Patent Publication Number: US-7915262-B2

Title: Combination preparations comprising SLV308 and a dopamine agonist

Description:
This is a divisional of application Ser. No. 11/762,206, filed Jun. 13, 2007, which claims the benefit of U.S. Provisional Application No. 60/814,051, filed Jun. 16, 2006, the disclosure of each of which is incorporated herein by reference. 
    
    
     Constant tremors in hands and legs, body movements that gradually become stiffer, slower and weaker, and mask-like facial expressions, are symptoms that have been observed throughout the history of mankind. In 1817 James Parkinson described this cluster of symptoms as ‘paralysis agitans’, and shortly thereafter the disease was named after the physician who first described it in detail. The pathological cause of Parkinson&#39;s disease involves destruction of nerve cells in the substantia nigra, the part of the brain involved with muscle movements. Loss of around 80% of striatal dopamine in Parkinson&#39;s disease results in cardinal symptoms of akinesia, rigidity and bradykinesia (Hornykiewicz, O., Dopamine (3-hydroxytyramine) and brain function, Pharmacol Reviews, 18, 925-964 (1966)). These patients have problems initiating movement and exhibit postural instability and loss of coordination. 
     Current Parkinson&#39;s disease pharmacotherapy is based on recovery of dopaminergic function (Blandini at al., ‘ Functional changes of the basal ganglia circuitry in Parkinson&#39;s disease ’, Prog Neurobiol 62, 63-88 (2000); Lledó, A., ‘ Dopamine agonists: the treatment for Parkinson&#39;s disease in the XXI century ?, Parkinsonism Relat Disord. 7, 51-58 (2000)). Dopamine does not cross the blood brain barrier and cannot therefore be used to treat Parkinson&#39;s disease. Its immediate precursor, L-DOPA (the levorotatory enantiomer of 3,4-dihydroxyphenylalanine, also referred to as levodopa) is used instead, because it penetrates the brain where it is decarboxylated to dopamine. However, levodopa is decarboxylated in peripheral tissues too. Thus only a small portion of administered levodopa is transported to the brain. Carbidopa inhibits decarboxylation of peripheral levodopa, but cannot itself cross the blood brain barrier, and has no effect on the metabolism of levodopa in the brain. The combination of carbidopa and levodopa is considered to be the most effective treatment for symptoms of Parkinson&#39;s disease. Nevertheless, certain limitations become apparent within two to five years of initiating therapy. As the disease progresses, the benefit from each dose becomes shorter (“the wearing off effect”) and some patients fluctuate unpredictably between mobility and immobility (“the on-off effect”). “On” periods are usually associated with high plasma levodopa concentrations and often include abnormal involuntary movements, i.e., dyskinesias. “Off” periods have been correlated with low plasma levodopa and bradykinetic episodes (Jankovic, J., ‘ Natural course and limitations of levodopa therapy ’, Neurology 43: S14-S17 (1993); Rascol et al.,  A five - year study of the incidence of dyskinesia in patients with early Parkinson&#39;s disease who were treated with ropinirole or levodopa , N Engl J Med 342: 1484-1491 (2000)). This has prompted clinicians to delay the initiation of L-DOPA treatment by prior treatment with dopaminergic agonists. 
     However, the use of full dopamine receptor agonists such as apomorphine, bromocryptine, lisuride, pergolide, pramipexol or ropinirole, also has its limitations: They prime for dyskinesias, induce psychotic-like symptoms including hallucinations, orthostatic hypotension, somnolence, and other side-effects (Lozano et al.,  New developments in understanding the etiology of Parkinson&#39;s disease and in its treatment , Curr Opin Neurobiol 8; 783-90 (1998); Bennett and Piercey,  Pramipexole—a new dopamine agonist for the treatment of Parkinson&#39;s disease , J Neurol Sci 163: 25-31 (1999)). It has been suggested that this could be overcome by using partial dopamine D 2/3  receptor agonists, i.e., compounds that do not maximally stimulate dopamine D 2/3  receptors, (Jenner P.,  Pharmacology of dopamine agonists in the treatment of Parkinson&#39;s disease , Neurology 26: S1-8 (2002)). Such compounds would hypothetically be capable of stimulating dopamine D 2/3  receptors when the dopaminergic tone is low, while being able to counteract excessive stimulation of the dopamine D 2  receptor when the dopaminergic tone is high, thereby resulting in “stabilisation” of dopaminergic transmission in the brain (Jenner R,  Pharmacology of dopamine agonists in the treatment of Parkinson&#39;s disease , Neurology 26: S1-8 (2002)). 
