Combinatorial Solid Phase Synthesis of Multiply Substituted 1,4-Benzodiazepines and Affinity Studies on the CCK 2 Receptor (Part 1)

Abstract

One hundred sixty-eight multiply substituted 1,4-benzodiazepines have been prepared by a five-step solid-phase combinatorial approach using syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido linkage (Wang linker). The substituents of the 1,4-benzodiazepine scaffold have been varied in the -3, -5, -7, and 8-positions and the combinatorial library was evaluated in a chole cys to kinin (CCK) radioligand binding assay. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B (CCK2) 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 [S]3-propyl-5-phenyl-1,4-benzodiazepin-2-one, [S]NV-A, has shown a CCK-B selective binding at about 180 nM. Fifty-eight compounds of this combinatorial library were purified by preparative TLC and 25 compounds were isolated and fully characterized by TLC, IR, APCI-MS, and 1H/13C-NMR spectroscopy.

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…Ellman's and DeWitt's approaches were combined by Lattmann in a project aimed at preparing 1,4-benzodiazepines for the cholecystokinin (CCK) radioligand binding assay [29]. The Wang resin 51 was acylated with various Fmoc-amino acids that upon reaction with aminoketones gave the imine resin 53.…”

Strategies for the Design of Non-peptide CCK2 Receptor Agonist and Antagonist Ligands

“…In order to confer high *Address correspondence to this author at the James Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9JE; E-mail: barret.kalindjian@kcl.ac.uk CCK 2 affinity and selectivity over CCK 1 receptors these compounds have mainly retained the 3-ureido-substituent and 3R stereochemistry present in L-365,260. [17] Similar 3-alkyl-substituted compounds, such as 2 and 3, had previously been prepared by workers at Merck at an early phase of their CCK antagonist programme but had been discounted in favour of 3-amido and 3-ureido containing derivatives in pursuing CCK 1 and CCK 2 selective compounds respectively. [17] Similar 3-alkyl-substituted compounds, such as 2 and 3, had previously been prepared by workers at Merck at an early phase of their CCK antagonist programme but had been discounted in favour of 3-amido and 3-ureido containing derivatives in pursuing CCK 1 and CCK 2 selective compounds respectively.…”

Synthesis of Substituted 3‐Anilino‐5‐phenyl‐1,3‐dihydro‐ 2H‐1,4‐benzodiazepine‐2‐ones and their Evaluation as Cholecystokinin‐Ligands

“…Our early work on 1,4-benzodiazepines, based on asperlicin, provided asperlicin-analogues [22] and other libraries of N-alkylated 3-propyl-1,4-benzodiazepines. With two alkyl chains, a CCK 2 selectivity was achieved, combined with a very high lipophilicity [23].…”