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1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application

A -NO2, -NH2 technology, applied to compounds and compositions for 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 bioavailability degree of effect

Active Publication Date: 2016-02-24
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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  • 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application
  • 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application
  • 1-heterocyclyl-2-(heteroarylthio) benzene derivative and use method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0152] Example 14, 6-dimethoxy-2-((5-methyl-2-(piperazin-1-yl)phenyl)thio)pyrimidine

[0153]

[0154] Step 1) Synthesis of 1-(2-bromo-4-methylphenyl)piperazine

[0155]2-Bromo-4-methylaniline (2.00g, 10.75mmol), bis(2-chloroethyl)amine hydrochloride (2.23g, 12.90mmol) and potassium carbonate (4.46g, 32.25mmol) were added to n-butanol (30 mL), and then the reaction solution was reacted at room temperature for 50 hours. After the reaction, the reaction solution was poured into water (100mL), and extracted with dichloromethane (25mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column Purification by chromatography (dichloromethane / methanol (v / v)=10 / 1) gave the title compound as a black oily liquid (1.40 g, 50.9%).

[0156] MS(ESI,pos.ion)m / z:255.1(M+1).

[0157] Step 2) Synthesis of 4-(2-bromo-4-methylphenyl)piperazine-1-carboxylic acid t...

Embodiment 24

[0169] Example 24,6-Dimethyl-2-((5-methyl-2-(piperazin-1-yl)phenyl)thio)pyrimidine

[0170]

[0171] Step 1) Synthesis of tert-butyl 4-(2-((4,6-dimethylpyrimidin-2-yl)thio)-4-methylphenyl)piperazine-1-carboxylate

[0172] 4-(2-bromo-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.30g, 0.84mmol), 4,6-dimethylpyrimidine-2-thiol (0.14g, 1.01 mmol), Pd 2 (dba) 3 (39mg, 42μmol), bis(2-diphenylphosphine) phenyl ether (45mg, 84μmol) and sodium tert-butoxide (0.16g, 1.69mmol) were added to dimethyl sulfoxide (20mL), and the reaction solution was heated under nitrogen Under protection, the temperature was gradually raised to 125° C. for 30 hours. After the reaction, the reaction solution was cooled to room temperature, and slowly poured into water (20mL), then extracted with dichloromethane (15mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the resulting residue was purified by sil...

Embodiment 3

[0179] Example 32-((5-methyl-2-(piperazin-1-yl)phenyl)sulfanyl)-4-(trifluoromethyl)pyrimidine

[0180]

[0181] Step 1) Synthesis of tert-butyl 4-(4-methyl-2-((4-(trifluoromethyl)pyrimidin-2-yl)thio)phenyl)piperazine-1-carboxylate

[0182] The title compound of this step was prepared by referring to the method described in step 1 of Example 2, that is, tert-butyl 4-(2-bromo-4-methylphenyl)piperazine-1-carboxylate (0.30g, 0.84mmol), 4 -(trifluoromethyl)pyrimidine-2-thiol (0.23g, 1.27mmol), Pd 2 (dba) 3 (39mg, 42μmol), bis(2-diphenylphosphine) phenyl ether (45mg, 84μmol) and sodium tert-butoxide (0.16g, 1.69mmol) were reacted in dimethyl sulfoxide (20mL) to obtain the crude product, The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain the title compound as a yellow oily liquid (175 mg, 45.6%).

[0183] MS(ESI,pos.ion)m / z:455.2(M+1);

[0184] 1 HNMR (600MHz, CDCl 3 )δ (ppm): 8.70 (d, J = 4.8Hz, 1H), 7...

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Abstract

The present invention discloses a 1-heterocyclyl-2-(heteroarylthio) benzene derivative and a use method and application, and in particular, relates to a novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and a pharmaceutical composition containing the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative, and the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition can be used to inhibit 5-hydroxytryptamine reuptake. The present invention also relates to a preparation method of the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition, and application of the novel 1-heterocyclyl-2-(heteroarylthio) benzene derivative and the pharmaceutical composition in the treatment of central nervous system functional disorders, particularly affective disorders.

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, the present invention describes 1-heterocyclyl-2-(heteroarylthio)benzene derivatives 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-HTtransporter, 5-HTT / serotonintransporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes five-serotonin from the synaptic gap into the presynaptic neuron, directly Affects the concentration of serotonin in the synaptic cleft. [0003] Historically, pharmacol...

Claims

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Application Information

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IPC IPC(8): C07D239/60C07D239/38C07D213/70C07D401/12A61K31/506A61K31/496A61K31/444A61P25/00A61P25/18A61P25/20A61P25/22
CPCC07D213/70C07D239/38C07D239/60C07D401/12
Inventor 金传飞梁海平张英俊张霁李静许娟
Owner SUNSHINE LAKE PHARM CO LTD
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