Histone deacetylase inhibitor and its application

A compound and stereoisomer technology, applied in the field of histone deacetylase inhibitors, can solve the problems of poor metabolic properties and large side effects

Active Publication Date: 2022-07-26
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, most of the existing broad-spectrum HDAC inhibitors have defects such as poor drug metabolism and large side effects, which limit their application and development.

Method used

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  • Histone deacetylase inhibitor and its application
  • Histone deacetylase inhibitor and its application
  • Histone deacetylase inhibitor and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130]

[0131] synthetic route:

[0132]

[0133] Reagents and conditions: a) 5-bromoindanone, sodium azide, methanesulfonic acid, dichloromethane, 0°C to room temperature; b) methyl 4-bromomethylbenzoate, sodium hydride, N,N-dichloromethane Methylformamide (DMF), 0°C; c) dimethylamine hydrochloride, cesium carbonate, tris(dibenzylideneacetone)dipalladium (Pd) 2 (dba) 3 ), 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (XPhos), N,N-dimethylformamide, 110℃; d) Lithium hydroxide, tetrahydrofuran, water , 100℃; e) o-phenylenediamine, N,N-diisopropylethylamine (DIPEA), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU), N,N-dimethylformamide, room temperature.

[0134]a) 5-Bromoindanone (1.08g, 5.12mmol) was dissolved in 50mL of dichloromethane, methanesulfonic acid (3.32mL, 51.2mmol) was slowly added at 0°C, and then azide was slowly added to the reaction system in batches Sodium (0.665 g, 10.23 mmol), slowly warmed to room temperature and s...

Embodiment 44

[0151]

[0152] synthetic route:

[0153]

[0154] Reagents and conditions: Reagents and conditions: a) 5-bromoindanone, sodium azide, methanesulfonic acid, dichloromethane, 0°C to room temperature; b) methyl 4-bromomethylbenzoate, sodium hydride, N , N-dimethylformamide (DMF), 0°C; c) tert-butyl carbamate, N,N-dimethylethylenediamine, cuprous iodide, potassium carbonate, toluene, 110°C; 20% tris Fluoroacetic acid in dichloromethane, dichloromethane, 0°C; d) thiophene-2-sulfonyl chloride, pyridine, dichloromethane, 0°C; e) lithium hydroxide, tetrahydrofuran, water, 100°C; f) o-benzene Diamine, N,N-diisopropylethylamine (DIPEA), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU), N,N- Dimethylformamide, room temperature.

[0155] c) Add compound C (0.5 g, 1.336 mmol), tert-butyl carbamate (0.235 g, 2.004 mmol), N,N-dimethylethylenediamine (0.014 mL, 0.134 mmol) to 10 mL of toluene under argon protection ), potassium carbonate (0.369 g, 2.67 mmol), c...

Embodiment 49

[0162]

[0163] synthetic route:

[0164]

[0165] Reagents and conditions: a) 5-bromoindanone, sodium azide, methanesulfonic acid, dichloromethane, 0°C to room temperature; b) methyl 4-bromomethylbenzoate, sodium hydride, N,N-dichloromethane Methylformamide (DMF), 0°C; c) dimethylamine hydrochloride, cesium carbonate, tris(dibenzylideneacetone)dipalladium (Pd) 2 (dba) 3 ), 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (XPhos), N,N-dimethylformamide, 110°C; d) Lithium hydroxide, tetrahydrofuran, water , 100°C; e) tert-butyl-(4-fluoro-2-nitrophenyl)-carbamate, sodium dithionite, sodium carbonate, tetrahydrofuran, water, 80°C; f) Intermediate G, N, N-diisopropylethylamine (DIPEA), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU), N,N-dimethylformamide , room temperature; g) 20% trifluoroacetic acid solution in dichloromethane, dichloromethane, 0°C.

[0166] e) Compound F (3.2g, 12.49mmol) was dissolved in 40mL of tetrahydrofuran, sodium d...

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Abstract

The invention provides a histone deacetylase inhibitor and use thereof. Specifically, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the definitions of each group are as described in the specification. The present invention also provides a preparation method of such compounds. The compounds of formula (I) of the present invention can be used for the treatment of histone deacetylases (HDACs) by inhibiting histone deacetylases (HDACs), especially class I histone deacetylases (subtypes such as HDAC1, HDAC3, etc.). A series of diseases mediated, including the treatment of solid tumors, leukemia and other tumor diseases, and neurodegenerative diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and more particularly to a histone deacetylase inhibitor and application thereof. Background technique [0002] Cancer is one of the major diseases that threaten human health. According to the World Health Organization, cancer is one of the leading causes of death in the world. The data shows that in 2012, there were about 14.1 million new cancer cases and 8.2 million cancer deaths. With the in-depth and rapid progress of life science research, molecular biology research on tumor pathogenesis and pathogenesis has laid the foundation for the development of high-efficiency and low-toxicity anti-tumor drugs acting on specific targets. Studies have shown that tumorigenesis is closely related to the imbalance of acetylation and deacetylation of lysine residues at the N-terminal of nucleosome core histones. Histone modifications (such as methylation, acetylation, phosphorylation, ubiquitination, et...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/24C07D401/12C07D405/12C07D401/04C07D409/12C07D237/32C07D471/04C07D487/08C07D403/04A61K31/472A61K31/4725A61K31/506A61K31/496A61K31/497A61K31/5377A61K31/502A61K31/5025A61P35/00
CPCC07D217/24C07D237/32C07D401/04C07D401/12C07D403/04C07D405/12C07D409/12C07D471/04C07D487/08
Inventor 沈竞康熊兵赵乐乐李佳耿美玉马兰萍陈丹琦苏明波周宇波胡小蓓刘红椿沈爱军
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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