Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-15
2004-11-30
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S229500, C514S242000, C544S008000, C544S068000, C544S182000
Reexamination Certificate
active
06825192
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a clinically highly useful pharmaceutical preparation having non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptor antagonistic action, for example 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonistic action, which is useful specifically as an agent for preventing, treating and ameliorating nerve degeneration diseases, more specifically 1) acute nerve degeneration after cerebral ischemia and cerebrospinal injuries, 2) chronic nerve degeneration diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) or Huntington's chorea, 3) epilepsy, 4) pain, 5) spastic paralysis or 6) demyelinating diseases such as multiple sclerosis (MS), encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, HIV or HTLV myelopathy, and leukoencephalopathy.
PRIOR ART
Amino acids such as glutamic acid and aspartic acid are known as excitatory amino acids (hereinafter abbreviated to EAAs) governing excitatory neurotransmission in the central nervous system. It is reported that excessive release or accumulation of these EAAs in synaptic clefts in nerve cells causes abnormal excitation in the central nervous system, thus leading to nerve degeneration, mental disorders and motor function disorders observed after cerebral ischemia, traumas in the head, cerebrospinal injuries, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's chorea, AIDS-related nerve disorder, epilepsy or low-oxygen condition. It is also reported that the abnormal excitation in the central nervous system is related to pain and spasm. Further, it is reported that EAAs are involved in nerve disorders caused by toxins contained in foods. Accordingly, a chemical regulating the abnormal functions of EAAs is considered useful as a therapeutic agent for nerve degeneration and spiritual disorders. Furthermore, it is also considered useful as an analgesic for pain etc. originating in chronic pain, migraine, cancerous pain, diabetic nerve disorders, and as a muscle relaxant (Lipton and Rosenberg, N. Eng. J. Med., 330, 613, 1994, Lees, CNS Drugs, 5, 51, 1996, Turski et al., J. Pharmacol. Exp. Ther., 260, 742, 1992). The action of EAA is demonstrated via a glutamate receptor that is a specific receptor present in presynaptic membrane and postsynaptic membrane. This receptor is classified on the basis of electrophysiological or neurochemical properties into (1) N-methyl-D-aspartic acid (NMDA) receptor, (2) non-NMDA receptor, that is, 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and kainic acid receptor, and (3) metabolism antagonism type glutamate receptor.
EAAs activate the above glutamate receptor and transmits excitation in the central nervous system. Further, it is reported that nerve disorders occur when excess EAA, NMDA, AMPA or kainic acid acts on nerve cells (Meldrum, B., Brain Res. Reviews, 18, 293, 1993). It is known that a compound having AMPA receptor antagonistic action shows a nerve-protecting action in a model with ischemia. It is reported that a competitive inhibitor, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f-]quinoxaline (referred to hereinafter as NBQX) is effective in an experimental animal model with cerebral ischemia (Sheardown et al., Science, 247, 571, 1990). Further, a non-competitive inhibitor GYKI 52466 (1-(amino-phenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzoazepine hydrochloride) exerts a nerve-protecting action in a rat model with cerebral ischemia (Le Peillet et al., Brain Research, 571, 115, 1992). These reports suggest that the AMPA inhibitor inhibits nerve degeneration after cerebral ischemia. The compound having AMPA receptor antagonistic action is reported as follows. WO 96/10023 and WO 94/25469 disclose quinoxalinedione compounds having a competitive inhibitory action on AMPA receptors. Further, WO 95/01357, WO 97/43276 and DE 19643037 disclose compounds having non-competitive inhibitory action on AMPA receptors.
Cerebral ischemia is a highly frequent acute degeneration disease in the central nervous system. This disease is caused by occlusion of vessels for supplying blood to the brain or by systemic circulatory disturbance such as cardiac standstill, and irreversible necrosis of nerve cells in the brain is caused by shortage of blood supplied. As a result, disturbance such as motor disturbance including paralysis in hands and legs, hindrance of sensibility, abnormal behavior, etc. is brought about as sequelae. Therapy for preventing necrosis of brain nerve cells at an acute stage from a few hours to a few days after onset is very important for relieving sequelae. Further, there is an attempt at recovering blood stream at a stage called an ultra-acute stage, but symptomatic treatment against brain edema and general control are merely conducted, and there is no established method effective in many cases.
Traumas in the head and spinal injuries are acute degeneration diseases in cells in the central nervous system, and are often accompanied by cerebral ischemic conditions. These diseases cause paralysis, hindrance of sensibility, abnormal behavior etc. as sequelae. After onset, protection of the cells by early therapy is important, but therapeutic methods conducted so far are symptomatic treatment such as inhibition of edema and surgical removal of damaged sites, which does not necessarily lead to a reduction in the sequelae.
Chronic nerve degeneration diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's chorea occur due to degeneration of nerve cells in the brain and spinal cord. Detailed causes for these diseases remain unclear, and no therapeutic method is established for inhibiting the degeneration of nerve cells in these diseases.
Epilepsy is a repetitive spasmodic disorder caused by abnormal excitation of cerebral nerve cells and may be accompanied by hindrance of consciousness or hindrance of sensibility. For therapy of epilepsy, administration of an anti-spastic agent is conducted, but there may occur severe hepatic disturbance or side effects such as poor-regeneration anemia, skin mucous membrane eye syndrome etc.
Pain (sharp pain) is a clinical symptom caused by various diseases. For treatment of pain, administration of an antalgic is usually conducted, but there is a certain pain not responding to a conventional antalgic.
Spastic paralysis is a clinical symptom caused by promotion of abnormal muscular tension, to cause motor disturbance. For treatment of spastic paralysis, a muscular relaxant is administered, but side effects such as drowsiness, sense of exhaustion and sedative action occur highly frequently.
Demyelinating diseases are diseases caused by various causes. These diseases are accompanied by paresthesia, pain, spastic paralysis, micturition disturbance etc. Among these diseases, multiple sclerosis that is a demyelinating disease in the central nervous system is a recurring progressive disease, and there is no established therapeutic method.
There is no practical therapeutic, ameliorating or preventive agent for acute nerve degeneration diseases after cerebral ischemia and cerebrospinal injuries, chronic nerve degeneration disease, epilepsy, pain, spastic paralysis, and demyelinating disease by use of non-NMDA excitatory amino acid receptor antagonistic action, particularly AMPA receptor antagonistic action, and its development is desired.
DISCLOSURE OF THE INVENTION
The present inventors paid attention to compounds having non-NMDA excitatory amino acid receptor antagonistic action, particularly AMPA receptor antagonistic action, and made extensive study. As a result, they succeeded in synthesizing a novel heterodiazinon compound represented by the formula:
as well as a pharmacologically acceptable salt thereof. Further, they found that these compounds have an excellent pharmacological action, are excellent in safety and can solve the problem describe
Fukushima Tatsuto
Hanada Takahisa
Hatakeyama Shinji
Ito Koichi
Kajiwara Akiharu
Eisai Co. Ltd.
Kifle Bruck
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