Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-12-02
2000-09-19
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544354, A61K 31498, C07D40310, C07D40314
Patent
active
061212644
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to an imidazole-substituted quinoxalinedione derivative or a salt thereof which has of glutamate receptor antagonism, particularly AMPA receptor and/or NMDA-glycine receptor antagonism, kainic acid neurotoxicity inhibition action and audiogenic seizure inhibition action, as well as excellent water-solubility and blood-solubility. It also relates to pharmaceutical compositions which comprise said imidazole-substituted quinoxalinedione derivative or a salt thereof and a pharmaceutically acceptable carrier, particularly a pharmaceutical composition which is useful as a glutamate receptor antagonist, an AMPA receptor antagonist, an NMDA-glycine receptor antagonist, a kainic acid neurotoxicity inhibitor, an anti-ischemia drug or a psychotropic drug.
BACKGROUND ART
Amino acids such as L-glutamic acid, L-aspartic acid are known to be central nerve system neurotransmitters. It is said that extracellular accumulation of these excitatory amino acids and their continuous excessive stimulation of to nerves lead to Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease, senile dementia and neurodegeneration or deficiency in mental and motor functions observed after the condition of cerebral ischemia, oxygen deficiency or hypoglycemia.
In consequence, it has been considered that regulator of the abnormal activity of an excitatory amino acid is useful for the treatment of neurodegeneration and mental diseases, and it is considered also that such a drug will be effective for drug dependence and alcohol dependence.
Excitatory amino acids exhibit their action through glutamate receptors which are specific receptors existing at postsynaptic or presynaptic region. Such receptors are presently classified into the following three groups based on the electrophysiological and neurochemical studies. receptor
The compound of the present invention has glutamate receptor antagonism (particularly, AMPA receptor antagonism), kainic acid neurotoxicity inhibition action and audiogenic seizure inhibition action, so that it is useful as an anti-ischemia drug or a psychotropic drug.
L-Glutamic acid and L-aspartic acid activate the aforementioned glutamate receptors and transmit excitation. Nervous disorders occur when an excess amount of NMDA, AMPA or kainic acid is allowed to act on nerves. It has been reported that 2-amino-5-phosphonovalerianic acid or 2-amino-7-phosphonoheptanoic acid as a selective antagonist against NMDA receptors is effective in nervous disorders induced by the action of NMDA and in experimental animal models suffering from epilepsy and cerebral ischemia (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1987); Science, 226, 850 (1984)).
It has been reported that NMDA receptors are allosterically regulated by glycine receptors (EJP, 126, 303 (1986)), and that a glycine receptor antagonist HA-966 is also useful in an experimental animal model suffering from cerebral ischemia (American Society for Neuroscience, 1989).
In addition, it has been reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline) which is a selective antagonist against the AMPA receptor is also useful in an experimental animal model suffering from cerebral ischemia (Science, 247, 571 (1990)).
On the other hand, it has been shown that all of the cloned non-NMDA receptors have affinity for kainic acid. Among these receptors, a receptor having low affinity for kainic acid (AMPA/kainate receptor) has been indicated to be related to the neuronal death at the time of ischemia such as cerebral infarction (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). This AMPA/kainate receptor has high affinity for AMPA too, but the binding sites of AMPA and kainic acid are not clear. However, it has been reported that AMPA and kainic acid show different electrophysiological responses to the AMPA/kainate receptor. It has been reported also that AMPA alone shows weak action in a neurotoxicity test which uses a neuronal culture sy
REFERENCES:
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patent: 5849743 (1998-12-01), Lubisch et al.
L. Turski et al., "Pharmacology of ZK200775 and ZK202000, Competitive Non-NMDA Glutamate Receptor Antagonists", Soc. Neurosci. Abstr., Abstract No.604.6, vol. 22, Part 2, P. 1529, 1996.
Ohmori Jun-ya
Okada Masamichi
Sakamoto Shuichi
Sasamata Masao
Shishikura Jun-ichi
Bernhardt Emily
Yamanouchi Pharmaceutical Co. Ltd.
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