Development of Novel Monoamine Oxidase-B (MAO-B) Inhibitors with Reduced Blood-Brain Barrier Permeability for the Potential Management of Noncentral Nervous System (CNS) Diseases.

Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that do not permeate the blood-brain barrier (BBB) the MAO-B-selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para-OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k, and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal, and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-glycoprotein (P-gp) substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k, and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous, and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in noncentral nervous system (CNS) inflammatory disease models.

Intra- and intermolecular alkylation of N,O-acetals and π-activated alcohols catalyzed by in situ generated acid.

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally N,O-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take advantage of the ability of this solvent to continuously release small amounts of HCl by thermolytic elimination. A study of the reaction led to several improved protocols such as (1) preheated TCE, (2) microwave-assisted reactions, and (3) flow or sealed-tube conditions, which allow significant reaction rate enhancements and made possible some challenging reactions such as the α-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to the alkylation using proelectrophiles such as π-activated alcohols, which are normally unreactive toward HCl catalysis. This work represents the first successful use of HCl, the simplest strong Brønsted acid, as an efficient alkylation catalyst.

Synthetic studies on cyclobuta[a]indanes: stereocontrolled access to C9-substituted derivatives.

We report the preparation of novel ethyl cyclobuta[a]indane derivatives of pharmacological interest. The synthesis of compounds 5 was used as a model to study stereocontrolled access to C9-substituted cyclobutane from the corresponding cyclobutanone 1. Progress was made on two complementary aspects: (1) catalytic hydrogenation from the appropriate cyclobutene precursors; and (2) delivery of the C9 substituent through an intramolecular process. The level of diastereoselectivity obtained through hydrogenation of cyclobutene depends both on the metal used as catalyst and the nature of the functional group proximal to the double bond. The intramolecular delivery approach was diastereospecific, provided that the spiro-intermediate 7 does not ring open during the stereoinduction step. The latter route should allow preparation of quaternary carbon at C9 not available through hydrogenation.

One-pot synthesis of 2,3-dihydro-pyrrolopyridinones using in situ generated formimines.

A novel one-pot methodology is described for the synthesis of functionalized pyrrolopyridinones using in situ generated formimines and an ortho-lithiated pyridinecarboxamide species. Depending on the reaction conditions, this procedure allows versatile access to aminomethylated pyridinecarboxamides, 2,3-dihydro-pyrrolopyridinones, or 1,1-dialkylated 2,3-dihydro-pyrrolopyridinone derivatives. [reaction: see text]