Therapeutic guanidines

Details Therapeutic guanidines Therapeutic guanidines

1995-06-05

2001-01-16

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S239500, C514S247000, C514S319000, C514S325000, C514S329000, C514S415000, C544S154000, C544S155000, C544S164000, C544S230000, C544S232000, C544S294000, C546S171000, C546S203000, C546S204000, C546S205000, C546S206000, C546S223000, C548S469000, C564S230000, C564S237000, C564S238000, C564S239000

Reexamination Certificate

active

06174924

ABSTRACT:

BACKGROUND OF THE INVENTION
This application is a continuation-in-part of copending U.S. application Ser. No. 08/191,793, which is incorporated herrein by reference.
1. Field of the Invention
The present invention pertains to certain substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such guanidines.
2. Background
Neurons of the mature central nervous system (“CNS”) are highly specialized and in general do not replace themselves. Consequently, death or degeneration of cells in the nervous system can have far more serious consequences than cell death or degeneration in other organs. Abnormal neuronal death can be rapid and widespread as in traumatic brain injury, or can occur over many years among very specific populations of neurons as in chronic neurodegenerative diseases.
Substantial evidence now points to pernicious overactivity of normal neurotransmitter systems as a contributory mechanism in many instances of pathological neuronal degeneration. In particular, overstimulation of neuronal receptors for L-glutamate, the brain's most prevalent excitatory amino acid (“EAA”) neurotransmitter, has been recognized as a causal or exacerbating factor in several acute neurological disorders, and has been proposed to underlie a number of chronic neurodegenerative diseases as well [Choi, D. W.,
Neuron.,
1:623 (1988); Choi, D. W.,
Cerebrov. and Brain Metab. Rev.,
2:105 (1990); Albers, G. W., et al.,
Ann. Neurol.,
25:398 (1989)]. Indeed, it is believed that glutamate neurotoxicity is involved in acute injury to the nervous system as observed with seizure, hypoxia, hypoglycemia, and trauma, as well as in chronic degenerative diseases such as Huntington's disease, olivopontocerebellar atrophy associated with glutamate dehydrogenase deficiency and decreased glutamate catabolism, amyotrophic lateral sclerosis/Parkinsonium-dementia, Parkinson's disease, and Alzheimer's disease [Choi, D. W.,
Neuron,
1:623-634 (1988); Choi, D. W.,
Cereb. Brain Met., Rev.
2:105-147 (1990); Courtier et al.,
Lancet,
341:265-268 (1993); Appel, S. H.,
Trends Neurosci.,
16:3-5 (1993)].
In the mammalian brain, glutamate interacts with three major classes of receptors, i.e., N-methyl-D-aspartate (“NMDA”) receptors, non-NMDA receptors and metabotropic receptors [Watkins, J. D., et al.,
Trends Neurosci.,
10:265 (1987); and Seeburg,
TIPS,
141:297 (1993)]. While triggering distinctive postsynaptic responses, all three classes of glutamate receptors can act to increase the intracellular concentration of free Ca
2+
in nerve cells [A. B. MacDermott,
Nature
321:519 (1986)]. Thus, binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca
2+
, leading to a large and rapid increase in intracellular Ca
2+
. A subclass of non-NMDA receptors has been found to be linked to a Ca-permeable cation channel [Sommer, B., and Seeburg, P. H.,
Trends Pharmacol. Sci.
13:291-296 (1992)]. Although non-NMDA receptors are in most other instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca
2+
entry into neurons by depolarizing the cell membrane, which in turn opens voltage-activated Ca
2+
-channels. The so-called “metabotropic receptor”, on the other hand, is not associated with an ion channel but can promote the release of Ca
2+
from intracellular stores via the second-messenger inositol triphosphate.
Irrespective of the triggering mechanism, prolonged elevation of cytosolic Ca
2+
is believed to be a key event in the initiation of neuronal destruction. Adverse consequences of elevated intracellular Ca
2+
include derangement of mitochondrial respiration, activation of Ca
2+
-dependent proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane [Choi, D. W.,
Neuron,
1:623-624 (1988)].
The NMDA subtype of excitatory amino acid receptors is strongly involved in nerve cell death which occurs following brain or spinal chord ischemia. Upon the occurrence of ischemic brain insults such as stroke, heart attack or traumatic brain injury, an excessive release of endogenous glutamate occurs, resulting in the over-stimulation of NMDA receptors. Associated with the NMDA receptor is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca
2+
and Na
+
into the cell and K
+
out of the cell. It is believed that this flux of ions, especially the influx of Ca
2+
ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death [see, e.g., Rothman, S. M. and Olney, J. W.,
Trends in Neurosci.,
10(7):299-302 (1987)]. Additionally, excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophysiology of epilepsy [(Porter, R. J.,
Epilepsia,
30(Suppl. 1):S29-S34 (1989); and Rogawski, M. A., et al.,
Pharmacol. Rev.,
42:224-286 (1990)].
Non-NMDA receptors constitute a broad category of postsynaptic receptor sites which, as is the case for NMDA receptors, are directly linked to ion channels. Specifically, the receptor sites are physically part of specific ion channel proteins. Non-NMDA receptors have been broadly characterized into two major subclasses based on compounds selective therefor: kainate receptors and AMPA/quisqualate receptors [see J. C. Watkins et al.,
Trends Neurosci.,
10:265 (1987)]. AMPA is an abbreviation for &agr;-amino-3-hydroxyl-5-methyl-4-isoazole propionic acid. These subclasses may be categorized as “non-NMDA” receptors.
Compared to NMDA receptors, non-NMDA receptors have received less pharmacological scrutiny—the existing antagonists are all competitive—and in vivo research in this area has been hampered by the lack of drugs that cross the blood-brain barrier. Nonetheless, in vivo studies have clearly demonstrate that non-NMDA receptor agonists can also be as excitotoxic, although longer exposures can be required. In addition, evidence from animal studies and from human epidemiological studies suggests that excitotoxicity mediated by non-NMDA receptors may be clinically important in certain pathologies. [see M. D. Ginsberg et al.,
Stroke,
20:1627 (1989)].
One such disorder is global cerebral ischemia or hypoxia, as occurs following cardiac arrest, drowning, and carbon monoxide poisoning. Transient, severe interruption of the cerebral blood supply and/or interruption of the delivery of oxygen to the brain of animals causes a syndrome of selective neuronal necrosis, in which degeneration occurs among special populations of vulnerable neurons (including neocortical layers 3, 5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, and small and medium sized striatal neurons). The time course of this degeneration is also regionally variable, and can range from a few hours (striatum) to several days (hippocampus).
NMDA antagonists generally have not proven highly effective in animal models of global ischemia; indeed, it has been suggested that positive results obtained using NMDA antagonists may largely be the artifactual result of induction of hypothermia rather that due to direct inhibition of NMDA receptor-linked Ca entry into brain neurons [Buchan, A. et al.,
J. Neurosci.,
11 (1991) 1049-1056]. In contrast, the competitive non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (“NBQX”) is dramatically effective in preventing delayed neuronal degeneration following transient forebrain ischemia in both gerbils and rats [M. J. Sheardown et al.,
Science,
247:571-574 (1990)].
At present, there is a critical need for effective treatments which limit the exte

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