TW200815031A - Combination preparations comprising bifeprunox and L-DOPA - Google Patents

Abstract

The invention concerns the use of a combination preparation of bifeprunox 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

200815031 IX. Description of the Invention: [Technical Field of the Invention] The present invention is a combined preparation comprising Bife Prunox and L-DOPA. 5 [Prior Art] Background of the Invention Long-lasting tremors of the hands and legs, the body movements become more rigid, slow and weak, and the false-faced facial table guesses are symptoms observed throughout human history. In 1817, James Parkins〇1^^ was described as having 10 symptoms of tremors, and shortly thereafter, the disease was named after the doctor who described it in detail. The pathological causes of Parkinson's disease include black. Destruction of cytoplasmic cells, which are part of the brain associated with exercise. About 80% of striatum dopamine loss in Parkinson's disease leads to basic symptoms of inability to exercise, stiffness and hypokinesia (Hornykiewicz, 1966). There are problems with the initial 15 movements, showing postural instability and coordination disorders. The drug therapy for Parkinson's disease is now based on restoring dopaminergic function (Blandini, 2000; Lled0, 2000). Dopamine does not cross the blood-brain barrier and therefore cannot For the treatment of Parkinson's disease, its direct precursor, levodopa (the left-handed enantiomer of 3,4-dihydroxyphenylalanine, also known as levodopa) 20 is used instead because it is worn Through the brain, where the carboxyl group is decarboxylated to become dopamine, but levodopa is also decarboxylated in the peripheral tissue. Only a small portion of the administered levodopa can be transported to the brain. Inhibition of peripheral levodopa decoupling 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 5 200815031 was forbearance The most effective treatment for the symptoms of Parkinson's disease. However, some limitations gradually become apparent during the first 5 to 5 years of treatment. As the disease progresses, the beneficial effects obtained from each dose become shorter and weaker. The effect"), as well as some patients with no predictable fluctuations between mobility and immobility ("switching phenomenon"). The "on" period is usually associated with high plasma levodopa. '$ includes abnormal involuntary movements, that is, movement disorders. During the "off" period, it was associated with low plasma levodopa and slow episodes (Jankovic, 1993; Rascol, 2000). This suggests that clinicians use pre-treatment with dopaminergic agonists to delay the onset of levodopa therapy. 10 However, the use of full agonists of dopamine receptors (such as apomorphine, clopidogrel, lisuride, pergolide, pramipexole or ropinirole) has its limitations: they are mainly used for Dyskinesia induces psychotic symptoms including hallucinations, orthostatic hypotension, lethargy, and other side effects (Lozano, 1998; Bennett, 1999). These side effects 15 have been suggested to be overcome by the use of dopamine Dm receptor partial agonists (i.e., compounds that are not the greatest stimulation of dopamine DM receptors) (Jenner 2002). Such compounds are hypothesized to stimulate dopamine receptors when polyamines have low tonicity, and can counteract dopamine when dopaminergic tone is high.

Excessive stimulation of the Dm receptor, thus leading to the maintenance of dopaminergic transmission in the brain, 20 Stable, (Jenner, 2002). 5-HT1a receptor agonists reduce dyskinesia because the 5_ht1a receptor agonist tandospirone reduces dyskinesia in patients with Parkinson's disease treated with levodopa (Kannari, 2002) and primate fluorofox. Alcohol-induced extrapyramidal side effects (Christoffersen, 1998). Recently recommended Sharizo 6 200815031 Tan, a 5-ΗΤ1Α receptor agonist and dopamine receptor ligand, can improve the symptoms of dyskinesia (〇lan〇w, 2〇〇4; Bara-Jimenez, 2005; Bibbiani ' 2001 ). The presence of a ΗΤ1Α receptor agonist is beneficial for the efficacy of D2/3 receptor partial agonists (Johnston, 2003). 5 Recently, different combination preparations containing levodopa and one or more other enzyme inhibitors have been introduced. Known are levodopa/carbidopa (eg Sinemet®), levodopa/section silk (eg Madopar®) and levodopa/carbidopa/entacapone A combination of (eg Staievo®, (jost, 2〇〇5)). More recently, catecholamine monomethyl-transferase ((:〇1^1^) inhibits 10 agents such as tolcapone and entacapone has been proposed as adjunctive therapy for levodopa. These compounds extend levodopa The plasma half-life does not significantly increase Cmax. Therefore, they reduce the gradual decrease in duration, but tend to increase the peak dose side effects, including peak dose dyskinesia. Tokappo appears to induce a significant fraction of patients. Hepatotoxicity 15. Another strategy for slowing dopamine metabolism is to use a combination of monoamine oxidase b (mao-b) inhibitor and levodopa. However, the administration of MA inhibitors is accompanied by many debilitating side effects. Limit their use. These effects include, for example, "disgusting, dizziness, dizziness, fainting, abdominal pain, confusion, hallucinations, dry mouth, multiple dreams, movement disorders, and headaches." 20 combination preparations are characterized by their presence. Different dose combinations, as usually higher doses of levodopa are necessary to maintain symptoms under control during the disease process. Formulation comprising a fixed amount of the drug in tablet form is easy to use, but also offers limited flexibility. A fixed combination is not generally a useful illustration of the fact that, for example, selective mao-_ 7 200815031 5

