Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-16
2003-06-24
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C514S314000, C546S153000, C546S159000
Reexamination Certificate
active
06583156
ABSTRACT:
The present invention relates to 4-quinolinylmethanol derivatives and their use in therapy. In particular, the present invention relates to 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.
There 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 anticholinergics (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. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. 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, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, 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.,
Trends Pharmacol. Sci.
1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W.,
Life Sci.
1994, 55, 61-65). The potential utility of adenosine A
2A
receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W.,
CNS Drugs,
1998, 10, 311-320).
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.,
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.
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
(Fredholn, B. B., et al.,
Pharmacol. Rev.
1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B.,
News Physiol. Sci.,
1995, 10, 122-128).
The design of P
1
receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F.,
Drug Dev. Res.,
1997, 39, 289-300; Baraldi, P. G. et al.,
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 Bumnstock, G.
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.
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.,
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.,
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.,
Neurosci. Lett.
1991, 130, 1624; Mandhane, S. N. et al.,
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.,
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.,
FEBS Lett.,
1993, 323, 141-144).
Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A
1
and A
2A
receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W.
J. Pharm. Pharmacol.
1994,46, 515-517).
KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A
2A
receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A
2A
receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperido
Adoms David Reginald
Gaur Suneel
Gillespie Roger John
Knutsen Lars Jacob Stray
Lerpiniere Joanne
Foley & Lardner
Seaman D. Margaret
Vernalis Research Limited
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