Imidazoloquinoxalinones for the treatment of central nervous dis

Details Imidazoloquinoxalinones for the treatment of central nervous dis Imidazoloquinoxalinones for the treatment of central nervous dis

1995-09-19

1996-07-23

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

A61K 31495

Patent

active

055389724

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00872 filed Mar. 13, 1994.
The present invention relates to the use of imidazoloquinoxalinones for the treatment of central nervous disorders.
Imidazoloquinoxalinones of the formula I have been disclosed in DE-A 30 04 750 and DE-A 30 04 751. An antiallergic action is reported for these compounds.
It is furthermore known that certain imidazoloquinoxalinones disclosed in EP-A 518 530 (= U.S. Pat. No. 5,153,196) have an antagonistic effect on the receptors of amino acids with excitatory activity. They are therefore suitable as neuroprotective agents and for eliminating neurological disturbances associated with this mechanism of action. Furthermore, a number of imidazoloquinoxalinones substituted in different ways have been disclosed as cAMP phosphodiesterase inhibitors with an effect on the circulation (EP-A 400 583 = U.S. Pat. No. 5,166,344) and as GABA receptor ligands for the treatment of various disturbances of the central nervous system (U.S. Pat. No. 5,182,386).
The present invention relates to the use of compounds of the formula I ##STR2##
where
X is a carboxyl group which can be in the form of its salt with a physiologically tolerated amine cation or metal cation; the radical ##STR3##
where R.sup.3 is C.sub.1-8 -alkyl or benzyl; or X is a hydroxymethyl, cyano, formyl, tetrazolyl, carbonylaminotetrazole, carbamoyl, oxime or C.sub.1 -C.sub.3 -alkoxime ether group and
R.sup.1 and R.sup.2 are identical and are hydrogen, chlorine or bromine atoms,
for the production of drugs for the treatment of disorders of the central nervous system.
Examples of relevant disorders of the central nervous system are epilepsy, brain damage, Parkinson's disease, Alzheimer's disease, emesis, and trauma of the head and spinal cord. The effect of the compounds derives from their glutamate-antagonistic properties.
The novel pharmacological activity of the compounds I was investigated on isolated membrane material from rat cerebra. To do this, the membrane material was treated in the presence of the compounds with the radiolabeled substances .sup.3 H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (.sup.3 H-AMPA) and .sup.3 H-5,7-dichlorokynurenic acid, these binding to specific receptors (AMPA and NMDA (N-methyl-D-aspartate) receptors respectively). The radioactivity in the treated membranes was subsequently measured by scintillation counting. The amounts of bound .sup.3 H-AMPA and .sup.3 H-5,7-dichlorokynurenic acid were calculated from the bound radioactivity. The active substance according to the invention was determined by iterative non-linear regression analysis using the statistical analysis system (SAS) on an IBM computer, similar to the "Ligand" program of P. J. Munson and D. Rodbard (Analytical Biochem. 107 (1980) 220, Ligand: Versatile Computerized Approach for Characterization of Ligand Binding Systems).
The following in vitro investigations were carried out:
1. Binding of .sup.3 H-2-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (.sup.3 H-AMPA)
To prepare the membrane material, freshly removed rat cerebra were homogenized together with 15 times the volume of a buffer solution A consisting of 30 mM .alpha., .alpha., .alpha.-tris(hydroxymethyl)methylamine hydrochloride (TRIS-HCl) and 0.5 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, using an Ultra-TURRAX. The suspension was centrifuged at 48,000 g for 20 minutes. After removal of the supernatant liquid, the protein-containing membrane material present in the sediment was washed three times by suspension in buffer solution A and subsequent centrifugation at 48,000 g for 20 minutes each time. The membrane material was then suspended in 15 times the volume of buffer solution A and incubated at 37.degree. C. for 30 minutes. Subsequently, the protein material was washed twice by centrifugation and suspension and stored at -70.degree. C. until used.
For the binding assay, the protein material was thawed at 37.degree. C. and washed twice by centrifugation at 48,000 g (20 minutes) and subsequent suspension in a buffer solution

REFERENCES:
patent: 4291033 (1981-09-01), Barnes et al.
patent: 5153196 (1992-10-01), McQuaid et al.
patent: 5166344 (1992-11-01), Davey
patent: 5182386 (1993-01-01), Albaugh et al.

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