Preparation of 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine] via an N-sulfonyl Pictet-Spengler reaction

A high yielding synthesis of variously substituted 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine] is reported. N-(2-nitrophenyl)sulfonyl was successfully used as both an activating and protecting group for the key Pictet-Spengler reaction.     

Determination of brain and plasma drug concentrations by liquid chromatography/tandem mass spectrometry

A method is described for the evaluation of drug concentrations in plasma and brain from treated rats. The analyte is recovered from plasma or brain homogenate by liquid-liquid extraction and subsequently analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). A simple experimental protocol renders the procedure valuable for obtaining information rapidly on brain penetration and plasma exposure of specific classes of compounds. This methodology has been applied to evaluate brain penetration with 30 different compounds from the same discovery program. In an attempt to increase throughput in our screening efforts, mixture dosing was evaluated. Results from single compound administration were compared with results following administration of a mixture of four compounds. Preliminary results, with specific classes of compounds, show no major differences (ranking order) in brain or plasma concentrations between mixture dosing and single compound administration, suggesting that mixture dosing could be applicable to brain penetration studies in the drug discovery phase.     

Facile functionalization at the C2 position of a highly substituted benzofuran

To expedite an SAR study of the C2 position of a highly substituted benzofuran ring system, we developed a method for the preparation of a key precursor, iodide 10. From iodide 10, a diverse set of compounds with different substituents at the C2 position were prepared efficiently.