Isonicotinamide derivative, its preparation method and application

A technology of drugs and compounds, applied in the field of isonicotinamide derivatives, its preparation and application, to achieve effective cell proliferation and effective inhibition

Active Publication Date: 2018-08-10
SHANGHAI ALLIST PHARM CO LTD
View PDF12 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] At present, the development of MEK inhibitors in China is in the preliminary stage, and no compound has yet entered the clinic

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
  • Isonicotinamide derivative, its preparation method and application
  • Isonicotinamide derivative, its preparation method and application
  • Isonicotinamide derivative, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1: 3-[(3-tert-butoxycarbonylamino)phenylthio]-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (Ie-1)

[0144]

[0145] Compound (d-1) was synthesized by referring to the preparation method of PCT patent WO2012 / 055953 intermediate 2.A. Compound (d-1) (0.35mmol), tert-butyl (3-mercaptophenyl)carbamate (0.455mmol), cesium carbonate (1.05mmol) were reacted at 60°C for 4 hours in DMF (7mL), added 20ml of water, and used Ethyl acetate was repeatedly extracted three times, and the organic phases were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. Preparation, separation and purification to obtain 0.25 mmol of solid 3-[(3-tert-butoxycarbonylamino)phenylthio]-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (Ie-1). The rate is 71.4%.

[0146] ESI (+) m / z: 581

Embodiment 2

[0147] Example 2: 3-(3-aminophenylthio)-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (If-2)

[0148]

[0149] Compound (Ie-1) (0.5mmol) was dissolved in 20ml of ethyl acetate, 5ml of trifluoroacetic acid was added at 0°C, stirred overnight at room temperature, neutralized by adding 40ml of saturated sodium bicarbonate solution, the organic phase was separated, and the organic phase was anhydrous sulfuric acid Sodium drying, separation and purification to obtain solid 3-(3-aminophenylthio)-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (If-2) 0.41mmol, yield 82 %.

[0150] ESI (+) m / z: 481

[0151] h 1 -NMR (deuterated DMSO): δ8.13(s, 1H), δ8.04(s, 1H), δ7.88(d, 2H), δ7.61(d, 1H), δ7.47(s, 1H), δ7.41(d, 1H), δ7.04(t, 1H), δ6.93(t, 1H), δ6.63(s, 1H), δ6.54(dd, 2H), δ5. 30(s, 2H).

Embodiment 3

[0152] Example 3: 3-[(3-acetylamino)phenylthio]-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (Ig-3)

[0153]

[0154] Compound (If-2) (0.26mmol) was dissolved in a mixed solvent of 3ml pyridine and 3ml dichloromethane, and acetyl chloride (0.52mmol) was added under ice-cooling. Stir at room temperature for 5 hours, add 10 ml of water and 10 ml of dichloromethane, separate the organic phase, and dry the organic phase over anhydrous sodium sulfate. Preparation, separation and purification to obtain solid 3-[(3-acetylamino)phenylthio]-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (Ig-3) 0.21mmol, yield 81 %.

[0155] ESI (+) m / z: 523

[0156] h 1 -NMR (deuterated DMSO): δ10.05(s, 1H), δ8.18(s, 1H), δ8.07(s, 1H), δ7.90-7.93(d, 2H), δ7.68( s, 1H), δ7.59(d, 1H), δ7.51(m, 2H), δ7.42(d, 1H), δ7.32(t, 1H), δ7.05(d, 1H), δ6.96 (t, 1H), δ7.05 (s, 3H).

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 present invention discloses an isonicotinamide derivative represented by a formula (I) and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and A are defined in the specification. The present invention further discloses a preparation method of the compounds, a drug composition containing the compound, and applications of the compounds in treatment of mammal, especially human overproliferation diseases and in preparation of drugs for treatment of mammal, especially human overproliferation diseases. The formula (I) is defined in the specification.

Description

technical field [0001] The present invention relates to isonicotinamide derivatives which can be used for treating hyperproliferative diseases of mammals such as tumors and preparation methods thereof, pharmaceutical compositions containing said compounds, and said compounds in the treatment of mammals, especially human hyperproliferative diseases and Application in the preparation of medicines for treating mammals, especially human hyperproliferative diseases. Background technique [0002] Cell signaling pathways play an important role in cell growth, proliferation and differentiation. Mitogen-activated protein kinase (MAPK) family signal transduction is an important signaling pathway in cells, including extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) / stress 4 pathways including activated protein kinase (SAPK), P38MAPK and ERK5 / BMK1. Among them, ERK (extracellular regulated kinase) is an important member of the MAPK family extracellular ...

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
Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81C07D401/14A61K31/44A61K31/4545A61P35/00
CPCC07D213/81C07D401/14
Inventor 匡荣仁
Owner SHANGHAI ALLIST PHARM CO LTD
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