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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, -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] agonists such as (PAR LODELTM), and (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 , 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 ; 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, 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 , 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 . 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 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 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 , 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 dyskinesia, drug-induced par When it binds to the orthosteric site of the mGluR4 receptor kinsonism, postencephalitic parkinsonism, progressive in an animal, in particular, a human. The mGluR4 receptor supranuclear palsy, multiple system atrophy, corticobasal allosteric potentiator binds to a site other than the orthosteric degeneration, parkinsonian-ALS dementia complex, basal site (an allosteric site) and positively augments the response ganglia calci?cation, akinesia, akinetic-rigid syndrome, of the receptor to an agonist. Because it does not induce bradykinesia, dystonia, medication-induced parkinsonian, desensitization of the receptor, activity of a compound as an Gilles de la Tourette syndrome, Huntington’s disease, mGluR4 receptor allosteric potentiator provides advantages tremor, chorea, myoclonus, tick disorder, and dystonia. over the use of a pure mGluR4 receptor allosteric agonist. Such advantages may include, for example, increased safety DESCRIPTION OF TH VENTION margin, higher tolerability, diminished potential for abuse, and reduced toxicity. [0013] The present invention is directed to the use of a [0019] By the term “mGluR4 receptor allosteric agonist” positive allosteric modulator of the mGluR4 receptor, alone is meant any exogenously administered compound or agent or in combination With other neuroleptic agents, for treating, that directly augments the activity of the mGluR4 receptor preventing the progression, ameliorating, controlling or in the absence of the endogenous ligand (such as glutamate) reducing the risk of movement disorders such as Parkinson’s in an animal, in particular, a human. The mGluR4 receptor disease, dyskinesia, tardive dyskinesia, drug-induced par allosteric agonist binds to the orthosteric glutamate site of kinsonism, postencephalitic parkinsonism, progressive the mGluR4 receptor and directly in?uences the orthosteric supranuclear palsy, multiple system atrophy, corticobasal site of the mGluR4 receptor. Because it does not require the degeneration, parkinsonian-ALS dementia complex, basal presence of the endogenous ligand, activity of a compound ganglia calci?cation, akinesia, akinetic-rigid syndrome, as an mGluR4 receptor allosteric agonist provides advan bradykinesia, dystonia, medication-induced parkinsonian, tages over the use of a pure mGluR4 receptor allosteric Gilles de la Tourette syndrome, Huntington’s disease, potentiator, such as more rapid onset of action. tremor, chorea, myoclonus, tick disorder, and dystonia. [0020] In a preferred embodiment of the present invention, [0014] An embodiment of the present invention is directed the compound that is an mGluR4 receptor positive allosteric to a method for treating, preventing the progression, ame modulator possesses balanced activity as an mGluR4 recep liorating, controlling or reducing the risk of a movement tor allosteric potentiator and as an mGluR4 receptor allos disorder in a patient in need thereof that comprises admin teric agonist. In an alternately preferred embodiment of the istering to the patient a therapeutically effective amount of present invention, combination therapy With a compound a positive allosteric modulator of the mGluR4 receptor or a that is an mGluR4 receptor allosteric potentiator and With a pharmaceutically acceptable salt thereof compound that is an mGluR4 receptor allosteric agonist may [0015] An embodiment of the present invention is directed be employed. to a method for treating, preventing the progression, ame [0021] In an embodiment of the present invention the liorating, controlling or reducing the risk of Parkinson’s mGluR4 receptor positive allosteric modulator is a positive disease in a patient in need thereof that comprises admin allosteric modulator of the human mGluR4 receptor. istering to the patient a therapeutically effective amount of an mGluR4 receptor positive allosteric modulator or a [0022] In an embodiment of the present invention the pharmaceutically acceptable salt thereof. mGluR4 receptor positive allosteric modulator possesses a selectivity for the mGluR4 receptor relative to each of the [0016] An embodiment of the present invention is directed other mGluR receptors of at least 3 fold as measured by the to a method for treating, preventing the progression, ame ratio of EC50 for the mGluR4 receptor to the EC50 for each liorating, controlling or reducing the risk of a dyskinesia in of the other mGluR receptors. In another embodiment of the a patient in need thereof Who is non-responsive to neuro present invention the mGluR4 receptor positive allosteric leptic agents or for Whom neuroleptic agents are contrain modulator possesses a selectivity for the mGluR4 receptor dicated, that comprises administering to the patient a thera relative to other mGluR receptors of at least 10 fold as peutically effective amount of an mGluR4 receptor positive measured by the ratio of EC50 for the mGluR4 receptor to allosteric modulator or a pharmaceutically acceptable salt the EC50 for other mGluR receptors. In another embodiment thereof. of the present invention the mGluR4 receptor positive [0017] By the term “mGluR4 receptor positive allosteric allosteric modulator possesses a selectivity for the mGluR4 modulator” is meant any exogenously administered com receptor relative to the other mGluR receptors of at least 30 pound or agent that directly or indirectly augments the fold as measured by the ratio of EC50 for the mGluR4 activity of the mGluR4 receptor in the presence or in the receptor to the EC50 for the other mGluR receptors. In US 2006/0166972 A1 Jul. 27, 2006

