Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-21
1998-12-22
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514247, 514248, 514255, 544349, 544353, 544354, 544355, 544356, A01N 4358, A61K 31495
Patent
active
058520163
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/03559 which was filed on Sep. 8, 1995.
BACKGROUND OF THE INVENTION
This invention relates to quinoxaline derivatives useful in therapy.
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. spermine), 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, for example, anoxia causes abnormally high concentrations of glutamic acid to be released, which leads 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 pathological conditions in which NMDA receptor activation is thought to be important. Examples of such conditions include neurodegenerative disorders including senile dementia and Alzheimer's disease and those arising from events such as stroke, transient ischaemic attack, peri-operative ischaemia and traumatic head injury to the brain or spinal cord. 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-convulsant and anxiolytic activity and may therefore be used to treat epilepsy and anxiety. They may also be useful in the treatment of pain.
NMDA antagonists may also attenuate the effects of alcohol withdrawal from physically dependent animals (K. A. Grant et al. J. Pharm. Exp. Ther. (1992), 260, 1017) and thus NMDA antagonists may be of use in the treatment of alcohol addiction.
Various derivatives of 1,2,3,4-tetrahydroquinoline-2,4-dione have been described as NMDA (glycine site) antagonists (see EP-A-0459561 and EP-A-0481676), while WO-A-91/13878 and JP-A-3220124 describe 1,4-dihydroquinoxalin-2,3-diones as glutamic acid antagonists. WO-A-94/00124 describes 1,4-dihydroquinoxalin-2,3-diones (including 6,7-dichloro-5-nitro-1,4-dihydroquinoxalin-2,3-dione) having high affinity for the glycine binding site with utility for treating stroke and related disorders.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a compound of formula 1, ##STR2## wherein A represents N or CH; CF.sub.3 ; cycloalkyl or aryl), C.sub.3--7 cycloalkyl, CF.sub.3 or aryl; substituted by OH, C.sub.1-4 alkoxy, aryl (optionally substituted by up to 3 substituents independently selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo and CF.sub.3), heterocyclyl (optionally substituted by up to 3 substituents independently selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, halo, CF.sub.3 and oxo and optionally benzo-fused), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.2-6 alkanoyl, CO.sub.2 H, C.sub.1-4 alkoxycarbonyl, NH.sub.2, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, NHSO.sub.2 CF.sub.3, CONR.sup.5 R.sup.6, NHCONR.sup.5 R.sup.6 or O(CH.sub.2).sub.n NR.sup.5 R.sup.6 !; together with the nitrogen atom to which they are attached they may represent a pyrrolidino, piperidino or morpholino group; and as "the compounds of the invention").
Pharmaceutically acceptable salts include salts of acidic or basic groups which may be present (for example sodium salts of carboxylic acid groups and hydrochloride salts of amino groups).
Preferably, A represents N.
"Halo" means fluoro, chloro, bromo or iodo. Preferred groups are fluoro, chloro and bromo.
Preferred gro
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patent: 4889855 (1989-12-01), Jacobsen et al.
patent: 5283244 (1994-02-01), Sakamoto et al.
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patent: 5614508 (1997-03-01), Nikam
Fray Michael Jonathan
Mowbray Charles Eric
Stobie Alan
Cintins Marianne M.
Ginsburg Paul H.
Jones Dwayne C.
Pfizer Inc.
Richardson Peter C.
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