Facile preparation of new 4-phenylamino-3-quinolinecarbonitrile Src kinase inhibitors via 7-fluoro intermediates: identification of potent 7-amino analogs

Bioorg Med Chem. 2008 Jan 1;16(1):405-12. doi: 10.1016/j.bmc.2007.09.028. Epub 2007 Sep 18.

Abstract

A more efficient preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (2), the penultimate intermediate in the synthesis of bosutinib (1a), was developed. New 7-alkoxy-4-phenylamino-3-quinolinecarbonitrile Src inhibitors were prepared from 5 and 9, the 6-ethoxy and 6-hydrogen analogs of 2. In addition, the fluoro group of 2 was readily displaced by primary and secondary amines to give 7-amino analogs. Two of these 7-amino analogs, 15 and 18, were potent Src inhibitors with in vivo activity.

MeSH terms

  • Amines
  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • Amines
  • Nitriles
  • Protein Kinase Inhibitors
  • Quinolines
  • src-Family Kinases