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In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a 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 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.

A theoretical study on cationic Rh(I)−N-alkenylamide complexes is presented, which are important intermediates in the asymmetric hydrogenation affording N-acylamino acids. The assumption of different intermediates investigated is based on the inter- and intramolecular equilibrium of diastereomeric complexes in the hydrogenation mechanism. The geometry optimizations were performed at the MP2 level of theory using relativistic pseudopotentials for rhodium, followed by QCISD(T) single-point calculations. The intermediates containing cis- or trans-coordinated phosphines have been compared structurally and energetically, and the influence of solvents is discussed. In the equilibrium consisting of uncoordinated substrate and substrate complexes, all tautomeric complexes were found in the calculation and have a minimum on the potential hypersurface. However, the occurrence of enamine/imine and amide/imine-ol tautomers could be excluded for the catalytic reaction, because they implement irreversible steps (C−H ac...