MX2008016226A - 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

COMBINATION PREPARATIONS COMPRISING BIFEPRUNOX AND L-DOPA FIELD OF THE INVENTION The invention relates to the use of a combination preparation of bifeprunox or its N-oxide or pharmaceutically acceptable salts of these compounds: Bifeprunox Bifeprunox-N-oxide and L-DOPA, for simultaneous, separate or sequential use in the treatment of disorders that require the recovery of dopaminergic function, in particular Parkinson's disease and restless legs syndrome.

BACKGROUND OF THE INVENTION Constant tremors in the hands and legs, body movements that gradually become stiffer, slower and weaker, and facial expressions similar to a mask, are symptoms that have been observed throughout the history of mankind. In 1817, James Parkinson described this set of symptoms as 'paralysis agitans', and shortly after the disease was named according to the doctor who first described it in detail. The pathological cause of Parkinson's disease involves the destruction of nerve cells in the substantia nigra, the part of the brain involved in muscle movements. The loss of approximately 80% of the striated dopamine in Parkinson's disease results in cardinal symptoms of akinesia, rigidity and bradykinesia (Hornykiewicz, 1966). Patients have problems starting a movement and exhibit postural instability and loss of coordination. The current pharmacotherapy of Parkinson's disease is based on the recovery of dopaminergic function (Blandini, 2000; Lledó, 2000). Dopamine does not cross the blood-brain barrier and therefore can not be used for Parkinson's disease, whereas L-DOPA (the levorotatory enantiomer of 3,4-dihydroxy-phenylalanine, also referred to as levodopa) is used. ), because it penetrates the brain where it is decarboxylated to dopamine. But levodopa is also decarboxylated in peripheral tissues. Therefore, only a small portion of the levodopa administered is transported to the brain. Carbidopa inhibits the decarboxylation of peripheral levodopa, but in turn can not 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 the most effective treatment for the symptoms of Parkinson's disease. However, within two to five years after the initiation of therapy, certain limitations are observed. As the disease progresses, the benefit of each dose becomes shorter ("the effect of end-of-dose deterioration" or "wearing off") and some patients fluctuate unpredictably between mobility and immobility (the effect of "on-off"). off "or fluctuation." On "periods (activity) are usually associated with high concentrations of levodopa in the plasma and often include abnormal involuntary movements, ie, dyskinesias." Off "periods were correlated many times with low concentrations of levodopa in plasma and episodes of bradykinesia (Jankovic, 1993, Rascol, 2000). This prompted clinns to postpone the initiation of treatment with L-DOPA using a previous treatment with dopamine agonists. However, the use of complete dopamine receptor agonists such as apomorphine, bromocriptine, lysuride, pergolide, pramipexole or ropinirole also has its limitations: These agonists exalt dyskinesias, induce symptoms similar to psychotic attacks including hallucinations, orthostatic hypotension, somnolence and other side effects (Lozano, 1998, Bennett, 1999). It was suggested that this could be overcome by the use of partial dopamine D2 / 3 receptor agonists (ie compounds that do not maximally stimulate dopamine D2 / 3 receptors (Jenner 2002). Such compounds would hypothetically be able to stimulate dopamine D2 / 3 receptors when the dopaminergic tone It is low, whereas they would be able to act against an excessive stimulation of the dopamine D2 receptor when the dopaminergic tone is high, thus producing a stabilization of the dopaminergic transmission in the brain. { Jenner, 2002). 5-HT1A receptor agonists can improve the induction of dyskinesia, since the 5-HT1A receptor agonist tandospirone reduced dyskinesia in patients with Parkinson's disease treated with L-DOPA (Kannari, 2002) and extrapyramidal side effects induced by haloperidol in primates (Christoffersen, 1998). More recently it was suggested that sarizotan, a 5-HT1A receptor agonist and dopamine receptor ligand, could improve dyskinetic symptoms. { Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, 2001). The presence of the 5-HT1A receptor agonist could be beneficial for the therapeutic effects of a partial D2 / 3 receptor agonist (Johnston, 2003). Recently, different combination preparations containing L-DOPA and one or more other enzyme inhibitors have been introduced. The combinations L-DOPA / carbidopa (for example Sinemet®), L-DOPA / benserazide (for example Madopar®) and L-DOPA / carbidopa / entacapone (for example Stalevo®, (Jost, 2005)) are well known. Plus recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone were proposed as joint therapy with L-DOPA. These compounds extend the