TW200813038A - Combination preparations comprising SLV308 and L-DOPA - Google Patents

Abstract

The invention concerns the use of a combination preparation of SLV308 or its N-oxide, or pharmacologically acceptable salts of those compounds: and L-DOPA, for simultaneous, separate or sequential use in the treatment of disorders requiring recovery of dopaminergic function, in particular Parkinson's disease and restless leg syndrome.

Description

200813038 IX. Invention description: Ming belongs to ^^ technology field 3

The present invention is directed to a combination of formulations comprising SLV308 and levodopa. Prior Art U Background of the Invention The permanent tremor of the hands and legs, the body movements become more rigid, slow and weak, and the mask-like facial expressions are symptoms observed throughout human history. In 1817 James Parkinson described the symptoms of this series as “tremor palsy”, and shortly thereafter, the disease was named after the first doctor who described it in detail. Pathological causes of Parkinson's disease include destruction of nigral nerve cells, which are part of the brain associated with exercise. About 80% of the striatum dopamine loss in Parkinson's disease leads to the inability to exercise, the basic symptoms of stiffness and slow movement 7966). The patient has problems with starting the exercise, presenting posture instability and coordination disorders. Drug therapy for Parkinson's disease is now based on restoring dopaminergic function (5 仏 pyridinium 2 (10) heart Z / -, 2 (10) 0). Dopamine does not pass the blood-brain barrier and therefore cannot be used to treat Parkinson's disease, its direct precursor, levodopa (the left-handed enantiomer of 3,4-dihydroxyphenylalanine, also known as levodopa ) is used instead because it penetrates the brain where it is decarboxylated to become dopamine. However, levodopa also decarboxylates in peripheral tissues. Thus only a small fraction of the administered levodopa can be delivered to the brain. Carbidopa inhibits the decarboxylation of peripheral levodopa but it does not pass the blood-brain barrier by itself 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 the symptoms of Parkinson's disease. Although as in 5 200813038, certain limitations gradually became apparent during the 2 to 5 years of starting treatment. As the disease progresses, the beneficial effects obtained from each dose become shorter (gradually weakening effect), and some patients unpredictably fluctuate between mobility and immobility ("switching phenomenon,"). "On," is usually associated with high plasma levodopa concentrations, often including abnormal involuntary movements, that is, dyskinesias. It is associated with low plasma levodopa and slow exercise (丄/卯3,· Πααο/, 2(9)0). This suggests that clinicians use pre-treatment with dopaminergic agonists to delay the onset of levodopa treatment. However, complete agonists of dopamine receptors (eg, apomorphine, bromo-concealed, ergot The use of urea, pergolide, pramipexole or ropinirole also has its limitations. They are mainly used for dyskinesia, which induce psychotic symptoms including orthostatic, orthostatic hypotension, lethargy, and Other side effects (6) ζ_, /Qing, .5_峨7 Jing). It has been suggested that these side effects can be overcome by using dopamine receptor partial agonists (that is, compounds that are not maximally stimulating dopamine receptors) (9) R 2 such as 2) Such compounds are hypothesized to stimulate dopamine D receptors when dopaminergic tone is low, and can counteract dopamine 〇2/3 when dopaminergic tone is high. Excessive stimulation, thus causing dopaminergic transmission in the brain to remain "☆" (Jenner, 2002, 5-HT1A receptor agonists can reduce dyskinesia because the receptor agonist tandospirone reduces levodos Ba-treated Parkinson's disease skeletal dyskinesia αη·, 2(9) 2) and primate fluazidin-induced antipyramidal side effects /99$). Recently constructed: 1 X哗Shali zoltan, a kind 5-HT1A receptor agonists and dopamine receptor ligands improve the symptoms of mobilization (Olanow, 2004; Bam-Jimenez, 2005. Bibbiani, 200". The presence of 5-HT1A receptor agonists Therapeutic A of D2/3 receptor partial agonists is Ά (Johnston, 2003) 〇 Recently, different combinations of formulations containing l-dopa and one or more other enzyme inhibitors have been introduced. L-D0PA is known. /Carbidopa (eg Sinemet@信尼麦), L-D〇PA/Bensem (eg Mad〇par@Medopa) and L-DOPA/Carbidopa/Entacapone (eg Stalev 〇(D, 〈/〇 from 2(9)5)). More recently, catecholamine monomethyltransferase (C0) MT) inhibitors such as tolcapone and entacapone have been proposed as adjuvant therapy for [-DOPA. These compounds extend the blood half-life of L_D〇pA without significantly increasing Cmax. Therefore, they reduce the gradual decrease The duration of side effects of peak doses, including peak dose dyskinesia, seems to induce a significant proportion of patients with hepatotoxicity. Another strategy for slowing dopamine metabolism is to use monoamine oxidase. (ΜΑ0~Β) inhibitor and L-DOPA combination. However, the administration