Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-29
2004-03-30
Rotman, Alan L. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S167000, C514S314000
Reexamination Certificate
active
06713491
ABSTRACT:
The present invention relates to a novel salt of enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid or a solvate thereof, to processes for its preparation, to pharmaceutical compositions containing it and to its use in therapy and in particularly its use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
The compound 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid of formula (I) is inter alia described in WO 99/64411 which also refers to physiologically acceptable salts thereof and more particularly it describes an enantiomer of the compound of formula (I), which is referred to therein as enantiomer A and a sodium salt thereof.
The enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid is a particularly potent antagonist of the NMDA receptor complex, and for its use in medicine there exists a need for the compound to be prepared in a form suitable for ease of isolation in a large scale manufacture and for ease of formulating into an acceptable product for administration to patients. These requirements are not conveniently met by either enantiomer A or sodium salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that the meglumine salt of enantiomer A can readily be prepared and isolated suitable in a pure form by a process that is suitable for use on a large scale, and the said salt can be conveniently obtained with the required high degree of purity and good stability and thus fulfils the exacting criteria required in the preparation of pharmaceutical compositions for administration to patients.
The present invention thus provides the meglumine salt of enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid of formula (I) or a solvate (e.g. hydrate) thereof (hereinafter referred to as the compound of the invention).
Particularly the invention provides the meglumine salt of enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid in a crystalline form.
More particularly, according to one embodiment, the invention provides for a hydrate crystalline form of the the meglumine salt of enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid (hereinafter referred to as form 1), characterised by the following X-ray powder diffraction pattern expressed as 2 Theta (&thgr;) value
Angle 2 &thgr;
4.356
18.641
22.993
11.263
18.725
23.681
11.659
20.546
25.043
12.757
21.362
25.598
12.877
22.234
26.823
13.962
22.379
28.753
15.482
22.801
17.242
22.921
According to a further embodiment of the invention there is provided for another crystalline form of the meglumine salt of enantiomer A of 7-chloro -4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid (hereinafter referred to as form 2) characterised by the following X-ray powder diffraction pattern expressed as 2 Theta (&thgr;) value
Angle 2 &thgr;
5.480
19.553
25.225
8.233
20.505
25.802
10.942
21.939
26.484
15.299
22.787
27.524
16.424
23.154
27.865
16.658
23.381
28.547
19.116
24.194
38.345
The compound of the invention can be obtained in more than one crystalline form. It is to be understood that the invention includes all such forms or mixture thereof. The compound of the invention is an excitatory amino acid antagonist. More particularly it is a potent antagonist at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such it is a potent antagonist of the NMDA receptor complex. This compound is therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compound is useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest. The compound of the invention is useful in the treatment of chronic neurodegenerative diseases such as: Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeration (e.g. AIDS, encephalopaties), Down syndrome, ocular neurodegeneration (e.g glaucoma), epilepsy, schizophrenia, depression, migraine, headaches including cluster headaches and or tension headaches, anxiety, pain (e.g inflammatory pain and neuropathic pain), neurogenic bladder, irritable bowel syndrome and or visceral hyperalgesia, emesis, irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine (e.g. smoking cessation) benzodiazepines and inhibition of tolerance induced by opioids (i.e. morphine).
The potent and selective action of the compound of the invention at the strychnine-insensitive glycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures. Thus the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al., J Neurochem 1981, 37, 1015-1024. The selectivity of the action of compounds of the invention for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors. Thus the compound of the invention was found to show little or no affinity for the kainic acid (kainate) receptor, a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor or at the NMDA binding site.
The compound of the invention may be found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C et al., Psychopharmacology (1990), 102, 551-552.
The neuroprotective activity of the compound of the invention may be demonstrated in the middle cerebral artery occlusion preparation in mice, using the procedure described by Chiamulera C. et al., European Journal of Pharmacology, 216 (1992) pp. 335-336.
The ability of compound of the invention to alleviate withdrawal symptoms from nicotine following smoking cessation may be demonstrated in conventional tests of nicotine induced relapse using the procedure described in C. Chiamulera et al., Arch. Pharmacol., 358, 1998.
The ability of the compound of the invention to inhibit pain may be demonstrated in conventional analgesic screen such as those described by Dubuisson and Dennis,
Pain,
1977, 4:161-174; J. J. Bennett and J. K Xue,
Pain,
1988, 41, 87-107.
The invention also provides for the use of the compound of the invention for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
The invention also provides for the use of the compound of the invention for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
According to a further aspect, the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of the compound of the invention.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylactics as well as the treatment of established diseases or symptoms.
It will further be appreciated that the amount of the compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800 mg per day, dependent upon the route of administration.
Thus for parenteral administration a daily dose wi
Coppins Janet L
Morgan Lorie Ann
Rotman Alan L.
SmithKline Beecham Corporation
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