Cyclic amidines useful as NMDA NR2B antagonists

Details Cyclic amidines useful as NMDA NR2B antagonists Cyclic amidines useful as NMDA NR2B antagonists

2000-04-17

2002-04-23

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S454000, C548S471000

Reexamination Certificate

active

06376530

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to novel compounds and method of treating NMDA mediated diseases comprising administration to a patient in need of such treatment a non-toxic amount of these compounds effective to block the NMDA NR2B receptor sub-unit. In particluar, this invention relates to cyclic amidines useful as NMDA NR2B antagonists. The compounds of the instant invention are useful for the relief of neurological and neurodegenerative diseases, including pain, (and in particular neuropathic pain), epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, Alzheimer's Disease, Huntington's Disease and Parkinson's Disease.
The analgesic effects of NMDA receptor antagonists in man is well established. However, ion channel antagonists such as ketamine and dextromethorphan produce hallucinations, sedation, and ataxia at doses only marginally higher than the analgesic dose. The NR2B receptor is found presynaptically on most small sensory fibres entering the spinal dorsal horn as well as postsynaptically unlike other NMDA receptors which are exclusively postsynaptic. This restricted distribution lowers the probability of side effects and makes the target highly attractive for the treatment of neuropathic and other pain conditions.
NMDA Receptor Background
Glutamate plays a key role in processes related to chronic pain and pain-associated neurotoxicity, largely acting through N-methyl-D-aspartate (NMDA) receptors. Much evidence points to the involvement of NMDA receptors in the development and maintenance of neuropathic pain. NMDA receptor antagonists, for example ketamine, dextromethorphan and CPP (3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) have been reported to produce symptomatic relief in a number of neuropathies including postherpetic neuralgia, central pain caused by spinal cord injury and phantom limb pain (Kristensen et al., 1992; Eide et al., 1995; Knox et al., 1995; Max et al., 1995). However, at analgesic doses psychotomimetic effects that include dizziness, headache, hallucinations, dysphoria and disturbances of cognitive and motor function prohibit their widespread use. In order to exploit NMDA receptor antagonists as possible treatment of neuropathic pain it is necessary to develop new agents with a reduced side-effect profile.
Native NMDA receptors are heterodimers composed of an NMDA R1 (NR1) subunit and at least one NMDA R2 (NR2) subunit. Receptor cloning strategies have identified multiple NMDA receptor subunits in the CNS including the NR1 subfamily (with eight isoforms derived from alternative splicing of a single gene) and four NR2 subunits (A, B, C, and D) each encoded by a single gene (for review, see Whiting & Priestly, 1996). Functional receptors have different physiological and pharmacological properties and are differentially distributed in the mammalian CNS, demonstrating the functional heterogeneity of NMDA receptors (Ishii et al., 1993; Wenzel et al., 1995; Laurie et al., 1997).
NR1 is found throughout the brain whereas NR2 subunits show a differential distribution. In particular whereas NR2C is heavily expressed and NR2A is moderately expressed in the cerebellum, there is negligible expression of NR2B in this structure. Immunocytochemical studies have demonstrated a restricted distribution of the NR2B subunit, with moderate labeling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibres and possible involvement in pain transmission (Boyce et al., 1999). The patterns of staining observed in the spinal cord, together with the data showing negligible expression of NR2B in the cerebellum, suggest that NR2B antagonists may possess antinociceptive effects, but with a reduced side effect profile than non-competitive NMDA antagonists or glycine site antagonists.
The NR2B selective antagonist CP-101,606 has been reported to possess antinociceptive activity in animal assays of inflammatory hyperalgesia (Taniguchi et al., 1997; Sakurada et al, 1998). In an animal assay of inflammatory hyperalgesia (carrageenan-induced mechanical hyperalgesia) NR2B antagonists CP-101,606 and Ro 25-6981 possess antinociceptive activity with a significant separation between analgesic doses and those which induced motor impairment (Boyce et al., 1999). NR2B antagonists are active in a wide range of animal nociceptive assays, suggesting a clinical utility for other painful conditions in addition to those caused by nerve damage. Moreover these compounds may have a reduced propensity to elicit ataxic effects of ketamine and other NMDA ion channel antagonists.
There is a wealth of in vitro and animal model data which suggests that changes in the glutamatergic system (receptors, uptake, release) increase neuronal sensitivity to previous physiological stimuli and thereby trigger secondary neuronal damage. The primary pathology underlying the generation of symptoms in Parkinson's disease is degeneration of dopaminergic neurons of the nigrostriatal pathway (Hornykiewcz, 1966). Subsequent to loss of striatal dopamine, a series of changes in activity of the basal ganglia circuitry arise, including increased activity in striatal outputs to the lateral segment of the globus pallidus. Overactivity of the striatolateral pallidal pathway is thought to be responsible for the generation of parkinsonian symptoms. It has been demonstrated that selective blockade of NR2B-containing NMDA receptors with the polyamine antagonists ifenprodil and eliprodil cause a significant increase in locomoter activity in a rodent model (Nash et al., 1999) and ifenprodil has demonstrated activity in a primate model of Parkinson's disease (Mitchell et al., 1995).
LITERATURE
Boyce, S., Chan, C.-C., Gordon, R., Li, C.-S., Rodger, I. W., Webb, J. K., Rupniak, N. M. J., Hill, R. G., 1994. L-745,337: a selective inhibitor of cyclooxygenase-2 elicits antinociception but not gastric ulceration in rats. Neuropharmacology 33, 1609-1611.
Boyce, S., Wyatt, A., Webb, J. K., O'Donnell, R., Mason, G., Rigby, M., Sirinathsinghji, D., Hill, R. G., & Rupniak, N. M. J. 1999. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology 38: 611-623.
Eide, K., Stubhaug, H., Oye, I., Breivik, H., 1995. Continuous subcutaneous administration of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine in the treatment of postherpetic neuralgia. Pain 61: 221-228.
Grimwood, S., Gilbert, E., Ragan, C. I., Hutson, P. H., 1996a. Modulation of 45 Ca 2++ influx into cells stably expressing recombinant human NMDA receptors by ligands acting at distinct recognition sites. J. Neurochem. 66, 2589-2595.
Grimwood, S., Le Bourdelles, B., Atack, J. R., Barton, C., Cockett, W., Cook, S. M., Gilbert, E., Hutson, P. H., McKernan, R. M., Myers, J., Ragan, C. I., Wingrove, P. B., & Whiting, P. J. 1996b. Generation and characterisation of stable cell lines expressing recombinant human N-methyl-D-aspartate receptor subtypes. Journal of Neurochemistry 66:2239-2247.
Hornykiewcz, O. 1966. Dopamine and brain function. Pharmacol. Rev. 18:925-964.
Ishii, T., Moriyoshi, K., Sugihara, H., Sakurada, K., Kadotani, H., Yokoi, M., Akazawa, C., Shigemoto, R., Mizuno, N., Masu, M. et al., 1993. Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J. Biol. Chem., 268, 2836-2843.
Knox, D. J., McLeod, B. J., Goucke, C. R., 1995. Acute phantom limb pain controlled by ketamine. Anaesth. Intensive Care 23, 620-622.
Kristensen, J. D., Svensson, B., Gordh Jr., T., 1992. The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans. Pain, 51, 249-253.
Laurie, D. J., Bartke, I., Schoepfer, R., Naujoks, K., Seeburg, P. H., 1997. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res. Mol. Brain Res. 51, 23-32.
Max, M. B., Byas-Smith, M. G., Gracely, R. H., Bennett, G. J., 1995. Intravenous i

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