of sputum inhibitors is accompanied by many debilitating side effects that limit their use. These effects include, for example, palpitations, dizziness, dizziness, fainting of 'abdominal pain', illusion, hallucinations, dry mouth, multiple dreams, dyskinesias, and headaches. The combination of jaws is characterized by their many different dose combinations. Usually higher doses of L-D Ο PA during the course of the disease are necessary to maintain symptoms under control. An example of the fact that a combination preparation contains a drug in a solid form in the form of a tablet, which is convenient to use, but also provides a limited flexibility, and which is not generally useful, is, for example, the choice of I* raw MAO Β The inhibitor selegiline is used in the treatment of Parkinson's disease. In the early stages of the disease 7 200813038, selegiline can be administered as a single sputum: the compound will slow down the metabolism of endogenous dopamine and control the symptoms within each limit. In the post-disease phase, L-d〇P>\The use of ywi UFA became necessary. House [-DOPA's effectiveness began to disappear] The first problem of the usual problem is that Tian used to take off her inhibitor like Carbidopa (see above), and when it was insufficient, the union with Sergei Treatment will restore the efficacy of L-DOPA by reducing the destruction of dopamine produced by L-D0PA. Therefore, in practice [D-age and selegiline are administered as separate preparations, which can be administered simultaneously or continuously in τ. Victims suffering from severely rested leg syndrome (RLS; also known as the Eckbom syndrome) are in fact unable to remain seated or even stand still. It may be difficult, if not impossible, to require (4) rest and rest, and activities such as transportation, transportation, transportation, transportation, or long-term meetings, lectures, movies, or other performances. The pain caused by these sensations will become more severe at night, and rls patients find that it is virtually impossible to fall asleep, which exacerbates their gradual decline in quality of life. The urgent need for mobility, which increases with the length of rest, can be completely eliminated by exercise such as walking. However, once the exercise stops, the symptoms of increased strength will return. If an RLS patient is forced to lie down, the symptoms will continue to act like a loaded spring, and eventually the leg will move unconsciously, which will immediately relieve the symptoms. If the patient tries to stay lie down, then the rhythm or half rhythm of the leg is observed. These movements are known as wake-up movement disorders (DMW) (%m. sigh, /卯0, or more commonly referred to as awake 8 200813038 when the periodic limb movement (PLMW). Clinically, when consistent with four The diagnostic criteria indicate an RLS: (1) a strong desire to move the limbs (usually the legs); (2) restlessness to reduce the feeling; (3) a symptom recovery or worse when resting; and (4) Significant circadian rhythm changes occur or severe RLS symptoms; more specifically, symptoms become worse at night or night (///(9), 2001) 〇RLS current treatment options are varied and have no hope Side effects. Therapies include dopamine receptor agonist administration, other dopaminergic agents, benzodiazepines, opiates and anticonvulsants. When RLS is caused by secondary conditions, such as pregnancy, end-stage renal disease, Treatment with erythropoietin, or iron deficiency, to remove these conditions, such as birth or treatment with traditional iron supplements, can at least reduce or eliminate the symptoms of some cases (4//2 continents). However, caused by non-secondary conditions RLS ("primary" RLS), proposed Greater therapeutic challenges. Dopaminergic agents such as levodopa usually provide effective initial treatment, but with continuous use, about 80% of RLS patients will have increased drug and symptom enhancement 〇4//^2, /990; This complication is also common in dopamine agonists/990. Other options, benzodiazepines, opiates and anticonvulsants are not as effective as dopaminergic agents (Chesson, 1999; Henirig, 1999). Although the treatment regimen has changed, all drug therapies have been found to be inadequate due to adverse reactions and limited treatment. 15 200813038 Λ Λ

SLV308 SLV308 N-oxide SLV308,7-[4-methyl-1-pyrazinyl]-2(3//)-benzofurazolone monohydrochloride, combined with dopamine D2-like receptor and 5-ΗΤ1Α Receptor. It is a partial agonist of the dopamine-like receptor and a full agonist of the serotonin 5-HT1 a style. On the cloned human dopamine 〇2 receptor, SLV308 acts as a potent but partial D2 receptor agonist (pEC5〇8.〇 and ΡΑ2=8.4), with 50% of forskolin-stimulated cAMP accumulation. % effectiveness. At the human recombinant dopamine D3 receptor, SLV308 is a partial agonist (67% of dopamine) in the induction of [35S]GTPrS binding, with a higher degree of potency compared to quinpirole (pEC5〇=9.2), antagonizing dopamine Induced [35S]GTPr S binding (pA2 = 9.0). SLV308 is similar to the 5-ΗΤ1Α receptor agonist 8-OH-DPAT, which plays 5-11 1 on the cloned human 5_ΗΤια receptor (ρΕ(:5〇=6.3) on the forskolin-induced cAMP accumulation. The role of the eight-receptor full agonist. In rat striatum, SLV3〇8 dose-dependently attenuated forskolin-stimulated cAMP accumulation, as expected for dopamine Dw receptor agonists. Slv308 antagonizes quinine The inhibitory effect of pyrroline on the release of κ+-stimulated [3h] dopamine from rat striatum (ρΑ2=8·5). In the same example, the A-part agonist Tegliflozin proved to be 喧There is a higher degree of antagonism in the presence of bipirin (ρΑ2=1〇·3), similar to the 〇2 antagonist fluorine σ guar (ΡΑ2=9·3), but less than SLV308 (ρΑ2=8· 5) In short, SLV3〇8 pairs of dopamine 〇2/3 receptors have high efficiency 10 200813038

