Piperidine derivatives as subtype selective...

Details Piperidine derivatives as subtype selective... Piperidine derivatives as subtype selective...

2001-11-30

2003-11-04

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S322000, C514S326000, C514S327000, C514S321000, C546S192000, C546S201000, C546S209000, C546S211000, C546S216000, C546S217000

Reexamination Certificate

active

06642256

ABSTRACT:

FIELD OF INVENTION
The invention relates to piperidine derivatives as N-Methyl-D-Aspartate (NMDA) antagonists useful in the treatment of diseases and disorders responsive to antagonism of NMDA receptors.
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. For example, U.S. Pat. Nos. 5,714,502; 6,124,317; 6,124,323; and 6,130,234 describes the piperidine-based NMDA receptor antagonists shown below.
U.S. Pat. No. 5,714,502 provides piperidines of formula
in which
R
1
and R
2
in each case independently of one another are unsubstituted or mono- to disubstituted phenyl radicals whose substituents can be A, OA, aryloxy having 6 to 10 C atoms, aralkyloxy having 7 to 11 C atoms, —O—(CH
2
)
n
—O—(bonded in directly adjacent positions or in the meta- or para-position to one another on the phenyl ring), —O—(CH
2
)
n
—OH, Hal, CF
3
, OH, NO
2
, NH
2
, NHA, NA
2
, NHR
3
, NAR
3
, SO
2
NH
2
, SO
2
NHA, SO
2
NA
2
, SO
2
NHR
3
(excluding R
3
═SO
2
A), SO
2
N(R
3
)
2
(excluding R
3
═SO
2
A) or R
3
,
R
3
is COH, CO-alkyl having 1 to 7 C atoms in the alkyl portion, CO-alkyl-aryl having 8 to 12 C atoms in the alkyl and aryl portions, CO-aryl having 7 to 13 C atoms in the aryl portion, or SO
2
A
A is an alkyl radical having 1 to 6 C atoms
n is 1 or 2
Hal is F, Cl, Br, or I,
and their physiologically acceptable salts. The invention also relates to the preparation of these novel compounds and their use as psychopharmacologically active substances.
U.S. Pat. No. 6,124,317 provides 2-substituted piperidine NMDA receptor antagonists of formula
or a pharmaceutically acceptable salt thereof wherein
Ar
1
and Ar
2
are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, a halogenated alkyl group, halogen, nitro, aryl, aralkyl, amino, a lower alkyl amino group or a lower alkoxy group;
each R
1
is independently hydrogen, alkyl or hydroxy;
each R
2
is independently hydrogen, alkyl or hydroxy;
X is —CH
2
—, O, S, or NR
3
, wherein R
3
is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
Y is —CH
2
—, —CH═CH—, —C≡C—, O, S or NR
3
;
m is 0, 1 or 2; and
n is 0, 1, 2, 3, 4 or 5,
provided that when m is 0 and X is —CH
2
—, or m is 1, R
1
is H and X is —CH
2
— that either Y is not —CH
2
— or at least one of R
2
is not hydrogen and further provided that when Y is —C═C— then X is not O.
U.S. Pat. No. 6,124,323 provides 4-substituted piperidine-based NMDA receptor antagonist

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