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Triple Reuptake Inhibitors (TRUI) Project

Objective

  • Discovery of novel highly potent and selective chemical entities able to influence the reuptake of three aminergic neurotransmitters (serotonin/noradrenaline/dopamine) by their transporters (SERT≥NET>DAT)

Challenge

  • To find synthetic pathways towards a novel class of potential triple monoamine reuptake inhibitors, with  a "cage" substructure not published previously

 

  • Secondary/tertiary amine fundamental for achieving the primary activity at the three transporters
  • Decoration of the aromatic region provides an appropriate “titration” of the SERT/NET/DAT components

 Key steps in synthetic approach

  • Synthesis of azabicyclo[4.1.0]heptane scaffold
  • Carboxylic acid C-1 homologation
  • Final cyclization of "cage" structure

 Synthesis of azabicyclo[4.1.0]heptane scaffold

  • Carboxylic acid C-1 homologation
  • 7 steps synthesis on 10 g scale of crucial carboxylic acid intermediate A was performed using known conditions, method robust enough for kg scale (44% yield)

Development of one-carbon carboxylic acid homologation by Arndt-Eistert reaction

Challenge

  • Avoiding the formation of dimer product due to the Boc-deprotection by HCl formed in the reaction mixture

Solution

  • Addition of base (TEA) in the first reaction step

Optimized reaction conditions

Synthesis of final “cage” compound

  • Two enantiomers separated by chiral HPLC
  • First ever synthesis of this molecule

Summary

  • Target compound was synthesized in 14 reaction steps  (overall yield: 7 %) 
  • Various synthetic methods utilized to generate the novel scaffold
  • Synthetic problems were successfully solved to generate a clinical candidate
  • Good levels of potency for all three transporters were achieved  with the core scaffold
  • GlaxoSmithKline 2009 Exceptional Science Award

References

  • Tricyclic azabicyclo [4.1.0] heptane derivatives as inhibitors of serotonin, dopamine and norepinephrine re-uptake
    WO2010146025
  • Azabicyclic compounds as inhibitors of monoamines reuptake
    WO2008031772
  • F. Micheli, M. Roscic et al., 6-(3,4-Dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: A new potent and selective triple reuptake inhibitor
    J Med Chem 2010, 53, 4989-5001
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