     5-HT 1A  receptor agonists may ameliorate the induction of dyskinesia since the 5-HT 1A  receptor agonist tandospirone reduced dyskinesia in L-DOPA treated Parkinson&#39;s disease patients (Kannari et al.,  Tandospirone citrate, a selective  5- HT   1A    agonist, alleviates L - DOPA induced dyskinesia in patients with Parkinson&#39;s disease , No To Shinkei 54; 133-137 (2002)) and haloperidol-induced extrapyramidal side effects in primates (Christoffersen and Meltzer,  Reversal of haloperidol - induced extrapyramidal side effects in cebus monkeys by  8- hydroxy -2-( di - n - propylamino ) tetralin and its enantiomers , Neuropsychopharmacology 18: 399-402 (1998)). More recently it has been suggested that sarizotan, a 5-HT 1A  receptor agonist and dopamine receptor ligand, could ameliorate dyskinetic symptoms (Olanow et al.,  Multicenter, open label, trial of sarizotan in Parkinson disease patients with levodopa - indiced dyskinesias  ( the SPLENDID Study ), Clin Neuropharmacol 27: 58-62 (2004); Bara-Jimenez W et al.,  Effects of serotonin  5- HT   1A    agonist in advanced Parkinson&#39;s disease,  Movement Disorders 20: 932-936 (2005); Bibbiani et al., Serotonin 5-HT 1A  agonist improves motor complications in rodent and primate parkinsonian models, Neurology 57: 1829-1834 (2001)). The presence of 5-HT 1A  receptor agonist could be beneficial to the therapeutic effects of a partial D 2/3  receptor agonist (Johnston, L. C., et al.,  Association between Intrinsic Activity and the Antiparkinsonian Effects of a Novel Dopamine D   2    Agonist series in the  1- methyl -4- phenyl -1,2,3,6- terahydropyridine Treated Primate Model of Parkinson&#39;s Disease , Eur. J. Neurol. 10: S1, 2158 (2003)). 
     Recently, different combination preparations containing L-DOPA and one or more other enzyme inhibitors have been introduced. Well known are the combinations L-DOPA/carbidopa (e.g., Sinemet®), L-DOPA/benserazide (e.g., Madopar®) and L-DOPA/carbidopa/entacapone (e.g., Stalevo®, Jost, W. H. et al., ‘ Efficacy and tolerability of Stalevo® in patients with Parkinson&#39;s disease experiencing wearing - off ’, Aktuelle Neurologie, 32, Suppl. 6, S318-S325 (2005)). More recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjunctive therapy to L-DOPA. These compounds extend the plasma half-life of L-DOPA, without significantly increasing C max . Thus, they decrease the duration of wearing-off, but tend to increase the intensity of peak-dose side effects including peak dose dyskinesias. Tolcapone appears to induce significant liver toxicity in a small percentage of patients. Another strategy aimed at slowing down the metabolism of dopamine is the use of monoamine oxidase-B (MAO-B) inhibitors in combination with L-DOPA. The administration of MAO inhibitors, however, is associated with a number of debilitating side effects that limit their use. These effects include, for example, nausea, dizziness, lightheadedness, fainting, abdominal pain, confusion, hallucinations, dry mouth, vivid dreams, dyskinesias, and headache. Characteristic for combination preparations is that they exist in many different dose combinations, because during the course of the disease usually higher doses of L-DOPA are necessary to keep the symptoms under control. Combination preparations in the form of tablets containing fixed amounts of drugs are easy to use, but simultaneously also offer limited flexibility. An illustration of the fact that fixed combinations are not universally useful is e.g. the use of the selective MAO-B inhibitor selegiline in the treatment of Parkinson&#39;s disease. In the early stage of the disease, selegiline may be given as monotherapy: the compound will slow down the metabolism of endogenous dopamine enough to keep the symptoms within tolerable limits. In later stages of the disease, the use of L-DOPA can become necessary. When the efficacy of L-DOPA starts to wear off, usually the first solution to that problem is the use of a decarboxylase inhibitor like carbidopa (see above), and when also that gets insufficient, co-therapy with selegiline will restore L-DOPA&#39;s efficacy by reducing the breakdown of the dopamine generated from the L-DOPA. Thus, in practice L-DOPA and selegiline are administered in separate preparations which may be given simultaneously or sequentially. 