Partial agonism (as dopamine stabilizer), and high potency and low potential serotonin 5-HT1A f receptor agonism effect / ^ ^ 7, FeM price α, 2 (nine) people. Johnston, 2001, · Hesselink, 2001, 2003 , McCreary, 2001, Paper · (10) 3). It is disclosed in WO 2007/023141 that the N-oxide of SLV308 is rapidly converted into SLV3〇8 in vivo, thus acting as a prodrug. SUMMARY OF THE INVENTION The purpose of the present invention is to develop a treatment method that is effective with L-DOPA, but without its side effects: in particular, there is no "switching phenomenon" characteristic of it, which is caused by "on," During the movement disorder, and during the "off, the period of exercise is too slow. Surprisingly, in the study of MPTP-treated marmosets, an animal model with predictive value for Parkinson's disease, it was found that the combination therapy of levodopa and slvove reduced the activity of levodopa alone (4). Peaks have been observed/over observed. The fine combination administration of slv increases the activity period after administration of levodopa ("open, period"). The subject of the present invention is SLV3〇8 or its N-oxide, or a pharmaceutically acceptable salt thereof , hydrates and solvates, and combinations of L-DOPA and, optionally, de-inhibitors and/or, any, COMT-inhibitors, and/or 'intentional' MA〇-B inhibitors, , respectively, or consistently applied to the treatment of conditions requiring recovery of dopaminergic function, particularly Parkinson's disease and 'hypermobile leg syndrome. The present invention relates to SLV308 or its L-DOPA-induced dyskinesia with its N-oxide ( A true "prodrug," or may be expected to induce dyskinesia in 11 200813038 applications. In such cases, the particular pharmacological activity of the compound, that is, the partial agonism of the dopamine-〇2 and dopamine VII receptors, and the complete agonistic effect on the serotonin 5·ΗΤια receptor, results in __ hindered without reducing the efficacy of levodopa. The present invention relates to a pharmaceutical preparation comprising: (1) SLV308, its oxime-oxide, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and: (9) levodopa, with a pharmaceutically acceptable adjuvant, diluent or The carrier is mixed. A further aspect of the invention relates to a kit component comprising: (1) comprising SLV308, its N-oxide, or a pharmaceutically acceptable salt, hydrate or solvate thereof (optionally with a pharmaceutically acceptable excipient, diluted a container of the agent or carrier, and: (ii) a container containing levodopa (optionally mixed with a pharmaceutically acceptable excipient, diluent or carrier), and: '(out) about SLV308 and levodopa Instructions for the administration of patients who need it continuously, separately or simultaneously. According to an aspect of the invention, there is provided a method of preparing a kit component as defined herein, the method comprising combining a component as defined above (〇 with component (ii) as defined above such that the two components are suitable for use with each other Administration: combining the two components with each other, components (i) and (1)) may: ω are provided as separate formulations (ie, independent of one another), which are then placed together and in combination with each other for combination therapy; or (Π) Packaged and supplied as separate components of the "combination pack" for use in combination therapy with 12 200813038. A further aspect of the invention relates to a method of treating a condition in a patient suffering from or susceptible to a need to restore or restore dopaminergic function, the method comprising finally treating the patient a total effective amount: (1) bifeprunox, its N-oxide, or a pharmaceutically acceptable salt, hydrate, and solvate of a, optionally in admixture with a pharmaceutically acceptable excipient, diluent or carrier; together with: ^ (11) levodopa, optionally with pharmaceutically acceptable excipients, Mix the diluent or carrier. Still another aspect of the invention relates to the use of a pharmaceutical formulation comprising: (i) SLV308, its N-oxide, or a pharmaceutically acceptable salt, hydroxide and solvate thereof, and: (ii) levodox A combination of a pharmaceutically acceptable excipient, diluent or carrier for use in the manufacture of a medicament for treating a condition in need or desired to restore dopaminergic function. Definitions Examples of decarboxylase inhibitors are: carbidopa and benserazide. Examples of catecholamine-0-methyltransferase (COMT) inhibitors are: entacapone, ticatica and tolcapone, and examples of monoamine oxidase (MA0-B) inhibitors include: propargylamine, (-) - propargyl amphetamine (selegiline), demethylpropargyl amphetamine, N-propargyl-1-(R)-aminoindan (Risajiran), stupid acetaminophen (Natal), anti Phenylpropanamine (parnate), CGP3466, furazosole-isocarbomer, pegillin, methotrexate and procarbazine. For the sake of a more concise description, there is a number 13 in the expression given in this article. 