10 Formulations are used in the treatment of Parkinson's disease. As early as the money, selegiline can be given as a monotherapy. The compound is fully reduced; the metabolism of endogenous dopamine is used to control symptoms within the limits of tolerance. At a later stage, the use of levodopa became necessary. When the efficacy of levodopa begins to disappear, usually the problem of the first solution is to use a de-enzyme inhibitor like carbidopa (see above), and when the deficiency is obtained, the combination therapy with selegiline The efficacy of levodopa will be restored by reducing the destruction of dopamine produced by levodopa, in which levodopa and selegiline are actually administered as I-series, which can be administered simultaneously or continuously. Severely suffering from restless leg syndrome (RLS; also known as Eckbom's syndrome) (4) victims, in fact, can not (4) reduce or even stop standing. Need to keep exercise muscle rest and limited cognitive stimuli such as traffic (> speeding, airplane, train, etc.) activities or activities that require long sessions, 4 seats, movies or other performances, can become difficult, if not Do not

15 possible words. The pain caused by these sensations will become more severe at night, and patients with RLS 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 a rLS suffers from 20 people being forced to lie down, the symptoms will continue to attack like a loaded yellow' and eventually the legs will move unconsciously, which will immediately relieve the symptoms. If the patient tries to stay lie down, a rhythmic or half-rhythm movement in the leg is observed (Pollmacher, 1993). These movements are known as awake dyskinesias (DMWXHening, 1986), or more commonly known as awake 8 200815031

Periodic physical movement (PLMW) at the time. Clinically, when the four diagnostic criteria are met, it indicates an RLS: (1) a strong desire to move the limbs (usually the legs); (2) restlessness to reduce the feeling; (3) when resting, the symptoms are recovered or Worse; and (4) significant circadian rhythm changes or severe RLS 5 symptoms; rather, symptoms become worse at night or night (Allen, 2001). 〇 RLS's current treatment options vary. And there are undesired side effects. Therapies include dopamine receptor agonist administration, other dopaminergic agents, benzodiazepines, opiates and anticonvulsants. When RLS is caused by a secondary disorder, such as pregnancy, end-stage renal disease, erythropoietin therapy, or iron deficiency, removing these conditions, such as birth or treatment with traditional iron supplements, can at least reduce or eliminate some Symptoms of the case (Allen, 2001). However, RLS ("primary" RLS) caused by non-secondary conditions presents a greater therapeutic challenge. Dopaminergic agents such as levodopa usually provide effective initial treatment, but with continuous use, approximately 80% of patients with RLS develop resistance and symptoms (Allen, 1996); this complication is also common in Dopamine receptor agonists (Earley, 1996). Among other options, benzodiazepine π ratios, opiates and anticonvulsants are not as effective as dopaminergic agents (Chesson, 1999; Hening, 1999). Although the treatment regimen has changed, all drug therapies have been found to be inadequate due to adverse reactions and limited treatment of the poor. 200815031

DU 127090,7-[4-([1,1,-biphenyl]_3_ylmethyl) hydrazinyl]-2(3H)-benzoxanthone, now called bifepmnox, combined with dopamine 5 D2-like receptor and 5-HT1A receptor; it is a partial agonist of dopamine d2/3 receptor and a partial agonist of serotonin 5-1^18 receptor (WO 97/36893; Van

