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A class of dicoumarins and preparation method and use thereof

A dicoumarin and compound technology, which is applied in the direction of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problems of inability to comprehensively examine the influence of linking partial kinase inhibitory activity, and the difficulty of compound synthesis.

Inactive Publication Date: 2017-07-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult to introduce side chain substituents into this connecting chain, and the influence of the connecting part on the kinase inhibitory activity cannot be fully investigated, and the compound is not easy to synthesize (patent: CN102558049A)

Method used

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  • A class of dicoumarins and preparation method and use thereof
  • A class of dicoumarins and preparation method and use thereof
  • A class of dicoumarins and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0039] (R)-N-(N-(7,8-dihydroxycoumarin-3-)-4-methyl-pentanamide-2-)-7,8-dihydroxycoumarin-3-amide ( Compound No.: 510-1)

[0040]

[0041] 7,8-Bis(methoxymethoxy)-coumarin-3-amine (120 mg, 0.427 mmol) (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su ;Barnhill,Hannah N.;Wang,Qian.Organic Letters,2004,vol.6,#24,p.4603-4606) and N-(9-fluorenylmethoxycarbonyl)-D-leucine (Fmoc-D -Leu-OH) (227 mg, 0.641) was dissolved in 5 mL of 30% pyridine / dichloromethane, added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), stirred at room temperature for 24 After 1 hour, the solvent was spun off, and 190 mg of intermediate 1 was obtained as a white solid by column chromatography, with a molar yield of 72%. 1 H NMR (300MHz, CDCl 3 )δ8.60(s,1H),8.57(br,1H),7.75(d,J=7.5Hz,2H),7.62-7.56(m2H),7.38(t,J=7.5Hz,2H),7.30( (t,J=7.2Hz,2H),7.18(d,J=8.7Hz,1H),7.13(d,J=8.7Hz,1H),5.32-5.18(m,5H),4.48(d,J= 6.0Hz,2H),4.38(s,1H),4.23(t,J=6....

preparation Embodiment 2

[0046] N-(1-((7,8-dihydroxycoumarin-3-)carbamoyl)cyclohexyl)-7,8-dihydroxycoumarin-3-amide (compound number: 522C)

[0047]

[0048] Referring to the method of Preparation Example 1, with 7,8-bis(methoxymethoxy)-coumarin-3-amine, 1-(9-fluorenylmethoxycarbonyl-amino)cyclohexylcarboxylic acid and 7, The target compound was prepared from 8-bis(methoxymethoxy)-coumarin-3-carboxylic acid as the starting material. 1 H NMR (300MHz, DMSO-d 6)δ10.73(br s,1H),9.94(br s,1H),9.61(br s,1H),9.31(br s,1H),9.09(s,1H),9.03(s,1H),8.72 (s,1H),8.38(s,1H),7.32(d,J=8.4Hz,1H),7.01(d,J=9.0Hz,1H),6.93(d,J=8.4Hz,1H),6.82 (d,J=8.1Hz,1H),2.28-2.18(m,2H),1.88-1.74(m,2H),1.72-1.56(m,3H),1.54-1.36(m,2H),1.35-1.20 (m,1H). 13 C NMR (75MHz, DMSO-d 6 )δ173.0, 161.5, 161.4, 158.0, 152.4, 148.9, 148.0, 144.2, 140.0, 132.1, 131.9, 126.4, 121.6, 120.3, 118.0, 113.8, 113.2 (double carbon), 112.1, 111.8), 59.2.8 (3 double carbon), ,24.71,20.92 (double carbon).

preparation Embodiment 3

[0050] (S)-N-(N-(7,8-dihydroxycoumarin-3-)-3-methyl-butyramide-2-)-7,8-dihydroxycoumarin-3-amide ( Compound No.: 496)

[0051]

[0052] Referring to the method of Preparation Example 1, with 7,8-bis(methoxymethoxy)-coumarin-3-amine, N-(9-fluorenylmethoxycarbonyl)-L-valine and 7, The target compound was prepared from 8-bis(methoxymethoxy)-coumarin-3-carboxylic acid as the starting material. 1 H NMR (300MHz, DMSO-d 6 )δ10.65(s,1H),9.94(s,1H),9.90(s,1H),9.60(s,1H),9.31(s,1H),9.13(d,J=8.7Hz,1H), 8.78(s,1H),8.46(s,1H),7.34(d,J=8.7Hz,1H),7.00(d,J=8.7Hz,1H),6.91(d,J=8.7Hz,1H), 6.81(d,J=8.4Hz,1H),4.97-4.90(m,1H),2.27-2.08(m,1H),1.05-0.85(m,6H). 13 C NMR (75MHz, DMSO-d 6 )δ170.89,161.5,161.2,157.7,152.3,149.1,148.1,144.2,140.3,132.0,131.9,127.9,121.5,120.1,118.1,113.6,113.0,112.8,112.1,117,111.94.3,57

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Abstract

The invention relates to a bishydroxycoumarin compound, a preparation method and a purpose of a protein tyrosine kinase inhibitor for preparing an antitumor drug. The bishydroxycoumarin compound has a structure having a general formula I, and has wide spectrum kinases inhibition activity and has direct inhibition activity for c-Met kinases, and the compound of the present invention can be used for preparing the antitumor drug.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical compounds, and in particular relates to a dicoumarin compound, its preparation method and its use as a protein tyrosine kinase inhibitor in the preparation of antitumor drugs. Background technique [0002] Tumors seriously endanger human health and life, and more and more attention has been paid to the research on tumor treatment. Since the beginning of the 21st century, with the great progress made in tumor pathology, cell biology, tumor genetics, etc., some key enzymes in cell signal transduction pathways related to tumor cell differentiation, proliferation and metastasis have been used as drug screening targets. Therefore, the development of new targeted anti-tumor drugs with high efficiency and low toxicity has become an important direction in the research and development of anti-tumor drugs. [0003] Protein tyrosine kinase plays a very important role in the intracellular signal tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/16A61K31/37A61P35/00
CPCC07D311/16
Inventor 南发俊耿美玉徐济民艾菁张仰明彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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