Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-27
2004-12-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S229000, C548S205000, C548S240000, C514S376000, C514S378000, C514S470000, C549S466000
Reexamination Certificate
active
06828341
ABSTRACT:
FIELD OF THE INVENTION
The invention provides cyclohexylamine derivatives as N-Methyl-D-Aspartate (NMDA) antagonists, pharmacological compositions comprising the derivatives, and methods of treating diseases and disorders responsive to antagonism of NMDA receptors using the derivatives.
BACKGROUND OF THE INVENTION
Many of the physiological and pathophysiological effects of the endogenous excitatory neurotransmitter glutamate are mediated via actions at N-Methyl-D-Asparate (NMDA) receptors. Over-excitation of the NMDA receptors on postsynaptic cells—mediated by excessive release of glutamate from nerve endings or glial cells—results in a massive calcium ion influx through a calcium ion channel into neuronal cells, leading to neuronal cell death. These events occur under ischemic or hypoxic conditions such as, for example, stroke, hypoglycemia, cardiac arrest, or acute physical trauma.
NMDA receptors in vivo form an NMDA receptor channel complex in cell walls comprising at least three binding domains, including a glutamic acid (or NMDA) recognition site, a channel blocking binding site, and a strychnine-insensitive glycine binding site. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor, thereby preventing calcium ion influx into cells. Accordingly, an NMDA receptor antagonist is therapeutically useful because it minimizes damage to the central nervous system induced by calcium ion influx under ischemic or hypoxic conditions.
A functional NMDA receptor is comprised of the combination of at least one subunit termed “NR1,” which has 8 splice variants including NR1A, and one (or more) subunit termed “NR2A,” “NR2B,” “NR2C,” and “NR2D.” The combinations are designated NR1/2A, NR1/2B, NR1/2C and NR1/2D, respectively. The different NR2 subunits have distinct developmental and anatomical distributions. This suggests that agents that selectively antagonize one NR1/NR2 combination would have therapeutic actions without the psychotomimetic or dysphoric side effects associated with antagonists which block multiple NR1/NR2 combinations.
A subtype-selective NMDA receptor antagonist may be identified by methods well-known in the pharmaceutical arts, such as, for example, screening compounds in an electrophysiology assay. In one such electrophysiology assay, different subunit combinations of recombinant NR1 and NR2 receptors are expressed in Xenopus oocytes, and a potential agent is administered at different concentrations. NMDA-based electrical currents are activated by co-administration of fixed concentrations of an excitatory amino acid such as, for example, glutamic acid or glycine. The ability of an agent to antagonize the activation of the electrical current by an excitatory amino acid is measured by recording the change in the current versus the change in the concentration of the agent.
Screening of compounds in recent years have identified a number of NMDA receptor antagonists that have been used in animal and clinical human studies to demonstrate proof of concept for use of such an antagonist in the treatment of a variety of disorders. Disorders known to be responsive to blockade of NMDA receptors include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, pain, including chronic and neuropathic pain, anxiety, and chronic neurodegenerative disorders such as Parkinson's disease. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control symptoms of withdrawal from addictive drugs. In fact, excessive excitation by neurotransmitters may be responsible for the loss of neurons in a wide variety of conditions. Additional conditions include cerebral vascular disorders such as cerebral ischemia or cerebral infarction resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such as from near drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's disease, and Huntington's disease. Other conditions amendable to treatment with an subtype-selective NMDA receptor antagonist include amyotrophic lateral sclerosis (ALS), epilepsy, and schizophrenia.
For example, studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial pharmacological effects on patients suffering from Parkinson's disease. In Parkinson's disease, there is a loss of dopamine neurons in the substantia nigra. Secondary to this dopamine loss is a hyperactivity of specific brain glutamatergic pathways. This glutamatergic hyperactivity is thought to mediate some of the pathophysiological aspects of Parkinson's disease, as well as some of the side effects associated with the long-term treatment of the disease by dopamine agonists, such as L-DOPA, pergolide, ropinirole, or pramipexole. Clinical studies in humans have demonstrated that antagonists at NMDA receptors have beneficial effects in Parkinson's disease or in treating the side effects associated with the treatment of Parkinson's disease with dopamine agonists.
Pain is another example of a condition shown to be responsive to NMDA receptor antagonism. For example in previous studies, stimulation of NMDA receptors by afferent nerves transmitting painful stimuli has been demonstrated to be involved in hyperalgesic and neuropathic pain states. Animal studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial effects in treating hyperalgesic and neuropathic pain states.
However, while NMDA antagonists have been successfully used to demonstrate the proof of concept mentioned above, very few, if any, of these antagonists have shown a suitable drug profile in clinical studies. This is so even though numerous NMDA receptor antagonists have been synthesized and tested.
The difficulty referenced above with demonstrating clinical utility of NMDA receptor antagonists has been the antagonists' lack of NMDA receptor subtype selectivity and/or biological activity when dosed orally. Before the present invention, many of the drugs of the NMDA receptor antagonist class were nonselective antagonists of NMDA receptor subtypes that were administered intravenously (IV), which accounts for their undesired side effects and the present need for selective, orally efficacious agents, respectively. Given that the need for medicinal agents that treat diseases responsive to antagonism of NMDA receptors remains unmet, the search for NMDA receptor antagonists that are subtype-selective and orally efficacious continues.
We have discovered a series of novel cyclohexylamines that are subtype-selective NMDA receptor antagonists and are efficacious in vivo when dosed orally. All that is needed to practice the invention is to administer from 1 to 6 times daily to a patient in need thereof, a therapeutically effective amount of a compound of the invention. As is discussed below, determination of dosage forms and amounts of the invention compounds, routes of administration, and identification of patients in need of treatment, is within the average skill in the pharmaceutical and medical arts.
SUMMARY OF THE INVENTION
One embodiment of the present invention is a compound of Formula I
and pharmaceutically acceptable salts thereof, wherein:
* means cis or trans or mixtures thereof;
G and H are
but are never the same;
R is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, C(O)R
2
, C(O)OR
2
, C(O)NHR
2
, aralkyl, hydroxyalkyl, aminoalkyl, amino (hydroxy) alkyl, alkylaminoalkyl, carboxyalkyl, or OR
2
wherein R
2
is alkyl alkenyl or aralkyl;
R
1
is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkylaminoalkyl, hydroxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, carboxyalkyl, haloalkyl, and halogen;
g is an integer of from 0 to 3;
V is (CH
2
)
n
or (CH
2
)
m
—C═O, wherein n is an integer of from 1 to 4, and m
Deorazio Russell Joseph
Nikam Sham Shridhar
Scott Ian Leslie
Sherer Brian Alan
Ganjeizadeh Mehdi
Harvey Suzanne M.
Kurlandsky David R.
Liu Hong
Raymond Richard L.
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