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Phenylpiperazine derivatives, use method and application thereof

An alkyl and drug technology, applied to compounds and compositions of affective disorders, in the field of treatment of central nervous system dysfunction, can solve problems such as deterioration and delayed treatment of SSRIs, and achieve stable properties, good safety, and good metabolic stability. Effect

Active Publication Date: 2017-01-04
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, clinical studies of depression have highlighted the lack of response to known SSRIs. Another factor that is often overlooked in antidepressant treatment is that the therapeutic effect of SSRIs is often delayed, sometimes during the first few weeks of treatment. will get worse
Additionally, sexual dysfunction is a common side effect of SSRIs

Method used

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  • Phenylpiperazine derivatives, use method and application thereof
  • Phenylpiperazine derivatives, use method and application thereof
  • Phenylpiperazine derivatives, use method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Embodiment 1:1-(2-((4-chlorophenyl) thio) phenyl) -4- (oxetanyl-3-yl) synthesis of piperazine

[0150]

[0151] Step 1) Synthesis of 4-(2-((4-chlorophenyl)thio)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0152] 4-(2-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester (0.34g, 1.0mmol), p-chlorothiophenol (0.17g, 1.2mmol), bis(2-diphenylphosphine) Phenyl ether (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and anhydrous DMSO (10mL) were added to a 50mL reaction flask, and tris(dibenzylideneacetone)dipalladium ( 23 mg, 0.025 mmol). The reaction temperature was raised to 100° C. for 24 hours. After the reaction, cool to room temperature, dilute the reaction solution with water (40mL), extract with ethyl acetate (20mLx 3), collect the organic phase, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure. The obtained crude product is separated and purified by column chromatography (Petroleum ether / ethyl acetat...

Embodiment 2

[0160] Embodiment 2: the synthesis of 1-(2-((2,4-dichlorophenyl) thio) phenyl) -4- (oxetanyl-3-yl) piperazine

[0161]

[0162] Step 1) Synthesis of tert-butyl 4-(2-((2,4-dichlorophenyl)thio)phenyl)piperazine-1-carboxylate

[0163] The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate (0.34g, 1.0mmol), 2,4-dichloro Thiophenol (0.22g, 1.2mmol), bis(2-diphenylphosphine)phenyl ether (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) Dipalladium (23 mg, 0.025 mmol) was prepared by reacting in DMSO (10 mL) at 100° C. for 24 hours under nitrogen protection. The obtained crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate (v / v)=20 / 1) to obtain the title compound (white solid, 0.04 g, 10.0%).

[0164] MS(ESI,pos.ion)m / z:439.20[M+H] + ;

[0165] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.4...

Embodiment 3

[0171] Example 3: Synthesis of 1-(oxetanyl-3-yl)-4-(2-(p-methylphenylthio)phenyl)piperazine

[0172]

[0173] Step 1) Synthesis of 4-(2-(p-methylphenylthio)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0174] The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate (0.40g, 1.18mmol), p-methylthiophenol (0.175g, 1.41mmol), bis(2-diphenylphosphine) phenyl ether (0.54g, 0.1mmol), sodium tert-butoxide (0.283g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium ( 46mg, 0.05mmol) was prepared by reacting in DMSO (10mL) at 130°C for 24 hours under nitrogen protection. The obtained crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate (v / v)=30 / 1) to obtain the title compound (light yellow liquid, 0.30 g, 66.2%).

[0175] MS(ESI,pos.ion)m / z:385.25[M+H] + ;

[0176] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.36 (d, J = 8....

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Abstract

The invention relates to phenylpiperazine derivatives, a use method and application thereof, in particular to a class of phenylpiperazine derivatives and pharmaceutical compositions thereof which can be used for inhibiting reuptake of 5-hydroxytryptamine. The invention further relates to a method for preparing the compounds and pharmaceutical compositions, and application thereof in treating central nervous system dysfunction, especially in treating affective disturbance.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to compounds and compositions for treating central nervous system dysfunction, especially affective disorders, as well as methods and uses thereof. In particular, described herein are phenylpiperazine derivatives that are useful as serotonin reuptake inhibitors. Background technique [0002] 5-HT (serotonin), a neurotransmitter that transmits signals in the brain and nervous system, plays a role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. play an important role. The five-serotonin transporter (5-HT transporter, 5-HTT / serotonin transporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes five-serotonin from the synaptic cleft into the presynaptic neuron , which directly affects the concentration of serotonin in the synaptic cleft. [0003] Historically, pharmacological t...

Claims

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Application Information

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IPC IPC(8): C07D305/08A61K31/496A61P25/00A61P25/22A61P25/24A61P25/18A61P25/08A61P25/16A61P25/28A61P25/20A61P25/14A61P25/30
CPCC07D305/08
Inventor 金传飞易超张英俊薛亚萍
Owner SUNSHINE LAKE PHARM CO LTD
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