Vliet, 2000; Feenstra, 2001, 2002; Hesselink, 2003a, b; Mealy, 2004). It is disclosed in WO 2007/023141 that the N-oxide of bifeprunox is rapidly converted into the parent compound in vivo, and thus, the prodrug is used. SUMMARY OF THE INVENTION 2 ^ Detailed Description of the Invention - The object of the present invention is to develop a treatment method that is as effective as levodopa but does not have its side effects: in particular, without its characteristic, the switch is now - 15 This phenomenon causes movement disorders during the 'open' period, and during the "off," the period of exercise is too slow. Surprisingly, in a study of MPTP-treated marmosets, an animal model with predictive value for Parkinson's disease, it was found that combination therapy with levodopa and bifepmnox reduced the activity observed after levodopa alone. The peak value is such that no overactivity is observed. Co-administration by bifepmnox increases the duration of activity after administration of levodopa ("open, period"). 10 200815031 The subject of the invention is bifeprunox or its N-oxide, or a pharmaceutically acceptable salt thereof, Combinations of hydrates and solvates, and levodopa and, optionally, decarboxylase inhibitors and/or, optionally, c〇MT-inhibitors, and/or, arbitrary, MA0-B inhibitors, , 5 or continuously applied to the treatment of conditions requiring recovery of dopaminergic function, in particular Parkinson's disease and 'multi-leg leg syndrome. The present invention relates to bifeprunox or its N-oxide (real, prodrug) The use of levodopa to induce dyskinesia or can be expected to induce dyskinesia. In such cases, the compound has a particular pharmacological activity, 10 that is, partial agonism of dopamine VII and dopamine VII receptors. , and complete agonism of the serotonin 5-HT1A receptor, resulting in blocking dyskinesia without reducing the efficacy of levodopa. The present invention relates to pharmaceutical preparations, including: (i) Bifeprunox, its N - an oxide, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and: (11) levodopa, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier. References to kit components, comprising: (1) containing bifepninox, its N-oxide, or a pharmaceutically acceptable salt, hydrate, and solvate thereof (optionally with a pharmaceutically acceptable adjuvant, diluent or carrier) a mixed container, and: (ii) a container containing levodopa (optionally mixed with a pharmaceutically acceptable excipient, diluent or carrier), and (ill) about continuous and separate bifepnmox and levodopa Or at the same time 11 200815031 A specification for administration to a patient in need thereof. According to an aspect of the invention, there is provided a method of preparing a test gas component as defined herein, the method comprising the component (1) as defined above and the component (1) as above =) In combination, the two components are adapted to be administered to each other, and the two components are combined with each other. Components (i) and (ii) can be: , (1) provided as separate preparations (ie, Independent of each other They are then placed on one another and in combination with co-treatment using; or (ϋ) as a "combination pack ,, separately packaged components with each other and provide for Φ for use in combination with the treatment. 10 In another aspect, the invention relates to a method of treating a condition in which a patient has or is susceptible to a need or desire to restore dopaminergic function, the method comprising finally treating the patient a total effective amount: (i) bifepmnox, its N-oxidation Or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally mixed with a pharmaceutically acceptable auxiliary material, diluent or carrier; together with: (ii) levodopa, optionally in pharmacy Acceptable excipients, diluents or carriers are mixed. - A further aspect of the invention relates to the use of a pharmaceutical formulation comprising: (i) Bifeprunox, its N-oxide, or a pharmaceutically acceptable salt, hydroxide and solvate thereof, and: (Π) left-handed Dopa, ((1)) is used in combination with a pharmaceutically acceptable adjuvant, diluent or carrier for the manufacture of a medicament for the treatment of a condition in which it is desired or desirable to restore dopaminergic function. 12 200815031 Definition Examples of decarboxylase inhibitors are: carbidopa and benserazide. Examples of catechin--0-methyltransferase (COMT) inhibitors are: entacapone, exemplified by kapen and tokapeng, and examples of monoamine oxidase (MAO-B) inhibitors _ 5 including: propyne Amphetamine, (-)-propargyl amphetamine (selegiline), demethylpropargyl amphetamine, N-propargyl-HR)-aminoindane (rasagiline), phenelzine (Natal) 'Parnate, CGP3466, σ 喃 _, isocarbo, pajilin, methyl chlorothiazide and procarbazine. % In order to provide a more concise description, some of the quantitative expressions given in this article are not limited by the term "about". It will be understood that regardless of the term, whether or not the term '' is used explicitly or not, each quantity given herein is intended to refer to the actual value given, and is intended to refer to the approximation of the value given, common in the art. The skilled person can make reasonable inferences on this basis, including approximations resulting from the experimental values and/or measurement conditions given. 15 The word "comprises" and variations of the word, such as 'comprising' and 'comprises', are not intended to exclude other additives, ingredients, integers or steps throughout the specification and claims. - The term "composition" as used herein. "includes a product containing a particular predetermined amount or proportion of ingredients, as well as any product produced directly or indirectly by combining a particular amount of a particular ingredient. For a pharmaceutical composition, the term includes one or more active ingredients, and inert ingredients. The product of any carrier 'and directly or indirectly by the combination, complexation or polymerization of any two or more components' or by the decomposition of one or more components' or by other types of reactions or interactions of one or more components. Any product. In general, 13 200815031 ^The music composition is mixed by uniformly and intimately mixing the active ingredient with the liquid carrier = or finely dispersed or both, and then, if necessary, the processed product becomes desired. It is prepared by a preparation. The pharmaceutical composition is a compound of the active substance, and the product of the disease or the disease is produced. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable % indicates that the carrier 'slim' or the meaning must be The other ingredients of the formulation are compatible and not deleterious to the recipient. In the context of 忒claim, the term, combination preparation, includes both real and sputum, and bifepnmox and other drugs are physically combined into one preparation, such as tablets or injections, including, reagents. The cartridge component, which comprises bifepnmox and levodopa in separate dosage forms, together with instructions for use, optionally with further tools, facilitates the administration of the component compounds, such as labels or drawings. With regard to the true combination, drug therapy occurs simultaneously on definition 15. 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, such as the onset and duration of action, plasma concentration, clearance, etc., as well as on the disease, its stage, and the characteristics of the individual patient. The dosage of the composition administered is dependent on the relevant indication, the age, weight and sex of the patient, as determined by the physician. The dose is preferably from 〇〇i to 10 mg/kg. Typical daily doses of the active ingredient can vary widely, depending on factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, as determined by the physician. In general, oral 14 200815031 and two: Γ 曰 ο.1’. , ·, within the scope of the active ingredients. The therapeutically administrable condition of the composition of the present invention is in the treatment of:, = = sufficient to present a visible treatment or to improve the response, the effective amount depends on the volume and health of the treatment phase, the type and extent of treatment, Therapist (researcher, veterinarian, medical doctor or

