Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-05
1996-08-27
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514320, 544295, 544333, 544360, 544376, 546193, 546196, A61K 31495, A61K 31445, C07D40900, C07D21168
Patent
active
055501290
DESCRIPTION:
BRIEF SUMMARY
THIS APPLICATION IS A 371 OF PCT/EP93/02742, FILED OCT. 6, 1993.
The invention relates to benzopyranones whose basic structure can be derived from coumarin, processes for the preparation of these compounds, including the resultant reactive intermediate products, as well as drugs that contain these compounds.
The central nervous system (CNS) of mammals has high concentrations of excitatory amino acids (EAA) such as glutamate, aspartate and homocysteate, which act as neurotransmitters that cooperate with specific receptors.
The three best characterised receptor types are the N-methyl-D-aspartate- (NMDA), kainate- (KA) and quisqualate- (QA) receptors named after their selective agonists. All three receptors can be activated by glutamate and aspartate. It is known that, as a result of cerebral ischaemia, glutamate is released in relatively large amounts, and, among other things, binds to the NMDA receptor complex and leads to an enhanced calcium inflow as well as to an increased release of intracellular calcium in the neuronal cells.
The NMDA receptor complex includes, inter alia, binding sites for glutamate, glycine, phencyclidine, Mg.sup.2+ and Zn.sup.2+. Since a number of pharmacological results indicate that modulators of the NMDA receptor-mediated neurotransmission can influence the NMDA-mediated cytotoxicity, various selective NMDA antagonists have already been investigated with regard to their possible neuroprotective action (see G. L. Coilingridge, R. A. J. Lester: "Excitatory Amino Acid Receptors in the Vertebrate Central Nervous System", Pharmacol. Rev. 40, No. 2, p. 143-210 (1989); L. Turski: "N-methyl-D-aspartate-receptor complex", Arzneim. - Forsch. Drug. Res. 40 (I), No. 5, p. 511-514 (1990)). On account of undesirable side effects of the known NMDA antagonists there is furthermore an urgent need to provide new compounds with a NMDA-antagonist action that exhibit fewer side effects or have a different activity spectrum.
The object of the invention is accordingly to provide new compounds that have the lowest possible toxicity but still retain a NMDA-antagonist action and which can be used as active drug constituents, particularly in the treatment of chronic neurodegenerative diseases, in order to prevent or at least reduce neurodegeneration in the CNS caused by ischaemia/trauma or other pathological changes, and the occurrence of convulsions.
This object is achieved by the provision of the compounds and process according to the invention as well as by the use of these compounds as neuroprotective, anti-convulsive and anti-epileptic drugs. The compounds according to the invention in addition also exhibit remarkable anti-depressive, nootropic, antipsychotic and anxiolytic properties.
The object of the invention are accordingly: ##STR2## in which
R.sup.1 is a hydroxy radical, an alkoxy radical with 1 to 5 C atoms, a cycloalkoxy radical with 4 to 6 C atoms, or an alkyl- or arylsulphonyloxy radical R.sup.6 --SO.sub.2 O--, hydroxy radicals, alkoxy radicals with 1 to 4 C atoms, or cycloalkoxy radicals with 4 to 6 C atoms, radical, optionally substituted with in each case one or two C.sub.1 -C.sub.5 alkyl groups, with in each case 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, hydroxy, methylenedioxy or nitro, 4 to 6 C atoms or a phenyl radical, which is optionally substituted with in each case one or two C.sub.1 -C.sub.5 alkyl groups, with in each case one or two halogen atoms or with perfluoroalkyl with 1 to 3 C atoms, and with the exception however of 7,8-dimethoxy-4-methyl-3-[(4-phenyl-1-piperazinyl)methyl]-2H-1-benzopyran- 2one.
The compounds according to the invention are new. The compound 7,8-dimethoxy-4-methyl-3-[(4-phenyl-1-piperazinyl)methyl]-2H-1-benzopyran- 2-one, is already known, but has been tested only for its antibacterial action (R. Vyas, S. Bapat, R. H. Mehta, J. Indian Chem. Soc..67, No. 6, p. 482-484 (1990)).
Furthermore, compounds are known in which the coumarin radical and the piper
REFERENCES:
patent: 3538098 (1970-11-01), Beyerle et al.
patent: 3930003 (1975-12-01), Becker et al.
Vyas et al, J. Indian Chem. Soc. vol. 67, 1990, pp. 482-484.
Chatterjee Shyam S.
Hauer Hermann
N oldner Michael
Tsang Cecilia
Willmar Schwabe GmbH & Co.
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