Macrocyclic quinazoline derivatives as antiproliferative agents

Abstract

The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents O, CH, NH or S; in particular Z represents NH; Y represents —Calkyl-, —Calkenyl-, —Calkynyl-, —Calkyl-CO—NH— optionally substituted with amino, mono- or di(Calkyl)amino or Calkyloxycarbonylamino-, —Calkenyl-CO—NH— optionally substituted with amino, mono- or di(Calkyl)amino- or Calkyloxycarbonylamino-, Calkyl-oxy-Calkyl-, —Calkyl NR—, —Calkyl-, —Calkyl-NR—CO—Calkyl-, —Calkyl-CO NR—Calkyl-, —Calkyl-CO—NH—, —Calkyl-NH—CO—, —Calkyl-NH—CS-Het-, —Calkyl-NH—CO-Het, —Calkyl-CO-Het-CO—, -Het-CH—CO—NH—Calkyl-, —CO—NH—Calkyl-, —NH—CO—Calkyl-, —CO—Calkyl-, —Calkyl-CO—, —Calkyl-CO—Calkyl-, —Calkyl-NH—CO—CRR—NH—, —Calkyl-CO—NH—CRR—CO—, —Calkyl-CO—NR—Calkyl-CO—, Calkyl-NR—CH—CO—NH—Calkyl-, or NR—CO—Calkyl-NH—, Xrepresents a direct bond, O or —O—Calkyl-, CO, —CO—Calkyl-, NR, —NR—Calkyl-, —CH—, —O—N═CH— or —Calkyl-; Xrepresents a direct bond, O, —O—Calkyl-, CO, —CO—Calkyl-, NR, —NR—Calkyl-, —CH—, —O—N═CH— or —Calkyl-. The growth inhibitory effect anti-tumour activity of the present compounds has been demonstrated in vitro, in enzymatic on the receptor tyrosine kinase EGFR.