another embodiment of the present invention the mGluR4 propa[b]chromen-la-carboxamide (PHCCC) (Annoura, H., receptor positive allosteric modulator possesses a selectivity Fukunaga, A., Uesugi, M., Tatsouka, T. & HorikaWa, Y. for the mGluR4 receptor relative to the other mGluR recep (1996) Bioorg. Med. Chem. Len. 6, 763-766) Which has been tors of at least 100 fold as measured by the ratio of EC50 for identi?ed by the inventors as a potentiator of human and rat the mGluR4 receptor to the EC50 for the other mGluR mGluR4. The inventors have found that PHCCC does not receptors. In another embodiment of the present invention itself exhibit mGluR4 agonist activity. In contrast, the the mGluR4 receptor positive allosteric modulator possesses closely related analogue 7-(hydroxylimino)-cyclopropa[b] a selectivity for the mGluR4 receptor relative to the other chromen-la-carboxamide ethyl ester (CPCCOEt) (Annoura, mGluR receptors of at least 300 fold as measured by the H., Fukunaga, A., Uesugi, M., Tatsouka, T. & HorikaWa, Y. ratio of EC50 for the mGluR4 receptor to the EC50 for the (1996) Bioorg. Med. Chem. Lell. 6, 763-766) had no other mGluR receptors. mGluR4 potentiator activity. Characterization of PHCCC [0023] In an embodiment of the present invention the revealed that it does not potentiate or activate any other mGluR4 receptor positive allosteric modulator possesses an mGluR subtype but acts as an antagonist of some of the EC50 for binding to the mGluR4 receptor of 1 uM or less as mGluRs. In brain slice electrophysiological studies of the rat evaluated by the FLIPR as say. In another embodiment of the striato-pallidal synapse, PHCCC Was found to potentiate the present invention the mGluR4 receptor positive allosteric effect of the mGluR4 agonist L-AP4 in inhibiting transmis modulator possesses an EC50 for binding to the mGluR4 sion. Finally, PHCCC Was found to overcome inhibition of receptor of 300 nM or less as evaluated by the FLIPR assay. movement observed in a dopamine-depletion rat model of In another embodiment of the present invention the mGluR4 Parlinson’s disease. These studies support the use of an receptor positive allosteric modulator possesses an EC50 for mGluR4 receptor positive allosteric modulator alone or in binding to the mGluR4 receptor of 100 nM or less as combination With other neuroleptic agents, for treating, evaluated by the FLIPR as say. In another embodiment of the preventing the progression, ameliorating, controlling or present invention the mGluR4 receptor positive allosteric reducing the risk of movement disorders in accordance With modulator possesses an EC50 for binding to the mGluR4 the present invention. receptor of 30 nM or less as evaluated by the FLIPR assay. [0028] Althought the mGluR4 receptor positive allosteric In another embodiment of the present invention the mGluR4 modulator is useful alone for movement disorders, it Will be receptor positive allosteric modulator possesses an EC50 for appreciated that a combination of a conventional antipar binding to the mGluR4 receptor of 10 nM or less as kinsonian drug With an mGluR4 receptor positive allosteric evaluated by the FLIPR as say. In another embodiment of the modulator may provide an enhanced effect in the treatment present invention the mGluR4 receptor positive allosteric of akinetic-rigid disorders such as parkinsonism. Such a modulator possesses an EC50 for binding to the mGluR4 combination may enable a loWer dose of the antiparkinso receptor of 3 nM or less as evaluated by the FLIPR assay. In nian agent to be used Without compromising the ef?cacy of another embodiment of the present invention the mGluR4 the antiparkinsonian agent, thereby minimising the risk of receptor positive allosteric modulator possesses an EC50 for adverse side-effects. binding to the mGluR4 receptor of 1 nM or less as evaluated [0029] An embodiment of the present invention is directed by the FLIPR assay. to a method for treating, controlling, ameliorating or reduc [0024] In an embodiment of the present invention the ing the risk of an akinetic-rigid disorder in a patient in need mGluR4 receptor positive allosteric modulator is an orally therof, that comprises administering to the patient a thera active mGluR4 receptor positive allosteric modulator. In an peutically effective amount of an mGluR4 receptor positive embodiment of the present invention the mGluR4 receptor allosteric modulator or a pharmaceutically acceptable salt positive allosteric modulator is orally administered. In thereof and an amount of an antiparkinsonian agent, such another embodiment of the present invention the mGluR4 that together they give effective relief. receptor positive allosteric modulator is a non-peptidyl mGluR4 receptor positive allosteric modulator. [0030] An embodiment of the present invention is directed to a method for treating, controlling, ameliorating or reduc [0025] The mGluR4 receptor positive allosteric modulator ing the risk of a dyskinesia in a patient in need therof, that may be peptidyl or non-peptidyl in nature, hoWever, the use comprises administering to the patient a therapeutically of a non-peptidyl mGluR4 receptor positive allosteric modu effective amount of an mGluR4 receptor positive allosteric lator is preferred. In addition, for convenience the use of an modulator or a pharmaceutically acceptable salt thereof and orally active mGluR4 receptor positive allosteric modulator an amount of a neuroleptic agent, such that together they is preferred. Similarly, for convenience the use of a once give effective relief. a-day medicament is preferred. [0031] It Will be further appreciated that a combination of [0026] In