     Victims seriously afflicted with Restless Leg Syndrome (RLS; also known as Ekbom&#39;s syndrome), are virtually unable to remain seated or even to stand still. Activities that require maintaining motor rest and limited cognitive stimulation, such as transportation (car, plane, train, etc.) or attending longer meetings, lectures, movies or other performances, become difficult, if not impossible. Tortured by these sensations which become more severe at night, RLS patients find sleep to be virtually impossible, adding to the diminishing quality of their lives. The urge to move, which increases over periods of rest, can be completely dissipated by movement, such as walking. However, once movement ceases, symptoms return with increased intensity. If an RLS patient is forced to lie still, symptoms will continue to build like a loaded spring and, eventually, the legs will involuntarily move, relieving symptoms immediately. Rhythmic or semi-rhythmic movements of the legs are observed if the patient attempts to remain laying down (Pollmacher and Schulz, ‘ Periodic leg movements  ( PLM ):  their relationship to sleep stages , Sleep 16: 572-577 (1993)). These movements are referred to as dyskinesias-while-awake (DWA) (Hening et al.,  Dyskinesias while awake and periodic movements in sleep in restless leg syndrome: treatment with opioids , Neurology 36: 1363-6 (1986)) or more commonly, periodic limb movements while awake (PLMW). Clinically, RLS is indicated when four diagnostic criteria are met: (1) a sensation of an urge to move the limbs (usually the legs); (2) motor restlessness to reduce sensations; (3) when at rest, symptoms return or worsen; and (4) marked circadian variation in occurrence or severity of RLS symptoms; that is, symptoms worsen in the evening and at night (Allen and Earley,  Restless leg syndrome: a review of clinical and pathophysiologic features , J Clin Neurophysiol 18: 128-147 (2001)). 
     Current treatments for RLS are varied and plagued with undesirable side effects. Therapies have included the administration of dopamine agonists, other dopaminergic agents, benzodiazepines, opiates and anti-convulsants. In cases where RLS results from a secondary condition, such as pregnancy, end-stage renal disease, erythropoietin treatment, or iron deficiency, removing the condition, such as by giving birth or treating with traditional iron supplementation, can reduce or eliminate symptoms in at least some cases (Allen and Earley,  Restless leg syndrome: a review of clinical and pathophysiologic features , J Clin Neurophysiol 18: 128-147 (2001)). However, RLS resulting from non-secondary conditions (“idiopathic” RLS), presents a greater treatment challenge. Dopaminergic agents such as levodopa generally provide effective initial treatment, but with continued use, tolerance and symptom augmentation occur in about 80% of RLS patients (Allen and Earley ‘ Augmentation of the restless leg syndrome with carbidopa/levodopa , Sleep 19: 205-213 (1996)); this complication is also common for dopamine agonists (Earley and Allen,  Pergolide and carbidopa/levodopa treatment of the restless leg syndrome and periodic leg movements in sleep in a consecutive series of patients , Sleep 19: 801-810 (1996)). The other alternatives, benzodiazepines, opiates and anti-convulsants are not as uniformly effective as the dopaminergic agents (Chesson et al.,  Practice parameters for the treatment of restless leg syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Report. Standards of Practice Committee of the American Academy of Sleep Medicine , Sleep 22: 961-968 (1999); Hening et al.,  The treatment of restless leg syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Review , Sleep 22: 970-999 (1999)). Despite changes in their treatment regimes, 15-20% of patients find that all medications are inadequate because of adverse effects and limited treatment benefit. 
     One goal of the present invention was to develop a treatment for disorders requiring recovery of dopaminergic function that is as effective as L-DOPA, but without its side effects; in particular, without its characteristic “on-off effect,” causing dyskinesias during “on”-periods, and bradykinetic episodes during “off”-periods. 
     Surprisingly, in studies in MPTP-treated marmosets, an animal model with predictive value for Parkinson&#39;s disease, it was found that combined treatment with L-DOPA and SLV308 reduced peak locomotor activity as observed after treatment with L-DOPA alone, such that hyperactivity was not observed. The duration of activity (“on”-time) following L-DOPA was increased by co-administration of SLV308. 
