Cycloaddition of Fluorenone <i>N</i>‑Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4-ones

A facile synthesis of various spirofluorenylpiperidin-4-ones has been achieved in good yields from fluorenone <i>N</i>-aryl nitrones and methylenecyclopropanes. This method involved an initial cycloaddition to form a 5-spirocyclopropane-isoxazoline, which underwent a highly selective 1,3-rearrangement to give the desired product. The stereochemistry of the spirofluorenylpiperidin-4-one could be controlled by the cycloaddition and sequential rearrangement strategy. Furthermore, the spirofluorenylpiperidin-4-ones could be not only prepared in one-pot procedure but also converted to useful scaffolds by reduction or oxidation conditions

Discovery of 2‑(((1<i>r</i>,4<i>r</i>)‑4-(((4-Chlorophenyl)­(phenyl)­carbamoyl)­oxy)­methyl)­cyclohexyl)­methoxy)­acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of <b>5c</b> (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. <b>5c</b> had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration–time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, <b>5c</b> was selected for further development for the treatment of PAH