Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-05-03
1994-02-01
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142345, 514250, 544116, 544119, 544350, 544354, A61K 31495, A61K 31535, C07D40302, C07D41314
Patent
active
052832449
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a fused pyrazine derivative or a salt thereof, which has glutamate receptor antagonizing activity, particularly NMDA-glycine receptor antagonizing activity and AMPA receptor antagonizing activity.
BACKGROUND ART
Certain amino acids such as L-glutamic acid and L-aspartic acid are known to be central neurotransmitters. It is said that accumulation of these excitatory amino acids results in a persistent overstimulation of the nerves which, in turn, causes neuronal degeneration and mental and motor dysfunctions as are observed in Huntington's chorea, Parkinson's disease, epilepsy and senile dementia, or after cerebral ischemia, oxygen deficiency or hypoglycemia.
Therefore, it is by now considered that drugs which may modulate abnormal actions of these excitatory amino acids are useful for the treatment of neuronal degeneration and mental disease.
Excitatory amino acids exert their effects via the specific receptors present in the post- or presynaptic regions. These receptors have been classified into the following five groups based on electrophysiological and neurochemical evidence.
1) NMDA (N-methyl-D-aspartate) receptor
2) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)-propionic acid] receptor
3) Kainate receptor
4) Metabotropic glutamate receptor
5) AP-4 (2-amino-4-phosphobutanoic acid) receptor
L-Glutamic acid and L-aspartic acid activate the above-mentioned receptors to transmit stimuli. Permitting an excessive amount of NMDA, AMPA or kainate to act on nerves causes neuropathy. It is reported that 2-amino-5-phosphonovalerianic acid and 2-amino-7-phosphonoheptanoic acid, both of which are selective antagonists of NMDA receptor, were effective in NMDA-induced neuropathy and in animal models of epilepsy or brain ischemia (JPET, 250, 100 (1989); JPET, 240, 737 (1987); Science, 226, 850 (1984)).
While NMDA receptor is reported to be allosterically functioning by glycine receptor (EJP, 126, 303 (1986)), HA-966 which is a glycine receptor antagonist is reported to be effective in an animal model of brain ischemia (1989 Congress of American Society of Neuroscientists).
NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline), a selective antagonist of AMPA receptor, is also reported to be effective in an animal model of brain ischemia (Science, 247, 571 (1990)). On the other hand, there is no report with respect to selective antagonists of kainate, metabotropic glutamate and AP-4 receptors.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a diketoquinoxaline or diketopyridopyrazine compound having glutamate receptor antagonizing activity, particularly NMDA-glycine receptor and/or AMPA receptor antagonizing activity. Several diketoquinoxaline derivatives having NMDA-glycine antagonizing and/or AMPA antagonizing activity have been reported (JP-A-63-83074, JP-A-63-258466, JP-A-1-153680, JP-A-48578, JP-A-2-221263, and JP-A-2-221264; the term "JP-A" as used herein means an "unexamined published Japanese patent application"). However, the compound of the present invention is a novel compound which has structural characteristic that it has an imidazolyl or triazolyl group on the diketoquinoxaline or diketopyridopyrazine ring.
Thus, the present invention relates to a pyrazine derivative represented by the general formula: ##STR6## wherein ring A represents a benzene ring of the formula ##STR7## or a pyridine ring of the formula ##STR8## R.sup.1 represents ##STR9## (X represents a nitrogen atom, or a carbon atom substituted by R.sup.8, R.sup.6 represents a hydrogen atom or a lower alkyl group, R.sup.7 and R.sup.8 are the same or different and each represents hydrogen, lower alkyl, nitro or phenyl, or R.sup.7 and R.sup.8 are combined together to represent butadienylene (--CH.dbd.CH--CH.dbd.CH--) or 1,4-butylene (--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --)); R.sup.2 and R.sup.3 are the same or different and each represents hydrogen, fluoro, cyano, lower acyl, nitro, unsubstituted or fluorine-substituted lower alkyl, morpholino, or one of said specie
REFERENCES:
patent: 5028606 (1991-07-01), Venet et al.
Hidaka Kazuyuki
Kubota Hirokazu
Ohmori Jun-ya
Okada Masamichi
Sakamoto Shuichi
Ramsuer Robert W.
Yamanouchi Pharmaceutical Co. Ltd.
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