                         
SLV308, 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone mono hydrochloride, binds to dopamine D 2 -like receptors and 5-HT 1A  receptors. It is a partial agonist at dopamine D 2/3  receptors and a full agonist at serotonin 5-HT 1A  receptors. At cloned human dopamine D 2,L  receptors, SLV308 acted as a potent but partial D 2  receptor agonist (pEC 50 =8.0 and pA 2 =8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D 3  receptors, SLV308 acted as a partial agonist in the induction of [ 35 S]GTPγS binding (67% that of dopamine), had a higher degree of potency compared to quinpirole (pEC 50 =9.2) and antagonized the dopamine induction of [ 35 S]GTPγS binding (pA 2 =9.0). SLV308 acted as a full 5-HT 1A  receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT 1A  receptors (pEC 50 =6.3) similar to the 5-HT 1A  receptor agonist 8-OH-DPAT. In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D 2/3  receptor agonist, SLV308 antagonized the inhibitory effect of quinpirole on K + -stimulated [ 3 H]dopamine release (pA 2 =8.5) from rat striatal slices. In the same paradigm the partial D 2  agonist terguride demonstrated a greater degree of antagonism in the presence of quinpirole (pA 2 =10.3) similar to the D 2  antagonist haloperidol (pA 2 =9.3), but less than SLV308 (pA 2 =8.5). In conclusion, SLV308 combines high potency partial agonism at dopamine D 2/3  receptors (acting as a dopamine stabiliser) with full efficacy low potency serotonin 5-HMT 1A  receptor agonism. (WO 00/29397; Feenstra, et al., SLV308, Drugs of the Future, 26(2), 128-132 (2001); Johnston, L. C., et al., ‘ The novel dopamine - d 2  receptor partial agonist, SLV -308,  reverses motor disability in MPTP - lesioned common marmosets  ( Callithrix jacchus )’, Br. J. Pharmacol., 133, U-70 (2001); Johnston, L. C., et al., ‘ SLV -308:  Antiparkinsonian effects in the MPTP - treated common marmosets  ( Callithrix jacchus )’, Soc. Neurosci. Abstr., 27(1), page 531, (2001); Hesselink et al.,  SLV 308 , a molecule combining potent partial dopamine - D   2    receptor agonism with serotonin  5- HT   1A    receptor agonism: In vitro and in vivo neurochemistry ,’ Soc. Neurosci. Abstr., 27(1), page 531 (2001); Hesselink et al.,  DU  127090,  SLV 308  and SLV 318 : characterization of a chemically related class of partial dopamine agonists with varying degrees of  5- HT   1A    agonism,  Eur. J. Neurol. 10: S1, 2151 (2003); McCreary et al., ‘ SLV 308:  a Novel Antiparkinsonian Agent with Antidepressant and Anxiolytic Efficacy ’. Soc Neurosci Abstr 27: 220.2 (2001); McCreary et al.,  The in vitro characterization of SLV 308 : a novel dopamine D   2   /D   3    partial agonist and  5- HT   1A    full agonist for the treatment of Parkinson&#39;s disease.  Mov Dis. 21:S13, P93), (2006); Wolf, W. A., ‘ SLV 308  SOLVAY ’, Current Opinion in Investigational Drugs, 4(7), 878-882 (2003)). In WO 2007/023141 it was disclosed that in vivo the N-oxide of SLV308 is rapidly converted to SLV308, thus functioning as ‘prodrug’.
 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts the effect of SLV308 (0.26 mg/kg, po) on locomotor activity following treatment with L-DOPA (7.5 mg/kg po) in MPTP-lesioned common marmosets (n=6). In  FIG. 1 , points represent median total locomotor activity counts in 30 minute intervals over 7 hours. Arrow 1: SLV308 treatment; Arrow 2: L-DOPA treatment. Symbols: open squares vehicle group; filled squares L-DOPA 7.5 mg/kg po; open triangle SLV308 0.26 mg/kg po; and filled circles SLV308 followed by L-DOPA 7.5 mg/kg po. 
         FIG. 2  depicts the effect of SLV308 (0.26 mg/kg, po) on locomotor activity following treatment with L-DOPA (12.5 mg/kg, po) in MPTP-lesioned common marmosets (n=6). In  FIG. 2 , points represent median total locomotor activity counts in 30-minute intervals over 7 hours. Arrow 1: SLV308 treatment; Arrow 2 L-DOPA treatment. Symbols: empty squares vehicle group; filled squares vehicle group L-DOPA 12.5 mg/kg po; empty triangles SLV308 0.26 mg/kg po; and filled circles SLV308 followed by L-DOPA 12.5 mg/kg po. Dashed lines: Broken line—‘ON’ threshold; Unbroken line-hyperactivity threshold. Error bars are omitted for clarity. 
