AMPK agonist compound or pharmaceutically acceptable salt or ester or solvate thereof and application thereof

A solvate, compound technology, applied in the field of AMPK agonist compounds, salts or esters or solvates, to achieve the effect of potent AMPK agonist activity

Active Publication Date: 2021-07-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, although the broad-spectrum AMPK-β subunit agonist MK-8722 can lower blood sugar, it was found in rats and monkeys that the animal heart had irreversible cardiac hypertrophy as a side effect (Science 2017, 357, 507)

Method used

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  • AMPK agonist compound or pharmaceutically acceptable salt or ester or solvate thereof and application thereof
  • AMPK agonist compound or pharmaceutically acceptable salt or ester or solvate thereof and application thereof
  • AMPK agonist compound or pharmaceutically acceptable salt or ester or solvate thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] 2-(4-Chlorophenoxy)-N-(4-(4-fluorobenzyl)oxy)phenyl)-2-methylpropanamide (Compound A-1)

[0056]

[0057] Dissolve p-aminophenol (3.27g, 30mmol), imidazole (2.7g, 45mmol) in DCM (50mL), slowly add tert-butyldimethylsilyl chloride (TBSCl) (5.88g, 39mmol) under stirring at room temperature, and react at room temperature 1h. The reaction solution was filtered with suction, and the filtrate was concentrated to obtain a pale yellow oily liquid, compound I-2.

[0058] Add oxalyl chloride (5.1mL, 60mmol) dropwise to a solution of 2-(4-chlorophenoxy)-isobutyric acid (6.44g, 30mmol) in dichloromethane (30mL) under ice-bath conditions, add DMF (2drops) , react at room temperature for 3 hours. The organic solvent was distilled off under reduced pressure to obtain a residue, which was diluted with dichloromethane (15 mL) to obtain a freshly prepared acid chloride solution in DCM. It was added to compound I-2, TEA (6.3 mL, 45 mmol) in dichloromethane (25 mL) under ice-cooling,...

Embodiment 2

[0062] 2-(4-Chlorophenoxy)-N-(4-(4-methoxybenzyl)oxy)phenyl)-2-methylpropanamide (Compound A-2)

[0063]

[0064] With reference to the method of Example 1, 4-fluorobenzyl bromide was replaced by 4-methoxybenzyl chloride to obtain compound A-2: 1 H NMR (300MHz, DMSO-d 6 )δppm 9.84(s, 1H), 7.53(d, J=8.8Hz, 2H), 7.34(dd, J=8.3, 5.2Hz, 4H), 7.00-6.86(m, 6H), 4.98(s, 2H) , 3.75(s, 3H), 1.52(s, 6H). 13 C NMR (75MHz, DMSO-d 6 )δppm 171.70, 154.52, 153.64, 133.36, 131.75, 129.82, 129.71, 129.09, 126.13, 122.00, 121.34, 115.27, 114.99, 114.65, 80.85, 68.59, 24.72 / m - .

Embodiment 3

[0066] N-(4-((4-chlorobenzyl)oxy)phenyl)-2-(4-chlorophenoxy)-2-methylpropanamide (Compound A-3)

[0067]

[0068] With reference to the method of Example 1, 4-fluorobromobenzyl was replaced by 4-chlorobromobenzyl to obtain compound A-3: 1 H NMR (300MHz, DMSO-d 6 )δppm 9.86 (s, 1H), 7.54 (d, J = 8.9Hz, 2H), 7.45 (brs, 4H), 7.34 (d, J = 8.8Hz, 2H), 6.94 (dd, J = 8.9, 2.8Hz , 4H), 5.07(s, 2H), 1.52(s, 6H). ESI-MS: m / z 452.1 [M+Na] + .

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Abstract

The invention discloses an AMPK agonist compound with structures shown as I and II or pharmaceutically acceptable salt or ester or solvate thereof and application thereof. Benzyloxy aryl amide and piperidine urea compounds have strong AMPK agonist activity. Benzyloxy aryl amide and piperidine urea compounds can be used for preparing medicines for preventing or treating AMPK mediated diseases, and do not inhibit a mitochondrial complex I and cause myocardial hypertrophy when being used as an AMPK agonist.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to AMPK agonist compound or its pharmaceutically acceptable salt or ester or solvate and its application. Background technique [0002] 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, 1025). In recent years, the anti-inflammatory and anti-fibrotic effects of AMPK have attracted more and more attention (Nature 2013, 493, 346). The possible mechanism is that AMPK exerts anti-inflammatory and anti-inflammatory effects by enhancing the tra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/16C07C255/54C07C317/22C07C235/08C07D211/58A61K31/164A61K31/235A61K31/192A61K31/277A61K31/4468A61P5/48A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P9/06A61P9/12A61P9/04A61P1/16A61P19/06A61P11/00A61P11/06A61P1/00A61P13/12A61P15/00A61P19/00A61P17/06A61P17/00A61P1/18A61P13/10A61P31/04A61P25/16A61P25/04A61P25/28A61P25/24A61P21/00A61P43/00
CPCC07C235/16C07C255/54C07C317/22C07C235/08C07D211/58A61P5/48A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P9/06A61P9/12A61P9/04A61P1/16A61P19/06A61P11/00A61P11/06A61P1/00A61P13/12A61P15/00A61P19/00A61P17/06A61P17/00A61P1/18A61P13/10A61P31/04A61P25/16A61P25/04A61P25/28A61P25/24A61P21/00A61P43/00
Inventor 孙宏斌李浩斌尤燕平程亚龙钱铭周鑫煜温小安陈彩萍许庆龙袁浩亮
Owner CHINA PHARM UNIV
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