PPAR (Peroxisome Proliferator-Activated Receptor) gamma/delta dual agonist as well as preparation method and application thereof to medicine

A compound and alkyl technology, applied in the field of medicine, can solve the problems of PPARγ/δ dual agonists that have not been reported in the literature

Inactive Publication Date: 2019-02-22
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, PPARα/γ dual agonists, PPARα/γ/δ pan-agonists and PPARα/δ dual agonists have been reported i

Method used

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  • PPAR (Peroxisome Proliferator-Activated Receptor) gamma/delta dual agonist as well as preparation method and application thereof to medicine
  • PPAR (Peroxisome Proliferator-Activated Receptor) gamma/delta dual agonist as well as preparation method and application thereof to medicine
  • PPAR (Peroxisome Proliferator-Activated Receptor) gamma/delta dual agonist as well as preparation method and application thereof to medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] 2-(4-((6-methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)-2,6-dimethylphenoxy)acetic acid (I-1)

[0080]

[0081] 6-Methoxy-3-benzofuranone 1a (1.0g, 6.1mmol) and methyl 2-(4-formyl-2,6-dimethylphenoxy)acetate 2a (1.3g, 6.1mmol ) was dissolved in ethanol / DMF (20mL, 1:1, v / v) mixed solvent, and 2.3mL of 50% KOH aqueous solution was added dropwise at room temperature, and the solution was reacted at room temperature for 4 hours. After the reaction was detected by TLC, the reaction solution was poured into 30mL of water , adjusted the pH to 1-2 with concentrated hydrochloric acid under vigorous stirring, suction filtered after cooling, washed the filter cake with a small amount of cold water, recrystallized with methanol / DMF (1:1, v / v) to obtain 1.2 g of light yellow crystals, and the yield was 56 %.

[0082] 1 H NMR (300MHz, DMSO-d 6 )δ: 7.75-7.62(m, 3H), 7.13(d, J=1.9Hz, 1H), 6.86, 6.83(dd, J=8.6, 2.0Hz, 1H), 6.69(s, 1H), 4.45(s , 2H), 3.94(s, 3H), 2.31(s, 6H). 13 C...

Embodiment 2

[0084] 2-(4-((6-ethoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)-2,6-dimethylphenoxy)acetic acid (I-2)

[0085]

[0086] Referring to the preparation method of I-1, 0.64 g of light yellow crystals was obtained with a yield of 50%.

[0087] 1 H NMR (300MHz, DMSO-d 6 )δ: 7.76-7.62(m, 3H), 7.08(s, 1H), 6.81(d, J=8.5Hz, 1H), 6.68(s, 1H), 4.45(s, 2H), 4.22(q, J =6.8Hz, 2H), 2.31(s, 6H), 1.39(t, J=6.8Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 )δ: 181.97, 170.40, 168.41, 167.02, 157.19, 147.18, 132.37, 131.50, 128.20, 114.31, 112.32, 109.64, 100.35, 69.37, 65.04, 16.61, 14.78. - .Anal.calcd.For C 21 h 20 o 6 : C, 68.47; H, 5.47; Found: C, 68.62; H, 5.31.

Embodiment 3

[0089] 2-(4-((6-propoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)-2,6-dimethylphenoxy)acetic acid (I-3)

[0090]

[0091] Referring to the preparation method of I-1, 0.49 g of light yellow crystals was obtained with a yield of 35%.

[0092] 1 H NMR (300MHz, DMSO-d 6 )δ: 7.76-7.63(m, 3H), 7.11(d, J=1.6Hz, 1H), 6.84, 6.81(dd, J=8.5, 1.8Hz, 1H), 6.69(s, 1H), 4.45(s , 2H), 4.12(t, J=6.5Hz, 2H), 2.31(s, 6H), 1.85-1.73(m, 2H), 1.01(t, J=7.4Hz, 3H). 13 CNMR (75MHz, DMSO-d 6 )δ: 181.93, 170.42, 167.20, 162.52, 157.15, 147.20, 132.37, 131.53, 128.32, 114.31, 112.32, 109.64, 99.99, 70.77, 65.04, 22.25, 16.63, 10.18. - .Anal.calcd.For C 22 h 22 o 6 : C, 69.10; H, 5.80; Found: C, 69.35; H, 5.71.

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Abstract

The invention relates to a PPAR (Peroxisome Proliferator-Activated Receptor) gamma/delta dual agonist shown as a general formula (I), a preparation method thereof and application of a pharmaceutical composition containing the derivative to preparation of a medicine for preventing or/and treating abnormal glucose metabolism or/and abnormal lipid metabolism diseases. The PPARgamma/delta dual agonistprovided by the invention has excellent in vivo blood glucose lowering activity and blood lipid regulation effect, and can be used for preparing medicines for preventing or/and treating metabolic syndrome related diseases including diabetes mellitus, obesity, hyperlipidemia, atherosclerosis, fatty liver and the like; the PPARgamma/delta dual agonist has a wide application prospect. The formula (I) is shown in the description.

Description

technical field [0001] The invention relates to a class of PPARγ / δ dual agonists, a preparation method and application thereof, and belongs to the technical field of medicine. The derivative structures involved in the present invention are unique and novel in this field. 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, atherosclerosis Cirrhosis and fatty liver, etc. Among them, diabetic patients often have 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 more than 92 million diabetics. More...

Claims

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Application Information

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IPC IPC(8): C07D307/83A61P3/00A61P3/04A61P3/06A61P3/10A61P1/16A61P9/10A61K31/343
CPCA61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P9/10C07D307/83
Inventor 张陆勇李政周宗涛
Owner GUANGDONG PHARMA UNIV
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