         FIG. 3  depicts the effect of SLV308 (0.26 mg/kg, pa) on locomotor ‘ON’ time following treatment with L-DOPA (7.5 and 12.5 mg/kg, po). Bars represent median total counts over 6 hours after oral administration of SLV308 (0.26 mg/kg po; n=6). Bars represent median total ‘ON’ time in hours. In  FIG. 3 , there was an increase in ‘ON’ time across treatment (p′s&lt;0.001, Friedman Test). # p&lt;0.02, Significant difference compared to L-DOPA alone (Wilcoxon Test). 
         FIG. 4  depicts the effect of SLV308 (0.26 mg/kg, po) on cumulative locomotor activity counts following treatment with L-DOPA (7.5 and 12.5 mg/kg, po). Bars represent median total counts over 6 hours after oral administration of SLV308 (0.26 mg/kg pa; n=6). In  FIG. 4 , the increase in counts was significant across treatment (p′s&lt;0.001, Kruskall Wallis). *p&lt;0.002, significant difference compared to vehicle (Mann Whitney Test). 
         FIG. 5  depicts the effect of SLV308 (0.26 mg/kg, po) on motor disability reversal by L-DOPA (7.5 mg/kg, po) in MPTP-common marmosets (n=6). In  FIG. 5 , individual points represent the median total disability score in 30-minute intervals over the 7 hours after treatment with L-DOPA. Arrow 1: SLV308 treatment; Arrow 2 L-DOPA treatment. Symbols: empty squares vehicle group; filled squares L-DOPA (7.5 mg/kg, po); empty triangle SLV308 (0.26 mg/kg, po); and filled circles SLV308 followed by L-DOPA (7.5 mg/kg, po). Error bars are omitted for clarity. 
         FIG. 6  depicts the effect of SLV308 (0.26 mg/kg, po) on motor disability reversal by L-DOPA (12.5 mg/kg, po) in MPTP-common marmosets (n=6). In  FIG. 6 , individual points represent the median total disability score in 30-minute intervals over the 7 hours after treatment with L-DOPA. Arrow 1: SLV308 treatment; Arrow 2 L-DOPA treatment. Symbols: empty squares vehicle group; filled squares L-DOPA (12.5 mg/kg, po); empty triangles SLV308 (0.26 mg/kg, po); and filled circles SLV308 followed by L-DOPA 12.5 mg/kg po. Error bars are omitted for clarity. 
         FIG. 7  depicts the effect of SLV308 (0.26 mg/kg, po) on cumulative motor disability following treatment with L-DOPA (7.5 and 12.5 mg/kg po). In  FIG. 7 , bars represent median total counts over 6 hours after oral administration of SLV308 (0.26 mg/kg, po; n=6). The decrease in disability was significant across treatment (p&lt;0.0005, Kruskall Wallis). *p&lt;0.001, Significant difference compared to vehicle (Mann Whitney Test). # p&lt;0.002 compared to L-DOPA (7.5 mg/kg, po) (Mann Whitney Test). 
     
    
    
     The present invention relates to a composition comprising SLV308 or its N-oxide, or at least one pharmacologically acceptable salt, hydrate or solvate thereof, and L-DOPA or at least one pharmacologically acceptable salt thereof and, optionally, a decarboxylase inhibitor and/or, optionally, a COMT-inhibitor, and/or, optionally, a MAO-B inhibitor, for simultaneous, separate or sequential use in therapy of disorders requiring recovery of dopaminergic function, such as Parkinson&#39;s disease and Restless Leg Syndrome. 
     The invention relates to the use of SLV308 or its N-oxide, a true ‘prodrug’, in cases in which a L-DOPA induces dyskinesias, or can be anticipated to induce dyskinesias. In such cases, the specific pharmacological activities of the compound, viz., partial agonism on dopamine-D 2  and dopamine-D 3  receptors, as well as full agonism on serotonin 5-HT 1A  receptors, result in a blockade of the dyskinesias without reducing the therapeutic effect of L-DOPA. 
     One embodiment of the present invention relates to pharmaceutical formulations, comprising:
     (i) SLV308, its N-oxide, or at least one pharmacologically acceptable salt, hydrate or solvate thereof, and:   (ii) L-DOPA or at least one pharmacologically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.   

     Another embodiment of the present invention relates to kits of parts comprising:
     a vessel containing SLV308, or its N-oxide, or at least one pharmacologically acceptable salt, hydrate, or solvate thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:   (ii) a vessel containing L-DOPA or at least one pharmacologically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:   (iii) instructions for the sequential, separate or simultaneous administration of SLV308 and the L-DOPA, to a patient in need thereof.   

