Compound having dual functions to 5-HT and application thereof in depressive disorder treatment

A compound and solvate technology, applied in the field of application in the treatment of depression, can solve problems such as sexual dysfunction, low efficacy, suicidal tendencies, etc.

Inactive Publication Date: 2018-09-25
郝惠敏
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinically commonly used antidepressants such as serotonin reuptake inhibitors (Selective serotonin reuptake inhibitors, SSRIs) antidepressant fluo

Method used

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  • Compound having dual functions to 5-HT and application thereof in depressive disorder treatment
  • Compound having dual functions to 5-HT and application thereof in depressive disorder treatment
  • Compound having dual functions to 5-HT and application thereof in depressive disorder treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Synthesis of (E)-2-((3-(2,2-diphenyl-vinyl)phenyl)thio)quinoline

[0029] Synthesis of 1-1, 1-iodo-3-nitrobenzene:

[0030]

[0031] Add 70mL of DMF in a 500mL reaction flask, then add nitrobenzene (22.5g, 0.183mol) and potassium carbonate (25.2g, 0.182mol), and cool in an ice bath below 10°C. After stirring, iodine (41.6g, 0.164mol) was dissolved in 30mL DMF and added dropwise to the reaction system for 1 hour. The reaction mixture was stirred at 25°C for 16 hours until the reaction was complete, and sodium thiosulfate (22.3g, 0.141mol) and potassium carbonate were added (0.150g) in aqueous solution (150mL), while maintaining the internal temperature below 30°C, stirred for 30 minutes, added 200mL of water while stirring, solid precipitated, filtered with suction, washed the filter cake with water, and vacuum dried at 60°C for 12 hours to obtain a light yellow solid 1-iodo-3-nitrobenzene, 43.84g, yield 96.2%. 1 H-NMR (400MHz, CDCl3) δ: 7.35(t, 1H), 8.15...

Embodiment 2

[0044] Example 2: Synthesis of (E)-2-((3-(2,2-diphenyl-vinyl)phenyl)thio)-4-hydroxyl-quinoline:

[0045]

[0046] Add 175mL DMF and (E)-1-iodo-3-(2,2-diphenyl-vinyl)benzene (38.78g, 0.102mol) into a 500mL reaction flask, nitrogen protection, add [1,1'-bis (Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL, add 4-hydroxy-quinoline -2-thiol (0.105mol), heated to 80°C, reacted for 16 hours until the reaction was complete, removed DMF by rotary evaporation, cooled to room temperature, added 100mL of ethyl acetate, 150mL of water, stirred for 40 minutes, separated the organic phase, brine Wash, separate layers, dry the organic phase with sodium sulfate, filter, rotary evaporate to dryness, and flash column chromatography to obtain light yellow (E)-2-((3-(2,2-diphenyl-vinyl)phenyl )thio)-4-hydroxy-quinoline, 34.29g, yield 78%. LC-MS (ESI, pos, ion) m / z: 432 [M+H].

Embodiment 3

[0047] Example 3: Synthesis of (E)-2-((3-(2,2-diphenyl-vinyl)phenyl)thio)-4-fluoro-quinoline:

[0048]

[0049] Add 175mL DMF and (E)-1-iodo-3-(2,2-diphenyl-vinyl)benzene (38.78g, 0.102mol) into a 500mL reaction flask, nitrogen protection, add [1,1'-bis (Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL, add 4-fluoro-quinoline -2-thiol (0.105mol), heated to 80°C, reacted for 16 hours until the reaction was complete, removed DMF by rotary evaporation, cooled to room temperature, added 100mL of ethyl acetate, 150mL of water, stirred for 40 minutes, separated the organic phase, brine Wash, separate layers, dry the organic phase with sodium sulfate, filter, rotary evaporate to dryness, and flash column chromatography to obtain light yellow (E)-2-((3-(2,2-diphenyl-vinyl)phenyl )thio)-4-fluoro-quinoline, 34.89g, yield 79%. LC-MS (ESI, pos, ion) m / z: 434 [M+H].

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PUM

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Abstract

The invention discloses a compound having dual functions to 5-HT and application thereof in depressive disorder treatment. The formula is shown in the description, wherein R1, R2, R3 and R4 are independently selected from H, F or OH. In recent years, an antidepressant having the dual functions of 5-hydroxytryptamine 1A acceptor partial agitation and selective 5-hydroxytryptamine re-uptake inhibition becomes a hot point direction of a novel antidepressant drug research. In a [3H]5-HT uptake inhibiting effect experiment of a rat synaptosome and a h5-HT1A combined affinity experiment, the compound is verified to have the 5-HT re-uptake inhibiting effect and the agitating effect to a 5-HT1A acceptor. The fact that the compound can be used as a drug for treating human central nervous system disorders, such as a depressive disorder and an anxiety disorder, is demonstrated.

Description

technical field [0001] The invention belongs to the field of chemical medicine and relates to a compound with dual effects on 5-HT and its application in treating depression. Background technique [0002] Depressive disorder is a mental disorder with high morbidity rate, high disability rate and high suicide rate, and has become a serious social and public health problem. Clinically commonly used antidepressants such as serotonin reuptake inhibitors (Selective serotonin reuptake inhibitors, SSRIs) antidepressant fluoxetine and other first-line drugs generally have low effective rate, slow onset, sexual dysfunction, and suicide Tendency and many other defects. In recent years, antidepressants (serotoninpartial agonist and reuptake inhibitors, SPARIs) with dual effects of serotonin 1A receptor partial agonist and selective serotonin reuptake inhibition (SPARIs) have been developed because of their potential characteristics such as stronger efficacy and rapid onset of action. ...

Claims

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Application Information

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IPC IPC(8): C07D215/36C07D215/26C07D215/28A61K31/47A61P25/28A61P25/24A61P25/22A61P25/18A61P25/20A61P25/14A61P25/16A61P15/00A61P25/30
CPCC07D215/36A61P15/00A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30C07D215/26C07D215/28
Inventor 郝惠敏
Owner 郝惠敏
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