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

Abstract

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 (K_i = 5.4 nM) in this series. Methylation of the secondary amine cis-4b led to a slightly decreased σ₁ receptor affinity of cis-5b (K_i = 15 nM).