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3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments

A technology of cyanoanilinidine and its derivatives, which is applied in the field of 3-cyanoanilinoalkylarylpiperazine derivatives, which can solve the problems of large toxic and side effects, decreased addictive gastric motility, and slow onset of action, etc.

Active Publication Date: 2013-10-23
NHWA PHARMA CORPORATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] One of the technical problems to be solved in the present invention is to disclose a class of 3-cyanoaniline alkyl aryl piperazine derivatives to overcome the defects of existing drugs that have side effects such as addiction, respiratory depression, and gastric motility reduction. Clinical problems, to meet people's analgesic needs, especially anti-chronic neuropathic pain
[0017] The second technical problem to be solved in the present invention is to disclose the application of the above-mentioned compound as a novel antidepressant drug, improve the defects of existing antidepressant drugs such as large toxic and side effects, and slow onset of effects, and expand the application selection of clinical antidepressant drugs to meet the needs of depression patients. patient medication needs

Method used

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  • 3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments
  • 3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments
  • 3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments

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preparation example Construction

[0081] Preparation of intermediate compounds

[0082] 1. Preparation of 4-toluenesulfonic acid (2-((3-cyanophenyl)methylamino)ethyl) ester

[0083] 1) Preparation of 3-methylaminobenzonitrile

[0084] Add 4.05g (75mmol, 0.5eq) CH to 45ml methanol 3 ONa, dissolve 17.70 g (150 mmol, 1.0 eq) of 3-aminobenzonitrile in 60 ml of methanol and add dropwise to the methanol solution of sodium methoxide. After stirring for 0.5 h at room temperature, the above reaction solution was poured into a 90 ml methanol solution of 6.30 g (210 mmol, 1.4 eq) of paraformaldehyde. After stirring the reaction at room temperature for 5.0h, add 6.00g (150mmol, 1.0eq) NaBH in batches 4 (Content 96%). The reaction was stirred at room temperature for 10 min, and the temperature was raised to reflux for 10 min. Cool the reaction solution in an ice-water bath, add 90ml 10% NaOH(aq) dropwise, stir for 5min, evaporate the methanol under reduced pressure, extract with ethyl acetate (150ml*2), combine the organic pha...

Embodiment 1

[0117] 3-((2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)methylamino)benzonitrile (III-1) hydrochloride, hydrobromide and sulfate Preparation

[0118] 2.90g (8.8mmol, 11eq) 4-toluenesulfonic acid (2-((3-cyanophenyl)methylamino)ethyl) ester and 1.54g (8.0mmol, 1.0eq) 2-methoxyphenyl Piperazine, 1.33g (8.0mmol, 1.0eq) potassium iodide and 4.10g

[0119] (32mmol, 4.0eq) diisopropylethylamine was added to 50ml of acetonitrile, heated and refluxed for 12h, the reaction of the raw materials was complete. The solvent was evaporated under reduced pressure, 35ml of water was added to the residue, extracted with ethyl acetate (35ml*2), separated, the organic phase was washed once with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to obtain 3.06 g of crude product as brown oil. Purified by neutral alumina column chromatography, firstly with petroleum ether: ethyl acetate=3:1 (volume ratio), and then eluted with dichloromethane as the mobile phase to obtain compound (III-1), powdery ...

Embodiment 2

[0131] Preparation of 3-(methyl(2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl)amino)benzonitrile (III-2) hydrochloride

[0132] 2.79g (8.5mmol, 11eq) 4-toluenesulfonic acid (2-((3-cyanophenyl)methylamino)ethyl) ester and 1.77g (7.6mmol, 1.0eq) 3-trifluoromethylbenzene Piperazine, 1.26g (7.6mmol, 1.0eq) potassium iodide and 3.90g

[0133] (30.4mmol, 4.0eq) diisopropylethylamine was added to 46ml of acetonitrile, heated to reflux for 12h, and the reaction of the raw materials was complete. The solvent was evaporated under reduced pressure, 35ml of water was added to the residue, extracted with ethyl acetate (30ml*2), separated, the organic phase was washed once with saturated brine, anhydrous Na 2 SO 4 After drying and concentrating, 3.6 g of crude brown oily product was obtained. Purified by neutral alumina column chromatography, firstly with petroleum ether: ethyl acetate=3:1 (volume ratio), and then eluted with dichloromethane as the mobile phase to obtain compound (III-2) a...

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Abstract

The invention discloses a 3-cyanoaniline alkyl aryl piperazine derivative and application thereof in preparing medicaments. The 3-cyanoaniline alkyl aryl piperazine derivative disclosed by the invention has very useful pharmaceutical properties and excellent tolerance, and especially can be used as a novel analgesia, a novel antidepressant medicament, and a novel analgesic and antidepressant medicament. The compounds are 5-hydroxytryptamine regulated central analgesias, and also are 5-hydroxytryptamine regulated novel antidepressant medicaments. The compounds also are low in toxic and side effects and large in safety range. The 3-cyanoaniline alkyl aryl piperazine derivatives are compounds as shown in a formula (III), or free bases or salts thereof.

Description

Technical field [0001] The invention relates to a 3-cyanoaniline alkylarylpiperazine derivative and its application in preparing analgesic and antidepressant drugs. Background technique [0002] Severe acute and chronic pain refers to the excitement of nociceptors caused by various damaging stimuli, and the impulse of the messenger through nociceptive information is transmitted to the central nervous system to cause nociception and pain. Severe acute and chronic pain, including tumor pain, postoperative pain, various recurrent acute and chronic pain, etc., plagues tens of millions of patients, and is currently a major clinical problem. [0003] The analgesics widely used in clinical practice can be roughly divided into the following three categories: 1) non-steroidal anti-inflammatory analgesics 2) opioid analgesics 3) other non-opioid analgesics, including: local anesthetics, anti- Depressants, anti-epileptics, etc. [0004] In terms of clinical treatment, for acute pain and cance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/13C07D239/47A61K31/495A61K31/506A61P25/04A61P25/24A61P29/02
CPCA61K31/495C07D295/125C07D239/34C07D241/04C07D403/00C07D401/00C07D401/04A61P25/04A61P25/24A61P29/02C07D239/47C07D295/13
Inventor 李建其王冠张桂森李亚莉徐祥清陈晓文刘世成赵松于民权
Owner NHWA PHARMA CORPORATION
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