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Preparation of Heterocyclic Synthons for Dibenzo[e,h]azulenes

Objective

  • Design of novel tetracyclic compounds as potential anti-inflammatory drugs (inhibitors of TNF-a production)

Challenge

  • Use of dibenzo[b,f]oxepin- and thiepin-10(11H)-one (I) as common precursors for the synthesis of an array of five membered heterocycles (II – IX)

 Preparation of heterocyclic synthons for dibenzo[e,h]azulenes

Gram scale synthesis


Summary

From 1-thia-dibenzo[e,h]azulene class (II) 1 pre-clinical candidate compound obtained:
  • optimised and provided scale-up synthesis (HR 2003000914 A2)
  • 7 synthetic steps, up to 100 g of final product, 48% overall yield
  • no column chromatography, crystalline material as final product (salt form)
  • identification and isolation of metabolites

 

 


Summary

  • 1st award for the most perspective and inventive work presented at poster; XXI. European Colloquium on Heterocyclic Chemistry, 12-15 September 2004., Sopron, Hungary; 8 patent applications; 7 publications
  • Designed and optimized synthetic routes  to dibenzo[b,f]oxepin- and -thiepin-10(11H)-ones (I), key intermediate

References

Patents

  • WO 200108789
  • US 20030153750
  • HR 2003000914 A2
  • WO 2003084962
  • WO 2003097649
  • WO 2003099823
  • WO 2003099822
  • WO 2003084964
  • WO 2003099827
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