Recently, the elderly represent the most rapidly growing segment of society. This growth in the aged population has placed a substantial burden on health care and social support systems because of the increase in the incidence of chronic, degenerative illness such as senile dementia. Approximately 4 millions individuals over the age of 65 in the United States (or 15% of the population) has some degree of dementia, Two thirds of them(over 2.5 millions) are affected severely, remain home sitting and relying on family and community resources for their care. Approximately 55% of all case of dementia are known as Alzheimer's disease. The Alzheimer's disease patient gradually loses verbal communication skills, as evidenced by decreased ability to relate words to objects and impaired comprehension of their verbal output. Recent research efforts provide some information about the underlying pathophysiology of this illness of dementia. And of several causal theories, the major plausible hypothesis are based on the fact that differentiation, growth, and degeneration of neuron are closely related to hyper- and hypoactivity of neurotransmitters and nerve growth factor.
The amino acid L-glutamate is the most important fast excitatory neurotransmitter in neuronal circuits in the mammalian central nervous system(CNS). Almost all CNS neurons can be excited by L-glutamate, acting on a variety of different ligand-gated ion channel cell surface receptors.
These are classified into two main categories, those for which the synthetic glutamate analogue N-methyl-D-aspartate is a potent excitant (NMDA receptors) and those on which NMDA is not active (non-NMDA). It is known that NMDA receptors, widely distributed in brain and spinal cord, are cell surface protein complex that is involved in excitatory synaptic transmission and the regulation of neuronal growth.
An unusual feature of the NMDA is that it is in-operative when target cells are in a resting state, as under such conditions of negative intracellular membrane potential the ion channel associated with the NMDA receptor is fully blocked by Mg.sub.2+ ions. This block is voltage dependant, however, is removed if the target cell is partially depolarized by activation of non-NMDA receptors or other excitatory inputs. Thus, the NMDA receptor mechanism has a "conditional" feature, making it potentially an important "logic gate" in CNS circuits, especially relevant in processes of learning and memory.
The NMDA receptor has another unusual feature, as excessive activation of the receptor can lead to over-excitation of the target neurons to the point of cell death, probably caused by an excess accumulation of intracellular Ca.sup.2+. Much research has focused on the role of NMDA receptors in such "excitotoxic" cell death in recent years.
Direct treatment of glutamate in vitro to cultured neuronal cells results in rapid cellular swelling followed by delayed toxicity over the subsequent 24 hours. This excitotoxicity has been shown to be Ca.sup.2+ dependent. Following neuronal trauma a large Ca.sup.2+ influx into the neuron through gated ion channel, such as glutamate receptors, initiates a cascade of biochemical events that disrupt normal cellular processes and can feedback to accelerate the release of glutamate and excitotoxicity. Among these events are activation of proteases and lipases, breakdown of neuronal membranes and formation of free radical, and ultimately, cell death [J. W. Mcdold, M. V. Johnson, Brain Res, Reviews 15, 41 (1990)]. A great deal of evidence has been accumulated that it plays a key role in neurodegeneration and stroke related brain cell death.
Thus, NMDA antagonists are proposed to have a number of clinical indications including ischemia and epilepsy. They may also be useful in the prevention of chronic neurodegenerative disorders such as Alzheimer's disease, Huntington's disease and Parkinsonism [G.Johnson, Annu. Rep. Med. Chem. 24, 41 (1989); G. Johnson and C. F. Bigge, ibid. 26, 11 (1991); and Werling et al., J. Pharmacol. Exp. Ther. 255, 40(1990)]. It is also believed to be central to the concept of long term potentiation (LTP), which is the persistent strengthening of neuronal connections that underlie learning and memory.
Recent report suggested that the specific glycine site ligands, 1-aminocyclopropanecarboxylic acid methyl ester, D-cycloserine and R-(+)-3-amino-1-hydroxy-pyrrolidin-2-one(HA-966) have, respectively, been proposed to be useful for promoting memory and learning in cognitive and psychiatric disorders [Bliss, T. V. P, Collingride, G. L., Nature 345, 347(1990); GB 2231048A (1990)].
