Spiro[[1]benzothiophen-4,4′-piperidines] – carba analogs of potent σ1 ligands

Abstract

Spiro[[1]benzothiophene-4,4′-piperidines] 5 are structurally related to aminoethyl substituted 1-benzothiophenes 4 and spirocyclic thienopyrans 3. The spirocyclic ring system 13 was established in a four step synthesis starting from 1-benzothiophen-4-one 7. The conjugate addition of an acetonitrile anion to the electron deficient double bond of 10 activated by two electron withdrawing groups and the hydrolysis of dinitrile 12 with H₂O₂/NaOH represent the key steps of the synthesis of the spirocyclic scaffold 13. LiAlH₄ reduction of the spirocyclic imide 13 and subsequent reductive alkylation of the secondary amine 5a provided a set of spirocyclic σ ligands. Receptor binding studies revealed that exchange of the O-atom of the lead compound 3b (K_i = 0.31 nM) by a CH₂ moiety (5b: K_i = 10.5 nM) decreased the σ₁ affinity, whereas conformational restriction of the aminoethyl side chain of 4b (K_i = 49 nM) resulted in increased σ₁ affinity. Conformational restriction as well as the ring O-atom is important for high σ₁ affinity.