Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-12
1997-03-18
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514267, 544247, 544251, A61K 31505, C07D48702
Patent
active
056123442
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application filed under 35 USC 371 of PCT/EP93/03424, filed Dec. 6, 1993.
The present invention relates to the use of triazoloquinazolines for the treatment of central nervous disorders.
Triazoloquinazolines have been disclosed in EP-A 80 176. These compounds are reported to have an anti-allergic effect. It is furthermore known that certain pyrazoloquinazolines are suitable inter alia for the treatment of neurological disturbances (US-A 5 153 196).
The invention relates to the use of compounds of the formula I ##STR2## where X is carboxyl, where appropriate in the form of its salt with a physiologically tolerated amine cation or metal cation; the radical ##STR3## where R.sup.4 is C.sub.1-8 -alkyl, cycloalkyl with 3 to 8 carbons in the ring, benzyl, one of the radicals ##STR4## where n is 2, 3 or 4 and R.sup.5 and R.sup.6 are each C.sub.1-3 -alkyl; hydroxy-C.sub.1-4 -alkyl, nitrile-C.sub.1-4 -alkyl, tetrazolyl, carbonylaminotetrazole or carbamoyl, and hydrogen, fluorine, chlorine or bromine atoms, trifluoromethyl, nitro, amino, C.sub.1-5 -alkyl, mono- or di-C.sub.1-5 -alkylamino groups, a C.sub.1-6 -alkoxy group, a C.sub.1-6 -alkylthio, C.sub.1-6 -alkylsulfenyl, C.sub.1-6 -alkylsulfonyl, di-C.sub.1-6 -alkylaminosulfonyl radical, or C.sub.3-5 -alkylene group, of drugs for the treatment of central nervous disorders.
Compounds of the formula I are described in EP-A 80 176. The latter also lists a large number of compounds which are also suitable for the novel indication.
Examples of relevant central nervous disorders are epilepsy, brain damage, Parkinson's disease, Alzheimer's disease, emesis, and trauma of the head and spinal cord. The compounds of the formula I have the further advantage that they have spasmolytic, antiepileptic, anxiolytic and antidepressant properties. The effect of the compounds derives from their glutamate-antagonistic properties.
The pharmacological activity of the compounds I according to the invention was investigated on isolated membrane material from rat cerebra. To do this, the membrane material was treated in the presence of the compounds according to the invention 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). Subsequently the radioactivity on the treated membranes was measured by scintillation counting. The amounts of bound .sup.3 H-AMPA and .sup.3 H-5,7-dichlorokynurenic acid, or in each case the amounts of these radiolabeled substances displaced, were determined from the bound radioactivity. The dissociation constant K.sub.I (I=inhibitor) which results from this and which is a measure of the displacing effect of the active substance according to the invention was found 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., 220 (1980) 107, Ligand: Versatile Computerized Approach for Characterization of Ligand Binding Systems).
The following in vitro investigations were carried out: (.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 composed 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 4,000 g for 20 minutes. After removal of the supernatant liquid, the proteinacious membrane material contained in the sediment was washed three times by suspending it in buffer solution A and subsequently centrifuging 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. The protein material was subsequently washed twice by centrifugation and suspension and stored at -
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patent: 4713383 (1987-12-01), Francis et al.
patent: 5153196 (1992-10-01), McQuaid et al.
Synthesis and Benzodiazepine Binding Activity of a Series of Novel . . . Francis et al., Am. Chem. So. 1991, pp. 281-290, vol. 34, No. 1.
Ligand: A Versatile Computerized Approach . . . , Analytical Biochemistry, vol. 107, pp. 220-239 (1980).
Behl Berthold
Hofmann Hans P.
Schlecker Rainer
Treiber Hans-J org
BASF - Aktiengesellschaft
Grumbling Matthew V.
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