Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-05
2000-08-01
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514 81, 544337, 544354, A61K 31498, C07D40310
Patent
active
060967439
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a quinoxalinedione derivative or a salt thereof which has glutamate receptor antagonizing action, has high affinity with AMPA receptors which are non-NMDA receptors, has potent inhibitory action against kainic acid neurotoxicity and audiogenic seizure inhibitory action, and has high solubility. The present invention also relates to an agent for inhibiting kainic acid neurotoxicity, which comprises the quinoxalinedione derivative or a salt thereof as an effective ingredient. The present invention further relates to a pharmaceutical composition comprising the quinoxalinedione derivative or a salt thereof and a pharmaceutically acceptable carrier.
BACKGROUND ART
Amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system neurotransmitters. It is said that extracellular accumulation of these excitatory amino acids and their continuous of excessive stimulation of the nerves lead to Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease, senile dementia or neurodegeneration or deficiency in mental and motor functions observed after the condition of cerebral ischemia, oxygen deficiency or hypoglycemia.
It has come to be considered that a regulator of the abnormal activity of an excitatory amino acid is useful for the therapeutic treatment of neurodegeneration or psychic diseases.
Excitatory amino acids exhibit their action through glutamate receptors which are specific receptors existing at postsynapse or presynapse. At present, such receptors can be classified into three groups based on electrophysiological and neurochemical studies. receptor
The compound according to the present invention has glutamate receptor antagonizing action and inhibitory action against kainic acid neurotoxicity and is useful as an anti-ischemia or as an psychotropic.
L-glutamic acid or L-aspartic acid activates the above-described glutamate receptors and transmits excitation. When an excess amount of NMDA, AMPA or kainic acid is caused to act on the neuron, neuronal death occurs. It is reported that 2-amino-5-phosphonovalerianic acid or 2-amino-7-phosphonoheptanic acid which is a selective antagonist against the NMDA receptor is effective for experimental animal models suffering from neuropathy, epilepsy or cerebral ischemia (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1987); or Science, 226, 850 (1984)).
It is reported that NMDA receptor functions are allosterically regulated by a glycine receptor (Eur. J. Pharmacol., 126, 303 (1986)), while it is reported that HA-966 which is an antagonist against the glycine receptor is effective in experimental animal models suffering from cerebral ischemia (Annual meeting of Society for Neuroscience, 1989).
It is also reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline) which is a selective antagonist against the AMPA receptor is also effective in experimental animal models suffering from cerebral ischemia (Science, 247, 571 (1990)).
On the other hand, it has been shown that all the non-NMDA receptors subjected to cloning have affinity with kainic acid and it is suggested that among these receptors, a receptor having low affinity with kainic acid (the AMPA/kainate receptor) has a relation with neuronal death at the time of ischemia such as cerebral infarction (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1933)). This AMPA/kainate receptor has high affinity with AMPA but the binding sites of AMPA and kainic acid are not known. It is however reported that AMPA and kainic acid exhibit different electrophysiologic responses against the AMPA/kainate receptor. It is reported that in a neuronal toxicity test using a neuronal culture system, kainic acid itself causes marked neuronal cell death, while the action of AMPA alone is weak (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). Accordingly, there is a possibility that neuronal death caused by excessive excitation by glutamic acid at the time
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Fujii Mitsuo
Inami Hiroshi
Okada Masamichi
Sakamoto Shuichi
Sasamata Masao
Bernhardt Emily
Yamanouchi Pharmaceuticals Co., Ltd.
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