Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-10-16
2003-03-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S661000, C544S330000, C544S332000, C544S362000, C546S208000, C546S276400, C546S279100, C548S530000, C548S540000
Reexamination Certificate
active
06531511
ABSTRACT:
The present application is a national stage application of PCT Application No. PCT/GB00/00207, filed Jan. 26, 2000, which claims the benefit of United Kingdom Application No. GB 990691.7, filed Jan. 26, 1999.
BACKGROUND OF THE INVENTION
The present invention relates to compounds and compositions for use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission.
The excitatory neurotransmission underlying brain function is primarily (about 80 per cent) dependent on the action of glutamate and other related neurotransmitters on specific receptors activated by the excitatory amino acids. These receptors fall into several categories, one of which is the glutamate receptor specifically sensitive to the agonist N-methyl-D-aspartate (the NMDA receptor). NMDA receptor subtypes are ubiquitously expressed in mammalian brain and have unique properties underlying their role in synaptic function and plasticity. In view of the central role of these receptors in normal central nervous system function, numerous suggestions have been made as to the utility of drugs acting at this receptor to modulate the processes underlying various disease states. The NMDA receptor has been studied with particular interest in relation to its apparent involvement in the pathophysiology of neurodegenerative diseases.
Non-competitive antagonists at this receptor should be particularly advantageous in the treatment of diseases since such compounds would have activity that should not be overcome by high levels of endogenous agonists and would act equally well independent of the endogenous agonist activating the receptor. This is important since high levels of endogenous glutamate can occur in certain pathological processes and there are a variety of different endogenous agonists that can act through a variety of specific modulatory agonist binding sites on the receptor.
A number of NMDA antagonists have been disclosed which operate by binding to the ion-channel of the NMDA receptor. The advantage of channel blockers is that they operate only on the “open” channel and therefore do not affect unactivated receptors. In addition they are effective regardless of the mechanism of receptor stimulation and their effect will not be diminished by large concentrations of endogenous agonist.
Given that the NMDA receptor plays a primary role in normal central nervous system function, it is not surprising that certain drugs acting to block or antagonise the function of this receptor affect normal function within the brain. This may be manifested as central nervous system side effects such as hallucinations, confusion, paranoia, aggression, agitation and catatonia. These side effects can be described as a psychotic state and the drugs that induce them are known as psychotomimetic NMDA antagonists. Such side effects limit the utility of these compounds in treating disease states. NMDA receptor antagonists that have efficacy in treating central nervous system disorders but without such psychotomimetic side effects would have a clear therapeutic advantage. Thus, in view of the crucial role played by the NMDA receptor in either the progression or expression of the disease pathology and process, it is an object of this invention to provide compounds for the treatment of central nervous system disorders which modulate the activity of the NMDA receptor but which are well-tolerated in the sense of having a markedly reduced propensity to induce psychotomimetic side effects.
The present invention is particularly concerned with the treatment of neurodegenerative disorders. There is a large body of evidence to suggest that either an excitotoxic or slow excitotoxic pathological over-activation of the NMDA receptor induces the death of neurons in a variety of disorders such as ischaemic stroke, other forms of hypoxic injury, haemorrhagic brain injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and other dementing diseases. There is thus clear evidence that antagonism of the NMDA receptor will reduce or prevent the neurodegeneration that underlies the disease process in these and related conditions. There is also evidence to suggest that a well-tolerated compound will allow effective symptomatic treatment of the manifestations of the disease process in these disorders as well as reducing the primary underlying neurodegeneration process. Also, it is known that disorders previously described as involving acute neurodegeneration have longer than expected elevations in glutamate release and consequently require longer than expected treatment with NMDA antagonists. There would therefore be a therapeutic advantage for new drugs which are well-tolerated and which can therefore be administered chronically.
The published literature contains references to a number of compounds and classes of compounds purported to be useful as NMDA antagonists.
The compounds Amantadine and Memantine and related anti-viral agents have been known for many years.
Patent applications have been filed directed to the use of Memantine in the treatment of Parkinson's Disease in the 1970s and as an NMDA antagonist in 1990 (see EP-A-0392059 and U.S. Pat. No. 5,061,703). Furthermore, International Patent application WO94/05275 proposes the use of Amantadine and related compounds such as Memantine in the treatment and prevention of non-ischaemic, long term NMDA receptor-mediated neuronal degeneration. An increase in affinity for the NMDA receptor due to substitution of the adamantane ring of Amantadine with alkyl groups was noted and published by Komhuber et al. (Eur. J. Pharmacol., 1991, 206, 297-300). Structure-activity relationships relating to 1-(adamantyl)alkanamines are reported by Kroemer et al. (J. Med. Chem.,1998, 41, 393-400), by Parsons et al. (Neuropharmacology, 1995, 34, 1239-1258) and by Fytas et al. (Il Farmaco,1994, 49, 641-647).
As discussed above, psychotomimetic side-effects are observed during the use of a number of well known NMDA channel blockers and therefore it will be a considerable advantage to identify clinically well-tolerated antagonists where such side effects are minimised. Porter and Greenamyre (J. Neurochem. 1995, 64, 614-623; incorporated herein by reference) demonstrated that well-tolerated and psychotomimetic NMDA receptor channel blockers could be differentiated on the basis of their relative affinities for forebrain and cerebellar receptors irrespective of absolute affinities. Selectivity for cerebellar NMDA receptors over forebrain NMDA receptors is observed for well-tolerated compounds. The basis of this observation may be related to different populations of NMDA receptor subtypes in these brain regions.
The use of a number of the known NMDA antagonists such as Dizocilpine, PCP, Cerestat and Ketamine gives rise to a number of side effects which render these compounds unsuitable for use in treatment. In particular, administration of the compounds is associated with perceptual and cognitive disturbances of a kind that resemble naturally-occurring psychotic states.
In addition, the perceptual and cognitive side effects of the compounds become more pronounced after the onset of puberty and sexual maturation, and these compounds are therefore particularly unsuitable for the treatment of adults. This developmental change has been demonstrated empirically in both experimental animals and in man, and is paralleled in experimental animals by brain hypermetabolism.
In summary, there is a need for an NMDA antagonist which is well-tolerated and does not give rise to the side effects associated with previous clinically investigated NMDA antagonists.
SUMMARY OF THE INVENTION
A number of compounds have now been found that show affinity for the NMDA receptor and are useful in the treatment of conditions generally associated with abnormalities in glutamatergic transmission such as stroke, traumatic brain injury and neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. It has also been found that the compounds have a surpris
Bird Andrew James
Gillespie Roger John
Monck Nathaniel Julius Thomas
Ward Simon Edward
Foley & Lardner
Jones Dwayne C.
Vernalis Research Limited
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