Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-11-06
2004-12-07
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S453000, C564S454000, C564S455000, C546S192000, C514S317000, C514S579000, C514S659000
Reexamination Certificate
active
06828462
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
Unsaturated 1-Amino-alkylcyclohexane compounds which are systemically-active as NMDA, 5HT
3
, and nicotinic receptor antagonists, pharmaceutical compositions comprising the same, method of preparation thereof, and method of treating CNS disorders which involve disturbances of glutamatergic, serotoninergic, and nicotinic transmission therewith, for treating immunomodulatory disorders, and for treating infectious diseases.
2. Prior Art
NMDA Antagonists
Antagonism of glutamate receptors of the N-methyl-D-aspartate (NMDA) type has a potentially wide range of therapeutic applications [19]. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site, strychnine-insensitive glycine site (glycine
B
), polyamine site, and phencyclidine site located inside the cation channel. The NMDA receptor channel blockers act in an uncompetitive “use-dependent” manner, meaning that they usually only block the channel in the open state. This use-dependence has been interpreted by many to mean that stronger activation of the receptor should lead to a greater degree of antagonism. Such a mode of action has further been taken to imply that this class of antagonist may be particularly useful when overactivation of NMDA receptors can be expected, such as in epilepsy, ischaemia, and trauma. However, initial clinical experience with the selective, high affinity, strongly use-dependent uncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) has been disappointing. Namely, therapeutic efficacy in epilepsy was poor while some psychotropic side effects were apparent at therapeutic doses. These observations, together with the fact that phencyclidine abusers experience similar psychotropic symptoms, has led to the conclusion that uncompetitive antagonism of NMDA receptors may not be a promising therapeutic approach.
However, the use of more elaborate electrophysiological methods indicates that there is no equality between different uncompetitive antagonists since factors such as the speed of receptor blockade (on-off kinetics) and the voltage-dependence of this effect may determine the pharmacodynamic features in vivo, i.e., therapeutic safety as well. Paradoxically, agents with low to moderate, rather than high, affinity may be desirable. Such findings triggered a reconsideration of the concept of uncompetitive antagonism of NMDA receptors in drug development [19, 22]. Uncompetitive NMDA receptor antagonists, such as amantadine and memantine—which fulfill the above criteria—have been used clinically for several years in the treatment of Parkinson 's disease and dementia respectively, and do indeed rarely produce side effects at the therapeutic doses used in their respective indications.
In view of the above mentioned evidence, we have developed a series of novel uncompetitive NMDA receptor antagonists based on the unsaturated 1-aminoalkylcyclohexane structure. The present study was devoted to compare the NMDA receptor antagonistic properties of these unsaturated 1-aminoalkylcyclohexane derivatives in receptor-binding assays, electrophysiological experiments, one convulsion model and two models of motor impairment. The substitutions of these unsaturated 1-aminoalkylcyclohexanes are detailed in Table 6.
5-HT
3
Receptor Antagonists
5-HT
3
receptors are ligand gated ionotropic receptors permeable for cations. In man 5-HT
3
receptors show the highest density on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents and the area postrema of the brain stem, which forms the chemoreceptor trigger zone.
Since 5-HT
3
receptors not only have a high density in the area postrema but also in the hippocampal and amygdala region of the limbic system, it has been suggested that 5-HT
3
selective antagonists may have psychotropic effects (Greenshaw & Silverstone, 1997).
Indeed, early animal studies suggested that the 5-HT
3
receptor antagonists, in addition to their well recognized anti-emetic use, may well be clinically useful in a number of areas. These include anxiety disorders, schizophrenia, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, Alzheimer's disease, cerebellar tremor, Parkinson's disease treatment-related psychosis, pain (migraine and irritable bowel syndrome), and appetite disorders.
Neuronal Nicotinic Receptor Antagonists
At present, ten alpha subunits (alpha 1-10) and four beta (beta 1-4) subunits for nicotinic receptors are known. &agr;4&bgr;2 receptors are probably the most common in the CNS, especially in the hippocampus and striatum. They form non-selective cation channels with slowly, incompletely desensitizing currents (type II). Homomeric &agr;7 receptors are both pre- and postsynaptic and are found in the hippocampus, motor cortex and limbic system as well as in the peripheral autonomic nervous system. These receptors are characterized by their high Ca
2+
permeability and fast, strongly desensitizing responses (type 1A). Changes in nicotinic receptors have been implicated in a number of diseases. These include Alzheimer's disease, Parkinson's disease, Tourette's syndrome, schizophrenia, drug abuse, nicotine abuse, and pain.
Based on the observation that the nicotinic agonist nicotine itself seems to have beneficial effects, drug development so far aimed at the discovery of selective nicotinic agonists.
On the other hand, it is unclear whether the effects of nicotinic agonists in, e.g., Tourette's syndrome and schizophrenia, are due to activation or inactivation/desensitization of neuronal nicotinic receptors.
The effects of agonists on neuronal nicotinic receptors is strongly dependent on the exposure period. Rapid reversible desensitization occurs in milliseconds, rundown occurs in seconds, irreversible inactivation of &agr;4&bgr;2 and &agr;7 containing receptors occurs in hours and their upregulation occurs within days.
In other words: the effects of nicotinic “agonists” may in fact be due to partial agonism, inactivation and/or desensitization of neuronal nicotinic receptors. In turn, moderate concentrations of neuronal nicotinic receptor channel blockers could produce the same effects as reported for nicotinic agonists in the above mentioned indications.
THE PRESENT INVENTION
It has now been found that a range of unsaturated 1-aminoalkylcyclohexanes have pronounced and unexpected NMDA, 5HT
3
, and nicotinic receptor antagonistic activity. Owing to the aforementioned property, the substances are suited for the treatment of a wide range of CNS disorders which involve disturbances of glutamatergic, serotoninergic, and nicotinic transmission, immunomodulatory effect, and anti-infectious diseases properties. These compounds are preferably in the form of a pharmaceutical composition thereof wherein they are present together with one or more pharmaceutically-acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel pharmaceutical compounds which are unsaturated 1-aminoalkylcyclohexane NMDA, 5HT
3
, and nicotinic receptor antagonists and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable CNS disorders which involve disturbances of glutamatergic, serotoninergic, nicotinic transmission, for treating immunomodulatory disorders, and for treating infectious diseases by employing a compound of the invention or a pharmaceutical composition containing the same. An additional object of the invention is the provision of a process for producing the unsaturated 1-aminoalkylcyclohexane active principles. Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art.
SUMMARY OF THE INVENTION
What we therefore believe to be
Danysz Wojciech
Gold Markus
Henrich Markus
Jirgensons Aigars
Kalvinsh Ivars
Davis Brian J.
Merz Pharma GmbH & Co. KGAA
The Firm of Hueschen and Sage
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