NMDA receptor antagonists have also been shown to possess analgesic, antidepressant antischizophrenic and anxiolytic effects as indicated in recent reports [Dickenson, A. H. and Aydar, E., Neuroscience Lett. 121, 263(1990); R. Trullas and P. Skolnick, Eur. J. Pharmacol. 185, 1(1990); J. H. Kehne, et al., Eur. J. Pharmacol. 193, 283 (1991) and P. H. Hutson, et al., Br. J. Pharmacol. 103, 2037(1991)].
The crucial role of NMDA receptor in synaptic plasticity has been emphasized by recent developments in the understanding of the physiological functions and structural details of the subunits on the receptor. The NMDA receptor comprises a ligand gated ion channel which is subject to complex allosteric modulation at several different sites. Currently there are at least five pharmacologically distinct sites through which compounds can alter the activity of this receptor [Kumar K. N., et al., Nature 354, 70-73(1991); Nakanishi, S., et al., Nature 354, 31-37(1991); Monyer, H., et al., Science 256, 1217-1221(1992)]. They include (a) a transmitter binding site, which binds L-glutamate; (b) an allosteric modulator site, which binds glycine; (c) a site within the channel that binds phencyclidine and related compounds; (d) Mg.sup.2+ bing site; and (e) an inhibitory divalent cation site Zn.sup.2+ [Lynch, D. R., et al., Mol. pharmacol. 45, 540-545 (1994); Kuryatov, A., et al., Neuron 12, 1291-1300 (1994); Nakanishi, S., Science 256, 1217-1221 (1992)].
The NMDA receptor is activated by co-agonists glutamate and glycine. The associated Ca.sup.2+ permeable channel is blocked physiologically by Mg.sup.2+ in voltage dependent manner, and Zn.sup.2+, which may have its own regulatory site, also decreases synaptic activity of the NMDA receptor [Lynch, D. R., et al., Mol. pharmacol. 45, 540-545(1994); Kuryatov, A. et al., Neuron 12, 1291-1300 (1994); Nakanishi, S., Science 256, 1217-1221(1992)].
Under the above circumstances, the pharmacological interest has so far been focused primarily on the NMDA receptor, and a number of potent and selective agonists and antagonists dependent on each distinct binding sites have been found as candidates for therapeutically useful agents during the last two decades. Of them, the most promising approach for regulating the NMDA receptor activity has involved in development of allosteric modulators of glycine binding site.
The stimulatory action of glycine on the NMDA receptor was studied by Johnson and Ascher who showed that the magnitude of the electrophysiological response of cultured neurons to applied NMDA is greatly reduced or absent if glycine is rigorously excluded from the external medium. Thus, the glycine site on the NMDA receptor was discovered in 1987 by them. The glycine site on the NMDA receptor is clearly distinguishable from the previously described glycine receptor, a glycine- gated chloride ion channel which is important in inhibitory synaptic transmission in spinal cord and brainstem. The latter receptor is blocked by low concentrations of the convulsant alkaloid strychinine, whereas the glycine/NMDA site is strychinine-insensitive.
Since the discovery of glycine site, there has been a rapid development of potent pharmacological agents that interact selectively with this site. A kinetic studies was suggested that the glycine- and glutamate-recognition sites exists in the same protein, and there is a negative allosteric coupling between the glycine- and glutamate-recognition sites and the binding of an agonist at glutamate-recognition site reduces the affinity of glycine for its recognition site. Similar studies also indicate that antagonist binding at glutamate recognition site is enhanced by some, but not all, glycine site antagonists and vice versa [Beneveniste, M., et al. J. Physiol. 428, 333 (1990); Leser, R. A.; Tong, G. and Jahr, C. E., J. Neurosci. 13, 1088 (1993); Clements, J. D.; Westbrook, G. L., Neuron. 7, 605 (1991)].
