N, N-(4-piperidyl, aryl)-3-aminophenol derivative, pharmaceutical composition and application thereof

A technology based on aminophenol and piperidinium, which is applied in the field of medicine, can solve the problems of unseen and no pharmacological activity, and achieve the effects of simple and easy preparation method, high triple agonist activity, and high yield

Pending Publication Date: 2022-01-28
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, in the prior art, there are no reports of novel N,N-(4-piperidinyl, aryl)-3-aminophenol derivatives, and no reports of their pharmacological activity

Method used

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  • N, N-(4-piperidyl, aryl)-3-aminophenol derivative, pharmaceutical composition and application thereof
  • N, N-(4-piperidyl, aryl)-3-aminophenol derivative, pharmaceutical composition and application thereof
  • N, N-(4-piperidyl, aryl)-3-aminophenol derivative, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Synthetic general formula:

[0049]

[0050] Synthesis of intermediate 31:

[0051] Add 3-aminophenol (5.0g, 45.9mmol, 1.0eq) dissolved in 1,2-dichloroethane (150mL) under stirring at room temperature into a reaction flask treated with anhydrous and oxygen-free treatment, and then add N-tert-butoxy Carbonyl-4-piperidone (9.2 g, 45.8 mmol, 1.0 eq), sodium triacetoxyborohydride (14.6 g, 68.7 mmol, 1.5 eq) and glacial acetic acid (4.1 mL, 68.7 mmol, 1.5 eq). After 24h, it was quenched by adding 1N sodium hydroxide solution (76.1mL, 76.1mmol). The post-experiment treatment was performed according to the general experimental procedure, and the intermediate 31 (9.9g, 74.7%) was obtained by column chromatography purification.

[0052] Synthesis of Intermediate 32:

[0053] Add compound 31 (5.0 g, 17.1 mmol, 1.0 eq) dissolved in ultra-dry dichloromethane (35 mL) under stirring at room temperature into a pressure bottle treated with anhydrous and oxygen-free treatment, and th...

Embodiment 2

[0091] biological activity. Evaluation of the agonist activity of the compounds of the invention on opioid receptors (MOR, DOR, KOR).

[0092] In order to evaluate the agonistic effect of the compounds of the present invention on opioid receptors (MOR, DOR, KOR), the present invention uses drugs DAGO (MOR agonist), DPDPE (DOR agonist), U50488 (KOR agonist) as positive controls. Compound EC 50 Values ​​were determined by concentration-effect curve generation calculations.

[0093] 1. Experimental principles and methods

[0094] Experimental principle: By establishing a cell line that co-transforms the target receptor and Gα16, the activation of the receptor can cause the activation of Gα16 protein, and then activate phospholipase C (PLC) to produce IP3 and DAG, and IP3 can bind to the endoplasm in the cell Reticulum binds to the IP3 receptor on the mitochondria, thereby causing the release of intracellular calcium. Therefore, measuring the change of intracellular calcium ca...

Embodiment 3

[0102] Preparation of tablets:

[0103] Take N,N-(4-piperidinyl, aryl)-3-aminophenol derivatives (any one or any combination of compounds 2-30) and their polymorphs, according to their weight ratio with excipients Add excipients at a ratio of 1:5-1:10, granulate and compress into tablets.

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PUM

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Abstract

The invention provides an N, N-(4-piperidyl, aryl)-3-aminophenol derivative, a preparation method and application thereof, and a pharmaceutical composition taking the N, N-(4-piperidyl, aryl)-3-aminophenol derivative as an active component, a preparation method and application thereof, and belongs to the technical field of medicines. According to the invention, a N, N-(4-piperidyl, aryl)-3-aminophenol compound has obvious opioid receptor agonist activity, has triple agonist activity to MOR receptors, DOR receptors and KOR, and has higher agonist activity to the MOR receptors and the DOR receptors than the KOR receptors, and the compound and the pharmaceutical composition thereof can be used as novel analgesic drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a class of N,N-(4-piperidinyl, aryl)-3-aminophenol derivatives, a preparation method thereof, and a pharmaceutical composition using such compounds as active ingredients. and its application in the preparation of novel powerful analgesic drugs. Background technique [0002] The target of opioids in the body is the opioid receptor, which has attracted extensive attention in the fields of clinical medicine and public health due to its potent analgesic ability. Opioids are often accompanied by side effects such as euphoria, physical dependence, respiratory depression and constipation, so finding safer and more effective painkillers is an important topic in the field of opioid research. [0003] Opioid receptors belong to the class A family of G protein-coupled receptors (GPCRs). So far, four opioid receptor subtypes have been cloned, namely μ-opioid receptor (Mu Opioid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D409/12C07D409/14A61K31/4545A61K31/4535A61P25/04
CPCC07D401/12C07D401/14C07D409/12C07D409/14A61P25/04
Inventor 汪亮亮曹峰蒋绚张树群
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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