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Dicoumarol compound, as well as preparation method and application thereof

A technology of dicoumarins and compounds, applied in the fields of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc.

Inactive Publication Date: 2012-07-11
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, in this literature, the protein tyrosine kinase inhibitory activity of compound 400 itself has not been reported. On this basis, the inventors optimized, modified and evaluated its structure to obtain a series of compounds with further development potential

Method used

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  • Dicoumarol compound, as well as preparation method and application thereof
  • Dicoumarol compound, as well as preparation method and application thereof
  • Dicoumarol compound, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0049] Preparation Example 1 3,3'-methylenebis(4,7,8-trihydroxycoumarin) (compound number: 400-1)

[0050]

[0051]4,7,8-trihydroxycoumarin (preparation method: starting from 2,3,4 trihydroxy-acetophenone (commercially available), utilizing 2 equivalents of methoxymethyl chloride to protect the 3-position and 4-position The hydroxyl group is then reacted with NaH / diethyl carbonate in tetrahydrofuran (THF) to form a 4-hydroxyl substituted coumarin, and this intermediate can be deprotected by hydrochloric acid to obtain 4, 7, 8 - Trihydroxycoumarin) 500mg was dissolved in ethanol (10mL), added paraformaldehyde 50mg, and Et 3 N (0.5 mL) was reacted at room temperature for 24 h, filtered, washed with citric acid, and dried in vacuo to give off-white solid 400 (460 mg, 89%).

[0052] 1 H NMR (300MHz, DMSO-d6): 10.05(bs, 6H), 7.27(d, J=8.7Hz, 2H), 6.83(d, J=8.7Hz, 2H), 3.71(s, 2H).ESI- MS(m / z): 401.4(M+1) +

preparation Embodiment 2

[0053] Preparation Example 2 N-(7,8-dihydroxy-2(1H)-quinolinone-3-)-7,8-dihydroxyl-2(1H)-quinolinone-3-amide (compound number: 395-1)

[0054]

[0055] 7,8-bis(methoxymethoxy)-2(1H)quinolinone-3-acid (50mg, 0.16mmol) and 7,8-bis(methoxymethoxy)-2(1H) Quinolinone-3-amine (46 mg, 1 eq, 0.16 mmol) (prepared by reference method: Saari, Walfred S.; Wai, John S.; Fisher, Thorsten E.; Thomas, Craig M.; Hoffman, Jacob M. ; Etc. Journal of Medicinal Chemistry, 1992, vol.35, #21 p.3792-3802) was dissolved in 0.7mL DCM / 0.3mL pyridine solvent and then added EDCI, reacted at room temperature for 3h, the system changed from clear to turbid, filtered, washed with methanol , to obtain 55mg of solid compound, molar yield: 60%.

[0056] The above compound was dissolved in 3N HCl in ethyl acetate solution, and after adding 1d of methanol, the compound was obtained as a gray-green solid 38 mg. Molar yield: 100%.

[0057] 1 H NMR (300MHz, DMSO-d6): 12.42(s, 1H), 11.16(s, 1H), 10.87(s, 1H),...

preparation Embodiment 3

[0058] Preparation Example 3 7,7',8,8'-tetrahydroxy-4,4'-dimethyl-3,3'-dicoumarin (compound number: 382-1)

[0059]

[0060] 3-Bromo-4-methyl-7,8-bis(methoxymethoxy)-coumarin (100 mg, 0.278 mmol) (prepared according to literature methods: Bowden, Keith; Battah, Sinan Journal of the Chemical Society , Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1998, p.1603-1606), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (16mg, 0.05eq) and Cesium carbonate (135mg, 1.5eq, 0.417mmol) was dissolved in 10mL of anhydrous dioxane, degassed and added Pd(OAc) 2 (6mg, 0.05eq), raised to 100°C, 10% citric acid was carefully added after 12h to acidify, extracted, concentrated through column (DCM / MeOH=10 / 1), and 30mg compound was obtained. Molar yield: 39%. The above compound was dissolved in 3N HCl in ethyl acetate solution, and after adding 1 drop of methanol, 20 mg of the compound was obtained as a gray-green solid. Molar yield: 100%.

[0061] 1 H NMR (300MHz, CDCl 3 ): 9...

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Abstract

The invention relates to a dicoumarol compound shown in a general formula I, wherein definition of each substituent is described in the specification. The invention also relates to a preparation method of the dicoumarol compound, and application of the dicoumarol compound serving as protein tyrosine kinase inhibitor in the field of tumor resistance.

Description

technical field [0001] The invention relates to a dicoumarin compound, a preparation method thereof and an anti-tumor application as a protein tyrosine kinase inhibitor. Background technique [0002] The treatment of cancer has always been a problem that has plagued human beings. Although the world has huge research funding every year, the treatment of tumors is still a difficult problem that the scientific community cannot make breakthroughs in. At present, the commonly used antineoplastic drugs in clinical practice are mainly cytotoxic drugs, which have unavoidable disadvantages such as poor selectivity, strong toxic and side effects, and easy drug resistance. In recent years, with the rapid development of life science research, various basic processes such as signal transduction in malignant tumor cells, regulation of cell cycle, induction of apoptosis, angiogenesis and interaction between cells and extracellular matrix are being investigated. step by step. Taking some ...

Claims

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Application Information

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IPC IPC(8): C07D215/54C07D311/16A61K31/4709A61K31/37A61K31/496A61P35/00
CPCC07D471/04C07D311/76A61P35/00
Inventor 南发俊耿美玉刘晟艾菁刘振凯张仰明余琳千
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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