plasma half-life of L-DOPA, without significantly increasing Cmax. In this way, these compounds decrease the end-of-dose deterioration duration (wearing-off), but they have the effect of increasing the intensity of the side effects of the peak dose, including dyskinesias of the peak dose. It seems that tolcapone induces significant hepatic toxicity in a small percentage of patients. Another strategy with the purpose of slowing down the metabolism of dopamine is the use of inhibitors of monoamine oxidase B (MAO-B) 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, dizziness, fainting, abdominal pain, confusion, hallucinations, dry mouth, intense dreams, dyskinesias, and headache. A feature of combination preparations is that they exist in many different dose combinations, since higher doses of L-DOPA are usually needed during the course of the disease to keep the symptoms under control. Combination preparations in the form of tablets containing fixed amounts of drugs are easy to use, but simultaneously they also have limited flexibility. An illustration of the fact that fixed combinations are not always useful is, for example, the use of the selective MAO-B inhibitor selegiline in the treatment of Parkinson's disease. In the early stage of the As a disease, selegiline can be administered as monotherapy: the compound will slow the metabolism of endogenous dopamine sufficiently to keep the symptoms within tolerable limits. In later stages of the disease, the use of L-DOPA will be necessary. When the efficacy of L-DOPA begins to deteriorate, the first solution for this problem is usually the use of a decarboxylase inhibitor such as carbidopa (see above), and when this is also insufficient, co-therapy with selegiline will restore the efficacy of L-DOPA, reducing the depletion of dopamine generated by L-DOPA. Therefore, in practice L-DOPA and selegiline are administered in separate preparations that can be administered simultaneously or sequentially. Victims severely affected by Restless Legs Syndrome (RLS, also known as Ekbom's syndrome) are virtually unable to sit still or even stand still. Activities that require maintaining motor rest and limited cognitive stimulation, such as transportation (automobile, airplane, train, etc.) or attending extended meetings, conferences, films or other activities, become difficult, if not impossible. Tortured by these sensations that are more severe during the night, patients with RLS find it virtually impossible to fall asleep, which further decreases their quality of life. The impulse to move, which increases during periods of rest, can be dissipated completely by movements, such as walking. However, once the movement, the symptoms return with increased intensity. When a patient with RLS is forced to lie still, the symptoms will continue to rise like a tensed spring and, eventually, the legs will move involuntarily, relieving the symptoms immediately. Rhythmic or semi-rhythmic movements of the legs are observed if the patient tries to remain lying down (Pollmacher, 1993). These movements are referred to as dyskinesias in the awake state (dyskinesias-while-awake (DWA) (Hening, 1986) or, more commonly, periodic movements of the members in the awake state (period limb movements while awake (PLMW).) Clinically, RLS is indicated when four diagnostic criteria are met: (1) a feeling of impulse to move the limbs (usually the legs); (2) motor restlessness to reduce sensations; (3) return or worsening of symptoms during rest; and (4) a marked circadian variation in the occurrence or severity of RLS symptoms; that is, worsening of the symptoms during the evening and night. { Alien, 2001). Current RLS treatments are several and plagued with undesirable side effects. Therapies include the administration of dopamine agonists, other dopaminergic agents, benzodiazepines, opiates and anti-convulsants. When RLS is a consequence of a secondary condition, such as pregnancy, end-stage renal disease, treatment with erythropoietin or iron deficiency, the symptoms can be reduced or eliminated in at least some cases by removing the condition, such as by birth or treatment with traditional iron supplements. { Alien, 2001). However, the treatment of RLS resulting from non-secondary conditions ("idiopathic" RLS) presents a greater challenge. Dopaminergic agents, such as levodopa, generally provide effective initial treatment, but with continued use there is drug tolerance and an increase in symptoms in approximately 80% of patients with RLS (Alien, 1996); This complication is also common with dopamine agonists (Earley, 1996). The other alternatives, benzodiazepines, opiates and anticonvulsants do not achieve as uniform an effect as dopaminergic agents (Chesson, 1999, Hening, 1999). Despite modifications in their treatment regimens, 15-20% of patients find that all medications are inadequate due to adverse effects and limited benefits of treatment.

