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2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof

A technology of indolinone and derivatives is applied to 2-indolinone derivatives as histone deacetylase inhibitors, its preparation method and application field, and can solve the problems of ineffective curative effect on solid tumors and the like, achieve excellent curative effect

Active Publication Date: 2009-04-01
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although HDAC is a promising drug target, the current SAHA developed by Merck is only limited to the treatment of cutaneous T-cell lymphoma, and the effect on solid tumors is not obvious

Method used

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  • 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof
  • 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof
  • 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] 4-((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)methyl)benzoic acid and

[0068] Preparation of 3-((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)methyl)benzoic acid

[0069]

[0070]Add 1.51g (10mmol) 5-fluoro-2-indolinone (US7,179,910 B2, Examplel), 1.50g (10mmol) 4-carboxybenzaldehyde (purchased from Alfa Aesar company), 1.28g (15mmol) in the reaction flask ) piperidine and 25ml of absolute ethanol, heated to reflux for 6 hours, cooled to room temperature, and filtered. Transfer the filter cake into a beaker, add 100ml of water, neutralize to pH=4 with 2M hydrochloric acid, collect the solid by filtration, wash the solid with water, and dry in vacuo to obtain a brown solid 4-((5-fluoro-2-oxo-1,2 - Dihydro-indol-3-ylidene)methyl)benzoic acid (1.33 g, 47% yield). LC-MS (m / z) 284 (M+1).

[0071] Using 5-fluoro-2-indolinone and 3-carboxybenzaldehyde (purchased from Alfa Aesar) as raw materials, 3-((5-fluoro-2-oxo-1,2-dihydro- Indol-3-ylidene)methyl)benzoic acid, LC-MS...

Embodiment 2

[0073] 5-(((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)hydrazono)methyl)-

[0074] Preparation of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid and other compounds

[0075]

[0076]

[0077] Add 8.25g (50mmol) 5-fluoroisatin (purchased from Aldrich) and 150ml 50% hydrazine hydrate into the reaction bottle, react at 80-90°C for 3 hours, cool to room temperature, filter, wash with water, collect the solid, and dry it in vacuum to obtain Yellow solid 5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidenehydrazine (6.0 g, 67% yield). LC-MS (m / z) 180 (M+1).

[0078] Add 1.79g (10mmol) 5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene hydrazine, 1.67g (10mmol) 5-formyl-2,4-dimethyl Base-1H-pyrrole-3-carboxylic acid (US 7,179,910 B2, Examplel), 1.28g (15mmol) piperidine and 25ml absolute ethanol, heated to reflux for 6 hours, cooled to room temperature, and filtered. Transfer the filter cake to a beaker, add 100ml of water, neutralize to pH=4 with 2M hydrochloric acid, collect the solid by filtr...

Embodiment 3

[0087] 2-(5-(((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)hydrazono)methyl)-2,4-dimethyl-

[0088] Preparation of 1H-pyrrole-3-amido)methyl acetate

[0089]

[0090] 328 mg (1 mmol) of 5-(((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H -Pyrrole-3-carboxylic acid was dissolved in 8 ml of DMF, then 384 mg (2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 162 mg (1.2 mmol) of 1 - Hydroxybenzotriazole, 404 mg (4 mmol) triethylamine and 151.8 mg (1.2 mmol) glycine methyl ester hydrochloride. The mixture was stirred at room temperature for 24 hours. Then dilute with 400ml saline. The solid was collected by vacuum filtration. The solid was washed with water. Dry in vacuo to give red solid 2-(5-(((5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)hydrazono)methyl)-2,4-dimethyl (244 mg, 61% yield). LC-MS (m / z) 400 (M+1).

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Abstract

The invention discloses 2-isatin derivatives, the preparation method and the application. The structure of the invention is shown as the formula (I), wherein, the definitions of R<1>, R<2>, R<3>, R<4>, R<5>, X, Ar and n are shown in the description of instruction. The compound is provided with the restraining activity against histone deacetylase so as to treat the diseases relevant to the abnormal condition of the histone deacetylase, including Rubinstein-Taybi II-syndrome, fragile x syndrome, leukemia, cancer, immunological diseases, cardiac hypertrophy, bone diseases, nervous system diseases and neurodegenerative diseases.

Description

technical field [0001] The present invention relates to the synthesis of 2-indolinone derivatives with histone deacetylase inhibitory activity and their clinical application in treating diseases related to the abnormal activity of histone deacetylase. Background technique [0002] Histone deacetylase (HDAC) proteins play a key role in regulating gene expression in vivo by altering the accessibility of transcription factors to genomic DNA. In particular HDACs remove the acetyl group of acetylated lysine residues in histones, resulting in nucleosome remodeling (Grunstein, M., 1997, Nature, 389:349-352). Since HDAC proteins play a key role in gene expression, they are closely related to many cellular functions, including cell cycle regulation, cell proliferation, differentiation, programmed gene expression, and carcinogenesis (Ruijter, A-J-M., 2003, Biochem.J. , 370:737-749; Grignani, F., 1998, Nature, 391:815-818; Lin, R-J., 1998, 391:811-814; Marks, P-A., 2001, Nature Review...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D209/40A61K31/404A61P43/00A61P35/00A61P9/00A61P25/00
Inventor 鲁先平李志斌余金迪山松马保顺吴仲闻王祥辉宁志强
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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