Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-18
2003-06-03
Raymond, Richard (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06573265
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, 1-diethylaminoethyl-3-quinoxaline-2-on derivatives of the formula
wherein R
3
is hydroxy, methoxy, ethoxy or hydrogen, or pharmaceutically acceptable salts thereof, for the preparation of novel pharmaceutical compositions.
2. Description of the Prior Art
The pharmaceutical activity of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives has been known for many years and, in particular, 1-diethylaminoethyl-3-(p-methoxybenzyl)-1,2-dihydroquinoxaline-1-on, whose non-proprietary name is Caroverine, has already been employed as an effective spasmolyticum in the gastrointestinal region. In that case, the efficacy of that substance is attributed, in particular, to its calcium-blocking properties, blocking the calcium-mediated activation of myofibrillar ATP.
EP-A 0 032 564 describes the use of Caroverine or its pharmaceutically safe salts for a plurality of angiocardiopathies and as a preparation for inhibiting platelet aggregation in human blood, as a preparation enhancing blood circulation and also as a substance for treating angina pectoris, myocardial infarctions, hypertonic conditions and the like. The effect of Caroverine in EP-A 0 032 564 was attributed to the fact that it is a specific Ca antagonist and that Caroverine is capable of inhibiting up to 50% of the Ca
2
+
ion flux into cells.
In Subsidia med. 22, 3, pages 78-85 (1970) Möslinger reported that Caroverine could suppress epileptic seizures. Also the use of Caroverine in the treatment of acute alcohol withdrawal symptoms and its application in alkaloid withdrawal symptoms have already been described.
From EP-A 0 542 689, the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives as neuroprotective substances is to be taken, its use in glutamate-induced and glutamate-receptor-mediated neurotoxic dysfunctions and functional disorders of the central nervous system and, in particular, of the internal ear and of the retina being particularly described. That document also speaks of the use of those substances for treating degenerative processes of neurons in the central nervous system such as, for instance, Alzheimer's disease, Huntington's disease, Parkinson's disease, Wernicke-Korsakoff and Jakob-Creutzfeld syndromes. The action of the specific quinoxaline derivatives mentioned is attributed to the selective blocking of the NMDA and non-NMDA receptors without influencing other receptors such that the pharmaceuticals described in that document appear to be suitable only for application in glutamate-induced and glutamate-receptor-mediated neurotoxic dysfunctions, such as functional disorders of the internal ear and of the retina, and for the degenerative processes mentioned.
From Derwent Abstract, Publication No. AN 83-45789 K, the action of Caroverine and, in particular, 1-(2-dialkylaminoalkyl)-3-(p-alkoxybenzyl)-1,2-dihydroquinoxaline-2-on substances as active substances in the control of the inflow and outflow of anticancer agents can be taken, wherein the anticancer activity is developed as the anticancer agents are transferred into the cells through the cell membranes. With the usual anticancer agents, the effect will decrease in the course of time, because the cancer cells are getting resistant against the same, on the one hand, and the anticancer agents are streaming out of the cancer cells or emerge slowly from the same, on the other hand, which is impeded according to that prior art by the administration of quinoxaline derivatives, since said quinoxaline derivatives [prevent]
sic
the anticancer agent from flowing out of the cells, thus ensuring the retention of the high concentrations of anticancer agent within the cells.
DE-A 25 21 905 describes a medicament containing 1-diethylaminoethyl-3-(p-methoxybenzyl)-2,1,2-dihydroquinoxaline-2-on, which is said to exhibit effects on the cerebral vessels and the cerebral blood circulation.
SUMMARY OF THE INVENTION
The present invention aims at providing, in addition to the initially mentioned use of specific 1-(aminoalkyl)-3-quinoxaline-2-on derivatives, novel pharmaceutical applications and, therefore, relates to the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, 1-diethylaminoethyl-3-quinoxaline-2-on derivatives of the formula
wherein R is hydroxy, methoxy, ethoxy or hydrogen, or pharmaceutically acceptable salts thereof, for the preparation of compositions acting as antioxidants for preventing or treating diseases caused by free radicals of the oxygen cell metabolism, for stimulating the growth of nerve cells, antagonizing glutamate receptors and/or stimulating the growth of, in particular glutamatergic, nerve cells. In extensive studies on the structure of the molecules and their potential mode of action, the Applicant found that the 1-diethylaminoethyl-3-quinoxaline-2-on derivatives used according to the invention were extremely strong antioxidants and that, as a result, they exhibited, in particular, an extremely high capacity as radical interceptors, primarily vis-à-vis the hydroxyl, peroxyl and peroxynitrite radicals, which are responsible for the causation of a plurality of diseases. Their actions as antioxidants and hence as radical interceptors is attributed to the structural conditions inherent in these specific substances, which are quinoxalines with electron-rich aromatic ring systems including redoxoactive oxygen and nitrogen atoms. Due to the large number of electrons available in the molecule, it could be proved that the compounds were able to bind free radicals so as to enable the treatment, or prevent the outbreak, of diseases brought about by free radicals and, in particular, diseases brought about by free radicals of the oxygen cell metabolism, by means of the specific 1-diethylaminoethyl-3-quinoxaline-2-on derivatives used according to the invention. Moreover, it has been shown in a surprising manner that specific 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, Caroverine are capable of antagonizing metabotropic glutamate receptors. Since glutamate receptors and, in particular, metabotropic glutamate receptors have been recognized as promoters or catalysts of intracellular metabolism, Caroverine and other 1-(aminoalkyl)-3-quinoxaline-2-on derivatives are capable of antagonizing, i.e., markedly retarding, in particular, that intracellular metabolism.
Since the quinoxaline-2-on derivatives used according to the invention are known to be pharmaceutically applicable without noticeable side effects, attempts were made in the course of the studies to define and optimize the range of action of the substance as an antioxidant and radial interceptor by increasing the dose of administration. During those studies, it was surprisingly found that the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, in addition to their known activity as neuroprotective substances and on grounds of the antioxidative action discovered in the course of the studies leading to the present invention exhibit a neuroregenerative effect if administered in higher doses. This is because radicals block the intrinsic neurotrophines in a manner that, in case a radical interceptor is applied, neurotrophine activity will be reconstituted and the neuroregenerative action of the substances used according to the invention will commence. It was, therefore, feasible in the course of the studies to not only protect against further destruction damaged nerves and, in particular, nerve paths impaired or destroyed in the course of degenerative processes by neurons occurring in the central nervous system as already stated in EP-B 0 542 689, but to restore the destroyed nerve paths in a manner that, in addition to the known neuroprotective activity of such substances, also a neuroregenerative action surprisingly entered into effect, which resulted in a remarkable reduction of the signs of neurodegenerative diseases and in an improvement in the patient
Ehrenberger Klaus
Felix Dominik
König Peter
Poeggeler Burkhard
McKenzie Thomas C.
Phafag Aktiengesellschaft
Raymond Richard
LandOfFree
Use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives for the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives for the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives for the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3115952