2.3g of white solid, Yield 74.5%...

Embodiment 3

[0106] Preparation of 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethoxy)benzonitrile (Ⅲ-3)hydrochloride

[0107] With m-cyanophenol 0.95g (8.0mmol, 1.0eq), 1-(3-chloroethyl)-4-(2,3-dichlorophenyl) piperazine 2.35g (8.0mmol, 1.0eq), K 2 CO 3 4.42g (32mmol, 4.0eq), 1.33g (8.0mmol, 1.0eq) of potassium iodide was dissolved in 50ml of acetonitrile, heated to reflux, stirred and reacted for 5h, stopped heating, distilled off the solvent under reduced pressure, added 50ml each of water and ethyl acetate, and stood Separate the layers, extract the aqueous phase with 20ml ethyl acetate for 3 times, combine the organic phases, wash with saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by column chromatography to obtain a light yellow oil Add 30ml of ethyl acetate to dissolve, add dropwise 5M HCl / EtOAc to adjust pH<3, solid precipitates, filter, and vacuum dry to obtain 2.2g of white solid, yield 66...

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Abstract

The invention discloses a 3-cyanophenoxyalkyl aryl piperazine derivative and applications in the preparation of drugs. The 3-cyanophenoxyalkyl aryl piperazine derivative shows the effect on central nervous systems, especially on 5-HT<1A> receptor selective high affinity interaction, but has no obvious affinity interaction on dopamine D1 and D2 receptors, adrenergic receptor alpha 1 and alpha 2, SERT (5-HT transporter protein), NET (adrenergic transporter protein), DAT (dopamine transporter protein) and other central related receptors and proteins. Various physiological and pharmacological effects are brought into play in the body; and the compound can be used as a pharmaceutical active substance, especially used for diseases like anti-depression, anti-anxiety and anti-neuropathic pain, andcan also be used as an intermediate to prepare other pharmaceutical active compounds. The compound is fast in effect and small in toxic and side effect, and can meet demands of clinical applications;and the compound is a compound having the following structural formula or a free base or salt thereof. The structure of the compound is shown in the description.

Description

technical field [0001] The invention relates to a 3-cyanophenoxyalkylarylpiperazine derivative and its application in the preparation of antidepressant and antianxiety drugs. Background technique [0002] Depression is a common mental illness that is chronic and prone to relapse. According to the World Health Organization, about 350 million people around the world suffer from depression. It is estimated that by 2020, depression will become the second disease affecting the quality of human life. At present, the mechanism of action of antidepressant drugs has not been fully elucidated. Drugs with clear curative effects basically act on the synaptic site of nerve endings, and exert therapeutic effects by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to 5-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach) and γ-aminobutyric acid (GABA) in the cent...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D213/72A61K31/495A61K31/496A61P25/00A61P25/04A61P25/18A61P25/22A61P25/24A61P25/14A61P25/16A61P25/28
CPCC07D213/72C07D295/088
Inventor 李建其王冠张桂森徐祥清汪涛陈园园赵松
Owner NHWA PHARMA CORPORATION
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