     Another embodiment of the invention relates to a method of making a kit of parts as defined above, wherein the method comprises bringing a component (i), as defined above, into association with a component (ii), as defined above, thus rendering the two components suitable for administration in conjunction with each other. Bringing the two components into association with each other, includes that components (i) and (ii) may be:
     (i) provided as separate formulations (i.e., independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or   (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.   

     Yet another embodiment of the invention relates to methods for treatment of a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired, which method comprises administering to the patient a therapeutically effective total amount of:
     (i) SLV308, its N-oxide, or at least one pharmacologically acceptable salt, hydrate or solvate thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with:   (ii) L-DOPA or at least one pharmacologically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.   

     Still another embodiment of the invention relates to the use of pharmaceutical formulations, comprising:
     (i) SLV308, its N-oxide, or at least one pharmacologically acceptable salt, hydrate or solvate thereof, and:   (ii) L-DOPA or at least one pharmacologically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in the manufacture of a medicament for the treatment of a condition in which recovery of dopaminergic function is required or desired.   

     DEFINITIONS 
     Examples of decarboxylase inhibitors are: carbidopa and benserazide. Examples of catechol-amine-O-methyl transferase (COMT) inhibitors are: entacapone, nitecapone and tolcapone, and monoamine oxidase-B (MAO-B) inhibitors include: deprenyl, (−)-deprenyl (selegiline), desmethyldeprenyl, N-propargyl-1-(R)-aminoindan (rasagaline), phenelzine (nardil), tranyl-cypromine (parnate), CGP3466, furazolidone, isocarboxazid, pargyline, methyclothiazide and procarbazine. 
     To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. 
     Throughout the description and the claims of this specification the word “comprise” and variations of the word, such as “comprising” and “comprises” is not intended to exclude other additives, components, integers or steps. 
     The term “composition” as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 
     Within the context of this application, the term ‘combination preparation’ comprises both true combinations, meaning SLV308 and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as ‘kit-of-parts’, comprising SLV308 and L-DOPA in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g., label or drawings. With true combinations, the pharmacotherapy by definition is simultaneous. The contents of ‘kit-of-parts’, can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient. 
     The dose of the composition to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. In one embodiment of the present invention, the dosage is in a range of from 0.01 mg/kg to 10 mg/kg. The typical daily dose of the active ingredients varies within a broad range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In some embodiments, oral and parenteral dosages may be in the range of 0.1 to 1,000 mg per day of total active ingredients. 
     The term “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating the conditions listed herein. The precise effective amount for a subject will depend upon the subject&#39;s size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance. 
     The term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid. 
     “Administration in conjunction with”, includes that respective formulations comprising SLV308 and L-DOPA are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition, which condition may be acute or chronic. In some embodiments, the two formulations are administered (optionally repeatedly) sufficiently closely in time for there to be a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either of the two formulations are administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the person skilled in the art. Thus, the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component. When used in this context, the terms “administered simultaneously” and “administered at the same time as” include that individual doses of SLV308 and L-DOPA are administered within 48 hours, e.g., 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, or 30 minutes of each other. 
     The term “treatment” as used herein refers to any treatment of a mammalian, such as a human condition or disease, and includes: (1) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease. 
     As used herein, the term “medical therapy” intends to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. 
     The term “subject” as used herein, refers to an animal, for example, a mammal, such as a human, who has been the object of treatment, observation or experiment. 
     EXAMPLES 
     Treatment with the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) leads to depletion of dopamine in the caudate-putamen and ‘parkinsonian-like’ behavior in non-human and human primates (Lange K. W. et al.,  Terguride stimulates locomotor activity at  2  months but not  10  months after MPTP - treatment of common marmosets , Eur J of Pharmacology, 212, 247-52 (1992); Langston et al.,  MPTP - induced parkinsonism in humans and non - human primates—Clinical and experimental aspects , Acta Neural Scand 70, 49-54 (1984); Langston and Irwin,  MPTP: Current concepts and controversies , Clin Neuropharmacol 9, 485-507 (1986)). 
     Example 1 
     Interaction Between SLV308 and L-DOPA at Therapeutically Relevant Doses 
     Animals: adult common marmosets of either sex ( Callithrix jacchus ; n=6, weighing 320-450 g, aged 2-3 years) were used in this study. Animals were housed singly or in pairs under standard conditions at a temperature of 24±2° C. and relative humidity of 50%, employing a 12 hour light-dark cycle, with free access to food and water. All experimental work was carried out in accordance with the Animals (Scientific Procedures Act) 1986, project license nr PPL 70/4986. 
