PPAR (peroxisome proliferator-activated receptor) alpha-gamma dual agonist and application thereof

A dual agonist, methyl technology, applied in the field of medicine, can solve the problem of single action

Active Publication Date: 2018-04-17
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of the treatment of metabolic syndrome, the hypoglycemic drugs or lipid-lowering drugs currently used in clinical practice have single effects, and none of

Method used

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  • PPAR (peroxisome proliferator-activated receptor) alpha-gamma dual agonist and application thereof
  • PPAR (peroxisome proliferator-activated receptor) alpha-gamma dual agonist and application thereof
  • PPAR (peroxisome proliferator-activated receptor) alpha-gamma dual agonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] a) Ethyl 2-methyl-2-(4-acetylphenyl)oxypropionate

[0118] Add 27.2g (0.2mol) of p-hydroxyacetophenone to 250ml of acetonitrile, add 83g (0.6mol) of anhydrous potassium carbonate under stirring, and after stirring for 15min, continue to add 43.0g (0.22mol) of ethyl bromoisobutyrate ), back flow reaction 4h. After the reaction was completed, filter and concentrate the filtrate to obtain a tan oil, add 80 ml of 1 mol / L sodium hydroxide solution, and extract with dichloromethane (80 ml×2). The organic layers were combined, washed with water (50ml×2), and washed with saturated brine (50ml×1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 12.3 g of light yellow oily liquid with a yield of 49.2%.

[0119] b) Ethyl 3-{4-[(2-methyl-1-ethoxy-1-oxopropyl)-2-oxyl]phenyl}-3-oxopropionate

[0120] 3.8g (0.096mol) of 60% sodium hydride and 22.7g (0.192mol) of dry diethyl carbonate were dissolved in 100ml of ...

Embodiment 2

[0124] 2-Methyl-2-[4-(6-fluoro-2-oxo-2H-1-benzopyran-3-carbonyl)phenoxy]propanoic acid ethyl ester

[0125] 0.32g (0.001mol) of 3-{4-[(2-methyl-1-ethoxy-1-oxopropyl)-2-oxyl]phenyl}-3-oxopropionic acid ethyl For ester, 0.15g (0.0011mol) of 5-fluorosalicylaldehyde was dissolved in 10ml of absolute ethanol, 5 drops of piperidine and 1 drop of glacial acetic acid were added, and the reaction was refluxed at 80°C for 1h under the protection of nitrogen. After the reaction was completed and cooled to room temperature, a white solid was precipitated, filtered with suction, washed with absolute ethanol, and dried in vacuo to obtain 0.2 g of a white solid with a yield of 50.2%. m.p.101.4~101.9℃. ESI-MS: m / z 399.1[M+H] + ,421.1[M+Na] + ,437.1[M+K] + . 1 H NMR (400MHz, DMSO-d 6 ):δ8.31(s,1H,chromene-4-H),7.91(d,J=8.9Hz,2H,phenyl-H),7.70(dd,J=8.4,3.0Hz,1H,chromene-8- H), 7.61(td, J=8.8Hz, 8.5Hz, 3.0Hz, 1H, chromene-7-H), 7.56(dd, J=9.1, 4.5Hz, 1H, chromene-5-H), 6.86(d ,J=8.9Hz,2H...

Embodiment 3

[0127] 2-Methyl-2-[4-(6-chloro-2-oxo-2H-1-benzopyran-3-carbonyl)phenoxy]propanoic acid ethyl ester

[0128] Using 5-chlorosalicylaldehyde as the raw material, the preparation method was the same as in Example 2 to obtain 0.21 g of white powdery solid with a yield of 50.6%. m.p.100.6~101.0℃. ESI-MS: m / z 415.1[M+H] + ,437.1[M+Na] + . 1 H NMR (400MHz, DMSO-d 6 ): δ8.30(s,1H,chromene-4-H),7.95(d,J=2.5Hz,1H,chromene-5-H),7.91(d,J=8.9Hz,2H,phenyl-H) ,7.76(dd,J=8.9,2.6Hz,1H,chromene-7-H),7.54(d,J=8.9Hz,1H,chromene-8-H),6.86(d,J=8.9Hz,2H, phenyl-H), 4.17(q, J=7.1Hz, 2H, OCH2 ),1.61(s,6H,CH 3 ), 1.15(t, J=7.1Hz, 3H, CH 3 ).

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Abstract

The invention discloses a PPAR (peroxisome proliferator-activated receptor) alpha-gamma dual agonist and an application thereof. The PPAR alpha-gamma dual agonist contains an effective quantity of a derivative represented by the formula I or the formula II in the description and a pharmaceutically acceptable salt of the derivative, wherein definition of each substituent group is as claimed in theclaims and the description. Experiments prove that the compound represented as the formula I or the formula II can remarkably improve PPAR alpha-gamma transcriptional activity and mRNA level of related target genes, has PPAR alpha-gamma dual agonist activity and can be taken as an effective component of the PPAR alpha-gamma dual agonist. The PPAR alpha-gamma dual agonist can be applied to preparation of drugs and healthy food for preventing or/and treating metabolic syndromes, particularly can be applied to preparation of drugs and healthy food for preventing or/and treating abnormal glucose metabolism or/and abnormal lipids metabolism diseases, and has broad application prospect.

Description

technical field [0001] The invention relates to a PPARα / γ dual agonist and application thereof, belonging to the technical field of medicine. Background technique [0002] Metabolic syndrome is a common disease characterized by abnormal glucose and lipid metabolism, accompanied by elevated low-density lipoprotein and low high-density lipoprotein cholesterol. The common symptoms are obesity, diabetes, hyperlipidemia and atherosclerosis hardening. Among them, diabetic patients are often complicated by hyperlipidemia, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and other diseases. [0003] According to the World Health Organization, more than 220 million people worldwide suffer from diabetes. Among them, China has become the country with the largest number of diabetics in the world, with a total of 92 million diabetics. According to the "New England Journal of Medicine" published on March 25, 2010 According to the data of the research report, there are cu...

Claims

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Application Information

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IPC IPC(8): C07D311/20C07D311/12C07D311/92C07D215/54A61K31/366A61K31/47A61P3/04A61P3/08A61P3/10A61P3/06A61P3/00A61P9/10A23L33/10
CPCA23V2002/00C07D215/54C07D311/12C07D311/20C07D311/92A23V2200/326A23V2200/328A23V2200/332
Inventor 王绍杰牛寒冬
Owner SHENYANG PHARMA UNIVERSITY
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