| Abstract
| - A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that functionas irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermalgrowth factor receptor (EGFR) kinases have been prepared. These compounds demonstratedenhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells comparedto our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare thesecompounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developedto prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved asafer cyclization step. We show that attaching a large lipophilic group at the para position ofthe 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also showthe importance of a basic dialkylamino group at the end of the Michael acceptor for activity,due to intramolecular catalysis of the Michael addition. This, along with improved watersolubility, resulted in compounds with enhanced biological properties. We present molecularmodeling results consistent with the proposed mechanism of inhibition. Binding studies of onecompound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressingxenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phaseI clinical trials for the treatment of cancer.
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