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Histone histone deacetylase inhibitor and application thereof

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

Active Publication Date: 2018-04-06
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 histone deacetylase inhibitor and application thereof
  • Histone histone deacetylase inhibitor and application thereof
  • Histone histone deacetylase inhibitor and application thereof

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-di Methylformamide (DMF), 0°C; c) dimethylamine hydrochloride, cesium carbonate, tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos), N,N-dimethylformamide, 110°C; d) lithium hydroxide, tetrahydrofuran, water , 100°C; 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 azidation was slowly added in batches to the reaction system Sodium (0.665g, 10.23mmol), slowly warmed up to room temperature, stirred for...

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 Dichloromethane solution of fluoroacetic acid, 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'-tetramethyluronium tetrafluoroboric acid (TBTU), N,N- Dimethylformamide, room temperature.

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

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-di Methylformamide (DMF), 0°C; c) dimethylamine hydrochloride, cesium carbonate, tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), 2-dicyclohexylphosphine-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'-tetramethyluronium tetrafluoroboric acid (TBTU), N,N-dimethylformamide , room temperature; g) 20% trifluoroacetic acid in dichloromethane, dichloromethane, 0°C.

[0166] e) Compound F (3.2g, 12.49mmol) was dissolved in 40mL of tetrahydrofuran, sodium dithionite (10g, 57.4...

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Abstract

The invention provides a histone histone deacetylase inhibitor and application thereof. Specifically, the invention provides a compound of formula (I) as shown in the specification, and a pharmaceutically acceptable salt of the compound, and in the formula, the groups are defined as shown in the specification. The invention further provides a preparation method of the compound. The compound of formula (I), which is provided by the invention, can be adopted to treat a series of diseases mediated by histone histone deacetylases by inhibiting histone histone deacetylases (HDACs), particularly type-I histone histone deacetylases (subtypes such as HDAC1 and HDAC3), particularly including tumor diseases such as solid tumor and leukemia, neurodegenerative diseases, and the like.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically to a histone deacetylase inhibitor and application thereof. Background technique [0002] Cancer is one of the major diseases threatening human health. According to data from the World Health Organization, cancer is one of the leading causes of death in the world. According to data, in 2012, there were about 14.1 million new cases of cancer worldwide, and the number of cancer deaths reached 8.2 million. With the in-depth and rapid progress of life science research, molecular biology research on tumor pathogenesis and pathogenesis has laid a foundation for the development of high-efficiency and low-toxic anti-tumor drugs that act on specific targets. Studies have shown that the occurrence of tumors 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, a...

Claims

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Application Information

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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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