A NEW SERIES OF PDGF RECEPTOR TYROSINE KINASE INHIBITORS - S-SUBSTITUTED QUINOLINE DERIVATIVES

A series of 63 3-substituted quinoline derivatives has been prepared a nd tested for inhibition of cell-free platelet derived growth factor r eceptor tyrosine kinase (PDGF-RTK) activity. The compounds were genera lly prepared either by a Friedlander condensation between an aryl-acet aldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupli ng between an aryl bromide or triflate and an organostannane or organo zinc chloride. The presence of 6,7-dimethoxy groups on the quinoline r ing was found to be advantageous although not essential for potent inh ibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-po sition contributed substantially to activity. The lipophilic groups ge nerally consisted of monocyclic aromatics or small alkynyl, alkenyl, a nd alkyl groups. Optimum activity of ca. less than or equal to 20 nM ( IC50) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl (17m), 3-fluorophenyl (17b), 4-hydroxyphenyl (24), 6-methoxypyridin-3-yl (15 o), 5-pyridin-2(1H)-one (23), trans-beta-styryl(15e), thiophene-3-yl ( 2e), 5-chlorothiophene-2-yl (15f), or cyclopentenyl (17n) groups. Most of the compounds in the series were tested for inhibition of cell-fre e epidermal growth factor receptor tyrosine kinase activity and found to be inactive.