Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-27
1998-12-15
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544349, A61K 31495, C07D40304
Patent
active
058497447
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel pyrrolyltetrahydrobenzoquinoxalinediones, processes for the preparation thereof and the use thereof for controlling diseases.
Excitatory amino acids, in particular glutamate, are widespread in the central nervous system. The excitatory amino acid glutamate acts as transmitter substance for receptors of which various subtypes are known. One subtype is called, for example, the NMDA receptor after the specific agonist N-methyl-D-aspartate. 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 on this glycine binding site may accordingly show antagonistic effects on the NMDA receptor and inhibit an overexcitation of this receptor.
Two other subtypes of glutamate receptors are the AMPA receptor and the kainate receptor which are each called after the specific agonists 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. In a similar way to the NMDA receptor already mentioned, antagonists of these receptors could 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 to treat these disorders. Glutamate antagonists, which include, in particular, NMDA antagonists, and their modulators (such as glycine antagonists) and the AMPA antagonists, are suitable for therapeutic use as remedies for neurodegenerative disorders (Huntington's chorea and Parkinson's diseases), 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 (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 not hydrogen are also known. Thus, EP 377 112 and EP 374 534 have mentioned N-hydroxyquinoxalines (II; R.sup.1 =OR.sup.4). EP 315 959, DE 4 135 871, WO 91/13 878 and WO 92/07 847 described alkyl radicals as R.sup.1 in II, it also being possible for the alkyl chain to be substituted by acids, esters or amides. Likewise, alkyl acids (=R.sup.1) are mentioned in Bioorg. & Med. Chemistry Lett. 3 (1993) 2801-4.
N-Hydroxyquinoxalinediones (II, R.sup.1 =OH) or O-alkylated derivatives have been described in EP 374 534 and EP 377 112. In EP 374 534 there was also synthesis of a N-hydroxytetrahydrobenzoquinoxalinedione (Example 5). Unsubstituted tetrahydrobenzoquinoxalinediones (II, R.sup.1 .dbd.R.sup.2 .dbd.H) were claimed in EP 283 959. Tetrahydrobenzoquinoxalinediones which carry a substituted alkyl radical in R.sup.1 or R.sup.2 have never been described to date.
Quinoxalinedione derivatives II which carry a heterocycle as substituent R.sup.3 have likewise been disclosed. Thus, EP 556 393 mentions imidazoles, triazoles and pyrazoles. Pyrroles (II, with R.sup.3 =pyrrolyl) have been described as glutamate antagonists in EP 572 852.
The invention relates to novel pyrrolyltetrahydrobenzoquinoxalinediones of the formula I ##STR3## and their tautomeric and isomeric forms, and their physiologically tolerated salts, in which the variables have the following meanings: can carry one or two different substituents of the formulae --COOR.sup.4, --CONHR.sup.4, --CO--R.sup.4, --OR.sup.4, --NHR.sup.4, --NH--CO--R.sup.4, --CONH--SO.sub.2 R.sup.4 or NHSO.sub.2 R.sup.4 where R.sup.4 is hydrogen, C.sub.1 -C.sub.4 -alkyl, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl, where the phenyl rings in R.sup.4 can be substituted by 1, 2 or 3 of the following substituents: C.sub.1 -C.sub.4 -
REFERENCES:
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Bigge et al, Chemical Abstracts, vol. 125, No. 114711 (Abstract fr WO 96 17832), (1996).
Lees, Pharmacology and Patholphysiology, 5, pp. 51-74, (1996).
Doble, Therapie, 50, pp. 319-337, (1995).
Lipton, Tins, 16, pp. 527-532, (1993).
Schousboe et al, Abstract for Clin. Neurosci. 4 pp. 194-198 (1997).
Bioorganic & Medicinal Chem. Lts., vol. 3, No. 12, pp. 2801-2804, 1993, Synthesis and Excitatory Amino . . . , Epperson et al.
Behl Berthold
Hofmann Hans Peter
Lubisch Wilfried
Vierling Michael
BASF - Aktiengesellschaft
Bernhardt Emily
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