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Novel 5-hydroxytryptamine and norepinephrine dual reuptake inhibitor and medical application thereof

A pharmaceutical and methyl technology, applied in the field of medicinal chemistry, can solve problems such as side effects, low response rate, and long onset time

Active Publication Date: 2020-06-16
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, these drugs generally have the disadvantages of low response rate, long onset time, and potential side effects.

Method used

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  • Novel 5-hydroxytryptamine and norepinephrine dual reuptake inhibitor and medical application thereof
  • Novel 5-hydroxytryptamine and norepinephrine dual reuptake inhibitor and medical application thereof
  • Novel 5-hydroxytryptamine and norepinephrine dual reuptake inhibitor and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 3-(4-methylphenoxy)-1-(thiophen-2-yl)-N,N-dimethylpropylamine hydrochloride (I 1 ) preparation

[0060]

[0061] 1.1 Preparation of 3-chloro-1-(2-thiophene)-acetone

[0062] Add trichloropropionyl chloride (63.5 g, 0.5 mol), anhydrous aluminum trichloride (100 g, 0.75 mol) and dichloromethane (400 mL) in a 1 L three-necked flask, slowly add thiophene ( 42.07g, 0.5mol) of dichloromethane solution, mechanically stirred for 3h. After the reaction was completed, the reaction solution was poured into 800 mL of ice water, stirred to separate the layers, and extracted with dichloromethane (3×200 mL). The organic phases were combined, washed with saturated sodium chloride solution (2×300 mL), dried over anhydrous magnesium sulfate, filtered with suction, and concentrated to obtain 82.5 g of crude product with a yield of 94.26%.

[0063] 1.2 Preparation of 3-chloro-1-(2-thiophene)-propanol

[0064] Add 82.5 g (0.47 mol) and 300 mL of methanol into a 1 L three-ne...

Embodiment 2

[0069] Example 2 3-(4-methylphenoxy)-1-(thiophen-2-yl)-N-methylpropylamine hydrochloride (I 2 ) preparation:

[0070]

[0071] 3.1 g (0.012 mol) of 3-(4-methylphenoxy)-1-(2-thiophene)-propanol, 1.8 g (0.018 mol) of triethylamine (TEA) and 80 mL of dry tetrahydrofuran (THF ) into a 250mL three-necked flask, and slowly dropwise added a THF solution containing 2.1g (0.018mol) of methanesulfonyl chloride under an ice-salt bath, and reacted for 5h. Then feed the dried methylamine gas into the three-necked flask to make the pH of the solution system about 13, and seal the reaction system. The reaction was stirred at room temperature for 48h. After the reaction was finished, THF was removed by distillation under reduced pressure,

[0072] Then add 200mL of water, extract with ethyl acetate (3×100mL), combine the organic phases, wash with saturated sodium chloride solution (2×100mL), dry over anhydrous magnesium sulfate, filter and distill off ethyl acetate under reduced pressur...

Embodiment 3

[0073] Example 3 3-(4-methoxyphenoxy)-1-(thiophen-2-yl)-N,N-dimethylpropylamine hydrochloride (I 3 ) preparation:

[0074]

[0075] 3.1 Preparation of 3-(4-methoxyphenoxy)-1-(2-thiophene)-propanol

[0076] According to the method of 1.3 in Example 1, 4-methoxyphenol was used instead of 4-methylphenol to obtain a white solid 7.82, with a yield of 91.2%.

[0077] 3.2 3-(4-methoxyphenoxy)-1-(thiophen-2-yl)-N,N-dimethylpropylamine hydrochloride (I 3 ) preparation

[0078] According to the method of 1.4 in Example 1, replace 3-(4-methylphenoxy)-1-(2 -thiophene)-propanol participated in the reaction to obtain 2.1 g of white solid with a yield of 65.4%. mp: 107-108°C. 1 H NMR (400MHz, DMSO-d 6 )δ ppm :7.69(d,J=5.0Hz,1H),7.34(d,J=3.3Hz,1H),7.15(m,2H),6.79(m,3H),4.81(q,J=9.3Hz,1H) ,3.90(m,2H),3.81(s,3H),2.63(s,6H),2.39-2.33(m,2H); MS(ESI,m / z):292(M+H) + .

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Abstract

The invention belongs to the field of medicinal chemistry, particularly relates to a novel serotonin and norepinephrine dual reuptake inhibitor and medical application thereof, and discloses a compound as represented by a formula I and a pharmaceutically acceptable salt thereof, and application of the compound and the pharmaceutically acceptable salt in preparation of antidepressant drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a novel dual reuptake inhibitor of 5-hydroxytryptamine and norepinephrine and its medical application. [0002] technical background [0003] Depression is the most common neuropsychiatric disease, seriously affecting people's physical and mental health. Currently, patients with depression account for 3-5% of the world's population. It is estimated that by 2020, depression may become the second leading disease after heart disease. [0004] Drug therapy is the main method for the treatment of depression. Clinically, the main therapeutic drugs include: tricyclic antidepressants such as clomipramine, protriptyline, etc.; monoamine oxidase inhibitors, such as moclobemide, etc.; selective serotonin Reuptake inhibitors, such as fluoxetine, paroxetine, etc.; selective norepinephrine reuptake inhibitors, such as reboxetine, etc.; serotonin / norepinephrine reuptake inhibitors, such as v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20C07D307/52A61K31/381A61K31/341A61P25/24
CPCC07D333/20C07D307/52A61P25/24
Inventor 李曲祥郭强刘志强邱印利季海莉孙义伟张杜娟许向阳
Owner NHWA PHARMA CORPORATION
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