10 15

According to the advice of the division's and therapies, or combination therapy, dosing options. This pre-specified - an accurate effective amount is useless. The term, pharmaceutically acceptable salts, refers to those salts which, in a reasonable medical condition, are suitable for contact with humans and lower animal tissues without: two matches. ::Reaction, etc., and with reasonable_risk to be in the final score = well known in the art. They can be prepared in situ by Huafeng 4 and purified (4) or (4), or separately reacted with a domain (4) non-toxic domain or acid, including inorganic or organic = broad-cut acid. Turning ± Acceptable - can be obtained by methods known in the art, for example by mixing a compound of the invention with a suitable acid, such as an inorganic or organic acid. /, the same administration '', including the various systems containing bifeprunox and levodopa "1", "ground" separately and / or simultaneously, in the treatment of related disorders, J: Φ, ten + _ /, dry conditions can be acute or chronic. Preferably, the term, ten ~ fully and timely application of two preparations (optionally repeated) to produce, fruit effect in the treatment of related conditions than two Any of the individual species (optionally repeated) (in the absence of another formulation) 15 200815031 Better in the same treatment. Determine if a combination provides for the condition during treatment of a particular condition A better beneficial effect will depend on the 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 both of the two formulations - The drug may be administered before, after, and/or at the same time as the other components. When used herein, the terms, concurrent administration, and, at the same time, include bifepnmox and levorotatory Each dose of dopa is at The other is administered within hours, such as 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes. 1 The term "treatment" as used herein refers to any of the mammals. The treatment, preferably a human condition or disease, comprises: (1) inhibiting the disease or condition, that is, preventing the development of sputum '(2) mitigating the disease or condition, that is, degrading the condition, or (3) stopping the symptoms of the disease. The term, drug therapy, as used herein, is meant to include a prophylactic, diagnostic, and therapeutic regimen for in vivo or in vitro administration to a human or other animal. The term, as used herein, refers to an animal, preferably a mammal, and most preferably a human, as a therapeutic, observation or test article. The diagram briefly illustrates the brother 1 map. In the MPTP/oral therapy common marmoset, bifeprun〇x (4 mg/kg/Ρ·〇.) alone or in combination with levodopa (7.5 mg/kg p 〇) The impact of mobility. Figure 2: Effect of bifepnm〇x (8 mg/kg/Ρ·〇·) alone or in combination with levodopa (7.5 mg/kg ρ·〇·) on activity in MPTP-treated common marmosets . 16 200815031 Figure 3: Effect of bifepnm〇X (4a activity) in common marmosets treated with MPTP for more than 7 hours. * and vehicle-vehicle contrast p < 0.05 (Mann Whitney) 〇 Figure 4: 5 bifepnm〇X (4 or 8 mg/kg/Po·) alone or with levodox in common marmosets treated with MPTP for more than 7 hours Ba (75 mg/kg Po) combination "moving 'open-period' effect" and vehicle-vehicle contrast p < 0.05 (Mann Whitney). Figure 5: bifePnm〇X in MPTP-treated common marmosets ( 4 mg/kg/Ρ.〇·) alone or in combination with levodopa (7.5 mg/kg pG) on the loss of ability score 10. Figure 6 bifepnm〇x (8 mg in MPTP-treated common thief monkeys) /kg/ Ρ·〇·) alone or in combination with levodopa (7.5mg/kgp···) on the loss of ability score. Figure 7: b bifepnmox in common marmosets treated with MPTP over ? Or 8 mg/kg/p. 〇·) alone or in combination with levodopa (7 5 Ρ Ρ 〇) on the total capacity loss score. * and vehicle-vehicle contrast p < 0.05 (Mann Whitney). Figure 8: bifeprunox (4 or 8 mg/kg/p. 〇·) alone or in combination with levodopa (75 mg/kg 20 P. 