Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-12-07
1995-10-31
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142335, 5142388, 514253, 514317, 514324, 514392, 514422, 514431, 514432, 514416, 514456, 514469, 514653, 514649, 514650, A61K 3138, A61K 31535, A61K 31495, A61K 31445, A61K 31415, A61K 3140, A61K 3135, A61K 3134, A61K 31135
Patent
active
054629659
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention is in the field of clinical neurology and relates specifically to a class of compounds, compositions and methods for CNS-disease treatment, such as for controlling or treating chronic or acute neuronoxic injury or brain damage resulting from ischemic conditions, and for treating certain neurodegnerative diseases.
These compounds would be particularly useful for treating neurotoxic injury which follows periods of hypoxia, anoxia, or ischemia associated with stroke, cardiac arrest, perinatal asphyxia or hypoglycemic events.
BACKGROUND OF THE INVENTION
Unlike other tissues which can survive extended periods of hypaxia, 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 the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman et al, Annals of Neurology, 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). Glutamate is believed to be a mixed agonist capable of binding to and exciting all three receptor types.
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 anoxia, hypoxia 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. In particular, compounds such as 2-amino-4-(2-phosphonomethylphenyl)butyric acid and 2-(2-amino-2-carboxy)ethylphenylphosphonic acid have been synthesized for evaluation as antagonists in blocking the action of the neurotransmitter compounds L-glutamic acid and L-aspartic acid [K. Matoba et al, Chem. Pharm. Bull., 32 (10), 3918-3925 (1984)].
There is other evidence that the NMDA receptor complex is involved in multiple physiological and pathological events, inasmuch as the NMDA receptor complex is a ligandgated ion channel that can be modulated by diverse substances acting at distinct recognition sites. For example, there is evidence that polyamines including spermine and spermidine profoundly enhance the binding of channel ligands, such as [.sup.3 H]TCP(N-1-[2-thienyl]cyclohexyl)piperidine) and [.sup.3 H]dizocilipine (MK-801) by acting as agonist modulators, like glycine. Polyamines may act by increasing the frequency of channel opening or by increasing the duration of the open state.
Certain piperidineethanol derivatives, such as i
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Beart Philip M.
Gillet Claude L.
Jarrott Bevyn
Rafferty Michael F.
Roba Joseph L.
Bulock Joseph W.
Criares Theodore J.
GD Searle & Co.
Keane J. Timothy
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