Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-14
2004-03-30
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S158000, C546S157000, C546S153000
Reexamination Certificate
active
06713490
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel 3,4-dihydroquinolin-2(1H)-one compounds. These compounds are useful as antagonists of NMDA (N-methyl-D-aspartate) NR2B receptor, and are thus useful for the treatment of pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety, migraine, or the like in mammalian, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.
BACKGROUND ART
Glutamate plays dual role in the central nervous system (CNS) as essential amino acid and the principal excitatory neurotransmitters. There are at least four classes of receptors, specifically N-methyl-aspartate (NMDA), 2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propionic acid (AMPA), kainate and metabotropic. There is considerable preclinical evidence that hyperalgesia and allodynia following peripheral tissue or nerve injury is not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depends on NMDA receptor-mediated central changes in synaptic excitability. In humans, NMDA receptor antagonists have also been found to decrease both pain perception and sensitization. Also, overactivation of NMDA receptor is a key event for triggering neuronal cell death under pathological conditions of acute and chronic forms of neurodegeneration. However, while NMDA receptor inhibition has therapeutic utility in the treatment of pain and neurodegenerative diseases, there are significant liabilities to many available NMDA receptor antagonists that can cause potentially serious side effects. NMDA subunits are differentially distributed in the CNS. Especially, NR2B is believed to be restricted to the forebrain and laminas I and II of the dosal horn. The more discrete distribution of NR2B subunit in the CNS may support a reduced side-effect profile of agents that act selectively at this site.
For example, NMDA NR2B selective antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in human with a reduced side-effect profile than existing NMDA antagonists (S. Boyce, et al., Neuropharmacology, 38, pp.611-623 (1999)).
International Publication Number WO 91/17156 and WO94/10166 discloses a variety of 3,4-dihydroquinolin-2(1H)-one compounds. Especially, a compound represented by the following formula is disclosed in WO 94/10166:
However, the known compounds have potential to prolong the QT-interval due to their potent inhibitory activity at HERG (human ether-a-go-go related gene) potassium channel. QT prolongation is known to have a potential liability to produce fatal cardiac arrhythmias of Torsades de Pointes (TdP). The ability to prolong the cardiac action potential duration was identified as being due to an action at the HERG potassium channel. For example, drugs withdrawn from the market due to QT prolongation, such as Cisapride and Terfenadine, are known to be potent HERG potassium channel blocker (Expert Opinion of Pharmacotherapy; 2, pp947-973, 2000). Therefore, it would be desirable if there were provided a novel NMDA NR2B selective antagonist with analgesic activity by systemic administration and with reduced inhibitory activity at HERG potassium channel.
BRIEF DISCLOSURE OF THE INVENTION
It has now surprisingly been found that a specific sub-set of compounds broadly covered by WO 91/17156 are NMDA NR2B selective antagonists with superior activity and with reduced inhibitory activity at HERG channel. Inhibitory activity at HERG channel was estimated from affinity for HERG type potassium channel was investigated by checking [
3
H]dofetilide binding, which can predict inhibitory activity at HERG channel (Eur. J. Pharmacol., 430, pp147-148, 2001).
The present invention provides a compound of the following formula (I):
wherein R
1
is fluoro, chloro, bromo, C
1-3
alkyl or C
1-3
alkoxy; and R
2
is hydrogen, fluoro, chloro, bromo, C
1-3
alkyl or C
1-3
alkoxy or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.
According to formula (I), R
1
is preferably fluoro, C
1-3
alkyl, e.g. methyl or C
1-3
alkoxy, e.g. methoxy. R
1
is most preferably fluoro.
According to formula (I), R
2
is preferably hydrogen.
According to formula (I), the asymmetric centre —C(OH)— is preferably in the (R) configuration.
A suitable sub-group of compounds of formula (I) are those represented by formula (I-a)
wherein R
1
is fluoro or methoxy; and R
2
is hydrogen or fluoro,
As used herein, the term “C
1-3
alkyl” includes methyl, ethyl, n-propyl, iso-propyl.
As used herein, the term “C
1-3
alkoxy” includes methoxy, ethoxy, n-propoxy, iso-propoxy.
Suitable compounds according to the present invention are selected from:
6-[1-hydroxy-2-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]ethyl]-3,4-dihydroquinolin-2(1H)-one;
5-fluoro-6-[1-hydroxy-2-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]ethyl]-3,4-dihydroquinolin-2(1H)-one; and
6-[1-hydroxy-2-[4-hydroxy-4-(3-methylphenyl)piperidin-1-yl]ethyl]-3,4-dihydroquinolin-2(1H)-one;
or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.
A preferred individual compound of this invention is:
(R)-6-[2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydroquinolin-2(1H)-one or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.
The 3,4-dihydroquinolin-2(1H)-one compounds of this invention have an antagonistic action towards NMDA NR2B receptor subtype selectively and are thus useful in therapeutics, particularly for the treatment of stroke or brain injury, chronic neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis (ALS), epilepsy, convulsive disorder, pain, anxiety, human immunodeficiency virus (HIV) related neuronal injury, migraine, depression, schizophrenia, tumor, post-anesthesia cognitive decline (PACD), glaucoma, tinnitus, tradive dyskinesia, allergic encephalomyelitis, opioid tolerance, drug abuse, alcohol abuse, or the like in mammalian, especially humans.
The compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain. Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is exclusively activated by noxious stimuli via peripheral transducing mechanisms (Millan 1999 Prog. Neurobio. 57: 1-164 for an integrative Review). These sensory fibres are known as nociceptors and are characterised by small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred after complex processing in the dorsal horn, either directly or via brain stem relay nuclei to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In
Ashbrook Charles W.
Aulakh Charanjit S.
Kurlandsky David R.
Pfizer Inc.
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