an embodiment of the present invention the a conventional neuroleptic drug With mGluR4 receptor mGluR4 receptor positive allosteric modulator is a CNS positive allosteric modulator or a pharmaceutically accept penetrant mGluR4 receptor positive allosteric modulator able salt thereof may provide an enhanced effect in the and is able to enter the brain and/ or central nervous system treatment of dyskinesias. Such a combination may enable a With suf?cient concentration to have a therapeutic effect. In loWer dose of the neuroleptic agent to be used Without a further embodiment of the present invention the CNS compromising the ef?cacy of the neuroleptic agent, thereby penetrant mGluR4 receptor positive allosteric modulator is minimising the risk of adverse side-effects. A yet further a compound that exhibits suf?cient concentration in the advantage of such a combination is that, due to the action of brain and/or central nervous system to have therapeutic mGluR4 receptor positive allosteric modulator, adverse ef?cacy upon oral administration. side-effects caused by the neuroleptic agent such as acute [0027] An embodiment of the present invention is directed dystonias, dyskinesias, akathesia and tremor may be reduced to use of the compound N-phenyl-7-(hydroxylimino)cyclo or prevented. US 2006/0166972 A1 Jul. 27, 2006

[0032] The present invention also provides a method for in the speci?ed amounts, as Well as any product Which the treatment or prevention of dyskinesias, Which method results, directly or indirectly, from combination of the speci comprises administration to a patient in need of such treat ?ed ingredients in the speci?ed amounts. Such term in ment of an amount of mGluR4 receptor positive allosteric relation to pharmaceutical composition, is intended to modulator or a pharmaceutically acceptable salt thereof and encompass a product comprising the active ingredient(s), an amount of a neuroleptic agent, such that together they and the inert ingredient(s) that make up the carrier, as Well give e?fective relief. as any product Which results, directly or indirectly, from [0033] As used herein, the term “movement disorders” combination, complexation or aggregation of any tWo or includes akinesias and akinetic-rigid syndromes, dyskine more of the ingredients, or from dissociation of one or more sias and medication-induced parkinsonism (such as neuro of the ingredients, or from other types of reactions or leptic-induced parkinsonism, neuroleptic malignant syn interactions of one or more of the ingredients. Accordingly, drome, neuroleptic-induced acute dystonia, neuroleptic the pharmaceutical compositions of the present invention induced acute akathisia, neuroleptic-induced tardive encompass any composition made by admixing a compound dyskinesia and medication-induced postural tremor). of the present invention and a pharmaceutically acceptable Examples of “akinetic-rigid syndromes” include Parkin carrier. By “pharmaceutically acceptable” it is meant the son’s disease, drug-induced parkinsonism, postencephalitic carrier, diluent or excipient must be compatible With the parkinsonism, progressive supranuclear palsy, multiple sys other ingredients of the formulation and not deleterious to tem atrophy, corticobasal degeneration, parkinsonism-ALS the recipient thereof. dementia complex and basal ganglia calci?cation. Examples of “dyskinesias” include tremor (including rest tremor, pos [0040] The terms “administration of’ and or “administer tural tremor and intention tremor), chorea (such as Syden ing a” compound should be understood to mean providing a ham’s chorea, Huntington’s disease, benign hereditary cho compound of the invention or a prodrug of a compound of rea, neuroacanthocytosis, symptomatic chorea, drug the invention to the individual in need of treatment. induced chorea and hemiballism), myoclonus (including [0041] This particular application of an mGluR4 receptor generalised myoclonus and focal myoclonus), tics (includ positive allosteric modulator provides unexpected bene?t ing simple tics, complex tics and symptomatic tics), and relative to the administration of other agents for the subject dystonia (including generalised dystonia such as iodiopathic indications. For example, the mGluR4 receptor positive dystonia, drug-induced dystonia, symptomatic dystonia and allosteric modulator may exhibit a rapid onset of action and paroxymal dystonia, and focal dystonia such as ble a reduced side-effect pro?le relative to conventional agents pharospasm, oromandibular dystonia, spasmodic dysphonia, used for the treatment of extrapyramidal movement disor spasmodic torticollis, axial dystonia, dystonic Writer’s ders and other types of movement disorders (eg idiopathic cramp and hemiplegic dystonia). Parlinson’s disease, secondary Parkinson’s disease, Hunt [0034] Another “movement disorder” Which may be ingdon’s disease, dystonia, chorea, tics, myoclonus and treated according to the present invention is Gilles de la athetosis). Tourette’s syndrome, and the symptoms thereof. [0042] For use in medicine, the salts of the compounds [0035] As used herein, the term “treatment” refers both to employed in this invention refer to non-toxic “pharmaceu the treatment and to the prevention or prophylactic therapy tically acceptable salts.” Other salts may, hoWever, be useful of the aforementioned conditions. in the preparation of the compounds according to the inven [0036] The term “therapeutically effective amount” shall tion or of their pharmaceutically acceptable salts. Salts mean that amount of a drug or pharmaceutical agent that Will encompassed Within the term “pharmaceutically acceptable elicit the biological or medical response of a tissue, system, salts” refer to non-toxic salts of the compounds of this animal or human that is being sought by a researcher or invention Which are generally prepared by reacting the free clinician. base With a suitable organic or inorganic acid. Representa tive