Bifeprunox Bifeprunox-N-oxide DU 127090, 7- [4 - ([1,1'-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone, now known as bifeprunox, binds to receptors similar to those of dopamine D2 and 5-HTiA receptors; is a partial agonist of dopamine D2 / 3 receptors and also a partial agonist of serotonin 5-HT-iA receptors (WO 97/36893, Van Vliet, 2000, Feenstra, 2001, 2002, Hesselink, 2003a b, Mealy, 2004 ). In WO 2007/023141 it was revealed that in vivo the N-oxide of bifeprunox is rapidly converted to the parent compound, thus functioning as a "prodrug".

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: The effect of bifeprunox (4 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on locomotor activity in common marmosets treated with MPTP.

Figure 2: The effect of bifeprunox (8 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on locomotor activity in common marmosets treated with MPTP. Figure 3: The effect of bifeprunox (activity 4 a) for 7 hours in common marmosets treated with MPTP. * p < 0.05 compared to vehicle-vehicle (Mann Whitney). Figure 4: The effect of bifeprunox (4 or 8 mg / kg, po) alone or in combination with L-DOPA (7.5 mg / kg po) on the duration ("ON time") of the activity for 7 hours in common marmosets treated with MPTP. * p < 0.05 compared to vehicle-vehicle (Mann Whitney). Figure 5: The effect of bifeprunox (4 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on the disability score in common marmosets treated with MPTP. Figure 6: The effect of bifeprunox (8 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on the disability score in common marmosets treated with MPTP. Figure 7: The effect of bifeprunox (4 or 8 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on the total disability scores for 7 hours in common marmosets treated with MPTP. * p < 0.05 compared to vehicle-vehicle (Mann Whitney). Figure 8: The effect of bifeprunox (4 or 8 mg / kg, p.o.) alone or in combination with L-DOPA (7.5 mg / kg p.o.) on the duration ("ON time") of Total disability for 7 hours in common marmosets treated with MPTP. * p < 0.05 compared to vehicle-vehicle (Mann Whitney).

DETAILED DESCRIPTION OF THE INVENTION The objective of the present invention was to develop such an effective treatment with L-DOPA, but without its side effects: in particular without its characteristic "on-off effect", which causes dyskinesias during the "on" periods and bradykinetic episodes during the periods "off" Surprisingly, in studies with marmosets treated with MPTP, an animal model with a positive prognosis for Parkinson's disease, it was found that a combination treatment with L-DOPA and bifeprunox reduced the peak locomotor activity observed after treatment with only L-DOPA, so hyperactivity was not observed. The duration of activity ("on" time) after administration of L-DOPA was increased by the co-administration of bifeprunox. The subject of the invention are combination preparations of bifeprunox or its N-oxide or the pharmacologically acceptable salts, hydrates and solvates thereof, together with L-DOPA and, optionally, a decarboxylase inhibitor and / or, optionally, an inhibitor of COMT and / or, optionally, an inhibitor of MAO-B, for the simultaneous, separate or sequential use in a therapy of disorders that require the recovery of the dopaminergic function, in particular Parkinson's disease and "restless legs syndrome". The invention relates to the use of bifeprunox or its N-oxide, a true "prodrug", in cases in which L-DOPA induces dyskinesias, or it can be anticipated that it induces dyskinesias. In such cases, the specific pharmacological activities of the compound, that is, a partial agonism on dopamine D2 receptors and dopamine D3i receptors as well as a complete agonism on receptors 5 - ???? of serotonin, result in a blockade of dyskinesias, without reducing the therapeutic effect of L-DOPA. The present invention relates to pharmaceutical formulations, comprising: (i) bifeprunox, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, and: (ii) L-DOPA, mixed with an adjuvant, diluent or carrier pharmaceutically acceptable. A further aspect of the present invention relates to kits of parts comprising: (i) a container containing bifeprunox, its N-oxide, or pharmacologically acceptable salts, hydrates and solvates thereof, optionally mixed with an adjuvant, diluent or pharmaceutically acceptable support, and: (ii) a container containing L-DOPA, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, and: (iii) instructions for the sequential, separate or simultaneous administration of bifeprunox and L-DOPA to a patient in need thereof. According to a further aspect of the invention, there is provided a method for manufacturing an equipment of parts as defined in the present invention, said method comprising gathering a component (i), as defined above, in association with a component (ii) , as defined above, thus making the two components suitable for joint administration. By bringing the two components together, components (i) and (ii) can: (i) be provided as separate formulations (ie, independently from each other), bringing together the components subsequently for their joint use in a combination therapy; or (ii) package and present the components together in the form of separate components of a "combination package" for use together in a combination therapy. Yet another aspect of the invention relates to methods for the treatment of a patient suffering from, or susceptible to, a condition in which the recovery of the dopaminergic function is required or desired, said method comprising administering to the patient an amount Therapeutically effective total of: (i) Bifeprunox, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; together with: (ii) L-DOPA, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Yet another aspect of the invention relates to the use of pharmaceutical formulations comprising: (i) bifeprunox, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, and: (ii) L-DOPA, mixed with an adjuvant , diluent or pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment of a condition in which the recovery of the dopaminergic function is required or desired.

