Quinoxaline derivatives useful in therapy

#This application is a 371 of PCT/EP95/03559 which was filed on Sep. 8, 1995.

#This invention relates to quinoxaline derivatives useful in therapy.

#L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg.sup.2+, Zn.sup.2+). Since the NMDA receptor has an absolute requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.

#The invention is illustrated by the following Examples. Intermediate compounds may be prepared as described in the following Preparations.

#Melting points were determined using a Buchi apparatus in glass capillary tubes and are uncorrected. Spectroscopic data were recorded on Perkin-Elmer 983 (Infra Red), Fisons Trio 1000 (Mass Spectrometer, thermospray using ammonium acetate in aqueous methanol as carrier), and Bruker AC300 and Varian Unity 300 NMR instruments (both 300 MHz), and were consistent with the assigned structures. Column chromatography was accomplished on Kieselgel 60, (230-400 mesh) from E. Merck, Darmstadt. Kieselgel 60 F.sub.254 plates from E. Merck were used for thin layer chromatography (TLC), and compounds were visualized with UV light or chloroplatinic acid/potassium iodide solution. In cases where compounds analyzed as hydrates, the presence of water was evident in the enhanced peak due to water in the proton NMR spectra. The purity of compounds was carefully assessed using analytical TLC and proton NMR (300 MHz), and the latter technique was used to calculate the amount of solvent in solvated samples. In multistep sequences, the purity and structure of intermediates were verified spectroscopically by proton NMR. Proton NMR shifts are quoted in parts per million downfield from tetramethylsilane.

#Some abbreviations familiar to those skilled in the art have been used in the Examples and Preparations, e.g. Me (methyl), Et (ethyl), Ac (acetyl), h (hour), m (in relation to silica gel-mesh).