200813038 These are not subject to the term "about," and it is understood that regardless of the term "about, whether it is used explicitly or not, Each quantity given herein is intended to refer to the actual value given, and is intended to refer to an approximation of the value given, and one of ordinary skill in the art can make reasonable inferences on this basis, including / or an approximation resulting from the measurement conditions. The word "comprising," and variations of the word, such as "comprising" and "comprises", are intended to exclude other additives, ingredients, integers or steps throughout the specification and claims. The term "composition" as used herein. "includes a product that contains a particular predetermined amount or ratio of ingredients, as well as any product that results, directly or indirectly, by the combination of a particular ingredient in a particular amount. With respect to a pharmaceutical composition, the term includes one or more active ingredients, and inert ingredients. A product of any carrier' and, directly or indirectly, by the combination, complexation or polymerization of any two or more components, or by decomposition of one or more components, or by other types of reactions or interactions of one or more components. Any product. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, processing the product into the desired formulation. The pharmaceutical composition includes sufficient active ingredient compounds to treat the disease The process or condition produces the desired effect. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier. "Pharmaceutically acceptable 3L means a carrier, a diluent or The excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. / In the context of the application, the term "combination preparation, including both true 14 200813038 combination" means that SLV308 and other drugs are physically combined into one preparation, such as tablets or injections, and "kits" The component, which comprises SLV308 and levodopa in separate dosage forms, together with instructions for use, optionally has further tools to facilitate the administration of the component compounds, such as labels or drawings. Regarding the true combination, drug therapy is defined as the same day. The contents of the kit components can be administered simultaneously or at different time intervals. Synchronous or continuous treatment will depend on the characteristics of the other drugs used, characteristics like the onset and persistence of the action, plasma / Chen, degree, etc., and depending on the disease, its stage, and the characteristics of the individual patient. The dose of the administered composition depends on the relevant indication, the age of the patient 'weight and sex, which can be determined by the physician The dosage is preferably from 〇〇1 to 10 mg/kg. The typical sputum dose of the active ingredient can vary widely, depending on factors such as the relevant indication, route of administration, age of the patient, weight and Gender, which can be determined by the physician. In general, oral and parenteral dosages are in the range of daily total 〇--〇mg total active ingredient. The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent that is used to treat a condition treatable by administering a composition of the invention. The amount is for a tissue or animal; i to present a visible treatment Or improving the use of the response. Efficacy may include, for example, treatment of the conditions listed herein. The precise and effective amount for the subject will depend on the subject's health and the type and extent of the condition being treated, (Research M, veterinarian, MD or other clinician) recommendations, and therapies, or combination therapies, dosing options. 