〇) for loss of total capacity in MPs treated with MPTP for more than 7 hours Open-term *. and vehicle-vehicle contrast p < 0.05 (Mann Whitney). [Embodiment 3 Example with neurotoxin ΜΡΤΡ (1-methyl phenyl-^ di-tetrahydropyridine) at 17 200815031 Depletion of dopamine in the caudate putamen of human and human primates and a decrease in Parkinson-like behavior (Lange, 1992; Langston, 1984; Langston, 1986). Example 1: Between Bifeprunox and Levodopa Interaction 5 Animals · This study used common simian monkeys (Callithrix jacchus) (n=6, ages 3–5 years old; 5 females and 1 male), previously using mPTP (2 mg/kg sc daily) After 5 days of treatment, it showed stable motor deficits. These animals were sensitive to left sputum and were not the first to be given experimental drugs (teSf drug naiiie). They were not pretreated with cerebral dysfunction by experimental methods, although Some dyskinesias.. Treatment: _: Mifesulfate Bifeprunox was suspended in 10% sucrose solution and then administered orally by gavage 2·0 ml/kg. Levodopa: L-3,4- Diphenylalanine (L-dopa) methyl ester (Sigma Chemi Cal Co, UK) was dissolved in 10% sucrose solution and then orally administered by gavage 2·〇 mi/kg. Card 15 Bidopa: (Merck, Sharp and Dohme, UK) Oral administration at 2.0 ml/kg in a morning suspension of 10% sucrose solution. t? melon double miso: (2·〇 mg/kg p〇 ’ Sigma UK) was dissolved in 10% strict sugar solution, and then uranium administered at 3ifepnmox for 60 minutes was administered at 2.0 ml/kg. Bifepmnox (4 or 8 mg/kg P〇 free domain) or its vehicle (10% sucrose) was administered alone and in combination with levodopa 20 bar (7.5 mg/kg p〇 free domain, and carbidopa) , 12.5 mg/kg P〇) combination of marmosets for treatment with MPTP (n=6). Animals were treated with Bifeprunox or its vehicle prior to administration of levodopa or its vehicle for 9 minutes. Carbidopa was administered 30 minutes prior to administration of levodopa. Domperidone was administered 60 minutes before bufepnmox administration. 18 200815031 Study •• In all studies, animals were adapted to behavioral cages 1 hour prior to treatment. 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 5 and their corresponding detectors, arranged for maximum motion evaluation. The ability to move is assessed by the movement of the animal at intervals of 1 minute until the number of beam breaks caused by the accumulation within 7 hours. Prior to dosing, animals were allowed to have a 6-minute environmental acclimation period in the active cage during the baseline activity assessment. "Open," threshold threshold is the 3 baseline activities of the apes treated with MPTP. Overactivity is defined as the 3 normal activities of the first monkey used for the experiment. Open, period is active, open 'threshold The time period in minutes. The animal ffibifeprun〇x, the mediator ί / or the left-handed sputum treatment. As the drug treatment progresses, as follows, the animal's activity ability and ability are lost until after the drug treatment. Animals used for the study in any of the study days did not exceed I5 over 8 days in automated cages and were allowed a recovery period of at least 3 days during drug treatment to ensure proper animal health considerations. Activity abilities, loss of exercise capacity, and dyskinesia were assessed as follows: In all studies, the animals were acclimated to behavioral cages 1 hour prior to bifepnm〇x treatment. The appropriate drug treatment was used to treat the animals. The auto-active cage was used to assess the animal's anti-shock numbness until 6 h ϋ the level of loss of ability was assessed by the observer who did not see the treatment. Exercise, open-phase, (〇n-time) was defined as the animal showed activity at 3 χ Above the line activity ability or activity ability is even higher than the time period.: With the progress of f treatment, before and after the administration of 19 200815031 bifeP_x, every hour after the ι〇 and dyskinesia _ hours. Use the following 5