Definitions Examples of decarboxylase inhibitors are: carbidopa and benserazide. Examples of catecholamine-O-methyltransferase (COMT) inhibitors are: entacapone, nitecapone and tolcapone, and monoamine oxidase B (MAO-B) inhibitors include: deprenyl, (-) - deprenyl (selegiline), desmethyldeprenyl, N-propargyl-1 - (R) -aminoindane (rasagalina), phenelzine (nardilo), tranil-cipromina (parnate), CGP3466, furazolidona, isocarboxazida, pargílina, methylclotiazida and procarbazina. To provide a more concise description, some of the quantitative expressions given in the present invention are not qualified with the term "approximately". It is understood that the term "approximately", whether used explicitly or not, means that any amount indicated in the present invention refers to the given real value and is also intended to refer to the approximation of said value that could reasonably be inferred by the person skilled in the art, including approximations due to experimental conditions or measurement of said given value. Throughout the description and the claims of this specification, the word "understand" and variations of the word, such as "comprising" and "comprises", are not intended to exclude other additives, components, numbers or additional steps. The term "composition", as used in the present invention, comprises a product that contains specific ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from the combination of specific ingredients in specified amounts. In relation to pharmaceutical compositions, this term comprises a product comprising one or more active ingredients and an optional support comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, formation of a complex or aggregate of any of two or more ingredients, or of the dissociation of one or more ingredients, or of other types of reaction or interaction of one or more ingredients. In general, the pharmaceutical compositions are prepared uniformly and intimately contacting the active ingredient with a liquid excipient or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes a sufficient amount of the active compound object of this invention to produce the desired effect on the progress or condition of diseases. Therefore, the pharmaceutical compositions of the present invention comprise any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to the recipient thereof. Within the context of this application, the term "combination preparation" includes both true combinations, which means bifeprunox and other medicaments physically combined in a single preparation, such as a tablet or an injectable fluid, as well as a "kit of parts". ", comprising bifeprunox and L-DOPA in separate dosage forms, together with instructions for use, optionally with additional means to facilitate the acceptance of the component compounds by the regulator, for example labels or drawings. With true combinations, pharmacotherapy is simultaneous by definition. The contents of a "team of parts" can be administered simultaneously or at different time intervals. If the therapy is concomitant or sequential will depend on the characteristics of the other medications used, characteristics such as onset and duration of action, plasma levels, elimination, etc., as well as the disease, its stage and the characteristics of the individual patient. The dose of the composition to be administered will depend on the relevant indication, age, weight and sex of the patient and can be determined by a physician. The dose will preferably be in the range of 0.01 mg / kg to 10 mg / kg. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, route of administration, age, weight and sex of the patient and can be determined by a physician. Generally, oral and parenteral dosages of the total active ingredients will be in the range of 0.1 to 1 thousand mg per day. The term "therapeutically effective amount", as used in the present invention, refers to an amount of a therapeutic agent for treating a treatable condition by administration of a composition of the invention. This amount is sufficient to exhibit a therapeutic response or detectable improvement in an animal or human tissue system. The effect may include, for example, treating the conditions listed here. The exact effective amount for a subject will depend on the size and health of the subject, the nature and severity of the condition to be treated, the recommendations of the attending physician (researcher, veterinarian, medical doctor or other clinician), and the products therapeutic or the combination of therapeutic products selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to those salts which, within the limits of a sound medical evaluation, are suitable for use in contact with the tissues of human and lower animals without toxicity, irritation, undue allergic response and the like, and that are commensurable with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be prepared in situ during the isolation and final purification of the compounds of the invention, or they can be prepared separately, by reacting the compounds of the invention with non-toxic pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. Pharmaceutically acceptable salts can be obtained by standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example an inorganic acid or an organic acid. "Administration in conjunction with" includes that respective formulations comprising bifeprunox and L-DOPA are administered, sequentially, separately and / or simultaneously, during the course of treatment of the relevant condition, which condition may be acute or chronic. Preferably, the term includes that the two formulations are administered (optionally repeatedly) in sufficiently close times for a beneficial effect to occur for the patient, effect during the course of the treatment of the relevant condition is greater than that produced by the administration (optionally repeatedly) of the two formulations alone, in the absence of the other formulation, during the same course of treatment. The determination of whether during the course of the treatment a combination provides a greater beneficial effect with respect to a particular condition will depend on the condition to be treated or prevented, but can be performed by the person skilled in the art on a routine basis. Thus, the term "in conjunction with" includes that either of the two formulations may be administered (optionally repeatedly) before, after and / or simultaneously with the other component. As used in this context, the terms "administered simultaneously" and "administered at the same time" include the administration of individual doses of bifeprunox and L-DOPA within 48 hours, for example, with a separation interval of 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes. The term "treatment", as used in the present invention, refers to any treatment of a condition or disease of a mammal, preferably a human, and includes: (1) inhibiting the disease or condition, i.e., stopping its development, (2) alleviate the disease or condition, that is, cause the condition to regress, or (3) stop the symptoms of the disease.

