Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-27
2001-03-06
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06197788
ABSTRACT:
This is a 371 of PCT/GB98/03536 filed Nov. 26, 1998.
The present invention relates to the use of (±)-(R*,S*)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and in particular (−)-(11S,2′R)-&agr;-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol in the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to adenosine receptors, and particularly adenosine A
2A
receptors, and to the treatment of movement disorders such as Parkinson's disease.
Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Alzheimer's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
These are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.
Current strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and antichloinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson's disease. In particular effective treatments requiring less frequent dosing are required.
Blockade of A
2
adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Adenosine A
2A
receptor antagonists as new agents for the Treatment of Parkinson's disease.
Trends Pharmacol. Sci.
1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., CGS 15943, an adenosine A
2
receptor antagonist, reduces cerebral ischaemic injury in the Mongolian Gerbil., Life Sci. 1994, 55, 61-65).
Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., Adenosine Receptors: Pharmacology, Structure-Activity Relationships and Therapeutic Potential.
J. Med. Chem.
1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Recent Progress in Modulators of Purinergic Activity.
Exp. Opin. Ther. Patents
1995, 5,547-558).
Adenosine receptors represent a subclass (P
1
) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A
1
, A
2A
, A
2B
(of high and low affinity) and A
3
(Fredholm, B. B., et al., Nomenclature and Classification of Purinoceptors.
Pharmacol. Rev.
1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., Adenosine receptors in the central nervous system.
News Physiol. Sci.,
1995, 10, 122-128).
The design of P
1
receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Recent developments in selective agonists and antagonists acting at purine and pyrimidine receptors.
Drug Dev. Res.,
1997, 39, 289-300; Baraldi, P. G. et al., Current developments of A
2A
adenosine receptor antagonists.
Curr. Med. Chem.
1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic neurotransmission and neuromodulation: a historical perspective.
Purinergic Approaches Exp. Ther.
(1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.).
The pharmacology of adenosine A
2A
receptors has been reviewed (Ongini, E.; Fredholm, B. B. Pharmacology of adenosine A
2A
receptors.
Trends Pharmacol. Sci.
1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A
2
adenosine receptors is the evidence of a functional link between adenosine A
2A
receptors to dopamine D
2
receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A
2
receptors decreases the affinity of dopamine D
2
receptors in rat striatal membranes.
Proc. Natl. Acad. Sci.
U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Evidence for the existence of antagonistic intramembrane adenosine A
2A
/dopamine D
2
receptor interactions in the basal ganglia: Analysis from the network to the molecular level.
Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol.,
[Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia.
Trends Neurosci.
1997, 20, 482-487).
As a result of these investigations into the functional role of adenosine A
2A
receptors in the CNS, especially in vivo studies linking A
2
receptors with catalepsy (Ferre et al., Stimulation of adenosine A
2
receptors induces catalepsy.
Neurosci. Lett.
1991, 130, 162-4; Mandhane, S. N. et al., Adenosine A
2
receptors modulate haloperidol-induced catalepsy in rats.
Eur. J. Pharmacol.
1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A
2A
receptors as potentially effective treatments for Parkinson's disease.
While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A
2A
antagonist therapy is that the underlying neurodegenerative disorder is also treated. The neuroprotective effect of adenosine A
2A
antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Adenosine A
2A
receptors and neuroprotection.
Ann. N.Y. Acad. Sci.
1997, 825 (Neuroprotective Agents), 30-48).
Xanthine derivatives have been disclosed as adenosine A
2
receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A
2
receptors, such as Parkinson's disease (see, for example, EP-A-565377).
One prominent xanthine-derived adenosine A
2A
selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., CSC 8-(3-chlorostyryl)caffeine (CSC) is a selective A
2
-adenosine antagonist in vitro and in vivo.
FEBS Lett.,
1993, 323, 141-144). New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo&lsq
Fletcher Allan
Knutsen Lars Jacob Stray
Porter Richard H. P.
Shepherd Joy Miriam
Shepherd Robin
Foley & Lardner
Henley III Raymond
Shepherd Joy Miriam
Vernalis Research Limited
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