10 Charm lost Pu _ force mourning cake points as follows. Often 0, sleep small reaction (normal 〇, reduce the slowness of the 2, § 戒 (正咸少1 ' does not exist 2); attention and 3 hearts) (: 0' Different claims 1), (4) (normal 〇, abnormal cast +1, abnormal limbs +1, tail + b or very abnormal 4); balance / coordination (positive f G, damaged 丨, not spontaneous fall 3); vocal ( Normal 〇, decrease i, does not exist 2); exercise = (normal 〇 'slow movement / excessive exercise!, exercise can not / exercise excessive 2). If it exists, take note of the sedation. The ability to lose, open-period, is defined as the time period during which the animal display loss score is 6 or lower ('n's open threshold, 〇n theshold).

Μ and statistics ϋΐ: The data is expressed as the median value (count/min) or loss of ability (10min/30min score) of activity 15 during the 7-hour experimental period or expressed as total activity capacity 〇min) or loss of ability (total score of 420min). Data were analyzed by Kruskall Wallis AN0VA and tested by the causal Man-Whitney test when appropriate. The formula was used to perform multiple comparisons to correct the analysis: 20 Probability of doubled = α / where α = 5% of comparisons Vehicles were treated with a separate group of animals from study animals and used for statistical comparison. Example 2: Effect of bifeprunox on levodopa-induced reversal of motor abilities 200815031 Activity ability: levodopa (7.511^/1^0〇) plus carbidopa (12.5 mg/kgpo, before levodopa 30 min) increased mobility immediately after administration compared to vehicle administration (Figures 1, 2, 3 and 4). Activity peaks were reached between 60 and 180 min after levodopa administration (median value 1627, range 5 was 832-2289 counts per 3 〇 min). The median duration of the activity (on-period) was 180 min/420 min (Fig. 4). Total activity and exercise, open-on, greater than mediation-treated animals (ρ<0.05, Mann Whitney).

Bifeprunox (4 mg/kg p〇) increased mobility immediately after administration as compared to vehicle administration (Figures 1 and 3). The peak of survival was reached between 6 〇 and 18 〇 10 min after dosing (median 685, ranged from 512-1967 counts every 30 min). The median duration of activity (open phase 1) is 24〇 min/42〇 min (Fig. 4). Total activity capacity and exercise 'open one' is greater than vehicle-treated animals (ρ<0·05, Mann Whitney) 〇

Bifeprun〇x (8 mg/kg po) increased mobility immediately after administration of the vehicle 15 (different 2 and 3). The peak activity was reached between 6〇 and 30〇1^11 after administration (median value 111〇, range 669_2〇58 count every 30 minutes). The median duration of activity (open phase 1) was 345 min/42 〇 min greater than the vehicle treatment group (Fig. 4). The total activity was greater than that of the vehicle-treated (ρ<0.05, Mann Whitney). 20 Pretreatment with BifePnmox (4 mg/kg po) in levodopa (7.5 mg/kg Ρ〇) plus carbidopa (12. 5 mg/kg ρ 〇, before levodopa as min Uranium 90 min' increased activity capacity immediately after administration compared to baseline (Figures 2 and 3). The peak activity was achieved between 60 and 39 〇 min after administration (median value 1581, range 556_2232 counts every 3 〇 min). The median duration of activity 21 200815031 (open phase, 390 min/420 min, panel 4) was slightly greater than that observed after levodopa alone and bifeprunox administration. Activity capacity tends to increase compared to levodopa alone and bifeprunox alone (4 mg/kg po) (Figures 1, 2, 3 and 4). 5 Pretreatment with Bifeprunox (8 mg/kg po), 90 min before levodopa (7.5 mg/kg ρο) plus carbidopa (12.5 mg/kg po, 30 min before levodopa) Activity capacity was increased immediately after administration compared to baseline (Figures 2 and 3). The activity peak was reached between 60 and 360 min after administration (median value 1211, ranged from 409 to 1342 counts per 30 min). The median duration of the activity (open one, 300 min/420 min, Figure 4) was slightly shorter than bifeprunox alone. Total activity capacity and duration of activity (open-period) did not differ 'when administered separately with bifeprunox (8 mg/kg po) and levodopa (7.5 mg/kg po) plus carbidopa (12.5 mg) /kg po 30 min before levodopa) when administered alone (Figures 2, 3 and 4). 15 can be lost: levodopa (7.5mg/kg p〇) plus carbidopa (12.5mg/kg po, 3〇min before levodopa) compared to vehicle administration immediately after administration Scores of loss of ability were reduced (Figures 5, 6, 7 and 8) (p < 0.05 ' compared with vehicle treated controls, Mann Whitney). Activity 20 peaks were reached between 30 and 300 (median value 75) min after levodopa administration (median score 3; score range 2 - 4). The ability to lose levodopa alone 'open one' is 120 min / 420 min.