15 200813038 Therefore, it is useless to prescribe a precise effective amount. Salt, which means that the salt, within the scope of sound medical judgment, is suitable for contact with humans and lower animal tissues without abnormal toxicity, weaving, aging, material, and matching the benefit/risk ratio of the combined. Pharmaceutically acceptable salts are well known in the art. They may be prepared in situ upon isolation and purification of the compounds of the invention, or separately from pharmaceutically acceptable non-toxic domains or acids. It should be prepared, including inorganic or organic domains and inorganic or pharmaceutically acceptable salts. The pharmaceutically acceptable salts can be obtained using standard methods known in the art, for example, by mixing a compound of the invention with a suitable acid, such as a mineral or organic acid. , 'a, including each formulation containing SLV3〇8 and levodopa, are administered separately and/or simultaneously, during the course of treatment of the relevant condition, wherein the condition may be acute or chronic. Preferably, the term includes administering the two formulations (optionally repeated) to the patient in a timely manner to produce a beneficial effect. The fruit is administered in a treatment of the relevant disorder more than any of the two formulations ( Optionally (repeatedly) (in the absence of another formulation) the effect is better in the same course of treatment. Determining whether the combination provides a better benefit for the condition during treatment of a particular condition will depend on A condition to be treated or prevented, but can also be routinely accomplished by those skilled in the art. Thus, the term "co-administered, includes one or the other of the two formulations may be in another ingredient Before drug, after, and / or administration at the same time. As used herein, the term "simultaneous administration," and "same-time administration, including each dose of SLV308 and levodopa, are administered within another private hour, such as 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 16 200813038 1 hour or 30 minutes. The term "treating" as used herein refers to any treatment, preferably a human condition or disease, in a mammal, including: (1) inhibiting the disease or condition, that is, preventing the development of sputum' (2) reducing the disease or condition, that is, Degenerate the condition, or (3) stop the symptoms of the disease. The term "pharmaceutical therapy" as used herein, is meant to include a regimen of prevention, diagnosis, and treatment that is administered to a human or other mammal in vivo or in vitro. The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human, as a therapeutic, observation or test article. EXAMPLES Treatment with neurotoxin MPTP (1-mercapto-4-phenyl-1,2,3,6-tetrahydrobite) resulted in depletion of dopamine in the caudate putamen of non-human and human primates Reduction in 'Parkinson-like' behavior (Z(10) team 7992/Zimg gamma/9, Langston, 1986). Example 1: Treatment of a dose-related interaction between SLV308 and levodopa Animals: Adult males of either sex were used in this study (Ca// said r/x cc/ms; n=6, Weight 320_450g, age 2_3 years old). The animals are placed individually or in pairs under standard conditions of 24 ± 2 ° C and 50% relative humidity. The 12-hour light-dark loop provides free access to food and water. All inspections are performed in accordance with the Scientific Procedures Act 1986, project license nr PPL 70/4986. MPTP to the younger brother: (1 ~ methyl - 4 - phenyl - i, 2, 3, 6 - 17 200813038 tetrahydrogen ° ° hydrochloride; Research Biochemical International, UK) dissolved in 0.9% sterile saline , administered by subcutaneous (sc) injection (cadaveral (10) rce, / phantom. In order to induce adequate lesions, MPTP (2.0 mg/kg, sc) was administered once daily for 5 days. During MPTP treatment and in the next 6 - For 8 weeks, animals were artificially fed with simian gelatinous food until they were fully rehabilitated to be able to feed themselves and their body weight remained stable. All animals were tested for levodopa administration before use. Only when the animals had The test was started only when the acute effects of MPTP treatment were restored. In this study, this was 70 days after the start of MPTP treatment. Cover SLV308 was dissolved in 1% sucrose, formulated into a volume of 2 ml/kg, and then administered orally. Gavage was administered. The dose was expressed as mg/kg free domain. Levodopa methyl ester (Sigma, UK) was dissolved in 10% sucrose to a volume of 2 ml/kg, and then administered by oral gavage. Carbideba (Merck Sharp and D〇hme, UK) suspended in 10% sucrose Dubbed volume 2ml kg / then administered directly into the mouth of the animal. The domperidone (Sigma, υκ)) was suspended in 1〇% sucrose dubbed volume 2 ml kg / animal and then administered directly into the mouth. The dose was based on previous studies with SLV3G8, which showed the best effect of SLV308 on the scores of activity and ability loss in the previous study was achieved at 〇26 mg/kg. The dose of levodopa was chosen to reflect the medium and high doses of levodopa (7 5 and 12·5 mg/kg, respectively). On the day of the test, the animals were weighed and used. Domperidone (2 mg/kg, po) was administered directly to the oral cavity, and (9) minutes later, gavage slv3〇8 (0.26 mg/kg, P0) or vehicle was administered orally. After, for example, minutes, carbidopa 18 200813038 (12·5 mg/kg, po) was administered, and after 30 minutes, levodopa (7.5 or 5 mg/kg p〇) or its vehicle was administered. A modified latin square design - week is used during the interim period between treatments. Animals were assessed