Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-30
2000-03-21
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142282, 5142328, 514254, 514323, 514365, 544 60, 544142, 544372, 546200, 548181, 548438, A61K 3140, A61K 31425, C07D20990, C07D41700, C07D40300
Patent
active
060403314
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel benzindole derivatives, processes for producing them, pharmaceuticals containing them, in particular, neuroprotective agents and prophylactics or therapeutics of those diseases which involve the degeneration, retraction and death of neurons, as well as analgesics.
BACKGROUND ART
Cerebrovascular disorders and neurodegenerative diseases rank as major diseases in middle-aged to elderly persons and their onset is triggered by dysfunction, retraction, degeneration, decrease, necrosis and so forth of neurons in general or specific regions due to ischemia, trauma, aging or etiology which is in most cases unknown for the cause. Drugs currently used against these diseases are nosotropic ones which are called cerebral metabolism activators, cerebral circulation modifiers or neurotransmitting function improvers. The mechanism of action of these drugs remains unknown in many points and they have only proved to be unsatisfactory in clinical therapeutic efficacy.
Cerebral infarctions such as cerebral thrombosis and embolism are classified as cerebrovascular disorders and their onset is triggered by the brain becoming ischemic due to the stenosis of blood vessels, brain thrombi or brain emboli. For the treatment of cerebral infarctions in an acute phase, anti-edema agents such as mannitol which improve post-ischemic cerebral edema, thrombolytic agents such as urokinase which remove occlusive thrombi, microcirculation modifiers such as ozagrel or cerebral metabolism activators such as citicoline. However, these therapeutics are only nosotropic and their efficacy is by no means satisfactory. In the chronic phase of cerebral infarctions, cerebral metabolism activators such as idebenone and bifemelane, cerebral circulation modifiers such as nicardipine and indeloxazine or neurotransmitting function modifiers such as aniracetam and lisuride are used against dyskinesia such as paralysis, affective disorders such as depression, subjective symptoms such as numbness or consciousness disorders such as delirium and although some of them have been found to be effective in achieving transient improvements in mental conditions, they are generally held to have little efficacy.
A recent finding about cerebral damages due to ischemia is that in addition to the mechanism of tissue necrosis due to energy insufficiency caused by the abolishment of oxygen and nutrient supply to the brain, the mechanism by which glutamic acid which plays the role of a principal neurotransmitter at normal time is released excessively to impair neurons in a positive manner is important (a theory called "excitoneurotoxicity"). In addition, the death of neurons caused by glutamic acid is known to include an immediate disorder due to a rapid elevation of intracellular Ca.sup.2+ and a delayed neuronal death that occurs several days after transient cerebral ischemia in gerbils as demonstrated by Kirino et al. in Brain Res., 239, pp. 57-69, 1982. Apoptosis which has recently gained interest as a mechanism for the death of cells has also been shown to be involved in this delayed neuronal death and other death cases of neurons in ischemic neuronal damages (Nitatori et al., J. Neurosci., 15, pp. 1001-1011, 1995).
Under the circumstances and from the viewpoint of the neurotoxicity of glutamic acid, active efforts have been made to develop drugs that relieve the toxicity of glutamic acid. Briefly, glutamic acid receptor blocking compounds such as dizocilpine, selphotel and YM90K and glutamic acid release suppressing lifarizine and BW619C89 have been demonstrated to be effective in experiments with cerebral ischemic animal models and their clinical efficacy is now under review. However, these drugs have encountered the difficulty that their side effects such as hallucination and hypotension become a dose limiting factor, making it impossible to administer sufficient doses to exhibit a neuroprotective effect.
Parkinson's disease which is a neurodegenerative disease is dyskinesia that involves selective degeneration of dopa
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Akada Yasushige
Itoh Manabu
Mukaihira Takafumi
Shimojo Masato
Yamamoto Ichiro
Coleman Brenda
Mochida Pharmaceutical Co. Ltd.
Shah Mukund J.
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