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Aminomethylpiperidine derivatives, preparation method and pharmaceutical use thereof

A technology of aminomethylpiperidine and derivatives, which is applied in the field of medicine for diseases, and can solve problems such as respiratory depression, addictive side effects, and clinical application limitations.

Active Publication Date: 2018-05-25
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that opioid analgesics have an irreplaceable role in pain treatment; opioid analgesics can act on three opioid subtype receptors in the body, μ, δ, and κ, among them, strong analgesics, such as Morphine, fentanyl, etc. are mostly μ receptor agonists, but there are severe respiratory depression and addictive side effects, which limit their clinical application.

Method used

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  • Aminomethylpiperidine derivatives, preparation method and pharmaceutical use thereof
  • Aminomethylpiperidine derivatives, preparation method and pharmaceutical use thereof
  • Aminomethylpiperidine derivatives, preparation method and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085]

[0086] 1-Benzyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0087] Preparation of compound FW-B-1

[0088] According to the general procedure 5, using compound 5 as raw material, and benzyl bromide, K 2 CO 3 A nitrogen atom alkylation reaction occurs to obtain compound FW-B-1. 1 H NMR (400MHz, DMSO-d 6)δ11.78(s,1H),7.73(s,2H),7.49(s,3H),7.34(t,J=7.8Hz,1H),7.06(d,J=6.9Hz,2H),6.88( d,J=8.1Hz,1H),5.85(s,1H),4.39(t,J=14.2Hz,2H),3.77(s,3H),3.17(d,J=8.5Hz,3H),3.05– 2.92(m,1H),2.68–2.35(m,10H),1.79(d,J=15.1Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ159.28, 146.76, 131.60, 129.57, 129.46, 129.27, 128.74, 116.93, 112.35, 111.18, 70.85, 58.66, 55.00, 54.89, 51.12, 46.09, 44.14, 37.84, 36.26.

[0089] ESI-MS m / z 355.3[M+H] + HRMS m / z calcd for C 22 h 30 NO 2 [M+H]+,340.2271;found,340.2281.

Embodiment 2

[0091]

[0092] 1-Phenylethyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0093] Preparation of compound FW-B-2

[0094] According to general operation method 5, with compound 5 as raw material, with bromophenylethane, K 2 CO 3 A nitrogen atom alkylation reaction occurs to obtain compound FW-B-2. 1 H NMR (400MHz, DMSO-d 6 )δ11.40(s,1H),10.61(s,1H),7.42–7.34(m,3H),7.29(dd,J=13.9,7.0Hz,3H),7.11(s,1H),7.07(d ,J=7.8Hz,1H),6.90(dd,J=8.1,2.3Hz,1H),5.94(s,1H),4.29(d,J=10.9Hz,1H),3.79(s,3H),3.59 –3.40(m,2H),3.30(dd,J=11.9,6.5Hz,4H),3.18(dt,J=17.3,9.4Hz,2H),3.05–2.91(m,1H),2.73–2.56(m ,4H),2.50–2.42(m,4H),1.85(d,J=14.7Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ159.81, 147.32, 137.60, 130.13, 129.18, 129.14, 127.29, 117.41, 112.85, 111.69, 71.41, 57.16, 55.74, 55.52, 51.02, 49.00, 44.78, 368.57, 337.20 +H] +

Embodiment 3

[0096]

[0097] 1-phenylpropyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0098] Preparation of compound FW-B-3

[0099] According to general operation method 5, with compound 5 as raw material, with bromophenylpropane, K 2 CO 3 A nitrogen atom alkylation reaction occurs to obtain compound FW-B-3. 1 H NMR (400MHz, DMSO-d 6 ) 1 H NMR (400MHz,DMSO)δ11.18(s,1H),10.24(s,1H),7.42–7.16(m,6H),7.15–6.99(m,2H),6.89(dd,J=8.1,2.2 Hz,1H),5.89(s,1H),4.02(d,J=11.2Hz,1H),3.77(s,3H),3.46(dd,J=16.3,9.2Hz,1H),3.24(dd,J =22.4,10.1Hz,3H),3.09(t,J=10.7Hz,2H),3.01–2.85(m,1H),2.79–2.56(m,6H),2.43(t,J=8.6Hz,4H) ,2.17(d,J=7.1Hz,2H),1.80(d,J=14.6Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ159.27,146.80,140.55,129.60,128.40,128.32,126.09,116.91,112.32,111.18,70.89,55.71,55.29,54.99,50.61,48.39,44.26,37.98,36.42,32.12,25.08.ESI-MS m / z 383.3 [M+H] +

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Abstract

The invention belongs to the field of pharmacy, and relates to aminomethylpiperidine derivatives of the general formula (I) or salts thereof, a preparation method thereof and the use of the compound in the preparation of medicines for treating diseases mediated by opioid receptors. The compounds of the present invention show affinity activity and agonistic or antagonistic activity to mu and delta opioid receptors in vitro experiments, and animal experiments in vivo show moderate analgesic activity. The compounds involved in the present invention can be prepared to treat opioids Drugs for receptor-mediated diseases not limited to pain, gastrointestinal disorders and depression as well as pruritus, addiction, etc.; the compounds of the present invention have significant potential clinical application in the treatment of pain.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to aminomethylpiperidine derivatives with general formula (I) or salts thereof, a preparation method thereof and the use of the compound in the preparation of medicines for treating diseases mediated by opioid receptors. Background technique [0002] According to the data, pain is a common symptom in the process of various diseases. Studies have shown that opioid analgesics have an irreplaceable role in pain treatment; opioid analgesics can act on three opioid subtype receptors in the body, μ, δ, and κ, among them, strong analgesics, such as Morphine and fentanyl are mostly mu receptor agonists, but they have severe respiratory depression and addictive side effects, which limit their clinical application. In recent years, studies have found that although the activation of the δ receptor itself cannot produce strong analgesic physiological effects, it has a regulatory effect on the physiologic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/52A61K31/4418A61P25/04A61P1/00A61P25/24A61P25/30A61P29/00
Inventor 付伟刘景根沈庆李炜徐学军
Owner FUDAN UNIV