As used in the present invention, the term "medical therapy" is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo with humans or other mammals. The term "subject", as used in the present invention, refers to an animal, preferably a mammal, more preferably a human, which has been the object of treatment, observation or experiment.

EXAMPLES Treatment with the MPTP neurotoxin (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine) leads to depletion of dopamine in the caudate-putamen and to a "Parkinsonian-like" behavior in non-human and human primates ( Lange, 1992; Langston, 1984; Langston, 1986).

EXAMPLE 1 Interaction between bifeprunox and L-DOPA Animals: The study used common marmosets (Callithrix jacchus) (n = 6, age between 3 and 5 years, 5 females and 1 male) previously treated with MPTP (2 mg / kg daily) for 5 days and exhibited stable motor deficits. . These animals were sensitive to L-DOPA and had been treated previously with the test drug. They had not been induced dyskinesia experimentally although they presented some dyskinesia.

Treatment with the drug: Bifeprunox mesylate was suspended in sucrose solution 10% and was orally administered by tube in a volume of 2.0 ml / kg. L-DOPA: L-3,4-dihydroxyphenylalanine (L-dopa) methyl ester (Sigma Chemical Co., UK) was dissolved in 10% sucrose solution and orally administered by gavage in a volume of 2.0 ml / kg. Carbidopa: (Merck, Sharp and Dohme, UK) was administered orally in the form of a suspension in 10% sucrose solution in a volume of 2.0 ml / kg. Domperidone: (2.0 mg / kg po, Sigma UK) was dissolved in 10% sucrose and administered 60 minutes before bifeprunox in a volume of 2.0 mg / kg. Bifeprunox (4 or 8 mg / kg po of free base) or its vehicle (10% sucrose) was administered alone and in combination with L-DOPA (7.5 mg / kg po of free base, administered in combination with carbidopa, 12.5 mg / kg po) to marmosets treated with MPTP (n = 6). 90 minutes before the administration of L-DOPA or your vehicle, the animals were treated with bifeprunox or your vehicle. Carbidopa was administered 30 minutes before the administration of L-DOPA. Domperidone was administered 60 minutes before the administration of bifeprunox.

