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Isonicotinamide derivative, preparation method and applications thereof

A compound, selected technology, applied in the direction of drug combination, pharmaceutical formula, active ingredient of heterocyclic compounds, etc., to achieve effective cell proliferation and effective inhibition

Active Publication Date: 2015-07-22
SHANGHAI ALLIST PHARM CO LTD
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  • 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

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  • Isonicotinamide derivative, preparation method and applications thereof
  • Isonicotinamide derivative, preparation method and applications thereof
  • Isonicotinamide derivative, preparation method and applications thereof

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).

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PUM

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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

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Application Information

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