3-Cyanophenoxyalkylarylpiperazine derivatives and their application in the preparation of medicines

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

Active Publication Date: 2022-07-12
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-Cyanophenoxyalkylarylpiperazine derivatives and their application in the preparation of medicines
  • 3-Cyanophenoxyalkylarylpiperazine derivatives and their application in the preparation of medicines
  • 3-Cyanophenoxyalkylarylpiperazine derivatives and their application in the preparation of medicines

Examples

Experimental program
Comparison scheme
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, dissolved in 50ml of acetonitrile, heated to reflux, stirred and reacted for 5h, stopped heating, evaporated under reduced pressure to remove the solvent, added 50ml of water and 50ml of ethyl acetate each, and allowed to stand The layers were separated, the aqueous phase was extracted three times with 20 ml of ethyl acetate, the organic phases were combined, washed with saturated brine, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After purification by column chromatography, a pale yellow oil was obtained. 30 ml of ethyl acetate was added to dissolve, and 5M HCl / E...

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), potassium iodide 1.33g (8.0mmol, 1.0eq) were dissolved in 50ml of acetonitrile, the temperature was refluxed, and the reaction was stirred for 5h. The solvent was distilled off under reduced pressure, 50 ml of water and 50 ml of ethyl acetate were added, and the layers were separated. The aqueous phase was extracted three times with 20 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and separated. The organic phase was washed with anhydrous sodium sulfate. Dry, filter, concentrate the filtrate, and purify by column chromatography to obtain a pale yellow oil, which is dissolved in 30 ml of ethyl acetate, and 5M HCl / EtOAc is added dropwise to adjust pH<3. The solid is precipitat...

Embodiment 3

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

[0107] 0.95g (8.0mmol, 1.0eq) of m-cyanophenol, 2.35g (8.0mmol, 1.0eq) of 1-(3-chloroethyl)-4-(2,3-dichlorophenyl)piperazine, K 2 CO 3 4.42g (32mmol, 4.0eq), 1.33g (8.0mmol, 1.0eq) of potassium iodide, dissolved in 50ml of acetonitrile, heated to reflux, stirred and reacted for 5h, stopped heating, evaporated under reduced pressure to remove the solvent, added 50ml of water and 50ml of ethyl acetate each, and allowed to stand The layers were separated, the aqueous phase was extracted three times with 20 ml of ethyl acetate, the organic phases were combined, washed with saturated brine, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After purification by column chromatography, a pale yellow oil was obtained. 30 ml of ethyl acetate was added to dissolve, and 5M HCl / EtOAc was added drop...

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Abstract

The invention discloses a 3-cyanophenoxyalkylarylpiperazine derivative and its application in the preparation of medicines. The role of the system, especially for 5‑HT 1A Receptor-selective high-affinity effect on dopamine D 1 and D 2 Receptors, adrenergic receptors α1 and α2, SERT (5-HT transporter protein), NET (adrenalin transporter protein), DAT (dopamine transporter protein) and other centrally related receptors and proteins have no obvious affinity effect. It exerts various physiological and pharmacological effects in vivo, and can be used as a pharmaceutical active substance, especially for diseases such as anti-depression, anxiolysis, and anti-neuropathic pain, and can also be used as an intermediate for the preparation of other active pharmaceutical compounds. The compound of the present invention has quick onset of action, small toxic and side effects, and can meet the needs of clinical application, and is a compound with the following structural formula or its free base or salt:

Description

technical field [0001] The invention relates to a 3-cyanophenoxyalkylarylpiperazine derivative and its application in the preparation of antidepressant and anxiolytic drugs. Background technique [0002] Depression is a common mental illness, characterized by chronicity and relapse. According to the World Health Organization, about 350 million people worldwide suffer from depression. By 2020, depression is expected to become the second most important 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 effect basically act on the synapse of nerve endings, and play a therapeutic role by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to 5 kinds of central serotonin (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach) and gamma-aminobutyric acid (GABA). relat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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