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A kind of belinostat derivative based on acetic acid and its preparation method and application

A technology of belinostat and its derivatives, applied in the field of acetic acid-based belinostat derivatives and its preparation, to achieve the effects of reducing the burden of medication, controlling drug costs, and reducing the number of steps in the reaction process

Active Publication Date: 2020-04-07
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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  • A kind of belinostat derivative based on acetic acid and its preparation method and application
  • A kind of belinostat derivative based on acetic acid and its preparation method and application
  • A kind of belinostat derivative based on acetic acid and its preparation method and application

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-glucopyranose Preparation of aldehyde acid-1-yl)-3-nitrobenzyloxycarbonyl]-2-aminoethyl}-formyl-belinostat (iii)

[0065] 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 added into formula (ii) Compound (1.3g, 1.34mmol); the reaction solution was kept at 25°C and stirred for 16 hours.

[0066] Then 20 mL of water was added to dilute and quench the reaction, and extracted with ethyl acetate (20 mL×2); the organic phases were combined, 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 = 3:1 to 1:1) to obtain a white solid, namely the following intermediate compound ...

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-belinostat (iv)

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

[0070] Hydrofluoric acid (4.8mL, 40% in H 2 O) Dissolved in acetonitrile (15.2 mL) to prepare a solution, this 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 liquid was concentrated to about 8 mL, and the following white solid iv (130 mg, 30.7%) was obtained by preparative HPLC separation.

[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=7.6Hz ,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=10.8...

Embodiment 3

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

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

[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] Pass argon for about 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 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(m,5H),6.89(d,J=16.0Hz,1H...

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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 invention relates to the field of antineoplastic drugs, in particular to an acetic 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 e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/203C07H1/00A61K31/7034A61P35/00
CPCC07H1/00C07H15/203Y02P20/55
Inventor 杜文婷谢妙红邵静静杜绍能张乾金俏柔
Owner ZHEJIANG MEDICAL COLLEGE
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