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Piperazine adenosine monophosphate activated protein kinase (AMPK) agonist and medical application thereof

A technology of pharmacy and prodrug, applied in the field of piperazine compounds

Active Publication Date: 2019-10-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to date no small molecule adiponectin receptor agonists have entered clinical trials

Method used

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  • Piperazine adenosine monophosphate activated protein kinase (AMPK) agonist and medical application thereof
  • Piperazine adenosine monophosphate activated protein kinase (AMPK) agonist and medical application thereof
  • Piperazine adenosine monophosphate activated protein kinase (AMPK) agonist and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] 5-(2,5-Dimethylphenoxy)-1-(1-(4-((4-fluorophenyl)sulfonyl)piperazinyl))-2,2-dimethyl-1- Pentanone (Compound 3)

[0099]

[0100] Compound I-1 (10 g, 40 mmol) was dissolved in dichloromethane (160 mL), and oxalyl chloride (6.77 mL, 80 mmol) and N,N-dimethylformamide (1 mL) were added dropwise under ice-cooling conditions. After reacting for about 5.5 hours, the solvent and unreacted oxalyl chloride were distilled off under reduced pressure to obtain acid chloride. Compound II-1 (11.175g, 60mmol) was dissolved in dichloromethane (100mL), and the above-prepared acid chloride and triethylamine (16.6mL, 120mmol) were added under ice-cooling conditions, and reacted for 12 hours. The reaction system was washed with water (100mL x 3), saturated sodium carbonate solution (100mL x 2), saturated brine (100mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography ( Eluent: petroleum e...

Embodiment 2

[0104] 5-(2,5-Dimethylphenoxy)-1-(1-(4-((4-chlorophenyl)sulfonyl)piperazinyl))-2,2-dimethyl-1- Pentanone (compound 1)

[0105] Compound 1 was obtained with reference to the method of Example 1: 1 H NMR (300MHz, CDCl 3 )δ7.64(d, J=8.6Hz, 2H), 7.42(d, J=8.6Hz, 2H), 7.02(d, J=7.5Hz, 1H), 6.68(d, J=7.4Hz, 1H) , 6.58(s, 1H), 3.86(t, J=5.4Hz, 2H), 3.77-3.68(m, 4H), 3.06-2.97(m, 4H), 2.31(s, 3H), 2.14(s, 3H ), 1.78-1.62 (m, 4H), 1.24 (s, 6H). ESI-MS: m / z 515.2 [M+Na] + .

Embodiment 3

[0107] 5-(2,5-Dimethylphenoxy)-1-(1-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazinyl))-2,2-di Methyl-1-pentanone (Compound 4)

[0108] Compound 4 was obtained by referring to the method of Example 1: 1 H NMR (300MHz, CDCl 3 )δ7.83(d, J=8.1Hz, 2H), 7.71(d, J=8.2Hz, 2H), 7.02(d, J=7.4Hz, 1H), 6.68(d, J=7.3Hz, 1H) , 6.58(s, 1H), 3.86(t, J=5.2Hz, 2H), 3.81-3.70(m, 4H), 3.06(m, 4H), 2.31(s, 3H), 2.14(s, 3H), 1.79-1.61 (m, 4H), 1.24 (s, 6H). ESI-MS: m / z 549.2 [M+Na] + .

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Abstract

The invention discloses a piperazine compound with AMPK agonist activity, and a preparation method and medical application of the piperazine compound. The piperazine compound is a compound shown as aformula (I) (please see the specifications for the formula), and a pharmaceutically acceptable salt or ester or a prodrug or N-oxide or solvate thereof. The compound can be used for preparing drugs for preventing or treating AMPK-mediated diseases.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a piperazine compound with AMPK agonist activity, and also relates to a preparation method of the compound and its medical use as an AMPK agonist. [0002] This patent application claims the priority of the Chinese patent application (application number 201810345939.X, application date: April 13, 2018, invention name: piperazine AMPK agonist and its medical use). Background technique [0003] AMPK (adenylate-activated protein kinase) is a key kinase that regulates energy metabolism and inflammatory responses in the body. Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood lipids (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammation, and anti-apoptosis. Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor, etc. (Physiol. Rev. 2009, 89, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/26C07D295/185C07D213/71C07D241/04C07D307/79C07D317/62A61K31/495A61K31/496A61P9/00A61P29/00A61P37/00A61P11/00A61P25/00A61P31/00A61P35/00
CPCC07D295/26C07D295/185C07D213/71C07D241/04C07D307/79C07D317/62A61P9/00A61P29/00A61P37/00A61P11/00A61P25/00A61P31/00A61P35/00
Inventor 孙宏斌晏顶霏冯志奇张佳姚智颖赵文峰张翔鹰孙更韩立帅吴文珍刘胜杰赵星李明雷喻生琪陈辉程亚龙汪鹏飞戴量温小安柳军
Owner CHINA PHARM UNIV
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