salts include the folloWing: Acetate, BenZenesulfonate, [0037] Accordingly, the present invention includes Within BenZoate, Bicarbonate, Bisulfate, Bitar‘trate, Borate, Bro its scope the use of an mGluR4 receptor positive allosteric mide, Calcium, Camsylate, Carbonate, Chloride, Clavulan modulator, alone or in combination With other agents, for the ate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, subject indications in a mammal. The preferred mammal for Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Gly purposes of this invention is human. collylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobro [0038] The subject treated in the present methods is gen mide, Hydrochloride, Hydroxynaphthoate, Iodide, lsothion erally a mammal, preferably a human, male or female. In the ate, Lactate, Lactobionate, Laurate, Malate, Maleate, present invention, it is preferred that the subject mammal is Mandelate, Mesylate, Methylbromide, Methylnitrate, Meth a human. Although the present invention is applicable both ylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine old and young people, in certain aspects such as cognition ammonium salt, Oleate, Oxalate, Pamoate (Embonate), enhancement it Would ?nd greater application in elderly Palmitate, Pantothenate, Phosphate/diphosphate, Polygalac people. The term “therapeutically effective amount” means turonate, Salicylate, Stearate, Subacetate, Succinate, Sulfate, the amount of the subject compound that Will elicit the Sulfonate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate. Furthermore, Where the compounds of the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, invention carry an acidic moiety, suitable pharmaceutically medical doctor or other clinician. acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., [0039] The term “composition” as used herein is intended calcium or magnesium salts; and salts formed With suitable to encompass a product comprising the speci?ed ingredients organic ligands, e.g., quaternary ammonium salts. US 2006/0166972 A1 Jul. 27, 2006

[0043] The mGluR4 receptor positive allosteric modulator istered in combination With a compound selected from the as employed in the present invention, may have chiral group consisting of: , , benZhexol, centers and occur as racemates, racemic mixtures and as bromocriptine, biperiden, , , individual diastereomers, or enantiomers With all isomeric , diaZepam, fenoldopam, ?uphenaZine, haloperi forms being included in the present invention. Therefore, dol, levodopa, levodopa With benseraZide, levodopa With Where a compound is chiral, the separate enantiomers, carbidopa, lisuride, , , molindolone, substantially free of the other, are included Within the scope naxagolide, , pergolide, , pimoZide, of the invention; further included are all mixtures of the tWo , , , tetrabenaZine, trihex enantiomers . yphenidyl, , thiothixene and tri?uoperaZine. [0044] An mGluR4 receptor positive allosteric modulator [0049] Suitable neuroleptic agents of use in combination may be used alone or in combination With other neruoleptic With the mGluR4 receptor positive allosteric modulator or a agents or With other compounds Which are knoWn to be pharmaceutically acceptable salt thereof include the phe bene?cial in the subject indications. An mGluR4 receptor nothiaZine, , heterocyclic dibenZaZepine, buty positive allosteric modulator and the other agent may be rophenone, diphenylbutylpiperidine and indolone classes of co-administered, either in concomitant therapy or in a ?xed neuroleptic agent. Suitable examples of phenothiaZines combination. For example, an mGluR4 receptor positive include chlorpromaZine, mesoridaZine, thioridaZine, allosteric modulator may be administered in conjunction acetophenaZine, ?uphenaZine, perphenaZine and tri?uopera With other compounds Which are knoWn in the art for the Zine. Suitable examples of include chlorpro subject indications. thixene and thiothixene. An example of a dibenZaZepine is [0045] It Will be appreciated that When using a combina cloZapine. An example of a butyrophenone is haloperidol. tion of the present invention, the mGluR4 receptor positive An example of a diphenylbutylpiperidine is pimoZide. An allosteric modulator and the antiparkinsonian or neuroleptic example of an indolone is molindolone. Other neuroleptic agent may be in the same pharmaceutically acceptable agents include loxapine, sulpiride and risperidone. It Will be carrier and therefore administered simultaneously. They appreciated that the neuroleptic agents When used in com may be in separate pharmaceutical carriers such as conven bination With the mGluR4 receptor positive allosteric modu tional oral dosage forms Which are taken simultaneously. lator may be in the form of a pharmaceutically acceptable The term “combination” also refers to the case Where the salt, for example, chlorpromaZine hydrochloride, compounds are provided in separate dosage forms and are mesoridaZine besylate, thioridaZine hydrochloride, administered sequentially. Therefore, by Way of example, acetophenaZine maleate, ?uphenaZine hydrochloride, ?ur the antiparkinsonian or neuroleptic agent may be adminis phenaZine enathate, ?uphenaZine decanoate, tri?uoperaZine tered as a tablet and then, Within a reasonable period of time, hydrochloride, thiothixene hydrochloride, haloperidol an mGluR4 receptor positive allosteric modulator may be decanoate, loxapine succinate and hydrochloride. administered either as an oral dosage form such as a tablet PerphenaZine, chlorprothixene, cloZapine, haloperidol, or a fast-dissolving oral dosage form. By a “fast-dissolving pimoZide and risperidone are commonly used in a non-salt oral formulation” is meant, an oral delivery form Which form. When placed on the tongue of a patient, dissolves Within [0050] The present invention includes Within its scope a about 10 seconds. pharmaceutical composition for the subject indications com [0046] In accordance With the present invention, an