for activity capacity and capacity loss as described below. Appropriate assessment of mobility: Animals were individually placed in a movable cage (50 X 60 X 70 cm) with clean plexiglass doors to provide good visibility for observation. Each cage is equipped with eight horizontally oriented infrared photocell emitters and their corresponding detectors, arranged for maximum motion evaluation. The ability to move is assessed by the number of beam breaks caused by the accumulation of animal movements at intervals of 1 minute until 7 hours. Prior to dosing, the animals were allowed to have a 60-minute environmental acclimation period in the active cage during the baseline activity assessment. The "on" threshold was defined as the 3 baseline activities of the apes treated with MPTP. The activity was too much for the first time the experimental monkeys had 3 normal activities. ‘On, period (〇n_time) is the time period in minutes above which the activity is above the 'on' threshold. The surviving cover of Shengyou: The experienced observers monitor the animals through a one-way mirror. These observers are unaware of the treatment and they evaluate the degree of motor dysfunction. Motor dysfunction scored according to the ability loss rating scale; alert (normal = 0, decrease = 1, sleep = 2); check (existence = 〇, decrease = 1, no presence = 2); posture (normal = 〇, abnormal torso +1, abnormal tail + 1, abnormal limbs +1, buckling = 4); balance (normal = 〇, damage = 卜 unstable = 2, spontaneous fall = 3); response to stimuli (normal = 〇, decrease =1, slow = 2, no presence = 3); vocal (normal, minus ^ 1 'nothing = 2), motility (normal = 〇, slow movement or excessive exercise 1 'exercise can not or severe hyperactivity = 2 ). These values total a total of 19 200813038 maximum score of 18. Enterprise, analysis and statistics.: Total activity ability count and total ability loss score were used for analysis followed by Friedman Test (SPSS, Version 10), followed by Wixoxon or Mann-Whitney post-hoc test, analysis of total activity capacity count and The total ability loss score is used to analyze the effects of the treatment to determine individual differences. The level of significance is set at 5%. Example 2: Effect of SLV308 on levodopa-induced reversal of motor abilities Straight motility _: SLV308 (0.26 mg/kg, po) increased mobility during 30 minutes of administration (Figure 1). The peak activity was observed at 18 minutes after treatment and the activity capacity lasted for 7 hours. Levodopa (7.5 and 12.5 mg/kg, p〇) produced an immediate increase in mobility, peaking at 60–9〇111丨11 after dosing (Figures 1 and 2). The duration of the event is 15〇_24〇 for 4 miles. The peak activity after administration of levodopa (7.5 and 12-5 mg/kg, p〇) was greater than that observed after SLV308 (0.26 mg/kg, p〇) alone. After pretreatment with SLV308 (〇·26 mg/kg, po), the peak activity and duration after administration of levodopa (7.5 mg/kg, po) was similar to SLV3〇8 (〇26 mg/kg, Po) Observed after administration alone (Fig. 1). Combination therapy with levodopa (7.5 mg/kg, po) plus SLV308 (0.26 mg/kg, po) reduced the peak activity of levodopa (7.5 mg/kg, P〇) after administration alone. Similar to the level observed after SLV308 (0.26 mg/kg, po) alone, so that hyperactivity was not observed (third). SLV3〇8 (〇26 mail~, po) failed to decrease, but did not increase levodopa (12. 5 mg/kg, peak activity observed after administration. However, levodopa (7.5 and 5)丨2·5 mg/kg, 20 200813038 P〇) The duration of activity ('open, period') was increased by the combined administration of SLV308 (〇·26 mg/kg, p〇), which reflects SLV308 activity duration (3rd) compared to a "skin treatment group (Fig. 4), the total activity month b force increased after all treatments 'although no other differences were observed. Levodopa (7.5 and 12.5) Mg/kgpo) produced a direct reversal of loss of capacity, which peaked at 90 minutes after dosing, with a score of 2.5 (Figures 5 and 6). When levodopa was 7.5 and 12.5 mg/kg P, respectively, The duration of no effect was 15 〇 and 180 minutes. SLV308 (0.26 mg/kg P〇) reduced the ability loss score immediately after administration (Figure 5). The greatest improvement in capacity loss (score 3) was maintained at After the drug, 丨7 hours. After pretreatment with SLV3〇8 (〇26 mg/kg) followed by levodopa (75 and 125 mg/kg p〇), the duration of reversal of capacity loss Similar to that observed after SLV308 (〇·26 mg/kg p〇) alone (the median duration of activity was 42〇min, 42〇min and 390 min, respectively). SLV3〇8 was administered alone (〇26 After mg/kg (10) or in combination with levodopa (7.5 mg/kg or 12_5 po), the total loss of ability score was reduced by 7 hours (different 7). To levodopa (7.5 mg/kg p〇) The addition of SLV308 (0·26 mg/kg po) resulted in an increase in total capacity loss score compared to levodopa (7.5 mg/kg p〇) alone (Figure 7). Test: These data confirmed left-handed rotation Dopa (7.5 and 12·5 mg/kg, p〇) and SLV308 (0·26 mg/kg, po) all reversed MPTP-induced motor inability and loss of ability. High-dose and low-dose levodopa There was a short duration of activity, and there was also a hyperactivity period. The duration of activity of SLV308 was significantly longer than that of levodopa, and no hyperactivity was observed. When administered in combination, pretreatment with SLV308 prevented administration of levodopa After the overactivity. 