Synthesis and σ receptor affinity of spiro[[2]benzopyran-1,1′-cyclohexanes] with an exocyclic amino moiety in the 3′-position

The main functions of σ1 receptors include the modulation of release and reuptake of neurotransmitters, the regulation of ion channels and the influence on intracellular signaling through modulation of calcium levels. Due to these properties, σ1 receptors are interesting drug targets for the treatment of various neurological disorders, pain and cancer. In order to modify the distance between the pharmacophoric elements (the benzene ring of 2-benzopyran and an amino moiety), a set of spiro[[2]benzopyran-1,1′-cyclohexan]-3′-amines was synthesized. The key step of the synthesis was a Parham cyclization of 1-bromo-2-(2-bromoethyl)benzene (6) with the mono ketal 7 of cyclohexane-1,3-dione, which led in a one-pot reaction to the spirocyclic framework 8. Reductive amination of ketone 9 stereoselectively provided secondary amines cis-4, which were methylated to afford tertiary amines cis-5. Whereas spirocyclic compounds cis-4a and cis-5a bearing a benzyl moiety at the exocyclic amino moiety showed rather low σ1 affinity, the corresponding cyclohexylmethyl derivatives cis-4b and cis-5b exhibited low nanomolar σ1 affinity. The secondary amine cis-4b displayed the highest σ1 receptor affinity (Ki = 5.4 nM) in this series. Methylation of the secondary amine cis-4b led to a slightly decreased σ1 receptor affinity of cis-5b (Ki = 15 nM).