Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-13
2001-06-26
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06251903
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of medicinal chemistry and relates to compounds that have a high affinity for the glycine binding site, lack PCP side effects, and cross the blood brain barrier at high levels. In particular, the present invention relates to novel alkyl, azido, alkoxy, fluoro-substituted, and fused 1,4-dihydroquinoxaline-2,3-diones and their use to treat or prevent neuronal degeneration associated with ischemia, pathophysiologic conditions associated with neuronal degeneration, convulsions, anxiety, chronic pain, and to induce anesthesia.
2. Description of the Related Art
Glutamate is thought to be the major excitatory neurotransmitter in the brain. There are three major subtypes of glutamate receptors in the CNS.
These are commonly referred to as kainate, AMPA, and N-methyl-D-aspartate (NMDA) receptors (Watkins and Olverman,
Trends in Neurosci.
7:265-272 (1987)). NMDA receptors are found in the membranes of virtually every neuron in the brain. NMDA receptors are ligand-gated cation channels that allow Na
+
, K
+
, and Ca
++
to permeate when they are activated by glutamate or aspartate (non-selective, endogenous agonists) or by NMDA (a selective, synthetic agonist) (Wong and Kemp,
Ann. Rev. Pharmacol. Toxicol.
31:401-425 (1991)).
Glutamate alone cannot activate the NMDA receptor. In order to become activated by glutamate, the NMDA receptor channel must first bind glycine at a specific, high affinity, glycine binding site that is separate from the glutamate/NMDA binding site on the receptor protein (Johnson and Ascher,
Nature
325:329-331 (1987)). Glycine is therefore an obligatory co-agonist at the NMDA receptor/channel complex (Kemp, J. A., et al.,
Proc. Natl. Acad. Sci. USA
85:6547-6550 (1988)).
In addition to the binding sites for glutamate/NMDA and glycine, the NMDA receptor carries a number of other functionally important binding sites. These include binding sites for Mg
++
, Zn
++
, polyamines, arachidonic acid, and phencyclidine (PCP) (Reynolds and Miller,
Adv. in Pharmacol.
21:101-126 (1990); Miller, B., et al.,
Nature
355:722-725 (1992)). The PCP binding site—now commonly referred to as the PCP receptor—is located inside the pore of the ionophore of the NMDA receptor/channel complex (Wong, E. H. F., et al.,
Proc. Natl. Acad. Sci. USA
83:7104-7108 (1986); Huettner and Bean,
Proc. Natl. Acad. Sci. USA
85:1307-1311 (1988); MacDonald, J. F., et al.,
Neurophysiol.
58:251-266 (1987)). In order for PCP to gain access to the PCP receptor, the channel must first be opened by glutamate and glycine. In the absence of glutamate and glycine, PCP cannot bind to the PCP receptor although some studies have suggested that a small amount of PCP binding can occur even in the absence of glutamate and glycine (Sircar and Zukin,
Brain Res.
556:280-284 (1991)). Once PCP binds to the PCP receptor, it blocks ion flux through the open channel. Therefore, PCP is an open channel blocker and a non-competitive glutamate antagonist at the NMDA receptor/channel complex.
One of the most potent and selective drugs that bind to the PCP receptor is the anticonvulant drug MK801. This drug has a K
d
of approximately 3 nM at the PCP receptor (Wong, E. H. F., et al.,
Proc. Natl. Acad. Sci. USA
83:7104-7108 (1986)).
Both PCP and MK801 as well as other PCP receptor ligands, e.g., If dextromethorphan, ketamine, and N,N′-disubstituted guanidines, have neuroprotective efficacy both in vitro and in vivo (Gill, R., et al.,
J. Neurosci.
7:3343-3349 (1987); Keana, J. F. W., et al.,
Proc. Natl. Acad. Sci. USA
86:5631-5635 (1989); Steinberg, G. K., et al.,
Neuroscience Lett.
89: 193-197 (1988); Church, J., et al., In:
Sigma and Phencyclidine
-
Like Compounds as Molecular Probes in Biology
, Domino and Kamenka, eds., Ann Arbor: NPP Books, pp. 747-756 (1988)). The well-characterized neuroprotective efficacy of these drugs is largely due to their capacity to block excessive Ca
++
influx into neurons through NMDA receptor channels, which become over activated by excessive glutamate release in conditions of brain ischemia (e.g. in stroke, cardiac arrest ischemia etc.) (Collins, R. C.,
Metabol. Br. Dis.