prising, as an active ingredient, an mGluR4 receptor positive mGluR4 receptor positive allosteric modulator is useful allosteric modulator in association With a pharmaceutical alone or in combination With other antiparkinsonian agents carrier or diluent. Optionally, the active ingredient of the for treating, controlling, ameliorating or reducing the risk of pharmaceutical compositions can comprise another agent in a movement disorder. addition to an mGluR4 receptor positive allosteric modula tor to minimiZe the side effects or With other pharmaceuti [0047] Suitable antiparkinsonian agents of use in combi cally active materials Wherein the combination enhances nation With the mGluR4 receptor positive allosteric modu ef?cacy and minimiZes side effects. lator include for example levodopa (With or Without a selective extracerebral decarboxylase inhibitor such as car [0051] The present invention is further directed to a bidopa or benseraZide), anticholinergics such as biperiden method for the manufacture of a medicament for the subject (optionally as its hydrochloride or lactate salt) and trihex indications in humans comprising combining a compound yphenidyl (benZhexol) hydrochloride, COMT inhibitors that is an mGluR4 receptor positive allosteric modulator such as entacapone, MOA-B inhibitors, antioxidants, A2a With a pharmaceutical carrier or diluent. adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists [0052] It Will be knoWn to those skilled in the art that there and agonists such as alentemol, bro are numerous compounds noW being used for movement mocriptine, fenoldopam, lisuride, naxagolide, pergolide and disorders. Combinations of these therapeutic agents some of pramipexole. It Will be appreciated that the dopamine ago Which have also been mentioned herein With an mGluR4 nist may be in the form of a pharmaceutically acceptable receptor positive allosteric modulator Will bring additional, salt, for example, alentemol hydrobromide, bromocriptine complementary, and often synergistic properties to enhance mesylate, fenoldopam mesylate, naxagolide hydrochloride the desirable properties of these various therapeutic agents. and pergolide mesylate. Lisuride and pramipexol are com In these combinations, an mGluR4 receptor positive allos monly used in a non-salt form. teric modulator and the therapeutic agents may be indepen dently present in dose ranges from one one-hundredth to one [0048] An mGluR4 receptor positive allosteric modulator times the dose levels Which are effective When these com or a pharmaceutically acceptable salt thereof, may be admin pounds and secretagogues are used singly. US 2006/0166972 A1 Jul. 27, 2006

[0053] To illustrate these combinations, an mGluR4 recep aqueous solutions, suspensions, or emulsions. Sterile com tor positive allosteric modulator e?‘ective clinically at a positions for injection may be formulated according to given daily dose range may be effectively combined, at conventional pharmaceutical practice by dissolving or sus levels Which are equal or less than the daily dose range, With pending the active substance in a vehicle such as Water for such compounds at the indicated per day dose range. Typi injection, a naturally occurring vegetable oil like sesame oil, cally, the individual daily dosages for these combinations coconut oil, peanut oil, cottonseed oil, etc., or a synthetic may range from about one-?fth of the minimally recom fatty vehicle like ethyl oleate or the like. Buffers, preserva mended clinical dosages to the maximum recommended tives, antioxidants and the like may be incorporated as levels for the entities When they are given singly. It Will be required. Examples of non-aqueous solvents or vehicles are readily apparent to one skilled in the art that an mGluR4 propylene glycol, polyethylene glycol, vegetable oils, such receptor positive allosteric modulator may be employed With as olive oil and corn oil, gelatin, and injectable organic esters other agents for the purposes of the present invention. such as ethyl oleate. Such dosage forms may also contain [0054] Naturally, these dose ranges may be adjusted on a adjuvants such as preserving, Wetting, emulsifying, and unit basis as necessary to permit divided daily dosage and, dispersing agents. They may be steriliZed by, for example, as noted above, the dose Will vary depending on the nature ?ltration through a bacteria-retaining ?lter, by incorporating and severity of the disease, Weight of patient, special diets sterilizing agents into the compositions, by irradiating the and other factors. compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions [0055] These combinations may be formulated into phar Which can be dissolved in sterile Water, or some other sterile maceutical compositions as knoWn in the art and as dis injectable medium immediately before use. Compositions cussed beloW. An mGluR4 receptor positive allosteric for rectal or vaginal administration may be suppositories modulator may be administered alone or in combination by oral, parenteral (e. g., intramuscular, intraperitoneal, intrave Which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository Wax. nous or subcutaneous injection, or implant), nasal, vaginal, Compositions for nasal or sublingual administration are also rectal, sublingual, or topical routes of administration and can prepared With standard excipients Well knoWn in the art. be formulated in dosage forms appropriate for each route of administration. [0059] It Will be appreciated that the amount of the [0056] Solid dosage forms for oral administration include mGluR4 receptor positive allosteric modulator Will vary not capsules, tablets, pills, poWders and granules. In such solid only With the compositions selected but also With the route dosage forms, the active compound is admixed With at least of administration, the nature of the condition being treated, one inert pharmaceutically acceptable carrier such as and the age and condition of