Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-06
2004-11-23
Henley, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S319000, C514S320000, C514S327000
Reexamination Certificate
active
06821985
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods of treating traumatic brain injury (TBI) or ischemic or hypoxic stroke, comprising administering to a patient in need of such treatment an NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist in combination with one or more other compounds that protect neurons from toxic insult, inhibit the inflammatory reaction after brain damage or promote cerebral reperfusion.
More specifically, this invention relates to methods of treating traumatic brain injury (TBI) or hypoxic or ischemic stroke, comprising administering to a patient in need of such treatment an NR2B subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist in combination with either: (a) a sodium channel antagonist; (b) a nitric oxide synthase (NOS) inhibitor; (c) a glycine site antagonist; (d) a potassium channel opener; (e) an AMPA/kainate receptor antagonist; (f) a calcium channel antagonist; (g) a GABA-A receptor modulator (e.g., a GABA-A receptor agonist); (h) an antiinflammatory agent; or (i) a matrix metalloprotease (MMP) inhibitor.
This invention also relates to methods of treating hypoxic or ischemic stroke comprising administering to a patient in need of such treatment an NR2B subtype selective NMDA receptor antagonist in combination with a thrombolytic agent.
Brain and spinal cord injury caused by stroke, trauma or hypoxia often result in lifelong disability and premature death. The cause of disability and death is the disruption of function and frank death of neurons and other cells in the central nervous system. Therefore, a clear benefit is anticipated from therapies that reduce or prevent neuronal dysfunction and death after ischemic, hypoxic or traumatic CNS insult.
One of the causes of neuronal dysfunction and death after CNS insult is toxicity caused by a prolonged elevation of glutamate and other excitatory amino acids (EAAs) and overactivation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Glutamate and other EAAs play dual roles in the central nervous system as essential amino acids and the principal excitatory neurotransmitters. There are at least four classes of EAA receptors, specifically NMDA, AM PA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid), kainate and metabotropic. These EAA receptors mediate a wide range of signaling events that impact all physiological brain functions. As neurotransmitters, EAAs are released from postsynaptic nerve terminals and then are rapidly resequestered by a variety of cellular reuptake mechanisms. Consequently, the physiological levels of EAAs in the brain parenchyma are maintained at a low level. However, after a CNS insult, the levels of EAAs in the parenchyma increase dramatically and may remain elevated for periods of hours to days. This results in pathological overactivation of EAA receptors and neuronal dysfunction and death.
Several lines of evidence suggest that the NMDA subtype of glutamate receptor is the principal mediator of the EAA-induced toxicity described above. Neurons in primary culture are exquisitely sensitive to the toxic effects of NMDA receptor activation and NMDA receptor antagonists protect cultured neurons from both NMDA and glutamate toxicity (Choi et al.,
J. Neurosci.,
1988, 8, 185-196; Rosenberg et al., 1989,
Neurosci. Lett.
103, 162). NMDA receptors are also implicated as mediators of neurotoxicity in vivo since NMDA receptor antagonists can reduce neuron loss in animal models of focal ischemia (McCulloch,
J. Neural. Trans.,
1994, 71-79) and head trauma (Bullock et al., Acta
Neurochir.,
1992, 55, 49-55). The neuroprotective effect of NMDA receptor inhibition is realized with several different classes of compounds that target different sites on the NMDA receptor-channel complex. These include competitive antagonists at the glutamate binding site such as (R,E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (d-CPPene) (Lowe et al., 1994,
Neurochem Int.
25, 583) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19,755) (Murphy et al., 1988,
Br. J. Pharmacol.
95, 932) and competitive antagonists at the glycine co-agonist (Johnson et al.,
Nature,
1987, 327, 529-531; and Kemp et al.,
Trends Pharmacol. Sci.,
1993, 14, 20-25) binding site such as 5,7-dichloro-4S-(3-phenyl-ureido)-1,2,3,4-tetrahydro-quinoline-2R-carboxylic acid (L-689,560) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021) (Leeson et al., 1994,
J. Med. Chem.
37, 4053). Compounds have also been identified which block the NMDA receptor-gated ion channel, including phencyclidine (PCP), (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cycloheptan-5,10-imine (MK-801) (Kemp et al., 1987,
Trends in Neurosci.
10, 294), and C-(1-napthyl-N′-(3-ethyl phenyl)-N′-methyl guanidine hydrochloride (CNS-1102) (Reddy et al., 1994,
J. Med. Chem.
37, 260).
The neuroprotective effect of NMDA receptor antagonists in experimental systems has prompted considerable interest in the therapeutic potential of this type of compound. Several prototype antagonists have been progressed into clinical trials, especially for stroke and head trauma (Muir et al., 1995,
Stroke
26, 503-513). However, side effects at therapeutic drug levels have been a significant problem that has hindered the development process (Muir et al., supra). In particular, both glutamate competitive antagonists and channel blocking agents cause cardiovascular effects and psychotic symptoms in man. Although the physiological basis for these side effects are not yet understood, in rodents these types of compounds also cause locomotor hyperactivity and a paradoxical neuronal hyperexcitability manifest as neuronal vacuolization in cingulate and retrosplenial cortices (Olney et al., 1991,
Science,
254, 1515-1518). Antagonists at the glycine coagonist site cause less locomotor activation and do not cause neuronal vacuolization at neuroprotective doses in rodents, suggesting that this class of antagonists may be better tolerated in man (Kemp et al., 1993,
Trends Pharmacol. Sci.
14, 20-25). Unfortunately, physicochemical problems associated with the quinoxalinedione nucleus (solubility, brain penetration, protein binding) have hindered efforts to bring this class forward in the clinic.
The compound (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol) (hereinafter referred to as “Compound A”) represents a fourth mechanistic class of NMDA receptor antagonist. This class is unique in that it is specific for a subtype of NMDA receptor, those containing the NR2B subunit that is expressed in the forebrain. As with other ligand gated ion channels, the functional NMDA receptor is composed of multiple protein subunits. Five subunits have been cloned to date, NR1 (of which there are eight splice variants) and NR2A-D. Expression studies indicate a composition of at least one NR1 subunit and one or more of the NR2 subunits (Monyer et al.,
Science,
1992, 256, 1217-1221; Kutsuwada et al., 1992,
Nature
358, 36; and Chazot et al., 1994,
J. Biol. Chem.
269, 24403). In situ hybridization and immunohistochemistry studies indicate that subunits are widely and differentially distributed throughout the brain (Monyer et al,
Neuron,
1994, 12, 529-540; Kutsuwada et al., supra; Ishii et al., 1993,
J. Biol Chem.
268, 2836; Wenzel et al., 1995,
NeuroReport
7, 45).
Compound A and other structurally related compounds have been found to be functionally selective for NMDA receptors containing the NR2B subunit. The fact that this class of NMDA receptor antagonist is neuroprotective in a variety of in vitro and in vivo experimental models (Di et al., 1997,
Stroke
28, 2244-2251; Okiyama et al., 1998,
Brain Res.
792, 291-298; Okiyama et al., 1997,
J. Neurotrauma
14, 211-222; Tsuchida et al., 1997,
Neurotrama
14, 409-417) suggests that NR2B subunit containing NMDA receptors are prominently involved in the EAA-induced toxic cascade. Furthermore, antagonists selective for NR2B subunit containing NMDA receptors have been found to produce less tox
Chenard Bertrand L.
Menniti Frank S.
Saltarelli Mario D.
Dorigo Andrea F.
Henley III Raymond J.
Pfizer Inc.
Richardson Peter C.
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