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Multi-target anti-tumor small molecule and derivative, preparation method, pharmaceutical composition and application thereof

A technology of antineoplastic drugs and small molecules, applied in antineoplastic drugs, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as enhanced side effects, unpredictable pharmacokinetic properties, etc., and achieve inhibition of topoisomerase activity , Low inhibitory effect on normal cells, high safety effect

Active Publication Date: 2021-12-24
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the combined drug has brought better curative effect, it has also caused defects such as enhanced side effects, drug-drug interaction and unpredictable pharmacokinetic properties.

Method used

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  • Multi-target anti-tumor small molecule and derivative, preparation method, pharmaceutical composition and application thereof
  • Multi-target anti-tumor small molecule and derivative, preparation method, pharmaceutical composition and application thereof
  • Multi-target anti-tumor small molecule and derivative, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of intermediate

[0040]

[0041] (1) Preparation of intermediate 2 (taking intermediate 2e as an example: R=H)

[0042] Dissolve 5.1g (37.2mmol) of reactant 1e (anthranilic acid) in 35mL of THF, add 6.6g (22.3mmol) of triphosgene (BTC) while stirring at 0°C, and react the mixture at 35°C for 12h, and the reaction ends After filtration, filter cake with Et 2 O wash (20 mL x 3) afforded a brown solid (Intermediate 2e).

[0043] 1 H NMR (600MHz, DMSO-d 6 )δ11.73(s,1H),7.91–7.89(m,1H),7.74–7.71(m,1H),7.25–7.22(m,1H),7.15(d,J=8.0Hz,1H)ppm.

[0044] (2) Preparation of intermediate 3 (taking intermediate 3e as an example: R=H)

[0045] 3.8g (23.3mmol) of intermediate 2e and hydrazine hydrate (85%) were successively added into a 50mL round-bottomed flask, refluxed for 3h, and the reaction process was detected by thin-layer chromatography. After the reaction was completed, it was cooled to 0° C. and filtered, and the filter cake was washed...

Embodiment 2

[0053] Embodiment 2: the preparation of compound I7

[0054] Intermediate 6a 1 (400mg, 0.88mmol) was dissolved in 15mL of THF, and lithium hydroxide (92.4mg, 2.2mmol) aqueous solution (5mL) was added dropwise, stirred at room temperature overnight, and the solvent was removed under reduced pressure to obtain a milky white solid, which was dissolved in 30mL of water and washed with 1M Adjust the pH to 5 with hydrochloric acid solution, filter to obtain a light yellow solid, dry it and stir it with TBTU (340.4mg, 1.06mmol) in DMF (10mL) solution at room temperature for 5min, add 115.4mg (1.14mmol) triethylamine and continue stirring for 2min, then Add 285.4mg (2.64mmol) of o-phenylenediamine and react at 35°C for 2h. The reaction solution was concentrated, and the concentrated solution was separated by silica gel column chromatography, and the eluent was CH 2 Cl 2 Mix solvent with MeOH (30:1) to obtain dark red solid 135.3 mg, yield: 30%.

[0055] 1 H NMR (600MHz, DMSO-d 6...

Embodiment 3

[0056] Embodiment 3: the preparation of compound I8

[0057] with intermediate 6a 2 instead of intermediate 6a 1 Prepared with reference to the method described in Example 1, a dark red solid was obtained with a yield of 35%.

[0058] 1 H NMR (600MHz, DMSO-d 6 )δ9.12(s,1H),8.80–8.77(m,1H),8.27(d,J=7.8Hz,1H),8.24(d,J=2.3Hz,1H),7.94–7.87(m,3H ),7.65(d,J=8.7Hz,1H),7.56(t,J=5.1Hz,1H),7.15(d,J=7.8Hz,1H),6.89–6.87(m,1H),6.72–6.70 (m,1H),6.53–6.50(m,1H),4.82(s,2H),3.51–3.48(m,2H),2.39(t,J=7.4Hz,2H),1.82–1.77(m,2H ),1.73–1.68(m,2H),1.51–1.46(m,2H)ppm; 13 C NMR (150MHz, DMSO–d 6 ): δ171.7, 156.7, 149.2, 145.1, 144.1, 142.4, 136.9, 133.5, 132.7, 129.8, 128.9, 128.7, 126.7, 126.2, 125.8, 124.1, 123.4, 122.0, 121.6, 1174.1, 113 28.2,26.9,25.7ppm.HRMS(ESI)m / z calcd for C 27 h 25 BrN 6 o 2 [M+H] + :545.1295,found:545.1309.

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Abstract

The invention discloses a multi-target anti-tumor small molecule and a derivative, a preparation method, a pharmaceutical composition and application thereof. The chemical structure of the small molecule is shown as a formula I, and the derivative relates to a pharmaceutically acceptable salt of the small molecule. The small molecule and the derivative thereof have efficient tumor inhibition effects in vivo and in vitro, have low toxicity to cells and organisms, and do not generate genotoxicity; the anti-tumor activity is achieved through the multi-target effect, the HDAC inhibition activity is provided, the p53 pathway can be effectively activated, the topoisomerase activity can be effectively inhibited, and the small molecule can be used for preparing anti-tumor drugs; the preparation method is simple and easy to operate.

Description

technical field [0001] The invention relates to a multi-target anti-tumor small molecule and its derivatives, preparation method, pharmaceutical composition and application, in particular to a kind of anti-tumor inhibitor with histone deacetylase inhibitor, topoisomerase inhibitor, p53 pathway activator A multi-target anti-tumor small molecule with at least one mechanism in an agent and its derivatives, preparation method, pharmaceutical composition and application. Background technique [0002] Histone acetylation and deacetylation are accomplished by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, which are key epigenetic modifications that regulate chromatin structure and gene transcription. HDACs are classified into different classes based on their homology to yeast proteins and cofactor dependence. HDAC classes I, II (subdivided into subtypes IIa and IIb) and IV are zinc-dependent enzymes, while HDAC class III are nicotinamide adenine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A61K31/519
CPCC07D487/04A61P35/00
Inventor 苟少华樊珂羽刘晴晴
Owner SOUTHEAST UNIV
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