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Belinostat derivative based on formic acid, and preparation method and applications thereof

A belistat and derivative technology, applied in the field of formic acid-based belistat derivatives and their preparation, to achieve the effects of solving drug side effects, controlling production costs, and improving water solubility

Active Publication Date: 2017-12-15
ZHEJIANG MEDICAL COLLEGE
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  • 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 formic acid, and preparation method and applications thereof
  • Belinostat derivative based on formic acid, and preparation method and applications thereof
  • Belinostat derivative based on formic acid, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1 O-{[N-methyl-N-4-(2,3,4-tri-O-tert-butyldimethylsilyl-6-allyl-β-D-glucopyranose Preparation of aldehyde acid-1-yl)-3-nitrobenzyloxycarbonyl]-2-aminoethyl}-formyl-belinostat (iii)

[0069] Bellinostat (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 compound ii (1.3 g, 1.34 mmol). The reaction solution was kept at 25°C and stirred for 16 hours. Afterwards, it was diluted with 20 mL of water and quenched, extracted with ethyl acetate (20 mL×2); the combined organic layers were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated with a rotary evaporator. The residue was separated by preparative chromatography (petroleum ether: ethyl acetate = 3:1to1:1) to obtain the following white solid iii (1.035g, 65.9%);

[0070] Characterization of the product: LCMS: ...

Embodiment 2

[0071] Example 2 O-{[N-methyl-N-4-(6-allyl-β-D--pyranoglucuronic acid-1-yl)-3-nitrobenzyloxycarbonyl]-2- Preparation of aminoethyl}-formyl-belinostat (iv)

[0072] Compound iii (400mg, 0.34mmol) was dissolved in a mixed solvent of tetrahydrofuran (20mL) and acetonitrile (20mL);

[0073] Hydrofluoric acid (4.8mL, 40% in H 2 O) Dissolve in acetonitrile (15.2mL) to prepare a solution, add the solution to the solution containing compound iii at 0°C; stir the reaction solution at 20°C for 2 days, then concentrate the reaction solution to about 8mL , Preparative HPLC gave the following white solid iv (130 mg, 30.7%).

[0074] 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=7.6Hz ,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),5.34-5.28(m,3H), 5.18(d, J=10.8Hz, 1H), 5.08(s, 2H), 4.61(d, J=4.0Hz, 2H), 4.36...

Embodiment 3

[0076] Example 3 O-{[N-methyl-N-4-(β-D-pyranoglucuronic acid-1-yl)-3-aminobenzyloxycarbonyl]-2-aminoethyl}-formyl - Preparation of Belinostat (II)

[0077] Compound iv (183mg, 0.22mmol) was dissolved in 12mL THF;

[0078] 95 μL of triethylamine and 7 μL of formic acid were dissolved in 190 μL of tetrahydrofuran, and the solution was added dropwise to the solution of compound iv in tetrahydrofuran;

[0079] Pass argon for 10 minutes, add a little tetrakistriphenylphosphopalladium, stir at room temperature for about 30 minutes until the raw material disappears, concentrate with a rotary evaporator, and separate the residue by preparative chromatography (acetonitrile: water = 20:1) to obtain the white target product II (134mg, 80%);

[0080] Characterization of the product: 1 H NMR (400MHz, DMSO-d 6 ):δ12.59(brs,1H),10.41(brs,1H),7.93-7.89(m,1H),7.66(s,1H),7.80-7.78(m,1H),7.51-7.49(m,1H ),7.45(d,J=16.0Hz,1H),7.16(m,2H),7.05-7.02(m,1H),6.97-6.95(m,5H),6.92(d,J=16.0Hz,1H) ,6....

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Abstract

The invention provides a belinostat derivative based on formic acid, and a preparation method and applications thereof. According to the belinostat derivative based on formic acid, belinostat with anti-tumor activity is taken as a parent drug, the dissolvability of belinostat is improved via introduction of water-soluble substituent groups via reaction, so that the dissolvability of the belinostat derivative based on formic acid is excellent, and side effects caused by the poor dissolvability of belinostat are avoided. The steps of the preparation method are few; operation is simple; and the preparation method is suitable for large scale production.

Description

technical field [0001] The invention relates to the field of antineoplastic drugs, in particular to a formic acid-based belistat derivative and its preparation method and application. Background technique [0002] Belinostat Belongs to the hydroxamic acid class of histone deacetylase inhibitors (HDACi). The overexpression or abnormal regulation of histone deacetylase (HDAC) will lead to excessive deacetylation of histones, which will remodel chromatin into a configuration that inhibits transcription, resulting in a decrease in the expression of corresponding genes, leading to carcinogenesis. Therefore, inhibition of HDACs is considered a promising anticancer drug target. Belinostat can directly act on the abnormal expression of genes, thereby inhibiting and correcting the excessive proliferation and abnormal differentiation of tumor cells. For common drug resistance problems, it can also be used in combination with drugs with other mechanisms of action. Belinostat can ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/203C07H1/00A61K31/7036A61P35/00
CPCC07H1/00C07H15/203Y02P20/55
Inventor 杜文婷李军黄文海林素
Owner ZHEJIANG MEDICAL COLLEGE
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