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Aminomethylpiperidine derivatives, and preparation method and pharmaceutical application thereof

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

Active Publication Date: 2016-06-08
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, and preparation method and pharmaceutical application thereof
  • Aminomethylpiperidine derivatives, and preparation method and pharmaceutical application thereof
  • Aminomethylpiperidine derivatives, and preparation method and pharmaceutical application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084]

[0085] 1-Benzyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0086] Preparation of compound FW-B-1

[0087] According to 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 HNMR (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 CNMR (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.

[0088] ESI-MSm / z355.3[M+H] + HRMSm / zcalcdforC 22 h 30 NO 2 [M+H]+, 340.2271; found, 340.2281.

Embodiment 2

[0090]

[0091] 1-Phenylethyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0092] Preparation of compound FW-B-2

[0093] 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 HNMR (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 CNMR (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, 38.57 / IMS.29.02 +H] + .

Embodiment 3

[0095]

[0096] 1-phenylpropyl-3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-piperidin-4-ol

[0097] Preparation of compound FW-B-3

[0098] 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 HNMR (400MHz, DMSO-d 6 ) 1 HNMR(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=8.1,2.2Hz ,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 CNMR (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-MSm / z383.3 [M+H] + .

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Abstract

The invention belongs to the field of pharmacy, and relates to aminomethylpiperidine derivatives as shown in a general formula (I) or salts thereof, and a preparation method for the aminomethylpiperidine derivatives and application of the aminomethylpiperidine derivatives in preparation of drugs used for treating opioid receptor mediated diseases. The aminomethylpiperidine derivatives provided by the invention show affinity activity and agonistic or antagonistic functional activity to mu and delta opioid receptors in an in-vitro experiment, and show analgesic activity with moderate intensity in an animal in-vivo experiment. The aminomethylpiperidine derivatives provided by the invention can be used for preparing the drugs used for treating the opioid receptor mediated diseases, wherein the diseases comprise but are not limited to pains, gastrointestinal diseases, depressive disorders, pruritus, addiction, etc.; and the aminomethylpiperidine derivatives have significant potential clinical application values in treatment of pains.

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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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