1:231-240 (1986); Collins, R. C., et al.,
Annals Int. Med.
110:992-1000 (1989)).
However, the therapeutic potential of these PCP receptor drugs as ischemia rescue agents in stroke has been severely hampered by the fact that these drugs have strong PCP-like behavioral side effects (psychotomimetic behavioral effects) which appear to be due to the interaction of these drugs with the PCP receptor (Tricklebank, M. D., et al.,
Eur. J. Pharmacol.
167:127-135 (1989); Koek, W., et al.,
J. Pharmacol. Exp. Ther.
245:969 (1989); Willets and Balster,
Neuropharmacology
27:1249 (1988)). These PCP-like behavioral side effects appear to have caused the withdrawal of MK801 from clinical development as an ischemia rescue agent. Furthermore, these PCP receptor ligands appear to have considerable abuse potential as demonstrated by the abuse liability of PCP itself.
The PCP-like behavioral effects of the PCP receptor ligands can be demonstrated in animal models: PCP and related PCP receptor ligands cause a behavioral excitation (hyperlocomotion) in rodents (Tricklebank, M. D., et al.,
Eur. J. Pharmacol.
167:127-135 (1989)) and a characteristic catalepsy in pigeons (Koek, W., et al.,
J. Pharmacol. Exp. Ther.
245:969 (1989); Willets and Balster,
Neuropharmacology
27:1249 (1988)); in drug discrimination paradigms, there is a strong correlation between the PCP receptor affinity of these drugs and their potency to induce a PCP-appropriate response behavior (Zukin, S. R., et al.,
Brain Res.
294:174 (1984); Brady, K. T., et al.,
Science
215:178 (1982); Tricklebank, M. D., et al.,
Eur. J. Pharmacol.
141:497 (1987)).
Drugs acting as competitive antagonists at the glutamate binding site of the NMDA receptor, such as, CGS 19755 and LY274614, also have neuroprotective efficacy because these drugs—like the PCP receptor ligands—can prevent excessive Ca
++
flux through NMDA receptor/channels in ischemia (Boast, C. A., et al.,
Brain Res.
442:345-348 (1988); Schoepp, D. D., et al.,
J. Neural. Trans.
85:131-143 (1991)). However, competitive NMDA receptor antagonists also have PCP-like behavioral side-effects in animal models (behavioral excitation, activity in PCP drug discrimination tests) although not as potently as MK801 and PCP (Tricklebank, M. D., et al.,
Eur. J. Pharmacol.
167:127-135 (1989)).
An alternate way of inhibiting NMDA receptor channel activation is by using antagonists at the glycine binding site of the NMDA receptor. Since glycine must bind to the glycine site in order for glutamate to effect channel opening (Johnson and Ascher,
Nature
325:329-331 (1987); Kemp, J. A., et al.,
Proc. Natl. Acad. Sci. USA
85:6547-6550 (1988)), a glycine antagonist can completely prevent ion flux through the NMDA receptor channel—even in the presence of a large amount of glutamate.
Recent in vivo microdialysis studies have demonstrated that, in the rat focal ischemia model, there is a large increase in glutamate release in the ischemic brain region with no significant increase in glycine release (Globus, M. Y. T., et at.,
J. Neurochemn.
57:470-478 (1991)). Thus, theoretically, glycine antagonists should be very powerful neuroprotective agents because they can prevent the opening of NMDA channels by glutamate non-competitively and, therefore, unlike competitive NMDA antagonists, do not have to overcome the large concentrations of endogenous glutamate that are released in the ischemic brain region.
Furthermore, because glycine antagonists act at neither the glutamate/NMDA nor the PCP binding sites to prevent NMDA channel opening, these drugs might not cause the PCP-like behavioral side effect seen with both PCP receptor ligands and competitive NMDA receptor antagonists (Tricklebank, M. D., et al.,
Eur. J. Pharmcol.
167:127-135 (1989); Koek, W., et al.,
J. Pharm
Cai Sui Xiong
Keana John F. W.
Kher Sunil
Weber Eckard
Cocensys Inc.
Lambkin Deborah C.
Sterne Kessler Goldstein & Fox P.L.L.C.
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