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 σ ₁ 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, σ ₁ 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 σ ₁ affinity, the corresponding cyclohexylmethyl derivatives cis-4b and cis-5b exhibited low nanomolar σ ₁ affinity. The secondary amine cis-4b displayed the highest σ ₁ receptor affinity (K _i = 5.4 nM) in this series. Methylation of the secondary amine cis-4b led to a slightly decreased σ ₁ receptor affinity of cis-5b (K _i = 15 nM).

Fig. 1. Spirocyclic cyclohexanamines 4 and 5 with an exocyclic amino moiety in the 3′-position were derived from spirocyclic piperidines 1 and 2 with an endocyclic amino moiety and spirocyclic cyclohexanamine 3 with an exocyclic amino moiety in the 4′-position. The stereodescriptors cis and trans refer to the relative orientation of the O- and N-substituents at the central cyclohexane ring.

Scheme 1. Synthesis of spirocyclic cyclohexanes cis-4a and b and cis-5a and b with an exocyclic amino function in the 3′-position. Reagents and reaction conditions: (a) THF, n-BuLi, cyclohexane-1,3-dione monoethylene ketal (7), 5 min, −88 °C, 1 h, rt, 28%. (b) Et₂O, 2 M HCl, 2 d, reflux, 85%. (c) RNH₂, CH₃CO₂H, NaBH(OAc)₃, THF, 24 h, rt, 90% (cis-4a), 80% (cis-4b). (d) Formalin 37%, NaBH(OAc)₃, CH₂Cl₂, 3 h, rt, 92% (cis-5a), 88% (cis-5b). Only one enantiomer of the racemic mixtures is shown. The stereodescriptor cis refers to the relative orientation of the O- and N-substituents at the central cyclohexane ring.