Behavioral studies: In all studies, the animals were acclimated to the cages for the behavioral study during 1 hour prior to the treatment. The animals were individually placed in activity cages (50 x 60 x 70 cm) equipped with a transparent perspex door to allow clear visibility for observation. Each cage was equipped with 8 horizontally oriented infrared emitting photocells and their corresponding detectors, arranged to allow a maximum evaluation of the movement. The locomotor activity was evaluated as the number of interruptions of the light beam caused by the movement of the animals, accumulated in intervals of 10 minutes for up to 7 hours. Before the administration of the drug, the animals were acclimatized for a period of 60 minutes in the activity cages, during which period the baseline activity was evaluated. The "on" threshold was defined as 3 times the activity of the baseline in marmosets treated with MPTP. Hyperactivity was defined as 3 times the normal activity of untreated marmosets. The "on" time was the period of time in minutes during which the activity was above the "on" threshold. The animals were treated with bifeprunox, vehicle and / or L-DOPA. After treatment with the drug, the animals were evaluated for locomotor activity and disability, as described below, for up to 6 hours after drug administration. The animals used in the study were not for more than 8 hours in the automatic activity cages on any day of study, and among the drug treatments, a recovery period of at least 3 days was allowed to ensure adequate protection of the animals. Locomotor activity, motor disability and the presence of dyskinesia were evaluated as follows: Locomotor activity: In all the studies, the animals were acclimated to the cages for the behavioral study during 1 hour prior to the treatment with bifeprunox. Then the animals were treated with the appropriate drugs. After treatment, the animals were evaluated for antiparkinson activity for up to 6 hours using the automatic activity cages and by classification of the disability by an observer who was not aware of the treatment (blind evaluation). The period of locomotor activity "ON" was defined as the period of time during which the animals showed an activity greater than 3 times the locomotor activity of the baseline or a locomotor activity of 00, always taking the highest.

Disability and dyskinesia scores: For up to 6 hours after treatment with the drug, disability and dyskinesia were evaluated before and during the last 10 minutes of each 30-minute period after the administration of bifeprunox. The following disability classification scales were used: Classification of disability: The disability of the animals was classified with the following scores: attention (normal 0, sleepy 2); reaction (normal 0, reduced 1, slow 2, absent 3); control of movements (present 0, reduced 1, absent 2); attention and eye movements (normal 0, abnormal 1); posture (normal 0, abnormal trunk +1, abnormal limbs +1, abnormal tail +1, or strongly abnormal 4); balance / coordination (normal 0, damaged 1, unstable 2, spontaneous failures 3); vocalization (normal 0, reduced 1, absent 2); mobility (normal 0, bradykinesia / hyperkinesia 1, akinesia / hyperkinesia 2). Sedation was noted, if present. The "ON" time of disability was defined as the period of time during which the animals showed a disability score of 6 or less ("ON threshold").

Data and statistical analysis Data are presented as average locomotor activity (counts / 30 min) or disability score (score for 10 min / 30 min) during the 7 hour period of the experiment, or as total locomotor activity (counts / 420 min) or disability (total score for 420 min). If appropriate, the data were analyzed by ANOVA according to Kruskall Wallis and the post-hoc Man-Whitney test. The analyzes were corrected for multiple comparisons using the formula: Acceptable probability = a / number of comparisons, where a = 5% A separate group of animals used in the study was treated with a vehicle and used for statistical comparison purposes.

