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Structure, preparation method and application of a series of quinoxalinone derivatives

A compound structure, technology of medicine, application in the prevention and/or treatment of diabetic complications, preparation, quinoxalinone derivatives as aldose reductase inhibitors in the field of structure, can solve the problem that can not easily penetrate biomembrane , low bioavailability and other issues, to achieve good inhibitory effect and high selectivity effect

Inactive Publication Date: 2019-05-24
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to their high ionization under physiological conditions, they cannot easily penetrate biomembranes, resulting in low bioavailability

Method used

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  • Structure, preparation method and application of a series of quinoxalinone derivatives
  • Structure, preparation method and application of a series of quinoxalinone derivatives
  • Structure, preparation method and application of a series of quinoxalinone derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: 2-(3-(3,4-dihydroxyphenyl)-2-ketoquinoxaline-1(2H)-alkyl)-N-(trifluoromethylsulfonyl)acetamide (compound 1 )

[0052]

[0053] Put 10.8g (100mmol) of o-phenylenediamine and 13.5g (150mmol) of oxalic acid into a round bottom flask, then add 100mL of water and 10mL of concentrated hydrochloric acid, heat, stir and reflux for 6 hours, and after returning to room temperature, filter the reaction solution, Repeated washing with water and drying gave quinoxaline-2,3(1H,4H)-dione (colorless crystals, yield 96%, 15.6g): 1 H NMR (400MHz, [D 6 ]DMSO): δ 7.063 (d, 2H, J = 6.4Hz), 7.114 (d, 2H, J = 6.4Hz), 11.893 (s, 2H).

[0054] Add 8.1g (50mmol) of quinoxaline-2,3(1H,4H)-dione, 11.9g (100mmol) of thionyl chloride, and 5mL of DMF into a round-bottomed flask containing 50mL of dichloromethane, and heat to reflux Stir until the starting material spot disappears as monitored by TLC. The reaction solution was cooled to room temperature, and poured into ice water car...

Embodiment 2

[0060] Example 2: 2-(3-(Styryl)-2-ketoquinoxaline-1(2H)-alkyl)-N-(trifluoromethylsulfonyl)acetamide (Compound 2)

[0061]

[0062] Add 0.504g of 2-(3-chloro-2-ketoquinoxaline-1(2H)-alkyl)methyl acetate into a 100mL two-necked round-bottomed flask, then weigh 0.022g of 5mol% acetic acid Palladium and 0.043 g of tri-o-methylphenylphosphine with a content of 10 mol % were added and mixed. Under the condition of nitrogen protection, 20ml of N,N-dimethylformamide was added, and stirred at room temperature for 30min until it was completely dissolved. Then weigh (0.344 mL, 3mmol) styrene, measure 6ml triethylamine, and keep nitrogen to protect the environment after adding to the reaction system, heat to 100°C, stir and reflux for 12h, use TLC to monitor and judge the raw material 2-(3-chloro- The reaction was stopped after the complete disappearance of methyl 2-ketoquinoxaline-1(2H)-alkyl)acetate. After the reaction solution was cooled to normal temperature, a small amount of wate...

Embodiment 3

[0065] Example 3: 2-(3-(4-hydroxystyryl))-2-ketoquinoxaline-1(2H)-alkyl)-N-(trifluoromethylsulfonyl)acetamide (Compound 3 )

[0066]

[0067] Replace 2-(3-(3,4 -dimethoxyphenyl))-2-ketoquinoxaline-1(2H)-alkyl)acetic acid, prepared according to the preparation method described in Example 1.

[0068] 1 H NMR (400MHz, [D 6 ]DMSO)δ9.92(s,1H),7.98(d,J=20.4Hz,1H), 7.80(d,J=7.7Hz,1H),7.73–7.42(m,4H),7.35(t,J =7.7Hz, 1H), 7.23(t, J = 6.5Hz, 1H), 6.84(d, J = 8.0Hz, 2H), 4.87(s, 2H); 13 C NMR (101MHz, [D 6 ]DMSO) δ171.20, 162.77, 159.51, 154.49, 152.34, 137.88, 133.09, 132.87, 130.03 (2C), 129.32, 127.55, 123.93, 120.79 (d, J=325.2Hz), 118.95, 1180.9, 319 ppm.HRMS(ESI)m / z calcd for[M-H] - 452.0533,found 452.0545.

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Abstract

The invention provides the structure and synthesis method of a compound shown in the formula I, and application of pharmaceutically acceptable salts of the compound or a mixture of the salts in preparation of drugs for preventing and / or treating diabetic complications. The compound acts as aldose reductase inhibitors and antioxidants and can effectively scavenge free radicals and inhibit the production of lipid peroxides by inhibiting the activity of aldose reductase, and thus the effect of preventing and / or treating the diabetic complications is achieved. The invention further provides a pharmaceutical composition containing the compound and having preventive and / or therapeutic effects on diabetic complications. The formula can be seen in the description.

Description

technical field [0001] The present invention relates to the fields of organic chemistry, medicinal chemistry and pharmacology, in particular to a series of novel quinoxalinone derivatives as the structure of the aldose reductase inhibitor, the preparation method, the anti-aldose reductase (Aldose Reductase, ALR2) and free radical inhibition and its application in the prevention and / or treatment of diabetic complications. Background technique [0002] Diabetes mellitus (DM) is a common chronic metabolic disease associated with severe degenerative complications such as neuropathy, nephropathy, retinopathy, cataract, atherosclerosis and myocardial infarction. Due to the high disability rate and high mortality rate of diabetes complications, it has become one of the main threats to the health and life expectancy of residents in most countries in the world. Indeed, their prevention and control remain challenging therapeutic issues. Epalrestat (Epalrestat) is currently the only ...

Claims

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Application Information

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IPC IPC(8): C07D241/44A61K31/498A61P3/10
Inventor 朱长进马兵吉云鹏
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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