4-methylpyrrole substituted indolone derivative and preparation method and medical application thereof

A technology of methylpyrrole and indolinone, applied in the field of indolinone derivatives or their pharmaceutically acceptable salts, can solve problems such as gaps, low chemical stability, and decreased purity

Active Publication Date: 2021-02-05
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
View PDF6 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in follow-up studies, we found that the chemical stability of compound 10d was not high, and impurities were formed after long-term storage at room temperature, resulting in a decrease in purity; under low temperature (-20°C) and vacuum drying, the purity ...

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 4-methylpyrrole substituted indolone derivative and preparation method and medical application thereof
  • 4-methylpyrrole substituted indolone derivative and preparation method and medical application thereof
  • 4-methylpyrrole substituted indolone derivative and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] (S,Z)-N-(5-((5-fluoro-2-oxindol-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)pyrrolidin-2- Synthesis of Formamide Hydrochloride (A01)

[0072]

[0073] Synthesis of intermediate III: at 0°C, POCl 3 (1 mL) was slowly added dropwise to anhydrous DMF (1.1 mL), and after stirring at room temperature for 0.5 hours, a DMF (2 mL) solution of compound II (0.80 g, 6.35 mmol) was added to the reaction solution, and then heated to 80°C for 0.5 hours. After the LC-MS monitoring reaction is complete, stop heating, cool to room temperature, under ice bath cooling, use saturated Na 2 CO 3 Solution Adjust the pH value of the reaction solution to 7, then extract with dichloromethane (20 mL×2), combine several layers, wash with water and saturated sodium chloride solution successively, and dry over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and purification by column chromatography (petroleum ether: ethyl acetate = 20:1-4:1) gave 0.79 g of a white sol...

Embodiment 2

[0083] (R,Z)-N-(5-((5-fluoro-2-oxindol-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)pyrrolidin-2- Synthesis of Formamide Hydrochloride (A02)

[0084]

[0085] Synthesis of intermediate VII-2: Compound VI-1 (0.40g, 1.55mmol) and Boc-D-proline (0.37g, 1.71 mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (1.05g, 2.02mmol) and DIPEA (0.77mL, 4.66mmol), react at room temperature for 12 hours. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and purification by column chromatography (dichloromethane:methanol=50:1~20:1) gave 0.53 g of a yellow solid with a yield of 75%, which was directly used in the next reaction.

[0086]

[0087] Synthesis of Compound A02: Compound VII-2 (100 mg, 0.22...

Embodiment 3

[0089] (R,Z)-N-(5-((5-fluoro-2-oxindol-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)pyrrolidin-3- Synthesis of Formamide Hydrochloride (A03)

[0090]

[0091] Synthesis of Intermediate VII-3: Dissolve compound VI-1 (0.40 g, 1.55 mmol) and (R)-1-Boc-3-carboxypyrrolidine (0.37 g, 1.71 mmol) in DMF (50 mL), add A mixture of PyBOP (1.05g, 2.02mmol) and DIPEA (0.77mL, 4.66mmol) was reacted at room temperature for 12 hours. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed with water and sodium chloride solution successively, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated, and purified by column chromatography (dichloromethane:methanol=50:1~20:1) to obtain 0.54 g of a yellow solid with a yield of 77%, which was directly used in the next reaction.

[0092]

[0093] Synthesis of Compound A0...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a 4-methylpyrrole substituted indolone derivative, and a preparation method and medical application thereof. The invention relates to the field of medicinal chemistry. Comparedwith a compound 10d discovered in the earlier stage, the 4-methylpyrrole substituted indolone derivative disclosed by the invention has better chemical stability, higher selectivity on FLT3-ITD, moreideal pharmacokinetic characteristics and stronger in-vivo anti-tumor activity, and particularly has lower effective dose for treating acute myeloid leukemia. Under the same dosage, the tumor inhibition rate is obviously superior to that of compounds 10d and sunitinib, and the drug resistance is not easy to generate.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a 4-methylpyrrole-substituted indolinone derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing these compounds, their preparation method and their anti-tumor properties the use of. Background technique [0002] Malignant tumor (cancer) is a major chronic disease that seriously threatens human health, and has become one of the most serious public health problems in China and the world in the 21st century. At present, the anticancer drugs widely used in clinic are still mainly cytotoxic drugs, but the traditional chemotherapeutic drugs have disadvantages such as drug resistance, strong toxicity, many adverse reactions, and poor curative effect. With the development of molecular biology and tumor pharmacology, the mechanism of tumorigenesis has been further elucidated, and the research on antineoplastic drugs is developing from ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D403/06C07D403/14C07D401/14C07D413/14A61K31/404A61K31/4439A61K31/496A61K31/5377A61P35/00
CPCC07D403/06C07D403/14C07D401/14C07D413/14A61P35/00Y02P20/55
Inventor 胡立宏王均伟康迪潘祥宋祎
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap