Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-05-13
2000-10-17
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 48, A61K 31542, C07D51304
Patent
active
061332585
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a potent inhibitor of kainic acid neurotoxicity based on noncompetitive antagonism upon AMPA receptor response, which comprises a pyridothiazine derivative or a salt thereof as an active ingredient. The present invention also relates to a pyridothiazine derivative or a pharmaceutically acceptable salt thereof which has an activity of inhibiting the kainic acid neurotoxicity to provide a neuroprotecting effect, an anti-neurodegeneration effect, an anti-psychiatric diseases effect, an anti-pain effect, and an anti-glaucoma effect.
BACKGROUND OF THE INVENTION
Excitatory amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system neurotransmitters. It is believed that excessive excitation by the excitatory amino acids causes neurodegeneration observed in Huntington's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, cerebral ischemia, anoxia, diabetes, hypoglycemia, drug dependence, head injury, etc, which leads to deficiency in mental and motor functions. Therefore, an agent which can control abnormality of the excitatory amino acid function is considered to be useful for protection from the aforementioned neurodegenerative diseases and psychiatric diseases. Further, recent studies show that such an agent is useful also for amyotrophic lateral sclerosis, multiple sclerosis, pain, glaucoma, etc.
Excitatory amino acids exert the effect via specific receptors located in postsynaptic or presynaptic sites. At present, based on electrophysiologic and neurobiochemical evidences, the receptors are classified into the following three groups: receptor,
L-glutamic acid or L-aspartic acid activates the aforementioned receptors to transmit excitation.
Exposure to an excess amount of NMDA, AMPA or kainic acid causes neuronal cell death. It has been reported that 2-amino-5-phosphonovaleric acid and 2-amino-7-phosphonoheptanic acid, both of which are selective NMDA antagonists, are protective against NMDA excitotoxicity or in experimental animal models for epilepsy, cerebral ischemia, etc. (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 the NMDA receptor is under allosteric control by glycine (Nature, 325, 529 (1987)).
Glycine exerts its effect via a glycine receptor located on the NMDA receptor. It has been reported that HA-966, which is a glycine antagonist, is effective in an experimental animal model for cerebral ischemia (Society for Neuroscience, Annual Meeting Abstract, 1989).
It has also been reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline), which is a selective AMPA antagonist, is effective in the experimental animal model for cerebral ischemia (Science, 247, 571 (1990)).
It has been reported that the AMPA receptor usually undergoes very rapid desensitization (Proc. Natl. Acad. Sci. USA, 85, 2834 (1988)). It is considered that this action protects neurons from excessive excitation by glutamic acid (Neuron, 5, 61 (1990)). As a desensitization inhibitor there has been found cyclothiazide (J. Neurosci., 13, 3904 (1993), which has been reported to accelerate AMPA-induced cell death (J. Neurochem., 60, 1171 (1993)). It has also been reported that GYKI52466, which had been known as a noncompetitive AMPA antagonist (Neurosci. Lett., 125, 5 (1993)), counteracts the inhibition of desensitization by cyclothiazide (Neuron, 10, 51 (1993)), and that this agent is effective in an experimental animal model for cerebral ischemia (Stroke, 23, 861 (1992)).
Some pyridothiazine derivatives have been reported (Collect. Czech. Chem. Commun., 48, (11), 3315 (1983); Rocz. Chem., 49 (4), 748 (1975); Acta. Polon. Pharm., 38 (2), 145 (1981); Il Farmaco. Ed. Sc., 41 (12), 964 (1986)). However, these pyridothiazine derivatives have been merely reported for the anti-serotonin, anti-spasm, antidepressant, and analgesic, and anti-inflammation effects. These pyridothiazine derivatives have nev
REFERENCES:
Koscik et. al. Collection Czechoslovek Chem. Commun. 48, 3315-28, 1983.
Zawisa et. al., Pyridothiazines . . . Roczniki Chemii, 49(4), 743-748, 1975.
Koscik et al. collection Czechoslovek Chem. Commun. 48, 3426-32, 1983.
Zawisza et al., Acta Polon. Pharm., 38, 145-152, 1981.
Zawisza et al., Polish Journal of Chemistry, 54, 1875, 1980.
Zawisza et al., I1 Pharmac, 41, 964 (1986).
Zawisza et al., I1 Pharmac, 40, 58 (1985).
Zawisza et al., I1 Pharmac, 40, 65 (1985).
J. Med. Chem., 37, 1616, 1994.
Synthesis, 816, 1988.
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Hirano Masaaki
Inami Hiroshi
Ohno Kazushige
Okada Masamichi
Sakamoto Shuichi
Balasubramanian V
Shah Mukund J.
Yamanouchi Pharmaceutical Co. Ltd.
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