Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

Abstract

In a previous communication, our efforts leading from <b>1</b> to the identification of spiro­[cyclohexane-dihydropyrano­[3,4-<i>b</i>]­indole]-amine <b>2a</b> as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead <b>2a</b>, toward <i>trans</i>-6′-fluoro-4′,9′-dihydro-<i>N</i>,<i>N</i>-dimethyl-4-phenyl-spiro­[cyclohexane-1,1′(3′<i>H</i>)-pyrano­[3,4-<i>b</i>]­indol]-4-amine (cebranopadol, <b>3a</b>), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain