Pyridine analogues of spirocyclic σ1 receptor ligands

Abstract

Spirocyclic benzopyrans 2 interact with high affinity and selectivity with σ1 receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ1 affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported. Homologation of the aldehyde 6 to afford the pyridylacetaldehyde derivative 8 was performed by a Wittig reaction. Bromine lithium exchange of the bromopyridine 8, addition to 1-benzylpiperidin-4-one and cyclization led to the spirocyclic pyrranopyridine 10. Hydrogenolytic removal of the N-benzyl moiety of 10 provided the secondary amine 11, which allowed the introduction of various N-substituents (12a–d). Cyclization of the hydroxy acetal 9 with HCl led to various modifications of the substituent in 3′-position. Generally the σ1 affinity of the pyridine derivatives is reduced compared with those of the benzene and thiophene derivatives 2 and 3. However, the relationships between the structure and the σ1 affinity follow the same rules as for the benzene and thiophene derivatives. The most promising σ1 ligand within this class of compounds is the pyranopyridine 15 with a double bond in the pyran ring revealing a Ki-value of 4.6nM and a very high selectivity (>217-fold) over the σ2 subtype.