Amido-quinoxalinediones, the preparation and use thereof

Details Amido-quinoxalinediones, the preparation and use thereof Amido-quinoxalinediones, the preparation and use thereof

1996-12-20

1998-06-30

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514250, 544344, 544354, A61K 31495, C07D40312

Patent

active

057734399

DESCRIPTION:

BRIEF SUMMARY
This is a national stage application filed under 35 U.S.C. .sctn.371, filed Jun. 16, 1995.
The present invention relates to novel amido-quinoxalinediones, processes for the preparation thereof and the use thereof for controlling diseases.
What are called excitatory amino acids, eg. glutamic acid, are widespread in the central nervous system. These excitatory amino acids function as transmitter substances for glutamate receptors, of which various subtypes are known. One subtype is, for example, named after the specific agonist the N-methyl-D-aspartate (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 can 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 called after the respective specific agonists 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Antagonists of these receptors could, in a similar way to the NMDA receptor already mentioned, likewise inhibit "overexcitation".
Elevated glutamate levels occur in a number of neurodegenerative disorders or psychological disturbances and may lead to states of overexcitation or toxic effects in the CNS.
Antagonists of the glutamate receptor subtypes can thus be used for the treatment of these disorders. Glutamate antagonists, which include in particular NMDA antagonists and their modulators (such as glycine antagonists) and the AMPA antagonists, are therefore suitable for use for the therapy of neurodegenerative disorders (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).
Derivatives of quinoxaline-2,3(1H,4H)-dione II ##STR2## have been described in several publications, such as EP 374,534 and EP 260,467, as glutamate antagonists. Many of the known derivatives are unsubstituted in the heterocyclic quinoxaline fragment (II, R.sup.1, R.sup.2 =hydrogen). However, some derivatives in which R.sup.1 in II is a radical which is not hydrogen are also known. Thus, EP 377,112 and EP 374,534 have claimed N-hydroxyquinoxalines (II; R.sup.1 =OR.sup.4). EP 315,959, DE 4,135,871, WO 91/13,878, WO 92/07,847 and WO 94/00,124 describe alkyl radicals as R.sup.1 in II, and the alkyl chain can also be substituted by acids, esters or amides. Alkyl acids (=R.sup.1) are likewise mentioned in J. R. Epperson et al. Bioorg. & Med. Chemistry Lett. 3 (1993) 2801-4. Said publications are, however, distinguished by predominantly describing alkyl esters and alkyl acids. By contrast, EP 315,259 mentions an acetamide (cf. R.sup.1) (Example 24), J. R. Epperson et al. (loc. cit.) mentions an acetanilide (Example 16) and EP 572,852 mentions various amides (cf. Example 56).
Few derivatives derived from N-aminoquinoxalinedione have been disclosed in the literature to date. 1-Aminoquinoxalinedione was described by Shin, and Rossi et al., Tetrahedron 24 (1968) 6395. Rossi et al. likewise prepared N-iminoquinoxalinediones. WO 93/08,173 claimed N-alkylaminoquinoxalines as glutamate antagonists, and EP 358,148 claimed N-amidoquinoxalinediones substituted by phthalimido radicals as pigments. Except in the last application mentioned, N-amidoquinoxalinediones have never been described to date. Pyrrolylquinoxalines have to date been mentioned only in EP 572,852.
We have now found novel N-amidoquinoxalinediones with novel types of actions.
The invention relates to novel amidoquinoxalinediones of the formula I ##STR3## where R.sup.1 is hydrogen or C.sub.1 -C.sub.4 -alkyl, phenyl, which can be substituted by a maximum of two of the following radicals: straight-chain or branched C.sub.1

REFERENCES:
patent: 5514680 (1996-05-01), Weber et al.
Arzneim.-Forsch./Drug Res., 40 (I), No. 5, 1990, pp. 511-514, Dingledine et al.
TIPS, 1990, vol. 11, pp. 334-338.
Drugs of the Future, vol. 14, No. 10, Oct. 1989, p. 1059.
Bioorganic & Medicinal Chem. Letters, vol. 3, No. 12, pp. 2801-2804, 1993, Epporson et al.

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