Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker

Antagonists/inverse agonists for the histamine H3 receptor (H3R) are subject to intensive research. Many chemical classes contain a 3-propoxy linker to connect an aromatic moiety and a basic amine. Rigidifying this linker by several moieties has proven successful. However, so far, a 3-cyclobutoxy constraint has not been disclosed in H3R research. Here, we present novel synthetic methodology toward compounds with this functionality. A condensation between piperidine and 1,3-cyclobutanedione followed by a reduction furnishes a versatile cis-3-piperidino-cyclobutanol building block which allows ready access to constrained compounds having a 3-piperidino-cyclobutoxy moiety. Pharmacological studies reveal that this particular rigidification leads to a significant increase in H3R affinity compared to the non-constrained counterpart. In all, the constrained 3-cyclobutoxy linker emerges as a novel, versatile and attractive motif for H3R ligands.