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Anthracedione derivatives and their preparation methods and applications

A derivative, the technology of anthracenedione, which is applied in the field of anthracenedione derivatives and its preparation, can solve the problems of high therapeutic index, high toxicity, and few types

Active Publication Date: 2020-03-27
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to address the deficiencies of the prior art, to provide a class of anthracenedione analogues, pharmaceutically acceptable salts or pharmaceutical compositions that have both topo IIα inhibitory activity and tumor targeting effect, which have been verified by experiments to have relatively Good anti-tumor effect is expected to become a clinical anti-tumor drug with high therapeutic index and low side effects, which solves the problem that there are few types of topo II inhibitors and insufficient efficacy in the treatment of solid tumors, lymphomas, and blood tumors in the prior art exactness and toxicity

Method used

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  • Anthracedione derivatives and their preparation methods and applications
  • Anthracedione derivatives and their preparation methods and applications
  • Anthracedione derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1 .(S)-2-(4-(((4-(hexyloxy)-9,10-dioxo-9,10-dihydroxyanthracene-1-yl)oxy)methyl)benzamide)propane acid (compound 5a 1 ) preparation

[0182] 1. Preparation of 1-(hexyloxy)-4-hydroxyanthracene-9,10-dione (intermediate 1a)

[0183] Under ice-bath conditions, weigh 1,4-dihydroxyanthracenedione (4.80g, 0.02mol) and dissolve it in redistilled DMF (35mL), add NaH (0.48g, 0.02mol) in batches, and the resulting solution was The reaction was carried out under nitrogen protection for 30 minutes, and then the temperature was raised to 60-75°C to continue the reaction for 1 hour, 1-bromo-n-hexane (14.0 mL, 0.10 mol) was added, and the resulting solution was reacted at 95°C for 42 hours until the reaction was completed by TLC monitoring. The reaction solution was poured into ice water, extracted twice with dichloromethane (2×15mL), the organic phase was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, and the solvent was concentrat...

Embodiment 2

[0193] Example 2. (S)-2-(4-(((4-(hexyloxy)-9,10-dioxo-9,10-dihydroxyanthracene-1-yl)oxy)methyl)benzamide)-3 -Phenylpropionic acid (compound 5a 2 ) preparation

[0194] According to compound 5a 1 The preparation method prepares compound 5a 2 . Yellow solid, 92.9% yield; melting point 217–219°C. 1 H NMR (600MHz, DMSO–d 6 )δ:12.86(brs,1H),8.65(d,J=7.1Hz,1H),8.09–8.02(m,2H),7.86–7.82(m,4H),7.69(d,J=8.2Hz,2H ),7.60(d,J=9.5Hz,1H),7.56(d,J=9.5Hz,1H),7.32(d,J=7.3Hz,2H),7.27(t,J=7.6Hz,2H), 7.18(t, J=7.3Hz, 1H), 5.33(s, 2H), 4.64–4.57(m, 1H), 4.09(t, J=6.4Hz, 2H), 3.21(dd, J 1 =13.7,J 2 =4.1Hz,1H),3.08(dd,J 1 =13.6,J 2 =10.6Hz,1H),1.77(q,J=7.0Hz,2H),1.52(q,J=7.4Hz,2H),1.39–1.28(m,4H),0.90(t,J=7.0Hz,3H ); ESI–MS m / z:604.5[M–H] – .

Embodiment 3

[0195] Example 3. (S)-2-(4-(((4-(hexyloxy)-9,10-dioxo-9,10-dihydroxyanthracene-1-yl)oxy)methyl)benzamide)-3 -Methylbutanoic acid (compound 5a 3 ) preparation

[0196] According to compound 5a 1 The preparation method prepares compound 5a 3 . Yellow solid, yield 84.5%, melting point 202–205°C; 1 H NMR (600MHz, DMSO–d 6 )δ:12.62(brs,1H),8.42(d,J=8.2Hz,1H),8.10–8.03(m,2H),7.95(d,J=8.3Hz,2H),7.85–7.81(m,2H ),7.72(d,J=8.3Hz,2H),7.62(d,J=9.5Hz,1H),7.57(d,J=9.5Hz,1H),5.35(s,2H),4.30(dd,J 1 =7.9,J 2 =7.1Hz, 1H), 4.09(t, J=6.4Hz, 2H), 2.24–2.16(m, 1H), 1.77(q, J=7.0Hz, 2H), 1.52(q, J=7.4Hz, 2H ),1.38–1.29(m,4H),1.04–0.93(m,6H),0.90(t,J=7.0Hz,3H); ESI–MS m / z:556.2[M–H] – .

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Abstract

The invention provides an anthracenedione derivative, and a preparation method and an the application of the derivative. The anthracenedione derivative has a structure shown as formula (X) as shown inthe specification, wherein an L group is selected from the following groups as shown in the specification; Aa is amino acid and selected from alpha-amino acid and beta-amino acid; R is selected fromOH and OR1; R1 is selected from C1-4 linear or branched alkyl; n is selected from 5-11; and m and p are independently selected from 3-4.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an anthracedione derivative and a preparation method and application thereof. Background technique [0002] DNA topoisomerase II (topoisomerase II, topo II) is an important target of anti-tumor drugs. At present, many clinical first-line antineoplastic drugs such as mitoxantrone (mitoxantrone), etoposide (etoposide, VP16), etc. are topo II inhibitors. Topo enzymes are a class of key ribozymes widely present in eukaryotic organisms, widely distributed in eukaryotic and prokaryotic cells, and play an important role in the cell life cycle, participating in DNA replication, transcription, recombination, repair and mitosis Its main function is to regulate and catalyze the breakage and reconnection of DNA. [0003] Human topoII mainly encodes two isoforms, α and β. The amino acid sequences of the two have about 70% homology, but their distribution and function in cells are quite different. T...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/42C07C217/22A61K31/198A61K31/138A61P35/00
CPCA61P35/00C07C217/22C07C235/42C07C2603/24Y02P20/55
Inventor 刘兆鹏李荀谢新文
Owner SHANDONG UNIV
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