the patient, and Will ultimately sucrose, lactose, or starch. Such dosage forms can also be at the discretion of the patient’s physician or pharmacist. comprise, as is normal practice, additional substances other [0060] The dosage of active ingredient in the compositions than inert diluents, e.g., lubricating agents such as magne of this invention may be varied, hoWever, it is necessary that sium stearate. Illustrative of the adjuvants Which may be the amount of the active ingredient be such that a suitable incorporated in tablets, capsules and the like are the folloW dosage form is obtained. The active ingredient may be ing: a binder such as gum tragacanth, acacia, corn starch or administered to patients (animals and human) in need of gelatin; an excipient such as microcrystalline cellulose; a such treatment in dosages that Will provide optimal phar disintegrating agent such as corn starch, pregelatiniZed maceutical e?icacy. The selected dosage depends upon the starch, alginic acid and the like; a lubricant such as magne desired therapeutic effect, on the route of administration, and sium stearate; a sWeetening agent such as sucrose, lactose or on the duration of the treatment. The dose Will vary from saccharin; a ?avoring agent such as peppermint, oil of patient to patient depending upon the nature and severity of Wintergreen or cherry. In the case of capsules, tablets and disease, the patient’s Weight, special diets then being fol pills, the dosage forms may also comprise buffering agents. loWed by a patient, concurrent medication, and other factors When the unit dosage form is a capsule, it may contain, in Which those skilled in the art Will recogniZe. Generally, addition to materials of the above type, a liquid carrier such dosage levels of betWeen 0.0001 to 10 mg/kg. of body as fatty oil. Various other materials may be present as Weight daily are administered to the patient, e.g., humans coatings or to otherWise modify the physical form of the and elderly humans. The dosage range Will generally be dosage unit. Tablets and pills can additionally be prepared about 0.5 mg to 1.0 g. per patient per day Which may be With enteric coatings and tablets may be coated With shellac, administered in single or multiple doses. Preferably, the sugar or both. dosage range Will be about 0.5 mg to 500 mg per patient per [0057] Liquid dosage forms for oral administration day; more preferably about 0.5 mg to 200 mg per patient per include pharmaceutically acceptable emulsions, solutions, day; and even more preferably about 5 mg to 50 mg per suspensions, syrups, the elixirs containing inert diluents patient per day. Speci?c dosages for administration include commonly used in the art, such as Water. Besides such inert 10 mg, 30 mg and 60 mg. diluents, compositions can also include adjuvants, such as Wetting agents, emulsifying and suspending agents, and [0061] Pharmaceutical compositions of the present inven sWeetening, ?avoring, and perfuming agents. A syrup or tion may be provided in a solid dosage formulation prefer ably comprising about 0.5 mg to 500 mg active ingredient, elixir may contain the active compound, sucrose as a sWeet ening agent, methyl and propyl parabens as preservatives, a more preferably comprising about 1 mg to 250 mg active dye and a ?avoring such as cherry or orange ?avor. ingredient. The pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 1 [0058] Preparations according to this invention for mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg parenteral administration include sterile aqueous or non active ingredient. US 2006/0166972 A1 Jul. 27, 2006

[0062] A minimum dosage level for the antiparkinsonian the absence of agonist, PHCCC had no effect on the activity agent Will vary depending upon the choice of agent, but is of mGluR4. Furthermore, PHCCC (10 uM) did not activate typically about 0.05 mg per day for the most potent com or potentiate responses to any other mGluR subtype exam pounds or about 20 mg per day for less potent compounds. ined. HoWever, 10 uM PHCCC partially blocked responses A maximum dosage level for the antiparkinsonian agent is of mGluRlb, mGluR2, mGluR5a, and mGluR8 to typically 30 mg per day for the most potent compounds or glutamate. 500 mg per day for less potent compounds. The compounds [0069] PHCCC potentiated the response of human are administered one to three times daily, preferably once or mGluR4 to 50 nM L-AP4 With an EC50 value of 4.1112 tWice a day, and especially once a day. uM. Similar values Were found using glutamate as the [0063] A minimum dosage level for the neuroleptic agent agonist, as Well as for rat mGluR4 using either L-AP4 or Will vary depending upon the choice of agent, but is typi glutamate as the agonist. L-AP4 concentration-response cally about 0.5 mg per day for the most potent compounds curves Were shifted to the left in the presence of 10 uM or about 20 mg per day for less potent compounds. A PHCCC. EC5O values for L-AP4 activation of human maximum dosage level for the neuroleptic agent is typically mGluR4 Were 484145 nM (n=3) in the absence of PHCCC 30 mg per day for the most potent compounds or 200 mg per and 71.4129 nM (n=3) With 10 uM PHCCC; for rat day for less potent compounds. The compounds are admin mGluR4, 8321100 nM (n=3) Without PHCCC and 67.6152 istered one to three times daily, preferably once or tWice a uM (n=3) With 10 uM PHCCC. The maximal effect of day, and especially once a day. L-AP4 Was increased approximately tWo-fold in the pres ence of 10 uM PHCCC, suggesting PHCCC also increases [0064] The folloWing examples are provided so that the the intrinsic ef?cacy of agonists. invention might be more fully understood. These examples are illustrative only and should not be construed as limiting [0070] CPCCOEt Was tested in the FLIPR assay for its the invention in any Way. ability to potentiate mGluR4. CPCCOEt did not have any [0065] Chemicals: PHCCC, CPCCOEt, L-AP4,6-cyano effect on the response of mGluR4 to agonists at concentra 7-nitroquinoxaline-2,3-dione (CNQX), D-(—)-2-amino-5 tions up to 30 uM, although at higher concentrations it phosphopentanoic acid (D-AP5) (2S)-3-[[1S)-1-(3,4-dichlo appears to be an mGluR4 antagonist (IC5O>100 uM). rophenyl)ethyl]amino-2-hydroxypropyl] Animals: All studies Were performed in an AAALAC (phenylmethyl)phosphinic acid (CGP 55845) and glutamate accredited facility in accordance With all applicable guide Were all purchased from Tocris-Cookson (Ellisville USA). lines regarding the care and use of animals. Animals Were [0066] Cell lines: Cell lines expressing mGluRlb, 2, 4, 5, group housed With access to food and Water ad libitum. 