Coumarin compound and drug combination and preparation and application methods thereof

A technology of coumarins and compounds, which is applied in the direction of drug combinations, active ingredients of heterocyclic compounds, pharmaceutical formulations, etc., can solve the problem of limiting the anti-tumor potential of Bromodomain protein, the small molecule inhibitor structure type of BRD4 protein, The effect still needs to be improved to achieve significant protein binding ability, good anti-tumor activity, and good protein inhibitory activity.

Active Publication Date: 2019-05-31
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, there are few structural types of small molecule inhibitors of BRD4 protein and the selectivity is not outstanding enough, which limits people's in-depth research on the biological functions of Bromodomain-containing proteins and their anti-tumor potential
In addition, the effect of existing BRD4 protein inhibitors needs to be improved, and the mechanism needs to be further elucidated. Therefore, it is a hotspot in epigenetic anti-tumor research to find new high-efficiency and highly selective small-molecule BRD4 protein inhibitors.

Method used

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  • Coumarin compound and drug combination and preparation and application methods thereof
  • Coumarin compound and drug combination and preparation and application methods thereof
  • Coumarin compound and drug combination and preparation and application methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) Synthesis of 6-nitro-2H-benzopyran-2-one (II):

[0055] Add HNO to a 250mL three-necked bottle 3 (1.3g, 20.1mmol) and H 2 SO 4 10mL, placed in an ice-salt bath and stirred, maintaining the temperature at 0°C, adding coumarin (2.9g, 20mmol) in H 2 SO 4 2mL, and then maintain the temperature at 0°C for about 2h. TLC detected that the reaction was complete. Pour the reaction liquid into 300mL ice-water mixture and stir while adding. After the ice melted, a solid precipitated out. Suction filtration and vacuum drying of the filter cake gave a yellow solid , yield 64.8%.

[0056] (2) 6-amino-2H-benzopyran-2-one (III):

[0057] Add iron powder (1.7g, 31mmol) and NH 4 Cl (0.8g, 15mmol), then add ethanol (30mL), water (10mL), add 6-nitro-2H-chromen-2-one (II) (1.5g, 7.8mmol) to the above system , reacted at 80°C for 2 hours, filtered with suction, distilled off the solvent by adding pressure, and separated by column chromatography to obtain 6-amino-2H-benzopyran-2-...

Embodiment 2

[0063] Synthesis of N-(2-oxo-2H-benzopyran-6-yl)cyclohexylsulfonamide (2): The specific preparation method is the same as in Example 1, and the yield obtained is 92.3%.

[0064] 1 H NMR (400MHz, DMSO) δ9.97(s, 1H), 8.09(d, J=9.6Hz, 1H), 7.56(d, J=2.4Hz, 1H), 7.45(dd, J=8.9, 2.5Hz ,1H),7.39(d,J=8.9Hz,1H),6.50(d,J=9.6Hz,1H),3.03(t,J=10.2Hz,1H),2.05(d,J=11.5Hz,2H ),1.76(d,J=12.9Hz,2H),1.59(d,J=12.0Hz,1H),1.43(m,2H),1.18(m,3H). 13 C NMR (101MHz, DMSO) δ160.31, 150.34, 144.55, 135.38, 124.39, 119.63, 118.65, 117.74, 117.23, 59.50, 26.45, 25.19, 24.77. HRMS (ESI) calcd.forC 15 h 18 NO 4 S([M+H] + )308.0957, found 308.0952.

Embodiment 3

[0066] Synthesis of N-(2-oxo-2H-benzopyran-6-yl)cyclopentasulfonamide (3): The specific preparation method is the same as in Example 1, and the yield obtained is 85.9%.

[0067] 1 H NMR (400MHz, DMSO) δ9.95 (s, 1H), 8.10 (d, J = 9.6Hz, 1H), 7.57 (d, J = 2.3Hz, 1H), 7.48–7.37 (m, 2H), 6.50 (d,J=9.7Hz,1H),3.64–3.49(m,1H),1.94–1.85(m,4H),1.65(m,4H),1.55(m,4H). 13 C NMR (101MHz, DMSO) δ160.31, 150.53, 144.52, 135.20, 124.93, 119.63, 119.25, 117.73, 117.23, 60.21, 27.77, 25.87. HRMS (ESI) calcd.for C 14 h 16 NO 4 S([M+H] + )294.0800, found 294.0794.

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Abstract

The invention discloses a coumarin compound with BRD (bromodomain-containing protein 4) inhibiting effects. The coumarin compound comprises a compound with a structure shown as the formula (I) and medically acceptable salts thereof. The coumarin compound in a brand-new structure containing coumarin nucleuses can inhibit BRD4 to various degrees and accordingly can be applied to preparing BRD4 inhibitors or to preventing and treating BRD4 activity-related diseases, and due to a huge variety of the related diseases, can be extremely wide in application range. The invention also discloses a preparation method of the coumarin compound. The preparation method of the coumarin compound is rich in material resources, simple in operation, mild in condition, low in cost and highly applicable large-scale industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to coumarin derivatives, their preparation methods, pharmaceutical compositions containing these compounds and their pharmaceutical use, especially the use as BRD4 protein inhibitor. Background technique [0002] In recent years, tumors have become one of the main causes of human death worldwide. Tumors generally have the characteristics of low overall cure rate and high recurrence rate. Therefore, prevention, treatment and suppression of tumor recurrence have important scientific research value. It is quite urgent and challenging to realize the prevention and cure of tumors. [0003] The abnormality of epigenetic regulation is one of the important factors leading to tumorigenesis. The latest research has found that BRD4 protein-mediated epigenetic abnormalities are closely related to the overexpression of oncogenes, and are closely related to the growth and proliferation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/14C07D409/12C07D407/12A61K31/37A61K31/381A61P35/00A61P35/02
Inventor 张智敏沈正荣黄文海王尊元马臻梁美好曾申昕章迟啸
Owner ZHEJIANG ACAD OF MEDICAL SCI
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