Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-10-08
1995-06-27
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514320, 514326, 544376, 546196, 546207, 549399, A61K 31495, A61K 31445, C07D40900, C07D31104
Patent
active
054280389
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 application of PCT/EP92/00739, filed Apr. 2, 1992.
The invention relates to benzopyranones, whose basic structure may be derived from coumarin, a method for the production of these compounds, including the reactive intermediates then produced, and furthermore medicaments, which contain these compounds.
The central nervous system (CNS) of mammals possesses high concentrations of excitatory amino acids (EAA) such as glutamate, aspartate, and homocysteate having the function of neurotransmitters and cooperating with specific receptors.
The three types of receptors which have been best characterized so far are those named after their selective agonists, namely N-methyl-D-aspartate (NMDA), kainate (KA) and quisqualate (QA) receptors. All three receptors may be activated by glutamate and aspartate. It is known that as a consequence of a cerebral ischemia glutamate is liberated in major quantities, and inter alia binds to the NMDA receptor complex and is responsible for an increased input of calcium and to an increased release of intracellular calcium into the neuronal cells. The NMDA receptor complex inter alia has binding sites for glutamate, glycine, phencyclidine, Mg.sup.2+ and Zn.sup.2+. Since a series of pharmacological investigations have indicated that modulators of neurotransmission mediated by NMDA receptors may influence cytotoxicity mediated by NMDA, various different selective NMDA antagonists already have been investigated as regards their possible neuroprotective action (see G. L. Collingridge, R. A. J. Lester: "Excitatory Amino Acid Receptors in the Vertebrate Central Nervous System", Pharamacol. Rev. 40, No. 2, pp. 143-210 (1989); L. Turski: "N-Methyl-D-aspartat-Rezeptorkomplex", in Arzneim.-Forsch/Drug Res. 40 (I), No. 5, pp. 511-514 (1990)). Owing to the undesired side effects of known NMDA antagonists there is still a substantial need for the provision of novel compounds with an NMDA antagonistic effect and which exhibit less side effects or have a different spectrum of action.
Therefore one object of the invention is to provide new compounds which have minimum toxicity while nevertheless having an NMDA antagonistic action and able to be utilized as medicament components, more particularly for the therapy of chronic neurodegenerative diseases in order to prevent neurodegeneration in the CNS caused by ischemia or trauma or by other pathological alterations and to prevent the occurrence of convulsions or at least to reduce the same. Furthermore the novel compounds may have additionally a broad antiallergic and anti-inflammatory spectrum with a prolonged period of action; in this case, however, such compounds are to be orally administrable.
This object is attained by the compounds and the methods in accordance with the invention and by the use of these compounds as a medicament which has a neuroprotective, anticonvulsive, anti-epileptic and, optionally, an anti-allergic and anti-inflammatory action.
The invention thus relates to: ##STR2## wherein: X denotes an alkylene group with 2 to 5 C. atoms or a 2-hydroxypropylene group, diphenylhydroxymethyl, pyridinyl or pyrimidinyl radical, which is optionally substituted with respectively one or two C.sub.1 -C.sub.5 alkyl groups, with respectively one or two halogen atoms, with halogen and simultaneously C.sub.1 -C.sub.5 alkyl, with perfluoroalkyl with 1 to 3 C. atoms, C.sub.1 -C.sub.5 alkoxy, methylenedioxy, hydroxy or nitro, atoms or a cycloalkyl radical with 4 to 6 C. atoms, phenyl radical, phenyl radical or a trifluoromethyl radical or equal to 3 or 4, and the addition compounds thereof with physiologically compatible acids.
The compounds in accordance with the invention are novel. Compounds are known which are derived from 7-hydroxycoumarin (umbelliferone), which however have a second alkoxy group corresponding to the R.sup.2 0-- radical of the general formula I missing. Such umbelliferone derivatives are described in the German patent publication 2,123,924 C3 and the European patent publication 0,171,645 A1, furthermore as
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Chatterjee Shyam S.
Hauer Hermann
Koch Egon
Noldner Michael
Dr. Willmar Schwabe GmbH & Co.
Tsang Cecilia
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