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Phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivative and uses thereof

A -NH2, -NO2 technology, used in compounds and compositions for affective disorders, phenyloctahydro-1H-pyrido[1,2-a]pyrazine derivatives, in the field of treatment of central nervous system dysfunction, capable of Solve the problems of deterioration and delayed treatment of SSRIs, and achieve the effect of stable properties, good safety, and good metabolic stability

Active Publication Date: 2018-08-17
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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  • Phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivative and uses thereof
  • Phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivative and uses thereof
  • Phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivative and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1: Synthesis of 2-(2-(pyrimidin-2-ylthio)phenyl) octahydro-1H-pyrido[1,2-a]pyrazine

[0161]

[0162] Step 1) Synthesis of 2-(2-nitrophenyl) octahydro-1H-pyrido[1,2-a]pyrazine

[0163] 1-fluoro-2-nitrobenzene (1.2g, 8.56mmol), octahydro-1H-pyrido[1,2-a]pyrazine (1.0g, 7.13mmol), N,N-diisopropyl Ethylamine (1.9 mL, 10.7 mmol) was added into N,N-dimethylformamide (20 mL), and the reaction temperature was raised to 90° C. for 4 hours under nitrogen protection. After the reaction, cool to room temperature, dilute the reaction solution with water (80mL), extract with dichloromethane (30mL×3), combine the organic phases, wash with water (50mL) and saturated brine (50mL) successively, and dry over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the obtained crude product was further purified by silica gel chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain the title compound (yellow oil, 1.74g, 93.4%).

[0164]...

Embodiment 2

[0180] Example 2: Synthesis of 2-(2-((4,6-dimethylpyrimidin-2-yl)thio)phenyl)octahydro-1H-pyrido[1,2-a]pyrazine

[0181]

[0182] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, namely 2-(2-iodophenyl)octahydro-1H-pyrido[1,2-a]pyrazine (0.30g, 0.88mmol) , 4,6-dimethylpyrimidine-2-thiol (0.18g, 1.3mmol), tris(dibenzylideneacetone)dipalladium (41mg, 0.044mmol), bis(2-diphenylphosphophenyl) Ether (72mg, 0.13mmol) and potassium tert-butoxide (0.20g, 1.8mmol) were reacted in DMSO (12mL) at 130°C for 30 hours under nitrogen protection. The obtained crude product was further purified by silica gel chromatography (petroleum ether:ethyl acetate (V:V)=2:1) ​​to obtain the title compound (yellow oil, 0.20 g, 64%).

[0183] MS(ESI,pos.ion)m / z:355.30[M+H] + ;

[0184] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.67 (dd, J = 8.1, 1.4Hz, 1H), 7.43 (dd, J = 7.8, 1.2Hz, 1H), 7.21 (t, J = 7.0Hz, 2H), 6.88 (s, 1H), 3.58(d, J=12.0Hz, 1H), ...

Embodiment 3

[0187] Example 3: Synthesis of 2-(2-((4,6-dimethoxypyrimidin-2-yl)thio)phenyl)octahydro-1H-pyrido[1,2-a]pyrazine

[0188]

[0189] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, namely 2-(2-iodophenyl)octahydro-1H-pyrido[1,2-a]pyrazine (0.42g, 1.2mmol) , 4,6-dimethoxypyrimidine-2-thiol (0.32g, 1.8mmol), tris(dibenzylideneacetone)dipalladium (57mg, 0.061mmol), bis(2-diphenylphosphophenyl ) ether (100mg, 0.18mmol) and potassium tert-butoxide (0.28g, 2.5mmol) were reacted in DMSO (12mL) at 130°C for 30 hours under nitrogen protection. The obtained crude product was further purified by silica gel chromatography (petroleum ether:ethyl acetate (V:V)=2:1) ​​to obtain the title compound (yellow oil, 0.11 g, 23%).

[0190] MS(ESI,pos.ion)m / z:387.25[M+H] + ;

[0191] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.63 (dd, J = 7.7, 1.4Hz, 1H), 7.31 (dd, J = 7.7, 1.2Hz, 1H), 7.09-7.07 (m, 1H), 7.04 (td, J = 7.6 ,1.1Hz,1H),5.71(s,1H),...

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Abstract

The present invention discloses a phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivative, a use method and uses thereof, and particularly relates to a class of new phenyl octahydro-1H-pyrido[1,2-a] pyrazine derivatives, and a pharmaceutical composition containing the compound, wherein the compounds and the pharmaceutical composition can be used for inhibiting 5-hydroxytryptamine reuptake. The invention further relates to a method for preparing the compounds and the pharmaceutical composition, and uses in treatment of central nervous system dysfunction, 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 phenyloctahydro-1H-pyrido[1,2-a]pyrazine 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-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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/506A61P25/00A61P25/24A61P25/22A61P25/16A61P25/28A61P25/30A61P25/14A61P25/20A61P25/18A61P25/08
CPCC07D471/04
Inventor 金传飞杜长峰张英俊
Owner SUNSHINE LAKE PHARM CO LTD