21 200813038 No such interaction between SLV308 and levodopa was observed in the loss of ability score. Because the combination of SLV3〇8 and levodopa is similar to the effect of SLV308 alone.Example 3: Pharmaceutical Formulations The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules. (including microcapsules), solutions, injections, ointments (emulsions and gels) 'suppositories, suspensions, and other types disclosed herein or apparent to those skilled in the art from the description and common general knowledge in the art. The compositions are administered orally, intravenously, subcutaneously, intratracheally, bronchially, intranasally, pulmonaryly, transdermally, orally, rectally, parenterally or otherwise. The pharmaceutical formulation contains at least one formulation of the invention in admixture with a pharmaceutically acceptable excipient, diluent and/or carrier. The total amount of active ingredient suitably comprises from about 0.1% (w/w) to about 95% (w/w) of the formulation, suitably from 5% to 5% (w/w), preferably from 1% to 25%. (w/w). The molar ratio between SLV308 (or its N-oxide) and levodopa may be about 1000: about 1 : 1 , suitably 3: 1 - 1 : 300, preferably 50: 1 — 1 : 5〇. The preparation of the present invention can utilize a lion substance such as a liquid or a solid 'remaining ingredient by a usual method, for example, a pharmaceutically acceptable liquid (iv) bulk filler and extender, a solvent, an emulsifier, a lubricant, a fragrance, a colorant and/or a buffer. A coffee suitable for administration is prepared. The auxiliary f used by f includes carbonic acid, titanium dioxide 'lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, powdered powder, powdered powder, cellulose and its derivatives. , animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, ethylene glycol and solvents, for example, sterile water and mono- 22 200813038 or polyols such as glycerol, and disintegrants and lubricants such as magnesium stearate, Calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. The active ingredient may be premixed with other inactive ingredients, respectively, prior to mixing to form the formulation. The active ingredients may also be mixed with each other prior to mixing with the inactive ingredients to form a formulation. Soft gelatin capsules may be prepared in a mixture capsule containing the active ingredient of the invention, vegetable oil, fat, or other excipients suitable for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredient. The hard gelatine capsules may also contain the active ingredient together with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, contiguous starch, cellulose derivatives or gelatin. The dosage unit for rectal administration can be formulated as (1) in the form of a suppository containing the active substance in admixture with a neutral fat base; (ii) active in admixture with vegetable oil, shi butterfly oil or other excipients suitable for gelatin rectal capsules; A form of gelatin rectal capsule of the substance; in the form of a pre-formed micro-eneus; or (iv) in the form of a dry micro-enema formulation that is reconstituted in a suitable solvent prior to administration. The liquid preparation may be in the form of a syrup, an elixir, a concentrated dropping pill or a suspension. For example, the active ingredient and the remaining ingredients include, for example, sugar or sugar alcohol and ethanol, water, glycerol, propylene glycol and polyethylene. a mixture/suspension of a mixture of alcohols. Such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents, if desired. The liquid preparations can also be prepared in the form of a dry powder which is reconstituted with a suitable solvent before use. A solution for parenteral administration can be prepared as a solution of the preparation of the present invention in a pharmaceutically acceptable solvent. These solutions may also contain a stabilizing ingredient, 23 200813038 Preservatives and ingredients. The stomach material can be made into a dry powder and reconstituted with a suitable solvent before use. This month also provides a formulation and a 'kit component containing one or more ingredients containing one or more of the ingredients of the present pharmaceutical composition for medical/oral purposes. Accompanying such a container may be a variety of written materials, such as ♦ 儿月玲 or prescribed by a government agency, to specify a drug product: a notice of use or sale, which reflects the government agency’s human or veterinary drug Approval of preparation, use or sale. The use of a formulation of the invention in the treatment of a condition in need of or in need of restoring dopaminergic function, and the method of treatment includes the administration of a treatment