EXAMPLE 2 Effects of bifeprunox on the reversal of motor abilities induced by L-DOPA Locomotor activity: The administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) increased the locomotor activity immediately after administration, compared to vehicle administration (figures 1, 2, 3 and 4). Peak activity (mean value 1627, range 832-2289 counts per 30 min) was reached between 60 and 180 min after the administration of L-DOPA. The average duration of activity (ON time) was 180/420 min (Figure 4). The total locomotor activity and the duration of the motor activity ("ON time") were greater than those of the animals treated with vehicle. Bifeprunox (4 mg / kg po) increased locomotor activity immediately after administration compared to vehicle administration (Figures 1 and 3). Peak activity was achieved (mean value 685, interval 512-1967 counts per 30 min) between 60 and 180 min after administration. The average duration of activity (ON time) was 240 min / 420 min (Figure 4). The total locomotor activity and the duration of the motor activity ("ON time") were greater than those of the animals treated with vehicle (p <0.05, Mann Whitney). Bifeprunox (8 mg / kg po) increased locomotor activity immediately after administration compared to vehicle administration (Figures 2 and 3). Peak activity was reached (mean value 1 1 10, interval 669-2058 counts per 30 min) between 60 and 300 min after administration. The average activity duration (ON time) was 345 min / 420 min, higher than that of the vehicle treatment (figure 4). The total locomotor activity was greater than that of the animals treated with vehicle (p <0.05, Mann Whitney). Pretreatment with bifeprunox (4 mg / kg po), 90 min before administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) increased locomotor activity immediately after administration compared to baseline activity. Peak activity (mean value 1581, interval 556-2232 counts per 30 min) was reached between 60 and 390 min after administration. The average duration of activity (ON time, 390 min / 420 min, figure 4) was slightly greater than that observed after administration of L-DOPA alone and bifeprunox alone. Locomotor activity tended to increase compared to L-DOPA alone and bifeprunox (4 mg / kg po) alone (Figures 1, 2, 3 and 4). Pretreatment with bifeprunox (8 mg / kg po), 90 min before administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) increased locomotor activity immediately after administration compared to baseline activity (Figures 2 and 3). Peak activity was achieved (mean value 121 1, interval 409-1342 counts per 30 min) between 60 and 360 min after administration. The average activity duration (ON time, 300 min / 420 min, figure 4) was slightly lower than that with only bifeprunox. Total locomotor activity and activity duration (ON time) did not differ from those observed with bifeprunox (8 mg / kg po) alone and L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) only (figures 2, 3 and 4).

Disability: The administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) decreased the disability scores immediately after administration compared to vehicle administration ( Figures 5, 6, 7 and 8) (p <0.05 compared to vehicle treatment control, Mann Whitney). Peak activity (mean score 3, range 2-4) was reached between 30 and 300 (mean value 75) minutes after the administration of L-DOPA. The duration ("ON time") of disability for L-DOPA was only 20 min / 420 min. Bifeprunox (4 mg / kg po) decreased disability scores immediately (30-60 min) after administration, compared with vehicle administration (Figures 5 and 7) (p <0.05 compared to treatment control with vehicle, Mann Whitney). Peak scores (mean score 3, score range 2-4) were reached between 30 and 240 min after administration. The average duration of activity (ON time) was 210 min / 420 min (Figure 8). Bifeprunox (8 mg / kg po) decreased disability scores immediately after administration compared to vehicle treatment (Figures 6 and 7) (p <0.05 compared to control vehicle treatment, Mann Whitney). The total decrease in disability was lower than that of animals treated with vehicle. The peak scores (mean score 4, score range 2-5) were reached between 30 and 150 min after administration. The duration of the activity (ON time) was 225 min / 420 min, greater than that of the vehicle treatment (figure 8). Pretreatment with bifeprunox (4 mg / kg po), 90 min before administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) decreased the disability scores during the study period, (figures 5 and 7). The peak scores (mean score 3, score range 2-4) were reached between 60 and 240 min after administration. The duration of the activity (ON time) was 360 min / 420 min. The duration of activity tended to increase compared to bifeprunox alone (figure 8). Pretreatment with bifeprunox (8 mg / kg po), 90 min before the administration of L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) decreased the scores of disability (figures 6 and 7). The peak scores (mean score 3, score range 2-5) were reached between 60 and 120 min after administration. The duration of the activity (ON time) was 165 min / 420 min. The duration of activity with only bifeprunox (8 mg / kg po) or with L-DOPA (7.5 mg / kg po) plus carbidopa (12.5 mg / kg po, 30 min before L-DOPA) did not show differences.

Conclusion: L-DOPA (7.5 mg / kg po) increased locomotor activity and decreased disability scores in common marmosets treated with PTP. Bifeprunox (4 and 8 mg / kg po) also increased locomotor activity and decreased disability scores. When administered in combination with L-DOPA, bifeprunox (4 or 8 mg / kg po) tends to increase total locomotor activity and duration ("ON time") of locomotor activity compared to L-DOPA alone.

