Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-06-21
1993-01-12
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514277, 514317, 514336, A61K 31445, A61K 31435, A61K 3144
Patent
active
051791099
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical compositions for neuroprotection containing arylcyclohexylamines.
More specifically, it relates to the use of arylcyclohexylamines having a structure close to that of phencyclidine (PCP), i.e. 1-(1-phenylcyclohexyl)-piperidine of formula: ##STR3## or that of ((2-thienyl)-1 cyclohexyl)-N-piperidine (TCP) of formula: ##STR4## Phencyclidine (PCP), whose pharmacological activity was studied in about 1958, was introduced as an analgesic and anesthetic under the name SERNYL and was then abandoned due to its secondary psychodysleptic effects.
Like PCP, TCP belongs to the series of arylcyclohexylamines and can be used in anesthesia as an additive or for the treatment of hyper-excitability due to its depressive effect and as is described in U.S. Pat. No. 2,921,076 of Parke, Davis & Co.
Thus, arylcyclohexylamines have never been used in neuroprotection. However, recent studies on PCP revealed that this molecule could act as a non-competitive antagonist of N-methyl-D-aspartate (NMDA), which is an interesting property for cerebral protection, particularly against the damage associated with the presence of glutamate.
Thus, the toxicity of exciting or excitatory amino acids such as glutamates is the main cause of damage to the brain encountered during ischemia, anoxia, hypoglycemia or epilepsy. It is also assumed that the toxicity of amino acids is involved in certain neurodegenerative disorders.
The molecules which act as NMDA antagonists can be used in neuroprotection. However, in the case of PCP, the secondary psychodysleptic effects prevent such a use.
In addition, research has been carried out to find other molecules acting as an NMDA antagonist and without suffering from said disadvantage.
The present invention is specifically directed to novel pharmaceutical compositions for neuroprotection and which contain arylcyclohexylamines having a non-competitive antagonizing effect with respect to NMDA receptors, but not having the disturbing secondary or side effects of PCP.
According to the invention, the pharmaceutical composition for neuroprotection comprises an arylcyclohexylamine in accordance with the formulas: ##STR5## in which:
R.sup.1 represents ##STR6## with R.sup.4 being a hydrogen atom, a fluorine atom, an iodine atom or a methyl radical, R.sup.2 represents a hydrogen atom, the radical OH or the radical CH.sub.3 and R.sup.3 represents a hydrogen atom or the radical CH.sub.2 R.sup.5 with R.sup.5 representing H, OH, Cl, Br or CH.sub.3 COO, provided that R.sup.2 and R.sup.3 are not both a hydrogen atom, or an addition salt to a pharmaceutically acceptable acid of said arylcyclohexylamine.
In this formula, when R.sup.1 represents the thienyl or furanyl radical, the latter can be connected to the cyclohexyl nucleus by a carbon in the ortho or meta position with respect to the heteroatom O or S of the furanyl or thienyl radical.
The arylcyclohexylamines used in the invention have a structure close to that of PCP or TCP, but differ therefrom by the presence of substituents giving them the properties of more selectively fixing to the site of the phencyclidine, while being non-competitive antagonists of NMDA, which are not fixed to the site of the NMDA and while having less affinity for the muscarinic receptors and opiate receptors than PCP, i.e. greatly reduced psychodysleptic properties.
Thus, these arylcyclohexylamines are non-competitive antagonists of the NMDA receptor of exciting amino acids. Thus, they are fixed to the receptor of the PCP and selectively block the entry of the Ca.sup.2+ and Na.sup.+ ions passing through the ionic channel activated by the agonists of the NMDA receptor. This property forms the basis for the neuroprotective properties which can be used for combating aging and acute cerebral attacks. Thus, the arylcyclohexylamines according to the invention can be used in cases of ischemia and cerebral traumatism and also for protection against aging.
In cerebral attacks, there is a large production of glutamate, which leads to necrosis of the cells.
REFERENCES:
Chemical Abstracts, vol. 109, 1988, p. 19, No. 85738p.
Chemical Abstracts, vol. 89, 1978, p. 29, No. 190857t.
Neurol. Neurobiol., vol. 46, 1988, Alan R. Liss, Inc. J. W. McDonald et al., Comparison of Neuroprotective Effects of Competitive and Non-Competitive MNDA Antagonists Against NMDA Mediated Neurotoxicity in an in Vivo Perinatal Rat Model, pp. 601-604.
Neurosci. Lett., vol. 91, No. 2, Aug., 1988, Elsevier Scientific Pub. Ireland Ltd., G. Rondouin et al.: "Non-Competitive Antagonists of N-Methyl-D-Aspartate Receptors Protect Cortical and Hippocampal Cell Cultures Against Glutamate Neurotoxicity", pp. 199-203.
Brain Research, vol. 490, Jun. 19, 1989, Elsevier Science Pub. B. V. (Biomedical Div.), M. D. Tricklebank et al.: The Behavioural Effects of MK-801: A Comparison With Antagonists Acting Non-Competitively and Competitively at the NMDA Receptor, pp. 127-135.
Faseb, J., vol. 1, No. 6, 1987, Faseb, M. B. Robinson et al.: Glutamate and Related Acidic Excitatory Neurotransmitters: From Basic Science to Clinical Application, pp. 446-455.
Brain Research, vol. 152, 1978, J. P. Vincent et al.: Interaction of Phencyclidines with the Muscarinic and Opiate Receptors in the Central Nervous System, pp. 176-182.
European Journal of Pharmacology, vol. 167, Aug. 11, 1989, Elsevier Science Publishers B. V. (Biomedical Division), M. D. Tricklebank et al.: "The Behavioural Effects of MK-801: A Comparison with Antagonists Acting Non-Competitively and Competitively at the NMDA Receptor", pp. 127-135.
Olney, John et al., Eur. J. Pharmacology 141(1987) 357-361.
Chicheportiche Robert
Kamenka Jean-Marc
Privat Alain
Rondouin Gerard
Centre National de la Recherche Scientifique
Gardner Diane
Waddell Frederick E.
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