Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.

The asymmetric epoxidation of substituted cinnamic acids has been obtained in the presence of different keto bile acid derivatives as optically active carbonyl inducers and Oxone as oxygen source. Predominant or almost exclusive formation of both enantiomeric epoxides is obtained (ee up to 95%) depending on the specific substitution at carbons C(7) and C(12) of the bile acid.

An efficient strategy for the solution-phase parallel synthesis of a library of pyrrole-amides is described. Key reactions include functional homologation of beta-ketoesters with a set of aldehydes followed by oxidation to produce a series of differently substituted 1,4-dicarbonyl compounds. Rapid cyclization using a microwave-assisted Paal-Knorr reaction provided a set of 24 pyrrole esters that were further functionalized through a trimethylaluminum-mediated aminolysis to obtain a larger library of 288 diverse pyrrole-3-amides. The tetrasubstitution allows a good exploration of the chemical space around the central pyrrole core. The last step was entirely automated with a Bohdan Myriad personal synthesizer.

Enantioselective syntheses Enantioselective syntheses O 0031Improved Enantioselectivity in the Epoxidation of Cinnamic Acid Derivatives with Dioxiranes from Keto Bile Acids. -3-Keto, 7-keto, 12-keto as well as di-keto and tri-keto bile acids (21 examples) are investigated in the title epoxidation. Best results are obtained with KBA (cf. scheme). -(BORTOLINI*, O.; FANTIN, G.; FOGAGNOLO*, M.; FORLANI, R.; MAIETTI, S.; PEDRINI, P.; J.

Pyrrole derivatives R 0120 Solution Phase Synthesis of a Library of Tetrasubstituted Pyrrole Amides. -A library of 288 tetrasubstituted pyrrole amides (V) is prepared. The desired products are obtained in medium to high yields and good purities. -(BIANCHI, I.; FORLANI, R.; MINETTO, G.; PERETTO, I.; REGALIA, N.; TADDEI, M.; RAVEGLIA*, L. F.; J. Comb. Chem. 8 (2006) 4, 491-499; NiKem Res., I-20021 Baranzate di Bollate, Milano, Italy; Eng.) -Bartels 49-111