Bifepnmox (4 mg/kg P〇) reduced the fraction of loss of ability ($ and 7) immediately after administration (30-60 min) compared to vehicle administration (ρ < 0·05, and vehicle one) Comparison of treated controls, M(10)n 22 200815031

Whitney). The peak score was reached between 30 and 240 min after administration (median score 3; score range 2 - 4). The median duration of activity ('open-phase,') was 210 min/420 min (Fig. 8).

Bifeprunox (8 mg/kg p〇) reduced the rate of loss of ability immediately after administration 5 compared with vehicle treatment (Figures 6 and 7) (ρ<〇·〇5, and vehicle-treated control group) Contrast, Mann Whitney). The total reduction in capacity loss was lower than in vehicle-treated animals (Figure 7). The peak score was reached between 3 〇 and 150 min after administration (median value 4; range 2 _ 5). The duration of activity ('open one') was 225 min/420 min, which is greater than the fraction of vehicle treatment (Fig. 8 10). Pretreatment with Bifeprunox (4 mg/kg p〇), 90 min before carbidopa (12.5 mg/kg p〇, 30 min before levodopa) on levodopa (7.5 mg/kg p〇) The score for loss of ability was reduced during the study (Figures 5 and 7). The peak score was reached between 60 and 240 min after administration (median value 153, range 2-4). The duration of the activity (open period) is 36〇min/42〇min. The duration of activity tends to increase compared to bifepnmox alone (Figure 8). Pretreatment with Bifeprunox (8 mg/kg p〇) before levodopa (75 mg/kg P〇) plus carbidopa (I2.5 mg/kg P〇, 30 min before levodopa) At 90 min, the score for loss of ability was reduced (Figures 6 and 7). The peak score was reached between 60 and 120 min after giving 20 doses (median value 3, range 2 - 5). The duration of the activity (open phase) is I65min/420min. Duration of activity with bifepnmox alone (8 mg/kg po) or levodopa (75 mg/kg p〇) plus carbidopa (12.5 mg/kg P〇, 3 〇 min before levodopa) ) is no different (Figure 8). 23 200815031 Conclusion: Levodopa (7.5 mg/kg po) increases activity and reduces the loss of ability in MPTP-treated common simian monkeys. Bifeprunox (4 and 8 mg/kg po) also increased mobility and reduced capacity loss scores. When administered in combination with levodopa, bifeprunox (4 or 58 mg/kg po) tends to increase total activity and exercise by one phase compared to levodopa 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 coagulum), 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, a diluent, and/or a carrier. The total amount of active ingredient suitably constitutes about 'O.iWw/w) of the formulation - about 95% (w/w), suitably 0. 5 ° / 〇 - 50 ° / 〇 (w / w), Choose 1% - 25 % (w/w). The molar ratio between bifeprunox (or its N-oxide) and levodopa may be from about 1000:1 to about 1:1000, suitably 300:1 to 1:300, preferably 50:1 to 1: 50. 20 The preparation of the present invention can utilize auxiliary substances such as liquid or solid, powdery ingredients, such as pharmaceutically acceptable liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, perfumes, colorants and/or by conventional methods. The buffer is formulated into a dosage form suitable for administration. Frequently used auxiliary substances include acid-stained towns, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars 24 200815031 six pages or sugar alcohol beta stone private 'gelatin, gelatin, starch, branch powder, cellulose and it Derivatives 'animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil 'polyethylene glycol and solvents, for example, sterile water and mono- or polyhydric alcohols such as glycerol, and disintegrants and lubricants such as magnesium stearate , 5 hard lunar acid feeding, sodium stearate and polyethylene glycol oxime. 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 with capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat, or other excipients suitable for soft gelatin capsules. Hard knee capsules may contain granules of the active ingredient. The hard gelatine capsules may also contain the active ingredient together with a solid powder component such as lactose, sucrose, sorbitol, mannitol, horse mash, corn gluten, starch, cellulose derivative 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) in an active ingredient in admixture with vegetable oil, sarcophagus or other suitable excipients for gelatin rectal capsules; a gelatin rectal capsule form of the substance; (iii) a pre-formed micro-enema form; or (iv) a 2 〇 form of a dry micro-enema formulation reconstituted in a suitable solvent prior to administration. The liquid preparation may be in the form of a trowel, an elixir, a concentrated drop pellet 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 solution or suspension of a mixture of diols. If desired, such liquid preparations may contain 25 200815031 colorants, flavoring agents "preservatives" quercetin and carboxymethylcellulose or other thickening agents. 