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 al., J. Neurochern. 57, 470-478 (1991)].
Thus theoretically, glycine antagonists should be able to diminish excessive excitation known to exist during glutamate excitotoxicity and should be very powerful neuroprotective agents, because they can prevent the opening of NMDA channels by glutamate non-competitively and therefore do not have to overcome the large concentrations of endogenous glutamate that are released in the ischemic brain region unlike competitive NMDA antagonists, i.e. modulation of the glycine site antagonists may result rather than complete inhibition of receptor function. This modulatory action might be more physiological than receptor blockage (compare with channel blockers), and thus glycine antagonists should have less propensity for side effects. That glycine antagonists may indeed be devoid of PCP-like behavioral side effects has been suggested by recent studies in which available glycine antagonists were injected directly into the brains of rodents without resulting in PCP-like behaviors [Tricklebank, M. D., et al., Eur. J. Pharmacol. 167, 127 (1989); Koek, W., et al., J. Pharmacol. Exp. Ther. 245, 969 (1989); Willets and Balster, Neuropharmacology 27, 1249 (1988)].
Such possible advantageous pharmaceutical profile of glycine site antagonists including a larger window between the desired and untoward effects of NMDA receptor blockade than other types of NMDA antagonists as well as the structural advantages of its ligands for BBB penetration makes it an attractive target for potential therapeutically useful new CNS acting drug particularly in treatment of neurological disorders.
Recent successes in identifying orally glycine receptor antagonists were reported several classes of 4-hydroxyquinolin-2(1H)-one derivatives as selective noncompetitive antagonists of NMDA receptors possessing potent in vivo activity [McOuaid, L. A., et al., J. Med. Chem. 35, 3423 (1992); Leeson, P. D. , et al. J. Med. Chem. 36, 3386 (1993); Kulagowski, J. J., et al., J. Med. Chem. 37, 1402 (1994); Cai, S. X., et al., J. Med. Chem. 39, 4682 (1996), and 39, 3248 (1996); EP 489,458; EP 459,561; EP 685,466 A1; WO 94/20470; WO 93/10783; EP 685,466 A1; and EP 481,676 A1]. Those have been appeared in literatures and are generally declaimed as therapeutically useful agents to prevent or treat neurodegenerative disorders, convulsion and schizophrenia.
Glycine-site antagonists have emerged on drugs acting on CNS because they have offered wide therapeutic window between the desired neuroprotective effects and adverse events such as behavioral stimulation that have been observed with competitive glutamate antagonists or channel blockers.
The followings are glycine-site antagonists which have been already developed.
2-Carboxyindole acrylamide developed by Glaxo Well-come; ##STR2##
Quinoxaline-2,3-dione developed by Ciba-Geigy; ##STR3##
Tricyclic quinoxalinedione developed by Ciba-Geigy; ##STR4##
Pyridazino quinolinedione developed by Zeneca; ##STR5##
Heterocyclic compound developed by Pfizer, ##STR6##
Heterocyclic compound developed by Ciba-Geigy; ##STR7##
Various compounds including above examples have been developed, but the compound, which has good CNS penetration and high solubility, has not been developed as glycine-site NMDA receptor antagonist having a large affinity for the receptor.
We have now found a novel class of quinolinic sulfide derivatives which are potent and specific antagonists at the strychnine insensitive glycine binding site on the NMDA receptor complex with an pharmacological advantageous profile. They may be useful in treatment or prevention of neurodegenerative disorders. Particularly, the compounds included in the present invention are especially useful for minimizing damage of the central nervous system arising as a consequence of ischemic or hypoxic condition such as stroke, hypoglycemia, cerebral ischemia, cardiac arrest, and physical trauma. They are also useful in prevention of chronic neurodegenerative disorders including epilepsy, Alzheimer's disease, Huntington's disease and Parkinsonism. By virtue of their NMDA receptor antagonist properties, the present compounds may also use as anticonvulsant, analgesic, antidepressant, anxiolytic, and antischizophrenic agent.