Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-12
1998-07-21
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142348, 514249, 540599, 544116, 544354, A61K 3155, A61K 31495, C07D40306
Patent
active
057835721
DESCRIPTION:
BRIEF SUMMARY
This invention relates to derivatives of 1,4-diydroqainoxalin-2,3-dione which are selective antagonists of N-methyl-D-aspartate receptors.
BACKGROUND OF THE INVENTION
L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. speimine), glycine and certain metal ions (e.g. Mg.sup.2+, Zn.sup.2+). Since the NMDA receptor has an absolute requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.
In the region of a cerebral infarct, anoxia for example, causes abnormally high concentrations of glutaric acid to be released, which lead to an over-stimulation of NMDA receptors, resulting in the degeneration and death of neurones. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo, may be useful in the treatment and/or prevention of any pathological condition in which NMDA receptor activation is thought to be important. Examples of such conditions include acute neurodegenerative disorders arsing from events such as stroke, transient ischaemic attack, peri-perative ischaemia and traumatic head injury to the brain or spinal cord. In addition NMDA antagonists may be of use in treating certain chronic neurological disorders such as senile dementia and Alzheimer's disease. They may also have utility in conditions in which peripheral nerve function has been impaired such as retinal and macular degeneration.
Furthermore, NMDA antagonists have been shown to possess anti-convlsant and anxiolytic activity and may therefore be used to treat epilepsy and axiety. NMDA antagonists may attenuate the effects of alcohol withdrawl from physically dependent animals (K. A. Grant et al. J. Pharm. Exp. Ther. (1992), 260, 1017) and thus NMDA antazonists may be of use in the treatment of alcohol addiction and pain.
Various derivatives of 1,2,3,4-tetrahydroquinaline-2,4-dione have been described as NMDA (glycine site) rector antagonists (see EP-A0459561 and EP-A-0431676) while WO 91/013873 and JO 322-0124 describe 1,4-dihydroquinoxaline-2,3-diones as glutamic acid antagonists. WO 94/00124 describes 1,4-dihydroquinoxaline-2,3-diones having high affinity for the glycine binding site with utility for Long stroke and red disorders.
EP-A-0377112 and EP-A-0572852 describe various quinoxaline -2,3-diones having CNS activity while EP-A-0260744 describes 1H-imidazol-1-yl-methyl-benzimidazole derivatives useful for treating androgenic hormone disorders. Chemical Abstracts no. 184281, 117(19), 1992 describes structure activity relationships and the physiological implications of NMDA inhibition of a number of quinoxaline derivatives.
SUMMARY OF THE INVENTION
The compounds of the present invention are not only highly potent antagonists of the NOMA (glycine site) receptor but are also highly selective having little or no affinity for the ABA receptor.
Thus the present invention provides compounds having the formula: ##STR2## and their pharmaceutically acceptable salts,
wherein R.sup.1 and R.sup.2 are each independently Cl, Br, CH.sub.3, CH.sub.2 CH.sub.3 or CF.sub.3 ; R.sup.3 is H, CH.sub.3 or CH.sub.2 CH.sub.3 ; and X is a 5-membered heterocyclic group containing up to four nitrogen atoms, attached via a nitrogen atom, the said group being optionally substituted by C.sub.1 -C.sub.6 alkyl or (CH.sub.2).sub.n NR.sup.4 R.sup.5, wherein n is an integer from 1 to 5 and R.sup.4 and R.sup.5 are each independently H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl or pyridyl, or R.sup.4 and R.sup.5 are linked to form, toge
REFERENCES:
patent: 5028606 (1991-07-01), Venet et al.
Doble, Therapie 50, pp. 319-337 (1995).
Kornberg et al, Chemical Abstracts vol. 126, No. 131475 (Abstract for WO 96 40650 Dec. 19, 1996), 1997.
Acklin et al, Chemical Abstracts vol. 126, No. 251169 (Abstract for WO 97 08155 Mar. 6, 1997).
Bull David John
Carr Christopher Lee
Fray Michael Jonathan
Mowbray Charles Eric
Stobie Alan
Bernhardt Emily
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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