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Benzo-aza-alkyl aryl piperazine derivative and applications in preparation of drugs

A technology for benzazepines and derivatives, which is applied to benzazepine alkylarylpiperazine derivatives and application fields in the preparation of medicines, can solve different structural characteristics, different pharmacological action mechanisms and different therapeutic indications , reduce adverse reactions and other issues

Active Publication Date: 2019-01-29
NHWA PHARMA CORPORATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

5-HT 1A Receptor agonists can overcome the delay in the onset of most clinical antidepressants, and stimulate the pre- and post-synaptic membrane 5-HT 1A receptors, reducing adverse reactions
[0014] This patent discloses a class of benzoazepine arylpiperazine derivatives. The inventors found that although the disclosed compounds have similarities with the above-mentioned compounds in chemical structure, they also have essential differences in structural features. directly cause the essential difference in the pharmacological action mechanism and therapeutic indications of the patented compound of the present invention

Method used

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  • Benzo-aza-alkyl aryl piperazine derivative and applications in preparation of drugs
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  • Benzo-aza-alkyl aryl piperazine derivative and applications in preparation of drugs

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preparation example Construction

[0089] 1. Preparation of intermediate compound III-1

[0090]

[0091] Intermediate III-1-4: Preparation of methyl 2-bromo-3-(3,4-dichlorophenyl)propionate

[0092] Add 16ml of 48% hydrogen bromide to 100ml of acetone solution, slowly add 3,4-dichloroaniline (8.1g, 50mmol), keep the internal temperature at -5°C and slowly add 100ml of an aqueous solution of 4.2g of sodium nitrite for 30min The inner drop is complete. Then add 43g of methyl acrylate and 7.5mg of CuBr powder to it, remove the ice bath, stir for 30min after the temperature rises slowly to 25°C, evaporate the solvent, distribute with 50ml of water and dichloromethane each, and invert the dichloromethane layer with water washed, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 14.2 g of the product.

[0093] Intermediate III-1-3: Preparation of 3,4-dichlorophenylpropionic acid

[0094] Dissolve 13.1g of methyl 2-bromo-3-(3,4-dichlorophenyl)propionate in 80...

Embodiment 1

[0120] 2-(3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propyl)-1,2,3,4-tetrahydroisoquinoline (IV-1) disalt Preparation of acid salt and 2-(3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propyl)-1,2,3,4-tetrahydroisoquinoline (IV -1) Preparation of hydrobromide

[0121] Take the compound 1-(2,3-dimethylphenyl)piperazine hydrochloride (0.1mol, 1.0eq.) and dissolve it in 150ml of dichloromethane, and add NaOH aqueous solution (5.2g, 50ml) dropwise to the above solution , stirred at room temperature for 0.5h, stood to separate layers, extracted the aqueous phase with 30ml of dichloromethane, combined the organic phases, concentrated to obtain an oil, dissolved in 30ml of acetone, added 1-bromo-3-chloropropane (0.11mol, 1.1equiv. ), add 18ml of 25% NaOH aqueous solution, stir at room temperature and react for 12h, stop stirring, let the layers stand, extract the water layer with dichloromethane, combine the organic phases, wash with saturated brine, separate the liquids, and dry the organic ...

Embodiment 2

[0130] 2-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-1,2,3,4-tetrahydroisoquinoline (IV-2) dihydrochloride salt preparation

[0131] Take compound 1-(2,3-dichlorophenyl)piperazine hydrochloride (0.1mol, 1.0eq.), add 150ml of dichloromethane to dissolve, and add NaOH aqueous solution (5.2g, 50ml) dropwise to the above solution , stirred at room temperature for 0.5h, stood to separate layers, extracted the aqueous phase with 30ml of dichloromethane, combined the organic phases, concentrated to obtain an oil, dissolved in 30ml of acetone, added 1-bromo-3-chloropropane (0.11mol, 1.1equiv. ), add 18ml of 25% NaOH aqueous solution, stir at room temperature and react for 12h, stop stirring, let the layers stand, extract the water layer with dichloromethane, combine the organic phases, wash with saturated brine, separate the liquids, and dry the organic phases through anhydrous sodium sulfate. Filtration, concentration, purification by silica gel column chromatography (eluent: d...

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Abstract

The invention discloses a benzo-aza-alkyl aryl piperazine derivative and applications in preparation of drugs. The derivative shows the effect on central nervous systems, especially on the double highaffinity activity of a 5-HT<1A> acceptor and a Sigma-1 acceptor. Various physiological and pharmacological effects are brought into play in the body; and the compound can be used as a pharmaceuticalactive substance, especially used for anti-depression, anti-anxiety, anti-bipolar affective disorder and anti-neuropathic pain, and can also be used as an intermediate to prepare other pharmaceuticalactive compounds. The compound is fast in effect and small in toxic and side effect, and can meet demands of clinical applications; and the compound is a compound or a free base or salt thereof havingthe following structural formula (IV). The structure of the compound or the free base or salt thereof is shown as the structural formula (IV).

Description

technical field [0001] The invention relates to a benzoazepine arylpiperazine derivative and its application in the preparation of antidepressant, antineuralgia and other drugs. Background technique [0002] Depression is a common mental illness that is chronic and prone to relapse. According to the World Health Organization, about 350 million people around the world suffer from depression. It is estimated that by 2020, depression will become the second disease affecting the quality of human life. At present, the mechanism of action of antidepressant drugs has not been fully elucidated. Drugs with clear curative effects basically act on the synaptic site of nerve endings, and exert therapeutic effects by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to 5-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach) and γ-aminobutyric acid (GABA) in the c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04C07D223/16A61K31/496A61K31/55A61P25/04A61P25/24A61P25/22A61P25/28A61P25/18A61P25/00
CPCC07D217/04C07D223/16
Inventor 李建其王冠张桂森徐祥清汪涛陈园园赵松
Owner NHWA PHARMA CORPORATION
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