Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof

A technology of protease inhibition and quinoxalinone, applied in the direction of organic active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve inappropriate problems

Inactive Publication Date: 2010-05-12
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, 28 mammalian MMP subtypes have been discovered, so many MMPs family members are classified, and because the high expression of MMPs participates in many physiological processes of the human body, it is obviously inappropriate to inhibit all MMPs family members

Method used

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  • Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof
  • Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof
  • Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] The preparation method of 2-(3-methyl-2-oxo-quinoxaline-1-(2H)-yl)acetohydrazide (lyg-31 in table 1)

[0076]Weigh o-phenylenediamine (10.81g, 0.10mol), add it to 250ml of absolute ethanol, stir at room temperature for 15min until dissolved, add ethyl pyruvate (12.77g, 0.11mol), a yellow solid is formed, continue to stir for 4h, react complete. Suction filtration gave a light yellow solid, which was recrystallized from ethanol to obtain 3-methylquinoxaline-2(1H)-one with a yield of 92.7%, m.p.241-243°C; weigh 3-methylquinoxaline-2 (1H)-ketone (8.01g, 0.05mol), anhydrous potassium carbonate (8.29g, 0.06mol) and ethyl chloroacetate (7.353g, 0.06mol), add 200ml of acetone to form a suspension, add tetrabutyl Ammonium bromide (0.5g, cat.), heated to reflux under oil bath conditions, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure, added 100ml of water and 200ml of ethyl acetate for extraction three times, spin-dried ethyl acetate ...

Embodiment 2

[0078] The preparation method of N-(2-3-methyl-2-oxo-quinoxalin-1-(2H)-yl) acetyl) phenylacetylhydrazide (lyg-32 in table 1)

[0079] Weigh o-phenylenediamine (10.81g, 0.10mol), add it to 250ml of absolute ethanol, stir at room temperature for 15min until dissolved, add ethyl pyruvate (12.77g, 0.11mol), a yellow solid is formed, continue to stir for 4h, react Complete. Suction filtration to obtain a light yellow solid, recrystallized from ethanol to obtain 3-methylquinoxaline-2(1H)-one, the yield is 92.7%, m.p.241-243°C; weigh 3-methylquinoxaline -2(1H)-ketone (8.01g, 0.05mol), anhydrous potassium carbonate (8.29g, 0.06mol) and ethyl chloroacetate (7.353g, 0.06mol), add 200ml of acetone to form a suspension, add four Butylammonium bromide (0.5g, cat.) was heated to reflux under oil bath conditions, TLC detected that the reaction was complete, the solvent was evaporated under reduced pressure, 100ml of water and 200ml of ethyl acetate were added for extraction three times, and ...

Embodiment 3

[0081] 2,6-dichloro-N'-(2-(3-methyl-2-oxo-quinoxalin-1-(2H)-yl)acetyl)phenylacetylhydrazide (lyg-34 in Table 1) Preparation

[0082] See Example 1 for the preparation of 2-(3-methyl-2-oxo-quinoxalin-1-(2H)-yl)acetylhydrazide. Weigh 2-(3-methyl-2-oxo-quinoxalin-1-(2H)-yl)acetohydrazide (0.23g, 1mmol), anhydrous sodium carbonate (0.12g, 1.1mmol), add 20ml anhydrous Then add 2,6-dichlorobenzoyl chloride (0.209g, 1mmol) into water tetrahydrofuran, stir at room temperature for 12h, and the reaction is complete. The solvent was evaporated under reduced pressure, washed with a small amount of water, and filtered; the filter cake was recrystallized with ethanol to obtain white powder 2,6-dichloro-N'-(2-(3-methyl-2-oxo-quinoxaline- 1-(2H)-yl)acetyl)phenylacetylhydrazide, yield 57.1%, m.p.294-296°C, ESI-MS 405.8(M+H), 1 H-NMR: (DMSO-d 6 , ppm) δ: 2.43 (s, 3H, CH 3 ), 5.048 (s, 2H, NCH 2 CO), 7.355-7.38 (m, 2H, ArH), 7.46 (d, J=8.4Hz, 1H, ArH), 7.517-7.582 (m, 2H, ArH), 7.72 (d, J=...

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Abstract

The invention discloses a quinoxalinone derivative with matrix metalloproteinase inhibitory activity and a preparation method and an application thereof, belonging to the technical field of pharmaceutical chemistry. The derivative has the structure shown in the general formula (I), wherein the meanings of R1, R2, R3, R4, R5 and R6 are shown in the patent specification. The compound of the invention is proven to have specific MMP-2 inhibitory activity in the in vitro enzyme inhibitory activity experiments and to be an effective matrix metalloproteinase inhibitor so that the quinoxalinone derivative is expected to be developed to be a new anti-cancer drug.

Description

technical field [0001] The invention relates to quinoxalinone derivatives capable of inhibiting matrix metalloproteinases, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Background technique [0002] Malignant tumors are one of the main diseases causing human death, and it is imminent to find highly selective anticancer drugs with high efficiency and low toxicity. Matrix metalloproteinases (Matrix metalloproteinases, MMPs) are a class of endopeptidases whose activity depends on zinc ions. Their main physiological function is to degrade and rebuild the extracellular matrix. Plays a key role in blood vessel growth. At present, 28 mammalian MMP subtypes have been discovered, so many MMPs family members are classified, and because the high expression of MMPs participates in many physiological processes of the human body, it is obviously inappropriate to inhibit all MMPs family members. People thus realize the importance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/44C07D405/12A61K31/498A61P35/00A61P29/00A61P25/00A61P1/02
Inventor 李荀李勇刚
Owner SHANDONG UNIV
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