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Substituted dihydrobenzofuran-piperidine-methanone derivatives, their preparation and use

A technology of substituents and drugs, applied in the field of dihydrobenzofuran-piperidine-methanone derivatives, can solve the problems of few Tankyrase small molecule inhibitors and the like

Active Publication Date: 2017-09-01
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the Wnt signaling pathway is a potential target for anti-tumor therapy, there are still few effective small-molecule inhibitors of Tankyrase

Method used

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  • Substituted dihydrobenzofuran-piperidine-methanone derivatives, their preparation and use
  • Substituted dihydrobenzofuran-piperidine-methanone derivatives, their preparation and use
  • Substituted dihydrobenzofuran-piperidine-methanone derivatives, their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] 2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidin-1-yl]methyl]-3, 5,7,8-Tetrahydropyrano[4,3-d]pyrimidin-4-one (Compound 1)

[0081] 2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8-tetrahydropyrano[4 ,3-d]pyrimidin-4-one

[0082]

[0083] The first step: tert-butyl 4-methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1B)

[0084] tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

[0085]

[0086] Dissolve N,N'-carbonyldiimidazole (21.0g, 0.13mol) in anhydrous dichloromethane (200mL), add dropwise 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (1A) (23.0g, 0.10 mmol) in anhydrous dichloromethane (100 mL), stirred for 30 minutes after dropping, added dimethylhydroxylamine hydrochloride (12.7 g, 0.13 mol) in batches, and reacted at room temperature for 3 hours. Add citric acid solution (wt=10%, 250mL) to the reaction solution, separate the layers, wash the organic phase with...

Embodiment 2

[0119] 2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidin-1-yl]methyl]-3H- Cyclohepta[d]imidazol-4-one (Compound 2)

[0120] 2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]meth yl]-3H-cyclohepta[d]imidazol-4- one

[0121]

[0122]

[0123] first step:

[0124] 2-[3-[4-(2,3-Dihydrobenzofuran-5-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidin-1-yl]acetonitrile (2B)

[0125] 2-[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]acetonit rile

[0126]

[0127] 3-4-(2,3-Dihydrobenzofuran-5-carbonyl)piperidin-1-yl)pyrrolidin-2-one (1G) (0.53 g, 1.68 mmol) was dissolved in dry THF (10 mL) 2-bromoacetonitrile (0.61g, 5.04mmol) was added, cooled to 0°C under nitrogen protection, sodium hydride (0.12g, 5.04mol) was added to the reaction solution, and reacted at 0°C for 30 minutes. Add water (10 mL) dropwise to quench the reaction, extract with dichloromethane (20 mL×2), combine the organic layers, wa...

Embodiment 3

[0145] 2-[[3-[4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidin-1-yl]methyl ]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one (Compound 3)

[0146] 2-[[3-[4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8 -tetrahydropyrano[4,3-d]pyrimidin-4-one

[0147]

[0148] The first step: 5-bromo-6-fluoro-2,3-dihydrobenzofuran (3B)

[0149] 5-bromo-6-fluoro-2,3-dihydrobenzofuran

[0150]

[0151] Add 48% hydrobromic acid solution (160 mL) to 6-fluoro-2,3-dihydrobenzofuran-5-amine (3A) (10.0 g, 65.30 mmol) at room temperature, and stir to dissolve. After cooling to 0° C., an aqueous solution (160 mL) of sodium nitrite (9.79 g, 142 mmol) was slowly added dropwise over 1 hour. Raise the temperature to room temperature and stir for 30 minutes, then cool to 0°C again, add cuprous bromide (14.20 g, 98.99 mmol) in batches, react at room temperature for 40 minutes after the addition, and heat to 140°C for 1.5 hours...

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Abstract

The present invention relates to a substituted dihydrobenzofuran-piperidine-ketone derivative, and a preparation and use thereof. In particular, the present invention relates to a substituted dihydrobenzofuran-piperidine-ketone derivative as shown by general formula (A), a stereoisomer or pharmaceutically acceptable salt thereof, the preparation method thereof, pharmaceutical compositions comprising them, and a use in the preparation of drugs for treating cancer-related diseases.

Description

technical field [0001] The present invention relates to a substituted dihydrobenzofuran-piperidine-methanone derivative represented by general formula (A), its stereoisomer or pharmaceutically acceptable salt, its preparation method and medicine containing them The composition and its application in the preparation of medicines for treating cancer-related diseases. Background technique [0002] The present invention provides a series of inhibitors of Wnt signaling pathway. These inhibitors can inhibit tumor cell proliferation and prevent tumor metastasis. [0003] The Wnt signaling pathway is a key regulator in various cellular processes, including stem cell maintenance, stem cell fate determination, and cell cycle control (Huang, Xie et al., 2006, J Immunol, 176, 4880-4887). It plays an important role in development and maintenance of adult homeostasis, and it is also abnormally activated in many types of tumors. The canonical Wnt signaling pathway is regulated by the st...

Claims

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Application Information

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IPC IPC(8): C07D491/052A61K31/519A61P35/00
CPCA61P35/00C07D405/14C07D491/052C07D513/04
Inventor 魏用刚邱关鹏郑苏欣刘建余钱枚林
Owner SICHUAN HAISCO PHARMA CO LTD