Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-04-01
1997-04-01
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544344, 546165, 546168, A61K 31495, C07D47106, C07D48706, C07D21548
Patent
active
056165862
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01375, filed Oct. 22, 1992.
TECHNICAL FIELD
This invention relates to a new class of tricyclic quinoxalinediones which are selective antagonists of glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors and AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Particularly, the compounds provided by the present invention antagonize the action of glycine at strychnine-insensitive glycine modulatory site of NMDA receptors and therefore, are especially useful for minimizing damage of central nervous system induced by ischaemic or hypoxylic conditions such as stroke, hypoglycaemia, cardiac arrest, and physical trauma, (see, J. McCulloch, Br. J. clin. Pharmacol., 34, 106 (1992)). The compounds are also useful in treatment of a number of neurodegenerative disorders including epilepsy, Huntington's chorea, Parkinson's disease, and Alzheimer's disease (reviews: G. Johnson, Annu. Rep. Med. Chem., 24, 41 (1989) and G. Johson and C. F. Bigge, ibid., 26, 11, (1991)). The present compounds may also have analgestic, antidepressant, anxiolitic, and anti-schizophrenic activities, by virtue of these NMDA-glycine antagonism, as indicated by recent reports, e.g. A. H. Dickenson and E. Aydar, Neuroscience Lett., 121,263 (1991), R. Trullas and P. Skolnick, Eur. J. Pharmacol., 185, 1 (1990), J. H. Kehne, et al., Eur. J. Pharmacol., 193,283 (1991) P. H. Hutson, et al., Br. J. Pharmacol., 103, 2037 (1991), in which the reagents affecting glycine-binding site of NMDA receptors have shown such activities. Excessive release of glutamic acid and/or glycine from synaptosome results in overexcitation of NMDA receptor-Ca.sup.2+ channel complexes and successive massive amount of Ca.sup.2+ influx into the cell, which leads to neuronal cell death. NMDA-glycine antagonist described in the present invention would obviously regulate the amount of Ca.sup.2+ influx from the glycine modulatory site of NMDA receptor-channel complex to maintain normal activities of neuronal cell. Therefore, the compounds of the present invention may be potential therapeutic agents for any diseases of animals including human caused by excessive glutamic acid and/or glycine release in addition to the diseases indicated above.
BACKGROUND ART
Nonsubstituted tricyclic quinoxalinediones, 6,7-dihydro-1H, 5H-pyrido[1,2,3,-de]quinoxaline-2,3-dione and 5,6-dihydro-1H-pyrrolo[1,2,3-de-quinoxaline-2,3-dione are described in A. Richardson, JR. and E. D. Amstutz, J. Org. Chem., 25 1138 and A. Richardson, JR., ibid., 25, 2589 (1965), respectively. Amine-substituted tricyclic quinoxalinedione,6,7-dihydro-6-(di-n-propylamino)-1H, 5H-pyrido[1,2,3,-de]quinoxaline-2,3-dione is disclosed in WO 90/15058, and M. W. Moon, et al., J. Med. Chem., 35, 1076 (1992) as an example of series of imidazoquinolinones and related compounds having dopaminergic and serotonergic activities, and especially, as a selective and potent D.sub.2 agonist. The compound described there would not be expected to exhibit antagonistic activities of glutamate receptors, since, to date, none of compounds possessing cross affinities to both glutamate and dopamine receptors have been appeared.
Certain quinoxalinediones and benzo[1,2-f]qunoxalinediones have been shown to have antagonist activities against glutamate receptors including glycine modulatory site of NMDA receptors and AMPA receptors (For example, D. E. Pellegrini-Giampietro, et al., Br. J. Pharmacol., 98, 1281 (1989), M. J. Sheardown, et al., Eur. J. Pharmacol., 174, 197 (1989), Y. Yoneda and K. Ogita, Biochem. Biophys. Res. Commun., 164, 841 (1989), and M. J. Sheardown, et al., Science, 247, 571 (1990)).
DISCLOSURE OF INVENTION
The present invention provides novel quinoxalinediones depicted by formula 1 and pharmaceutically acceptable salts thereof: ##STR2## wherein X represents alkyl, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, alkylamino, alkoxy, alkanoyl, alkoxycarbonyl, sulfamoyl, carbamoyl, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, alky
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Kodo Toru
Nagata Ryu
Tanno Norihiko
Berch Mark L.
Sumitomo Pharmaceuticals Company Limited
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