Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-12
2004-03-09
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S231000, C544S234000, C544S237000
Reexamination Certificate
active
06703390
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to sulfur containing dihydrophthalazine compounds useful as antagonists of excitatory amino acid receptors.
During the past twenty-five years a great deal of attention has been directed toward the excitatory amino acids (EAA's), glutamate and aspartate, since they are believed to be the neurotransmitters responsible for the fast excitatory transmission in the mammalian central nervous system. The ionotropic EAA receptors are generally sub-classified into NMDA and non-NMDA receptors. These classifications are defined by those receptors which preferentially bind N-methyl-D-aspartate (NMDA) and those that are not responsive to NMDA but responsive to &agr;-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) or kainic acid (KA).
Tarnawa et al, describe 2,3-benzodiazepines (
Eur. J. Pharmacol
., 167:193-199, 1989) which inhibit AMPA stimulated currents in neuronal cells. The 2,3-benzodiazepines such as GYKI 52466 and 53655 described by Tarnawa are non-competitive AMPA antagonists which bind to a novel modulatory site on the AMPA receptor. Meldrum (
Stroke
, 23:861, 1992 &
Brain Res
., 571:115, 1992) has shown that GYKI 52466 is effective in rat models of both global and focal ischemia. GYKI 52466 was effective in a middle cerebral artery occlusion (MCAO) model of ischemia when given either continuously for 2 hours just after occlusion or delayed for one hour. The compounds reduced cortical infarct volumes by 68% and 48% respectively. In another model of neurodegenerative disease, GYKI 52466 was as effective as the glutamate site competitive antagonist NBQX in rat common carotid arteries model of global ischemia.
These two animal models suggest that these compounds may be useful for the treatment of stroke and neurodegenerative ischemic conditions.
Efforts to find NMDA receptor antagonists and blockers which are neuroprotective have been very successful while efforts to find specific non-NMDA receptor antagonists have been much less successful. A number of pharmaceutical companies have pursued development of ion channel blockers or full antagonists of the NMDA receptor to protect against both chronic and acute neurodegenerative processes. Although some compounds have entered clinical trials, there has been only limited progress in developing a clinically useful NMDA receptor antagonist. Some useful compounds, namely substituted dihydrophthalazines, have been described for use as non-NMDA receptor antagonists (U.S. Pat. No. 5,716,956). These compounds are particularly useful because they bind to KA and/or AMPA receptors directly.
It is an object of the invention to provide compounds which are useful as non-NMDA glutamate receptor antagonists as well as methods for their synthesis.
It is a further object of the invention to provide non-NMDA receptor antagonists which are useful as sedatives or for the treatment of neuropsychopharmacological disorders such as stroke, ischemia and epilepsy.
It is yet another object of the invention to provide compounds which are useful for the treatment of neurological, neuropsychiatric, neurogenerative and functional disorders associated with excessive activation of the non-NMDA subtypes of the ionotropic EAA receptor.
BRIEF SUMMARY OF THE INVENTION
Compositions are provided which are active as non-NMDA ionotropic excitatory amino acid (EAA) receptor antagonists, in particular, which bind to the KA and/or AMPA receptors, and which therefore are useful for treating disorders associated with excessive activation of the non-NMDA subtypes of the ionotropic EAA receptors. The compounds further are useful as testing agents to identify and characterize other compounds for the treatment of these disorders.
Illustrative compounds include:
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-ethylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-n-propylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-n-butylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-ethylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-n-propylcarbamoyl-6-methylthiophthalazine,
4-(4-Aminophenyl)-1,2-dihydro-2-n-butylcarbamoyl-6-methylthiophthalazine.
The compositions may be provided in combination with a suitable carrier for oral or parenteral administration. The compounds may be administered orally or parenterally for the treatment of a variety of disorders associated with non-NMDA glutamate receptor function. The compositions may be used, for example, as sedatives or for the treatment of neuropsychopharmacological disorders such as stroke, ischemia and epilepsy.
REFERENCES:
patent: 5716956 (1998-02-01), Pelletier
patent: 6048853 (2000-04-01), Collins et al.
patent: 6329370 (2001-12-01), Napoletano et al.
patent: 196 17 863 (1997-10-01), None
patent: WO 96/40646 (1996-12-01), None
Chen, et al., “Evaluation of five methods for testing anticonvulsant activities,”Proc. Soc. Exp. Biol. Med.87:334-339 (1954).
Hussy, et al., “Functional properties of a cloned 5-hydroxytryptamine ionotropic receptor subunit: comparison with native mouse receptors,”J. Physiol.(Lond.) 481.2:311-323 (1994).
Le Peillett, et al., “The non-NDMA antagonists, NBQX and GYKI 52466, protect against cortical and striatal cell loss following transient global ischaemia in the rat,”Brain Research571:115-120 (1992).
Lipton & Rosenberg, “Excitatory amino acids as a final common pathway for neurologic disorders,”New England Journal of Medicine330:613-622 (1994).
Mcburney, “Therapeutic potential of NMDA antagoinsts in neurodegenerative diseases,”Neurobiology of Aging15:271-273 (1994).
Meldrum, “Excitatory amino acids in epilepsy and potential novel therapies,”Epilepsy Research12:189-196 (1992).
Remington's Pharmaceutical Sciences17th Edition, p. 1418 (1985).
Smith & Meldrum, “Cerebroprotective Effect of a non-N-methyl-D-aspartate antagonist, GYKI 52466, after focal ischemia in the rat,”Stroke23:861-864 (1992).
Tarnawa, et al., “Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466,”Eur. J. Pharmacol.167:193-199 (1989).
Yamaguchi, et al., “Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models,”Epilepsy Research15:179-184 (1993).
Li Baoqing
Maccecchini Maria-Luisa
Pei Xue-Feng
Bernhardt Emily
Johnson Keith A.
Transgenomic Inc.
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