Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-18
2000-09-19
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544346, A61K 31495, C07D48704
Patent
active
061212652
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel imidazoloquinoxalinones with heterocyclic substituents, to processes for their preparation and to their use for controlling diseases.
What are called excitatory amino acids, especially glutamic acid, are widespread in the central nervous system. This excitatory amino acid acts as transmitter substance for glutamate receptors, of which various subtypes are known. One subtype is, for example, named after the specific agonist N-methyl-D-aspartate the NMDA receptor. This NMDA receptor has various binding sites for agonists and antagonists. The amino acid glycine likewise binds to the NMDA receptor and modulates the effect of the natural agonist glutamic acid. Antagonists at this glycine binding site may accordingly show antagonistic effects on the NMDA receptor and inhibit overexcitation of this receptor.
Two other subtypes of glutamate receptors are the AMPA receptor and the kainate receptor, which are each named after the specific agonists 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Antagonists of these receptors might, similar to the abovementioned NMDA receptor, likewise inhibit overexcitation.
Elevated glutamate levels occur in a number of neurodegenerative diseases or psychological disturbances and may lead to overexcitation states or toxic effects in the CNS.
Antagonists of glutamate receptor subtypes may thus be used to treat these diseases. Glutamate antagonists, which include, in particular, NMDA antagonists and their modulators (such as glycine antagonists) and the AMPA antagonists, are therefore suitable for therapeutic use for neurodegenerative diseases (Huntington's chorea and Parkinson's disease), neurotoxic disturbances following hypoxia, anoxia or ischemia, as occur after stroke, or else as antiepileptics, antidepressants and anxiolytics (cf. Arzneim. Forschung 40 (1990) 511-514; TIPS, 11 (1990) 334-338 and Drugs of the Future 14 (1989) 1059-1071).
A number of imidazoloquinoxalinones of the formula II have been disclosed: ##STR2##
Thus, DE-A 3 004 750 and DE-A 3 004 751 describe substances which have antiallergic effects. Imidazoloquinoxalinones as phosphodiesterase inhibitors are furthermore claimed as cardiovascular agents in U.S. Pat. No. 5,166,344 (=EP 400583).
In the CNS sector, U.S. Pat. No. 5,182,386 claims imidazoloquinoxalines which are antagonists or inverse agonists of the GABA receptor and can be used to control anxiety states, sleep disturbances, convulsive states and to improve memory.
Glutamate antagonists described in numerous publications (eg. EP 374 534 and EP 260 467) are predominantly derivatives of quinoxaline-2,3-dione.
For example, WO 92/07847 relates to compounds with heterocyclic substituents in the benzenoid ring. U.S. Pat. No. 5,153,196 and U.S. Pat. No. 5,196,421, and WO 93/20077, relate to fused heterocycles, including the imidazoloquinoxalinone system. The latter also discloses substitution by heterocycles with 2-4 nitrogen atoms in the benzenoid part of the ring system.
However, the compounds published as glutamate antagonists have only alkyl, trifluoromethyl or phenyl substituents in the fused-on imidazole ring. It has now been found that substitution of the imidazoloquinoxalinone with heterocycles in the benzenoid part and carboxylic acids or esters thereof in the fused-on imidazole ring leads to novel, superior glutamate antagonists. They are therefore particularly suitable for the therapy of neurological disturbances which can be influenced thereby.
The invention relates to novel imidazoloquinoxalinones of the formula I ##STR3## where R.sup.1 is hydrogen, branched or straight-line C.sub.1-5 -alkyl or a phenyl, pyridyl or thienyl group which is unsubstituted or substituted by one or two chlorine atoms, one trifluoromethyl, one nitro or methylenedioxy group, group, R.sup.4 and R.sup.5 and has 1-4 nitrogen atoms or has 1-2 nitrogen atoms and one oxygen or sulfur atom, where each of the radicals R.sup.4 and R.sup.5, which can be identical or different, is hydrogen, C.sub.1-5 -alkyl, C.sub.1-5
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Behl Berthold
Hofmann Hans Peter
Lubisch Wilfried
Treiber Hans-Jorg
BASF - Aktiengesellschaft
Bernhardt Emily
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