EXAMPLE 3 Pharmaceutical preparations Types of pharmaceutical compositions that can 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 in the present invention or evident to a person skilled in the art starting of the specification and general knowledge in the art. The compositions are used orally, intravenously, subcutaneously, tracheally, bronchially, intranasally, pulmonarily, transdermally, buccally, rectally, parenterally or by other routes of administration. The pharmaceutical formulation contains at least one preparation of the invention mixed with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The total amount of active ingredients is suitably in the range of about 0.1% (w / w) of the formulation, suitably from 0.5% to 50% (w / w) and preferably from 1% to 25% (w / w) . The molar ratio between bifeprunox (or its N-oxide) and L-DOPA can be in the range of about 1000: 1 to about 1: 1000, conveniently in the range of 300: 1 to 1: 300, and preferably of 50: 1 to 1: 50. The preparations of the invention can be brought into forms suitable for administration by usual processes using auxiliary substances such as liquid or powdered solid ingredients, such as pharmaceutically customary liquid or solid fillers and solvents, solvents, emulsifiers, lubricants, flavors, colorants and solvents. the substances for pH regulation. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as oil of fish liver, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and monohydric or polyhydric alcohols such as glycerol, as well as disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into pellets or compressed into tablets. The active ingredients can be premixed separately with the other non-active ingredients, before preparing the final mixture to form a formulation. The active ingredients can also be mixed together, before being mixed with the non-active ingredients to form a formulation. Soft gelatin capsules can 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 gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients together with powdered solid ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (I) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a microenema prepared for use; or (iv) in the form of a dry microenema formulation that must be reconstituted in a suitable solvent immediately prior to administration. The liquid preparations can be prepared in the form of syrups, elixirs, drops or concentrated suspensions, for example solutions or suspensions containing the active ingredients, the remainder consisting of, for example, 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, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations can also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration can be prepared in the form of a solution containing a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or ingredients for pH regulation. Solutions for parenteral administration can also be prepared in the form of a dry preparation, reconstituted with a suitable solvent before use. The present invention also provides formulations and "parts kits" 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. With said container (said containers) can be associated several written materials, such as instructions for use or a note in the form required by a government agency that regulates the manufacture, use or sale of pharmaceutical products, note that reflects the approval by the manufacturing agency, the use or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for use in the treatment of a condition in which the recovery of dopaminergic function is required or desired, and methods of medical treatment comprising administering a total amount therapeutically effective of at least one preparation of the invention to a patient suffering from, or susceptible to, a condition in which the recovery of the dopaminergic function is required or desired.

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Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1 .- A combination preparation, comprising bifeprunox or its N-oxide Bifeprunox Bifeprunox-N-oxide or pharmacologically acceptable salts of these compounds, and (ii) L-DOPA or pharmacologically acceptable salts thereof, for the simultaneous, separate or sequential use in therapy of disorders requiring the recovery of dopaminergic function.

2. - The preparation according to claim 1, further characterized in that it comprises a decarboxylase inhibitor.

3. The preparation according to claim 1 or claim 2, further characterized in that it additionally comprises a COMT inhibitor.

4. The preparation according to any of claims 1, 2 or 3, further characterized in that it additionally comprises an inhibitor of MAO-B.

5. The use of a preparation of any of claims 1-4, for the manufacture of a medicament useful for the treatment of disorders that require the recovery of the dopaminergic function.

6. - The use as claimed in claim 5, wherein said disorder is Parkinson's disease.

7. The use as claimed in claim 5, wherein said disorder is the syndrome of restless legs.

8. - A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable excipient and / or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of a preparation according to any of claims 1-4, as active ingredients.

9. The use of bifeprunox or its N-oxide or a pharmacologically acceptable salt thereof, and an amount of L-DOPA, for the manufacture of a medicament useful for treating Parkinson's disease or restless legs syndrome in a human or animal patient, wherein said bifeprunox or its N-oxide or its pharmaceutically acceptable salt and L-DOPA are adapted to be administrating simultaneously, separately or sequentially.

10. The use as claimed in claim 9, wherein additionally an amount of a decarboxylase inhibitor and / or a COMT inhibitor and / or an MAO-B inhibitor is adapted to be administrable. 1 1 .- The use of bifeprunox or its N-oxide, for the manufacture of a medicine useful for the treatment of restless legs syndrome. 12. Bifeprunox or its N-oxide for use in the treatment of restless legs syndrome.