7 and 8 Were developed that Were compatible With Ca2+ [0071] Slice Preparation: All experiments Were performed sensitive ?uorescence assays. Cells expressing mGluR2, on slices from 26 to 30-d-old Sprague DaWley rats (Taconic, mGluR4, mGluR7 and mGluR8 Were coexpressed With GermantoWn, N.Y.). Animals Were killed by decapitation Gum, Gaqls, GO‘l5 and Gals, respectively. Cells Were evalu and brains Were rapidly removed and submerged in an ated using a ?uorometric imaging plate reader (FLIPR, ice-cold solution containing (in mM): choline chloride 126, Molecular Devices, Sunnyvale, Calif.), to measure their KCl 2.5, NaHZPO4 1.2, MgCl2 1.3, MgSO4 8, glucose 10, ability to mobiliZe Ca2+ in response to appropriate agonists and NaHCO3 26, equilibrated With 95% O2/5% CO2 (11). (i.e., glutamate and L-AP4). The brain Was glued to the chuck of a vibrating blade Fluorometric Imaging Plate Reader (FLIPR): microtome (Leica Microsystems, Nussloch GmbH) and parasagittal slices (300 |.J.II1I111C1()W€I‘€ obtained. Slices Were [0067] CHO or HEK cells expressing mGluR receptors immediately transferred to a 500 ml holding chamber con (mGluR CHO or HEK cells) Were plated (50,000-70,000 taining arti?cial cerebrospinal ?uid (in mM): NaCl 124, KCl cells/Well) in clear-bottomed, poly-D-lysine-coated plates 2.5, MgSO4 1.3, NaHZPO4 1.0, CaCl2 2, glucose 20, and (Becton-Dickinson) in glutamate/glutamine-free medium. NaHCO3 26, equilibrated With 95% O2/5% CO2 that Was The plated cells Were groWn overnight at 37° C. in the maintained at 32° C. After 20-min at 32° C., the holding presence of 6% C02. The folloWing day, the cells Were chamber Was alloWed to gradually decrease to room tem Washed With 3><100 pl assay buffer (Hanks Balanced Salt perature. In all experiments 5 uM glutathione, 500 uM Solution containing 20 mM HEPES, 2.5 mM probenecid, pyruvate, and 250 uM kynurenic acid Were included in the and 0.1% bovine serum albumin) using a Skatron Embla cell choline chloride buffer and in the holding chamber ACSF. Washer. The cells Were incubated With 1 uM Fluo-4AM (Molecular Probes, Eugene, Oreg.) for 1 h at 37° C. and 6% [0072] Electrophysiology: Whole-cell patch-clamp C02. The extracellular dye Was removed by Washing as recordings Were obtained (Marino et al., (2001) J. Neurosci. 21: 7001-7012. During recording, slices Were maintained described above. For potency determination, the cells Were pre-incubated in assay buffer With various concentrations of fully submerged on the stage of a 1 ml brain slice chamber compound for 5 min and then stimulated for 3 min With at 32° C. and perfused continuously With equilibrated ACSF either an EC2O or EC5O concentration of agonist (i.e. (2-3 ml/min). Neurons Were visualiZed using a differential glutamate or L-AP4) for potentiation measurements or interference contrast microscope and an infrared video sys tem. Patch electrodes Were pulled from borosilicate glass on antagonist measurements, respectively. Ca2+ ?ux Was mea a tWo-stage puller and had resistances in the range of 3-7 sured using a FLIPR. MQ When ?lled With the folloWing internal solution: (in [0068] The group I antagonist PHCCC (10 uM) potenti mM): potassium gluconate 125, NaCl 4, NaHZPO4 6, CaCl2 ated the response to glutamate (2 TM) 5.3-fold compared to 1, MgSO4 2, BAPTA-tetrapotassium salt 10, HEPES 10, glutamate alone measured in a FLIPR assay measuring Mg-ATP 2, Na2-GTP 0.3, pH=7.4. All recordings Were done increases of intracellular calcium in mGluR4 CHO cells. In using HEKA EPC9 patch clamp ampli?ers (HEKA Elek US 2006/0166972 A1 Jul. 27, 2006

tronik, Lambrecht/PfalZ, Germany). Inhibitory postsynaptic Induction and Measurement of Akinesia: currents (IPSCs) Were evoked in the presence of blockers of [0075] Rats Were injected With (5 mg/kg sc, AMPA (20 uM CNQX), NMDA (25 uM D-AP-5), and dissolved in 1% acetic acid) and kept in their home cages for GABAB (100 nM CGP 55845) receptors. Bipolar tungsten 1.5-2 hr post-injection. Activity Was measured by placing stimulation electrodes Were placed in the striatum near the rats in photocell activity cages (Hamilton-Kinder, Inc., border betWeen cortex and striatum. IPSCs Were evoked by PoWay, Calif.) equipped With 16x16 infrared beams. Fol single pulses that ranged from 30-90 V, 200-400 usec, loWing a 30 min baseline period, rats Were given a single icv delivered once every 30-60 seconds from a holding potential injection (0.5 ul/min) of either PHCCC (Tocris, 75 nmol/2.5 Was —50 mV. For hippocampal ?eld recordings a patch ul in vehicle), CPCCOEt (Tocris, 75 nmol/2.5 ul in vehicle) electrode ?lled With ACSF Was placed in the dendritic or vehicle control (2.5 pl 40% DMSO in 0.85% NaCl). Five region of CA1 or the dentate gyrus. Field excitatory postsyn min folloWing the injection of test compound or vehicle, aptic potentials (fEPSPs) Were isolated and characterized motor activity Was recorded for an additional 30 min for (Gereau, R. W. & Conn, P. J. (1995) J. Neurosci. 15, each rat. Motor activity (cumulative beam breaks/30-min 6879-6889; Macek, T. A., Winder, D. G., Gereau, R. W., period) Was recorded both pre- and post-drug treatment for Ladd, C. O. & Conn, P. J. (1996) J. Neurophysiol. 