Solid phase synthesis of 3-alkylated-1,4-benzodiazepines as non-peptidal cholecystokinin-(CCK)-antagonists

168 Multiply substituted 1,4-benzodiazepines have been prepared by a 5-step solid phase combinatorial approach using Syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido-linkage (Wang linker). In order to explore the SAR, the substituents have been varied in the -3, -5, -7 and 8-positions of the 1,4-benzodiazepine scaffold. The combinatorial library was evaluated in a CCK radioligand-binding assay and furnished a novel class of ligands for the CCK-B receptor subtype. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B receptor have been optimized on the lipophilic side chain, the ketone moiety and the stereochemistry at the 3-position. Various novel 3-alkylated compounds were synthesized and L-3-propyl-5-phenyl-1,4-benzodiazepin-2-one, L-Nva-A has shown a CCK-B selective binding at about 180 nM. 58 Compounds of this combinatorial library were purified by preparative TLC and 26 compounds were isolated and fully characterized by TLC, IR, APCI-MS, ¹H/ ¹³C-spectroscopy.