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, 5 preservatives and/or buffering ingredients. Solutions for parenteral administration can also be prepared as a dry powder which is reconstituted with a suitable solvent before use. The present invention also provides for a coating agent and a kit component comprising one or more containers having one or more of the pharmaceutical composition compositions of the present invention for medical treatment purposes. The notice reflects the government agency's human or veterinary drug as the container may be in various written materials, such as 10 instructions for use, or as prescribed by a government agency to specify the form of preparation, use, or sale of the drug product. Approval of preparation, use or sale. Use of a formulation of the invention in the manufacture of a condition for the treatment or desire to restore dopaminergic function, and a method of treatment comprising administering to a patient having or susceptible to a condition in need of or in need of recovery of dopaminergic function a therapeutically effective total amount At least one formulation of the invention. t _ simple description] 1 picture: the effect of bifeprunox (4 mg / kg / P · 0 ·) alone or in combination with levodopa (7.5 mg / kg po) on activity ability in MPTP-treated common monkeys . Figure 2: Effect of bifepmnox (8 mg/kg/P·0.) alone or in combination with levodopa (7.5 mg/kg p.o.) on activity in MPTP-treated common marmosets. Figure 3: Effect of bifePnm〇X (4a activity) in common marmosets treated with MPTP for more than 7 hours. * and vehicle-vehicle contrast p < 0.05 (Mann Whitney) 〇 Figure 4: bifeprun〇X (4 or 8 mg/kg/P.〇.) alone or with left-handedness in common marmosets treated with MPTP for more than 7 hours Dopa (7 5mg/kg .5 P. 〇) combination for sports, open-term, and scenery. *Comparative with vehicle-vehicle contrast p<0.05 (Mann Whitney) 〇Fig. 5: bifeprun〇x (4 mg/kg/Ρ·〇·) alone or with levodopa (7.5) in MPTP-treated common thief monkeys The effect of the combination of mg/kg ρ·0·) on the loss of ability. 10 弟6图·Effects of bifeprunox (8 mg/kg/Ρ·〇·) alone or in combination with levodopa (7.5 mg/kg ρ·〇·) on the loss of ability score in common marmosets treated with sputum . Figure 7: Effect of bifepmnox (4 or 8 mg/kg/p.o.) alone or in combination with levodopa (7e5 mg/kg 15 P·0) on total loss of ability score in common marmosets treated with sputum for more than 7 hours. *Compared with vehicle-vehicle-based ρ<0·05(Mann Whitney) 〇_弟8图·BifePrunox (4 or 8mg/kg/ρ·ο·) alone or in MPTP for more than 7 hours of MPTP treatment The effect of combination with levodopa (7.5 mg/kg Ρ·〇) on the total ability loss 'open one'. * and media one media 2 〇 contrast p < 〇. 〇 5 (Mann Whitney). [Main component symbol description], (none) 27 200815031 Reference

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Claims (1)

200815031 X. Patent application scope: 1. A combined preparation comprising (i) bifeprunox or its N-oxide: Bifeprunox bifeprunox 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 according to claim 1 or 2, further comprising a 10 C0MT inhibitor. 4. The preparation of any one of claims 1, 2 or 3, further comprising a MA0-B inhibitor. 5. The use of a formulation according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of a condition requiring restoration of dopaminergic function. The use according to claim 5, wherein the condition is Parkinson's disease. 7. The use of claim 5, wherein the condition is restless leg syndrome. 8. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least 20 pharmaceutically acceptable auxiliary substances, a pharmacologically effective amount of any one of claims 1 to 4 The formulation described is a sexual ingredient of 2008 32,310. 9. A method of treating Parkinson's disease or restless leg syndrome in a human or animal patient in need of such treatment, comprising simultaneously, separately or continuously administering to the patient a quantity of bifeprunox or its N-oxide, or A pharmaceutically acceptable salt, and a quantity of levodopa, wherein the amount is a therapeutically effective amount. 10. The method of claim 9, wherein an additional amount of a decarboxylase inhibitor and/or a COMT inhibitor and/or a MAO-B inhibitor is additionally administered. 10 33