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Belinostat derivative based on acetic acid, and preparation method and application thereof

A technology of belinostat and derivatives, applied in the field of acetic acid-based belistat derivatives and its preparation, to achieve the effects of controlling drug costs, reducing drug burden, and simple and easy-to-obtain raw materials

Active Publication Date: 2018-02-16
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it has been widely recognized in the effect of cancer treatment, in the process of practical application and development, belistat is still limited by its low water solubility (0.14mg / mL)

Method used

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  • Belinostat derivative based on acetic acid, and preparation method and application thereof
  • Belinostat derivative based on acetic acid, and preparation method and application thereof
  • Belinostat derivative based on acetic acid, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1 O-{[N-methyl-N-4-(2,3,4-tri-O-tert-butyldimethylsilyl-6-allyl-β-D-pyran grape Preparation of aldehyde-1-yl)-3-nitrobenzyloxycarbonyl)-2-aminoethyl)-formyl-belistat (iii)

[0065] Belistat (469mg, 1.47mmol) was dissolved in 6.4mL of tetrahydrofuran, and the system was cooled to 0°C; then 1.6mL of pyridine was slowly added dropwise; the mixture was first stirred at 25°C for 5 minutes, and then added to formula (ii) Compound (1.3g, 1.34mmol); the reaction solution was kept at 25°C and stirred for 16 hours.

[0066] Then add 20 mL of water to dilute and quench the reaction, and extract with ethyl acetate (20 mL×2); combine the organic phases, wash with 20 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate on a rotary evaporator. The residue was separated by preparative chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to obtain a white solid, which was the following intermediate compound (iii) (1.035 g, 65.9%).

[0067] Character...

Embodiment 2

[0068] Example 2 O-{[N-methyl-N-4-(6-allyl-β-D-pyranoglucuronic acid-1-yl)-3-nitrobenzyloxycarbonyl]-2- Preparation of aminoethyl}-formyl-belistat (iv)

[0069] Compound iii (400mg, 0.34mmol) was dissolved in a mixed solvent of tetrahydrofuran (20mL) and acetonitrile (20mL);

[0070] The hydrofluoric acid (4.8mL, 40% in H 2 O) was dissolved in acetonitrile (15.2 mL) to prepare a solution, and the solution was added to the solution containing compound iii at 0°C; the resulting reaction solution was stirred at 20°C for 2 days. The reaction solution was concentrated to about 8 mL, and a high performance liquid phase was prepared to obtain the following white solid iv (130 mg, 30.7%).

[0071] Characterization of the product: 1 H NMR (400MHz, DMSO-d6): δ12.39 (brs, 1H), 10.35 (brs, 1H), 7.99 (s, 1H), 7.89-7.86 (m, 2H), 7.74 (d, J = 7.6 Hz ,1H),7.68-7.58(m,3H),7.46(d,J=8.8Hz,1H),7.23(t,J=7.6Hz,2H),7.09(d,J=7.6Hz,2H),7.03 (t,J=7.6Hz,1H),6.60(d,J=16.0Hz,1H),5.93-5.85(m,1H),5.56-5.51(m,2H...

Embodiment 3

[0073] Example 3 O-{[N-methyl-N-4-(β-D-pyranoglucuronic acid-1-yl)-3-nitrobenzyloxycarbonyl]-2-aminoethyl}-formyl -Preparation of belistat (II)

[0074] Compound iv (183mg, 0.22mmol) was dissolved in 10mL tetrahydrofuran;

[0075] Dissolve 95 μL of triethylamine and 10 μL of acetic acid in 250 μL of tetrahydrofuran, and add the resulting solution to the tetrahydrofuran solution containing compound iv;

[0076] Blow argon for about 10 minutes, add a little palladium tetrakistriphenylphosphorus, stir at room temperature for about 30 minutes until the raw materials disappear, concentrate on a rotary evaporator, and separate the residue by preparative chromatography (acetonitrile: water = 20:1) to obtain the following white target Product II (144 mg, 83%).

[0077] Characterization of the product: 1 H NMR(400MHz, DMSO-d 6 ): δ12.62 (brs, 1H), 10.43 (brs, 1H), 7.95-7.91 (m, 1H), 7.65 (s, 1H), 7.83-7.80 (m, 1H), 7.52-7.46 (m, 1H) ),7.48(d,J=16.0Hz,1H),7.19(m,2H),7.08-7.05(m,1H),6.95-6.92(...

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Abstract

The invention provides a belinostat derivative based on acetic acid, and a preparation method and application thereof. The belinostat derivative based on acetic acid in the invention uses belinostat with tumor inhibition activity as a mother drug, and a water-soluble substituent is used for improving the dissolvability of belinostat, so the belinostat derivative has good water-solubility, and theproblem of side effects caused by belinostat can be effectively overcome; and the belinostat derivative can be further used for preparation of treatment drugs for tumors. Moreover, the preparation method of the invention has few procedures and simple operation steps and is suitable for large-scale production, etc.

Description

Technical field [0001] The present invention relates to the field of anti-tumor drugs, in particular to a belistat derivative based on acetic acid, and a preparation method and application thereof. Background technique [0002] Belistat It belongs to the hydroxamic acid class of histone deacetylase inhibitors (HDACi). The overexpression or abnormal regulation of histone deacetylase (HDAC) will cause excessive deacetylation of histones, which in turn causes chromatin to be remodeled into a transcription-inhibiting configuration, causing the corresponding gene expression to decline, and leading to cancer. Therefore, the inhibitory effect on HDAC is considered to be a promising anti-cancer drug target. Belistat can directly act on the link of abnormal gene expression, thereby inhibiting and correcting the excessive proliferation and abnormal differentiation of tumor cells. For common drug resistance problems, it can also be combined with drugs with other mechanisms of action. Bel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/203C07H1/00A61K31/7034A61P35/00
CPCC07H1/00C07H15/203Y02P20/55
Inventor 杜文婷吴一航赵锦妮李军
Owner ZHEJIANG MEDICAL COLLEGE
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