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(19) United States (12) Patent Application Publication (10) Pub US 20060166972A1 (19) United States (12) Patent Application Publication (10) Pub. N0.2 US 2006/0166972 A1 Conn et al. (43) Pub. Date: Jul. 27, 2006 (54) TREATMENT OF MOVEMENT DISORDERS Publication Classi?cation WITH A METABOTROPIC GLUTAMATE 4 RECEPTOR POSITIVE ALLOSTERIC (51) Int. Cl. MODULATOR A611; 31/5513 (2006.01) A611; 31/551 (2006.01) (76) Inventors: P. Je?rey Conn, BrentWood, TN (US); A611; 31/5415 (2006.01) Anthony G DiLella, Lansdale, PA A611; 31/553 (2006.01) (US); Gene G Kinney, Collegeville, PA A611; 31/198 (2006.01) (US); Michael J Marino, Souderton, A611; 31/445 (2006.01) PA (US); Guy R Seabrook, Blue Bell, A611; 31/48 (2006.01) PA (US); David L Williams, Telford, (52) US. Cl. .................... ..514/220;514/221;514/2258; PA (US) 514/284; 514/317; 514/567; 514/649 Correspondence Address: MERCK AND CO., INC (57) ABSTRACT P 0 BOX 2000 RAHWAY, NJ 07065-0907 (US) An mGluR4 receptor positive allosteric modulator is useful, (21) App1.No.: 10/564,029 alone or in combination With a neuroleptic agent, for treating or preventing movement disorders such as Parkinson’s dis (22) PCT Filed: Jul. 7, 2004 ease, dyskinesia, tardive dyskinesia, drug-induced parkin sonism, postencephalitic parkinsonism, progressive supra (86) PCT No.: PCT/US04/21776 nuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complex, basal Related US. Application Data ganglia calci?cation, akinesia, akinetic-rigid syndrome, bradykinesia, dystonia, medication-induced parkinsonian, (60) Provisional application No. 60/486,691, ?led on Jul. Gilles de la Tourette syndrome, Huntington’s disease, 11, 2003. tremor, chorea, myoclonus, tick disorder, and dystonia. US 2006/0166972 A1 Jul. 27, 2006 TREATMENT OF MOVEMENT DISORDERS WITH boxylase inhibitor, such as carbidopa or benseraZide, Which A METABOTROPIC GLUTAMATE 4 RECEPTOR themselves do not penetrate the brain. Levodopa combined POSITIVE ALLOSTERIC MODULATOR With carbidopa (SINEMETTM) or benseraZide (MADOPARTM) is noW the treatment of choice When BACKGROUND OF TBE INVENTION levodopa is indicated. Even then, this combination therapy may be associated With side-effects such as dyskinesias and [0001] The excitatory amino acid L-glutamate (sometimes psychiatric disturbances. referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission [0006] An anticholinergic such as benZhexol or Within the mammalian central nervous system (CNS). The orphenadrine may be used, hoWever, anticholinergics cause excitatory amino acids, including glutamate, are of great peripheral parasympathetic blockade Which may cause dry physiological importance, playing a role in a variety of mouth, blurred vision and constipation, and they may also physiological processes, such as long-term potentiation precipitate glaucoma, urinary retention and a toxic confu (learning and memory), the development of synaptic plas sional state. ticity, motor control, respiration, cardiovascular regulation, and sensory perception. [0007] Dopamine agonists such as bromocriptine (PAR LODELTM), lisuride and pergolide (CELANCETM) act [0002] Glutamate acts via at least tWo distinct classes of directly on dopamine receptors and have a similar side-effect receptors. One class is composed of the ionotropic glutamate pro?le to levodopa. (iGlu) receptors that act as ligand-gated ionic channels. V121 activation of the iGlu receptors, glutamate is thought to [0008] The dyskinesias, notably tremor, chorea, myoclo regulate fast neuronal transmission Within the synapse of nus, tics and dystonias, are treated With a variety of phar tWo connecting neurons in the CNS. The second general macological agents. Thus, for example, tremor may be type of receptor is the G-protein or second messenger-linked treated With benZodiaZepines such as diaZepam; chorea may “metabotropic” glutamate (mGluR) receptor. Both types of be treated With diaZepam, a phenothiaZide or haloperidol, or receptors appear not only to mediate normal synaptic trans tetrabenaZine; tics may be controlled With neuroleptics such mission along excitatory pathWays, but also participate in as haloperidol or pimoZide; and dystonias tend to be treated the modi?cation of synaptic connections during develop With levodopa, benZodiaZepines such as diaZepam, anticho ment and throughout life. Schoepp, Bockaert, and Sladec linergics such as benZhexol, phenothiaZines and other neu Zek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald roleptics such as haloperidol, and tetrabenaZine. and Johnson, Brain Research RevieWs, 15, 41 (1990). [0009] Treatment of psychotic disorders With neuroleptic [0003] The mGluR receptors belong to the Type III G-pro agents, such as haloperidol may be at the expense of a tein coupled receptor (GPCR) superfamily. This superfamily number of side-effects, including extrapyramidal symptoms, of GPCR’s Which includes the calcium-sensing receptors, acute dystonias, tardive dyskinesias, akathesia, tremor, GABAB receptors and pheromone receptors, are unique in tachycardia, droWsiness, confusion, postural hypotension, that they are activated by binding of agonists to a large blurring of vision, precipitation of glaucoma, dry mouth, amino-terminus portion of the receptor protein. The mGlu constipation, urinary hesitance and impaired sexual func receptors are thought to mediate glutamate’s demonstrated tion. There exist patient populations that are resistant to ability to modulate intracellular signal transduction path dopamine replacement therapy, as Well as populations in Ways. OZaWa, Kamiya and TsuZuski, Prog. Neurobio., 54, Whom dyskinesias are inadequately treated With existing 581 (1998). They have been demonstrated to be localiZed antiparkinsonian therapy. Furthermore, some patients may both pre- and post-synaptically Where they can regulate be adversely affected by the extrapyramidal side-effects of neurotransmitter release, either glutamate or other neu neuroleptic drugs. rotransmitters, or modify the post-synaptic response of [0010] Thus, existing therapy for movement disorders, neurotransmitters, respectively. especially Parkinson’s disease, has centered on replacement [0004] Diseases of the extrapyramidal motor systems of lost dopaminergic tone through the use of direct or cause either a loss of movement (akinesia) accompanied by indirect dopamine agonists. While these methods are ini an increase in muscle tone (rigidity) or abnormal involuntary tially successful, most patients experience a dramatic movements (dyskinesias) often accompanied by a reduction decrease in ef?cacy and the development of severe adverse in muscle tone. The akinetic-rigid syndrome called parkin side effects Within 5 years of beginning therapy. The mecha sonism, and the dyskinesias represent opposite ends of the nism of these adverse effects is not fully understood, hoW spectrum of movement disorders (for revieW see C. D. ever it is clear that they are related to the use of dopamine Marsden in Oxford Textbook of Medicine, 3rd Edition, replacement. In vieW of the short-comings of existing Oxford University Press, 1996, vol. 3, pages 3998-4022). therapy, there is a need for neW, safe and effective treatment for movement disorders. [0005] Treatment of akinetic-rigid conditions such as par kinsonism typically involves the use of levodopa, anticho [0011] In accordance With the present invention, agents linergics or dopamine agonists. Levodopa is converted into acting doWn-stream of the dopamine system as positive dopamine in the brain by the enZyme dopa decarboxylase. allosteric modulators of the mGluR4 receptor restore bal HoWever, this enZyme is also present in the gut Wall, liver, ance in the basal ganglia motor circuit. The use of a positive kidney and cerebral capillaries, thus the peripheral forma allosteric modulator of the mGluR4 receptor bypasses the tion of levodopa metabolites may give rise to side-effects dopamine system and Would provide long lasting palliative such as nausea, vomiting, cardiac dysrhythmias and postural bene?t Without producing the side effects associated With hypotension. This peripheral decarboxylation is largely pre dopamine replacement. In addition to providing palliative vented by the addition of a selective extracerebral decar relief from the symptoms of movement disorders, this re US 2006/0166972 A1 Jul. 27, 2006 normalization of circuit activity results in a decrease in absence of the endogenous ligand (such as glutamate) in an glutamate release in the substantia nigra pars compacta animal, in particular, a human. The term “mGluR4 receptor dopamine neurons thereby arresting degeneration of these positive allosteric modulator” includes a compound that is neurons in movement disorders such as Parkinson’s disease. an “mGluR4 receptor allosteric potentiator” or an “mGluR4 receptor allosteric agonist”, as Well as a compound that has SUMMARY OF THE INVENTION mixed activity as both an “mGluR4 receptor allosteric potentiator” and an “mGluR4 receptor allosteric agonist”. [0012] The present invention is directed to the use of a positive allosteric modulator of the mGluR4 receptor, alone [0018] By the term “mGluR4 receptor allosteric potentia or in combination With a neuroleptic agent, for treating, tor” is meant any exogenously administered compound or preventing the progression, ameliorating, controlling or agent that directly or indirectly augments the response reducing the risk of movement disorders such as Parkinson’ s produced by the endogenous ligand (such as glutamate) disease, dyskinesia, tardive
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