to a patient suffering from or susceptible to a condition in which he or she needs to recover dopamine. At least one effective amount of the formulation of the invention. [Simplified illustration] Figure 1: In the MPTP-damaged common marmoset (n=6), SLV308 (〇·26 mg/kg, po) after treatment with levodopa (7 5 called p〇) The role of the ability to move. The points represent (iv) the median total exercise capacity count for each 3 () minute interval of 7 hours. Arrow 1: SLV is still treated, arrow 2: levodopa is treated. Symbol: hollow square medium, group, solid square levodopa 7 5 mg/kg p〇, empty dihedral SLV308 0.26 mg/kg p〇, solid round levodopa 7 5 mg/kg PLV after administration of SLV308. Figure 2. Activity of SLV3〇8 (〇·26 mg/kg, po) in the treatment of levodopa (125 mg/kg p〇) in MPTP-injured common marmosets (n=6) effect. The dot represents the median count of total exercise capacity over a 3 hour interval of 3 hours. Arrow 1: SLV308 treatment, arrow 2: levodopa treatment. 24 200813038 Symbol: hollow square medium group, solid (black) square: levodopa 12.5 mg/kg po, empty triangle SLV308 0.26 mg/kg p〇, solid round levodopa 12.5 mg/kg p〇 after administration SLV308. Hidden line: Dotted line: ‘open, inter-value’ line of continuous performance: activity over-threshold. The error bars are omitted for clarity and conciseness. Figure 3: Effect of 81^308 (0.26 11^/1^,?〇) on the ‘opening’ phase of levodopa (75 and 12 mg/kg, po) after treatment. The bars represent the median total count of 6 hours after oral administration of slv308 (0.26 mg/kg p〇; n=6). The bar represents the total median "on" time in hours, after treatment, ‘open, period has increased (p’s < 0.001, Friedman Test). #ρ<0·02, and levodopa alone showed a significant difference (Wilcoxon Test). Figure 4: Effect of SLV308 (0.26 mg/kg, po) on cumulative activity capacity after treatment with levodopa (7.5 and 12.5 mg/kg, po). The bars represent the total median count of 6 hours after oral administration of SLV308 (0·26 mg/kg p〇; n=6). After treatment, the increase in count is significant (p, s < 0.001, Kruskall

Wallis). *ρ<〇·〇〇2, which is significantly different from the vehicle (Mann whitney

Test) Figure 5: In the MPTP-damaged common marmoset (n=6), SLV308 (〇·26 mg/kg, p〇) lost the ability to reversal of levodopa (75 p〇) effect. Each point represents the median score of total capacity loss at every 30^1⁄2 interval after 7 hours of treatment with levodopa. Arrow 1: SLV3〇8 treatment 'Before · 2: Levodopa treatment. Symbol: hollow square medium group, solid square levodopa (75 mg/kg p〇), empty triangle SLv3〇8 (1)% mg/kg po), and solid round levodopa 7 5 p〇 after administration 25 200813038 SLV308. Error bars are omitted for clarity and conciseness. Fig. 6 shows the effect of SLV308 (0.26 mg/kg, P〇) on the motor capacity loss of levodopa reversal in the MPTP-injured common marmoset (n=6). Each point represents the median score of total capacity loss at intervals of 7 hours after 7 hours of treatment with levodopa. Arrow i: (4) Therapy, the first 2 levodopa treatment. Symbol · hollow square medium group, solid square levodopa (12.5 mg/kg p〇), empty triangle SLV308 (〇26 mg/kg po), solid round levodopa 12.5 mg/kg p〇 after administration of SLV308 . The error bars are omitted for clarity and conciseness. Figure 7: Effect of SLV308 (0.26 mg/kg, p〇) on cumulative exercise capacity loss after treatment with levodopa (7.5 and 12.5 mg/kg, po). The bar represents the median value of the total count of 6 hours after administration of SLV308 (0.26 mg/kg po; n=6). After treatment, the reduction in loss of ability was significant (p, s < 0.0005, Kruskall Wallis). *ρ<0·001, which is significantly different from the vehicle (Mann Whitney Test). #与左旋多巴 (7.5 mg/kg, po) compared to ρ<0·002 (Mann Whitney Test) 〇 [Main component symbol description] (none) 26 200813038 References

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Claims (1)

200813038 X. Patent application scope: 1. A combined preparation comprising (i) SLV308 or its N-oxide: Or a pharmaceutically acceptable salt of these compounds, and (ii) levodopa 5 bar, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential treatment of a condition in need of restoring dopaminergic function. 2. The preparation of claim 1, further comprising a decarboxylase inhibitor. 3. The preparation of claim 1, further comprising a COMT 10 inhibitor. 4. The preparation of claim 2, further comprising a COMT inhibitor. 5. The preparation of any one of claims 1, 2, 3 or 4, further comprising a MAO-B inhibitor. A use of a preparation according to any one of claims 1, 2, 3, 4 or 5 for the preparation of a medicament for treating a condition requiring restoration of dopaminergic function. 7. The use of claim 6, wherein the condition is Parkinson's disease. The use according to claim 6, wherein the condition is restless leg syndrome. 32 200813038 9. A pharmaceutical composition comprising: in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically effective amount as claimed in claim 1 or 5 One of the preparations described as an active ingredient. 33