     Administration of MPTP: (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride; Research Biochemical International, UK) was dissolved in 0.9% sterile saline solution and administered by subcutaneous (sc) injection (Pearce, et al.,  De Novo Administration of Ropinirole and Bromocriptine Induces Less Dyskinesia than L - DOPA in the MPTP - treated Common Marmoset , Mov Dis, Mar, 13(2), 234-41, (1998)). To induce the full lesion, MPTP (2.0 mg/kg, sc) was administered once daily for 5 consecutive days. During MPTP-treatment and for the following six to eight weeks, animals were hand fed on a marmoset jelly diet until they had recovered sufficiently to feed themselves and their body weights had stabilised. All animals were determined responsive to L-DOPA administration prior to use. Testing commenced only when animals had recovered from the acute effects of MPTP treatment. In this study this was 70 days after commencement for MPTP treatment. 
     Drugs: SLV308 was dissolved in 10% sucrose and given in a volume of 2 ml/kg and administered by oral gavage. Doses are expressed as mg/kg free base. L-DOPA methyl ester (Sigma, UK) was dissolved in 10% sucrose in given in a volume of 2 ml/kg and administered by oral gavage. Carbidopa (Merck Sharp and Dohme, UK) was suspended in 10% sucrose in given in a volume of 2 ml/kg and administered directly into the mouth of the animal. Domperidone (Sigma, UK) was suspended in 10% sucrose in given in a volume of 2 ml/kg and administered directly into the mouth of the animal. Doses were based on a previous study with SLV308 in which it was shown that the optimal effect of SLV308 on locomotor activity and disability scores was achieved at 0.26 mg/kg, po. Doses of L-DOPA were chosen to reflect a moderate and high dose of L-DOPA (7.5 and 12.5 mg/kg, po respectively). 
     Procedure: On the day of experimentation, animals were weighed, treated with domperidone (2 mg/kg, po) directly into the mouth and after 60 minutes were treated with either SLV308 (0.26 mg/kg, po) or vehicle by oral gavage. After 30-minutes, carbidopa (12.5 mg/kg, po) was administered, and 30-minutes later L-DOPA (7.5 or 12.5 mg/kg, po) or its vehicle was administered. A modified latin square design was employed with one week wash-out periods between treatments. Animals were assessed for locomotor activity and disability as described below. 
     Assessment of locomotor activity: The animals were placed individually into activity cages (50×60×70 cm) fitted with a clear perspex door to allow clear visibility for observation. Each cage was equipped with 8 horizontally orientated infrared photocell emitters and their corresponding detectors arranged so as to permit maximum assessment of movement. Locomotor activity was assessed as the number of light beam interruptions caused by movement of the animals accumulated in 10-minute intervals for up to 7 hours. The animals were allowed a 60-minute acclimatisation period in the activity cages during which baseline activity was assessed, before drug administration. ‘On’ Threshold was defined as 3 times baseline activity in MPTP-treated marmosets. Hyperactivity was defined as 3 times normal activity in naive marmosets. ‘On’ time was the period of time in minutes that activity was above the ‘On’ Threshold. 
     Rating of disability: The animals were monitored through a one-way mirror by experienced observers, blinded to treatment, and rated for the degree of motor dysfunction. Motor dysfunction was scored on a disability rating scale; alertness (normal=0, reduced=1, sleepy=2); checking (present=0, reduced=1, absent=2); posture (normal=0, abnormal trunk+1, abnormal tail+1, abnormal limbs+1, flexed=4); balance (normal=0, impaired=1, unstable=2, spontaneous falls=3); reaction to stimuli (normal=0, reduced=1, slow=2, absent=3); vocalisation (normal=0, reduced=1, absent=2); motility (normal=0, bradykinesia or hyperkinesia=1, akinesia or severe hyperkinesia=2). These values were summed to give a maximum score of 18. 
     Analysis and Statistics: Total locomotor activity counts and total disability scores were analysed for the effect of treatment using the Friedman Test (SPSS, Version 10) followed by Wicoxon or Mann-Whitney post-hoc tests to determine individual differences. The significance level was set at 5%. 
