Characterisation of copper(II) dimers of the non-steroidal anti-inflammatory drug indomethacin

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDS), of which indomethacin (IndoH) is the most potent, are the mainstay of the treatment of inflammatory diseases in both animals and humans, with an estimated worldwide market of between $5—9B per annum. However, NSAIDS have serious gastro-intestinal (GI) side-effects, which not only limit their applications in the treatment of inflammation, particularly in elderly patients in whom these effects are most injurious, but also as potential preventative/ therapeutic agents in the treatment of other diseases such as colo—rectal cancer, multiple sclerosis and Alzheimer’s disease. A successful solution to the GI side effects was the development of [Cuzando)4(DMF)2] which was patented in 1994 by Biochemical Veterinary Research (BVR). [Cuzando)4(D1\/IF),_] is available in Australia in a number of pharmaceutical formulations for veterinary use. The lack of GI effects is highlighted by the fact that dogs, in which the administration of IndoH is usually fatal, can routinely be given the drug. The purpose of this thesis was to develop analytical methods for the characterisation of a series of [Cuzando)4L2] (L: DMF, DMA, NMP, 0H,] complexes in order that their applications could be extended into worldwide markets and into human clinical trials. Furthermore, DMF is not an ideal solvent for use in human pharmaceutical formulations, with alternate solvent adducts having the potential to alter both the nature and biological activity of the complex. Consequently, different solvent adducts of Cu— IndoH were prepared and characterised, e.g., [Cuzando)4(OH2)2], for use in pharmaceutical formulations. The synthesis and solid-sate characterisation of [Cu2(Indo)4LJ (L = DMF, DMA, NMP, 0H2] by various techniques, including EPR and X—ray absorption spectroscopies, are reported. Moreover, for the first time, the stability of [Cuzando)4(DMF),] in a number of pharmaceutical and biological media, including artificial “gastric juice”, was established.