Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-01
1998-04-14
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548578, A61K 3140, C07D295073, C07D295135
Patent
active
057391580
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is in the field of clinical neurology and relates specifically to a class of therapeutically useful compounds, compositions and methods for treatment of Central Nervous System (CNS) dysfunctions, neurotoxic damage, or neurodegenerative diseases. For example, these compounds are particularly useful for treating neurotoxic injury which follows periods of hypoxia, anoxia or ischemia associated with stroke, cardiac arrest or perinatal asphyxia. These compounds are also useful as antipsychotics and anticonvulsives.
BACKGROUND OF THE INVENTION
Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia--Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)!. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with hypoxia, anoxia, or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
It is known that compounds of various structures, such aminophosphonovalerate derivatives and piperidine dicarboxylate derivatives, may act as competitive antagonists at the NMDA receptor. Certain piperidineethanol derivatives, such as ifenprodil and known anti-ischemic agents, have been found to be non-competitive NMDA 1222-1232 (1988)!.
There are many classes of compounds known for treatment of psychotic disorders. For example, current therapeutic treatments for psychoses use compounds classifiable as phenothiazine-thioxanthenes, as phenylbutylpiperidines and also as certain alkaloids. An example of a phenylbutylpiperidine compound of current use in psychotic treatment Theraputics, 7th Edn., p. 404, MacMillan (1985)!.
Certain nitrogen-containing cyclohetero cycloalkylaminoaryl compounds are known for pharmaceutical purposes. For example, U.S. Pat. No. 4,204,003 to Szmuszkovicz describes N-(2-aminocyclopentyl)-N-alkanoylanilides as antidepressant agents.
Certain aminocycloaliphatic benzamides have been described for various uses. For example, U.S. Pat. No. 4,463,013 to Collins et al describes aminocyclohexylbenzamides for use as diuretic agents. The compound -acetamide has been evaluated for its selectivity as an amino acid same compound has been evaluated for its neuroprotective activity against (1989)!. U.S. Pa
REFERENCES:
patent: 4204003 (1980-05-01), Szmuszkovicz
patent: 4460600 (1984-07-01), Kaplan et al.
patent: 4463013 (1984-07-01), Collins et al.
patent: 4466977 (1984-08-01), McMillan et al.
patent: 4801604 (1989-01-01), Vonvoigtlander et al.
patent: 4855316 (1989-08-01), Horwell et al.
patent: 4876269 (1989-10-01), Pennev et al.
patent: 4891382 (1990-01-01), Lancaster et al.
patent: 5130330 (1992-07-01), de Costa et al.
Brian R. de Costa et al; Journal of Medicinal Chemistry, vol. 33, No. 11, Nov. 1990; pp. 3100-3110.
S.M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia-Ischemic Brain Damage," Annals of Neurology, vol. 19, No. 2, pp. 105-111; (1986).
C. Carter et al, J. Pharm. Exp. Ther., 247, (3), pp. 1222-1232; (1988).
A.F. Gilman et al, The Pharmacological Basis of Therapeutics, 7th Edn., p. 404, Macmillan: (1985).
C.G. Parsons et al, Neuropharm., 25 (2); pp. 217-220; (1986).
W. Larson et al, Brain Res., 482; pp. 333-339; (1989).
B.R. de Costa et al, J. Med. Chem., 32(8); pp. 1996-2002; (1989).
Bowen Wayne D.
Contreras Patricia C.
de Costa Brian R.
Gray Nancy M.
Jacobson Arthur E.
Powers Fiona T.
The United States of America as represented by the Department of
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