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BCL6-targeting aromatic ring five-membered aromatic heterocyclic micromolecular organic compound and derivative and application thereof

A technology of organic compounds and aromatic heterocycles, applied in the field of small molecule organic compounds with aromatic rings and five-membered aromatic heterocycles, can solve the problems of inability to up-regulate BCL6, low cell proliferation inhibitory activity, and no anti-tumor activity, etc., to achieve Significant anti-tumor activity, inhibition of proliferation, and inhibition of germinal center formation

Active Publication Date: 2021-03-23
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

79-6 is the first small molecule inhibitor of BCL6 reported in the literature, but its inhibitory activity on DLBCL cell proliferation is not high (>200μM) (Cancer Cell 2010,17,400-11)
Among them, BI3802 can inhibit the interaction between BCL6 and SMRT protein at the nM level, and can also effectively degrade BCL6. However, the bioavailability of this compound is very poor, thus limiting the further application of this compound at the animal level
Although BI3812 can inhibit the interaction between BCL6 and co-repressors at nM in vitro, the compound cannot up-regulate the target genes of BCL6 and has no anti-tumor activity. Therefore, it is urgent to develop new BCL6 inhibitors that are effective both in vivo and in vitro

Method used

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  • BCL6-targeting aromatic ring five-membered aromatic heterocyclic micromolecular organic compound and derivative and application thereof
  • BCL6-targeting aromatic ring five-membered aromatic heterocyclic micromolecular organic compound and derivative and application thereof
  • BCL6-targeting aromatic ring five-membered aromatic heterocyclic micromolecular organic compound and derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0171]The purity results of the compounds obtained in the experiment were all obtained from an Agilent 1200series LC system high-performance liquid chromatography analyzer (chromatographic conditions: Zorbax XDB-C18 (4.6×150nm, 5μm), column 40°C, mobile phase MeOH / H 2 0, the operating flow rate is 1.5mL / min, the ultraviolet detection wavelength is 254nm, and the injection volume is 10 μ L); the nuclear magnetic resonance spectrometer is Bruker 500 or Bruker 600 type (internal standard: TMS, and the use solvent is DMSO-d 6 ); the purification of the reaction intermediate and the final product all use a chromatographic column (200-300 mesh of silica gel used), and the silica gel used is purchased from Qingdao Ocean Chemical Factory. All solvents were re-distilled before use, and the anhydrous solvents used were obtained by drying according to standard methods; unless otherwise specified, all reactions were carried out under nitrogen protection and the progress of the reaction was...

Embodiment 1-2

[0186] Example 1-2: (2-((6-((5-((3S,5R)-3,5-dimethylpiperazinyl)-[1,2,4]triazolo[1,5 -a] Preparation of pyrimidin-7-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetyl)alanine (BL008).

[0187] Dissolve 3-hydroxy-1-methyl-6-nitroquinolin-2(1H)-one (713mg, 3.24mmol) and methyl 2-bromoacetate (991mg, 6.48mmol) in DMF (10mL), Cesium carbonate (3.17 g, 9.72 mmol) was added to the reaction liquid, and stirred overnight at room temperature. After the completion of the reaction, conventional processing, column chromatography to obtain 2-((1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl) oxy)methyl acetate ( 833mg, 88%)

[0188] Dissolve methyl 2-((1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate (833 mg, 2.85 mmol) in 30 mL of methanol in a mixed solvent with water (MeOH:H 2 O=4:1), LiOH (718 mg, 17.10 mmol) was added, and stirred overnight at room temperature. After the reaction, methanol was removed, then dilute hydrochloric acid was added dropwise to adjus...

Embodiment 1-3

[0193] Example 1-3: 2-((6-((5-((3S,5R)-3,5-dimethylpiperazinyl)-[1,2,4]triazolo[1,5- a] Preparation of pyrimidin-7-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-phenylacetamide (BL009)

[0194] Take 2-((6-((5-((3S,5R)-3,5-dimethylpiperazinyl)-[1,2,4]triazolo[1,5-a]pyrimidine-7 -yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)methyl acetate (BL007) (323mg, 0.66mmol) and LiOH (138mg, 3.27 mmol), dissolved in 30mL of mixed solvent of methanol and water (MeOH:H 2 O=4:1) and stirred overnight at room temperature. After the reaction, methanol was removed, and dilute hydrochloric acid was added dropwise to adjust the acidity until the solid was no longer precipitated, and the obtained solid 2-((6-((5-((3S,5R)-3,5-dimethylpiperene Azinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3 -yl)oxy)acetic acid (314 mg, 99%).

[0195] Take 2-((6-((5-((3S,5R)-3,5-dimethylpiperazinyl)-[1,2,4]triazolo[1,5-a]pyrimidine-7 -yl)amino)-1-meth...

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Abstract

The invention discloses an aromatic ring five-membered aromatic heterocyclic micromolecular organic compound or related analogues or pharmaceutically acceptable salts thereof. The structures of the compound are shown as formulas (I-IX). The invention also discloses an application of the aromatic ring five-membered aromatic heterocyclic micromolecular organic compound or the pharmaceutical composition thereof in preparation of drugs for preventing and / or treating various malignant tumors, autoimmune diseases, inflammation and the like, and an application of the aromatic ring five-membered aromatic heterocyclic micromolecular organic compound or the pharmaceutical composition thereof as an inhibitor of B cell lymphokine 6 (BCL6) in preparation of drugs for preventing and / or treating BCL6 mediated diseases.

Description

technical field [0001] The invention relates to a class of small molecular organic compounds with aromatic rings and five-membered aromatic heterocyclic rings, derivatives and uses thereof. The aromatic ring and five-membered aromatic heterocyclic compounds or pharmaceutical compositions containing such compounds can be used to prepare antineoplastic drugs for treating various malignant tumors, including tumor metastasis and other related diseases, as B cell lymphokine 6 (BCL6) inhibitors can be used to prevent and / or treat BCL6-mediated diseases (such as autoimmune diseases, allergy and inflammation). Background technique [0002] Malignant tumor is a disease that seriously threatens human health and life expectancy in today's society. "China's latest cancer data in 2017" shows that there are 4.29 million new cancer cases in China every year, accounting for 20% of the global new cases, and 2.81 million deaths. Moreover, with the increase in the overall life expectancy of ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P3/10A61P7/06A61P21/04A61P13/12A61P1/16A61P25/00A61P31/18A61P31/16A61P11/00A61P17/00A61P21/00
CPCA61P37/02A61P29/00A61P35/00A61P35/02A61P1/04A61P1/00A61P19/02A61P5/14A61P5/16C07D487/04A61P3/10A61P7/06A61P21/04A61P13/12A61P1/16A61P25/00A61P31/18A61P31/16A61P11/00A61P17/00A61P21/00
Inventor 陈益华郭伟凯谢玖清邢雅婧易正芳刘明耀
Owner EAST CHINA NORMAL UNIV
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