Sila-venlafaxine, a sila-analogue of the serotonin/noradrenaline reuptake inhibitor venlafaxine: Synthesis, crystal structure analysis, and pharmacological characterization

The serotonin/noradrenaline reuptake inhibitor rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-of (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-of (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-of derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)- or (-)-10-camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b center dot HCl, (R)-1b center dot HCl, (S)-1b-HCl, (R)-1b center dot HBr, rac-2, and rac-2 center dot HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b center dot HCl, (R)-1b center dot HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides for their efficacy in serotonin, noradrenaline, and dopamine reuptake inhibition assays. Sila-substitution (C/Si switch) of compounds rac-1a, (R)-1a, and (S)-1a (-rac-1b, (R)-1b, (S)-1b) was found to dramatically influence their pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition. (R)-Sila-venlafaxine ((R)-1b) was identified to have a refined selectivity profile consistent with selective noradrenaline reuptake inhibition. Compounds with this profile may provide therapeutic benefit in the treatment of various nervous system disorders.