76, each rat. Changes in motor activity Were analyZed using a 3798-3806.). Compounds Were applied to the bath using a repeated-measures tWo-factor analysis of variance, Where three-Way stopcock and Were alWays applied for 10 minutes treatment (pre- versus post-drug; Within factor) and drug in order to achieve a plateau concentration. (PHCCC, CPCCOEt, and vehicle; betWeen factor) values Were used for each rat. Post hoc comparisons Were per [0073] The compound PHCCC Was found to potentiate the formed using the Bonferroni test. Statistical signi?cance Was effects of a loW dose of the group III mGluR agonist L-AP4 achieved When p<0.05. Data are expressed as mean+/—one on striato-pallidal transmission. Application of 1 uM L-AP4 SEM. produced a small but signi?cant inhibition of transmission at Allosteric Potentiation of the mGluR4 Receptor Produces an the striato-pallidal synapse. Application of vehicle (1% Antiparkinsonian Effect in a Dopamine Depletion Akinesia DMSO) or 30 uM (1) PHCCC alone had no effect on Model: striato-pallidal transmission. HoWever, consistent With our ?ndings in recombinant systems, co-application of 30 uM [0076] The ability of PHCCC to reverse motor de?cits Was PHCCC and 1 uM L-AP4 produced a marked inhibition tested in a reserpine-induced akinesia rodent model of (p<0.01 paired t-test n=4). The effect of L-AP4 in the Parkinson’s disease. PHCCC produced a signi?cant increase presence of the potentiator Was signi?cantly greater than the in locomotor activity Whereas vehicle or CPCCOEt treat effect of L-AP4 alone (p<0.05 ANOVA, Fisher’s LSD). In ment had no effect under the same conditions. This obser order to determine if the selectivity for mGluR4 observed in vation Was con?rmed by the ?nding of signi?cant main our recombinant studies Was evident in the native slice effects for test drug, treatment (pre- versus post-drug), and preparation, We took advantage of tWo previously charac the interaction betWeen drug and treatment (drug effect, teriZed synapses in the hippocampus that are knoWn to be F(2,9)=6.53, p<0.05; treatment effect, F(1,9)=30.53, modulated by activation of other members of the group III p<0.001; drug>

carriers, as Well as the type of formulation and mode of 7. The method of claim 1 Wherein the mGluR4 receptor administration employed, and such expected variations or positive allosteric modulator or a pharmaceutically accept differences in the results are contemplated in accordance able salt thereof, is administered in combination With a With the objects and practices of the present invention. It is compound selected from the group consisting of: intended, therefore, that the invention be de?ned by the acetophenaZine, alentemol, benZheXol, bromocriptine, scope of the claims Which folloW and that such claims be biperiden, chlorpromaZine, chlorprothixene, cloZapine, interpreted as broadly as is reasonable. diaZepam, fenoldopam, ?uphenaZine, haloperidol, levodopa, 1. A method for treating, preventing the progression, levodopa With benseraZide, levodopa With carbidopa, ameliorating, controlling or reducing the risk of a movement lisuride, loxapine, mesoridaZine, molindolone, naxagolide, disorder in a patient in need thereof that comprises admin olanZapine, pergolide, perphenaZine, pimoZide, pramipex istering to the patient a therapeutically effective amount of ole, risperidone, sulpiride, tetrabenaZine, trihexyphenidyl, thioridaZine, thiothixene and tri?uoperaZine. an mGluR4 receptor positive allosteric modulator or a pharmaceutically acceptable salt thereof. 8-9. (canceled) 10. The method of claim 1 Wherein the mGluR4 receptor 2. (canceled) positive allosteric modulator is N-phenyl-7-(hydroxylimi 3. The method of claim 1 Wherein the movement disorder is selected from the group consisting of Parkinson’s disease, no)cyclo -propa[b ]chromen- 1 a-carboxamide. dyskinesia, tardive dyskinesia, drug-induced parkinsonism, 11. A pharmaceutical composition comprising an mGluR4 postencephalitic parkinsonism, progressive supranuclear receptor positive allosteric modulator or a pharmaceutically palsy, multiple system atrophy, corticobasal degeneration, acceptable salt thereof and an antiparkinsonian agent, and a parkinsonian-ALS dementia complex, basal ganglia calci? pharmaceutically acceptable carrier or excipient. cation, akinesia, akinetic-rigid syndrome, bradykinesia, dys 12. Apharrnaceutical composition comprising an mGluR4 tonia, medication-induced parkinsonia, Gilles de la Tourette receptor positive allosteric modulator or a pharmaceutically acceptable salt thereof and a neuroleptic agent, and a phar syndrome, Huntington’s disease, tremor, chorea, myoclo maceutically acceptable carrier or excipient. nus, tick disorder, and dystonia. 13. (canceled) 4-5. (canceled) 14. The method of claim 1 Wherein the movement disor 6. The method of claim 1 Wherein the mGluR4 receptor der is Parkinson’s Disaese. positive allosteric modulator or a pharmaceutically accept 15. The method of claim 1 Wherein the movement disor able salt thereof, is administered in combination With an agent selected from the group consisting of: levodopa, der is an akinetic rigid disorder. 16. The method of claim 1 Wherein the movement disor levodopa With a selective extracerebral decarboxylase der is dyskinesia. inhibitor, carbidopa, entacapone, an anticholinergic, a 17. The method of claim 15, Wherein the patient in need COMT inhibitor, an A2a adenosine , a cholinergic agonist, a , a butyrophenone thereof is non-responsive to antiparkinsonian agents or is a neuroleptic agent, a diphenylbutylpiperidine neuroleptic patient for Whom antiparkinsonian agents are contraindi cated. agent, a heterocyclic dibenZaZepine neuroleptic agent, a indolone neuroleptic agent, a neuroleptic 18. The method of claim 16, Wherein the patient in need thereof is non-responsive to neuroleptic agents or is a patient agent, a thioxanthene neuroleptic agent, an NMDA receptor antagonist, a metabotropic glutamate receptor potentiator for Whom neuroleptic agents are contraindicated. and a metabotropic glutamate receptor agonist. * * * * *