     Example 2 
     Effects of SLV308 on L-DOPA Induced Reversal of Motor Disabilities 
     Spontaneous Locomotor Activity: SLV308 (0.26 mg/kg, po) increased locomotor activity within 30 minutes of administration ( FIG. 1 ). Peak activity was seen 180 minutes after treatment and locomotor activity, and lasted for the 7 hour observation period. L-DOPA (7.5 and 12.5 mg/kg, po) produced an immediate increase in locomotor activity which peaked 60-90 min after administration ( FIGS. 1 and 2 ). The duration of activity was 150-240 min. Peak activity following L-DOPA (7.5 and 12.5 mg/kg, po) was greater than that seen following SLV308 (0.26 mg/kg, po) alone. Following pretreatment with SLV308 (0.26 mg/kg, pa), peak and duration of activity after L-DOPA (7.5 mg/kg, po) were similar to that seen following SLV308 (0.26 mg/kg, po) alone ( FIG. 1 ). Combined treatment with L-DOPA (7.5 mg/kg, po) plus SLV308 (0.26 mg/kg, po) reduced peak locomotor activity following L-DOPA (7.5 mg/kg, po) alone to a level similar to that seen after SLV308 (0.26 mg/kg, po) alone such that hyperactivity was not observed ( FIG. 1 ). SLV308 (0.26 mg/kg, po) failed to reduce, but did not increase, the peak activity seen after L-DOPA (12.5 mg/kg, po). However, the duration of activity (‘ON’ time) following L-DOPA (7.5 and 12.5 mg/kg, po) was increased by co-administration of SLV308 (0.26 mg/kg, po), reflecting the duration of activity of SLV308 ( FIG. 3 ). Total locomotor activity was increased following all treatments compared to a vehicle treated group ( FIG. 4 ) although no other differences were observed. 
     Motor Disability: L-DOPA (7.5 and 12.5 mg/kg po) produced an immediate reversal of disability that peaked at 90 minutes after administration, with a score of 2.5 ( FIGS. 5 and 6 ). The duration of this effect was 150 and 180 minutes for L-DOPA at 7.5 and 12.5 mg/kg po, respectively. SLV308 (0.26 mg/kg po) reduced disability scores immediately after administration ( FIG. 5 ). A maximum improvement in disability (score 3) was maintained from 1 to 7 hours after administration. Following pretreatment with SLV308 (0.26 mg/kg) followed by L-DOPA (7.5 and 12.5 mg/kg po), the duration of the reversal of disability were similar to that seen following SLV308 (0.26 mg/kg po) alone (median duration of activity: 420 min, 420 min and 390 min respectively). Total disability scores were reduced over the 7 hours after administration of SLV308 (0.26 mg/kg po) administered alone or in combination with L-DOPA (7.5 mg/kg or 12.5 pa) ( FIG. 7 ). Addition of SLV308 (0.26 mg/kg po) to L-DOPA (7.5 mg/kg pa), caused an increase in total disability score compared to L-DOPA (7.5 mg/kg po) alone ( FIG. 7 ). 
     Conclusion: Administering L-DOPA (7.5 and 12.5 mg/kg, po) and SLV308 (0.26 mg/kg, po) reverse the MPTP-induced akinesia and disability. Both the high and low doses of L-DOPA had short durations of action and produced periods of hyperactivity. The duration of activity of SLV308 was considerably longer than that for L-DOPA, but hyperactivity was not observed. When given in combination, pretreatment with SLV308 prevented the hyperactivity following L-DOPA. No such interaction between SLV308 and L-DOPA was observed in the disability scores, since the effect of the combination of SLV308 and L-DOPA resembled the effect of SLV308 alone. 
     Example 3 
     Pharmaceutical Preparations 
     Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer. The pharmaceutical formulation contains at least one preparation of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. In some embodiments, the total amount of active ingredients is in the range of from about 0.1% (w/w) to about 95% (w/w) of the formulation, such as from about 0.5% to about 50% (w/w) and further, for example, from about 1% to about 25% (w/w). The molar ratio between SLV308 (or its N-oxide) and L-DOPA may be in the range of from about 1000:1 to about 1:1000, such as in the range of from about 300:1 to about 1:300, and further, for example, from about 50:1 to about 1:50. 
     The preparations of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets. 
     The active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation. The active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation. 
     Soft gelatine capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active ingredients. Hard gelatine capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine. Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration. 
     Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use. 
     Also provided according to the present invention are formulations and ‘kits of parts’ comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for use in treating a condition in which recovery of dopaminergic function is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one preparation of the invention to a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired.