SA07280316B1 - Combination Preparations Comprising Bifeprunox and L-Dopa - Google Patents

Abstract

Combination Preparations Comprising Bifeprunox and L-Dopa Abstract The present invention relates to the use of a combination preparation of bifeprunox or the N-oxide thereof, or pharmaceutically acceptable salts of these compounds: the N-oxide of bifeprunox bifeprunox and L-Dopa, for concomitant use, or as a stand-alone, or sequential, treatment of disorders requiring restoration of dopaminergic function, in particular Parkinson's disease and restless leg syndrome.

Description

_Y—_

L-DOPA and bifeprunox combination preparations include

Combination preparations comprising bifeprunox and L-Dopa FULL DESCRIPTION BACKGROUND 1 The present invention relates to the use of a combination preparation of bifeprunox or N-oxide thereof.; or | For pharmaceutically acceptable salts of these compounds: 0 Ci 1 1 ] Hh OF mm A N= 0 { Ss NS 0 m N-oxide from bifeprunox bifeprunox DOPA -.] ; for simultaneous use; or a freelancer; or sequential; in the treatment of disorders requiring restoration of dopaminergic function; Especially Parkinson's disease and restless legs syndrome. Oe represents the constant trembling of the hands and feet; progressively harder and slower body movement (cals) and mask-like facial expressions; Label has been observed throughout human history. In 1811 James Parkinson described this group of symptoms as "Parkinson's" and soon after this timing the disease was named after the physician who first described it. The cause of Parkinson's disease involves the destruction of the WAN neurons in the substance

Co DS A

black; The part of the brain responsible for muscle movement. The loss of about 7860 striatal dopamine in Parkinson's disease leads to the emergence of major symptoms Jud akinesia, rigidity and bradykinesia (Hornykiewicz-1966), and patients suffer from problems initiating movement and

Unsteadiness in a certain position and lack of coordination. © The current Shall treatment for Parkinson's disease is based on restoring dopamine 0 (Blandini, 2000; Lledo, 2000) dopaminergic function that does not cross the blood-brain barrier and therefore cannot be used in the treatment of Parkinson's disease; The direct precursor L-DOPA “al (Co yond isomer) is used to cycle 3,4-dihydroxyphenylalanine; it is also referred to as Ya (levodopa) from dopamine + because it enters the brain where it takes place. He removed the Ye group 40 from it to turn it into dopamine.But levodopa is decarboxylated from it, La, in peripheral tissues.So a small part of the levodopa that is given to the patient gets into the brain.Carbidopad! By inhibiting terminal decarboxylation of levodopa but it itself cannot cross the blood-brain barrier and has no effect on brain metabolism of levodopa.The combination of Carbidopad! and levodopa is the most effective treatment Lally for the symptoms of 0 Parkinson's disease. However, there are some limitations within two to five years of starting treatment. As the disease progresses, the benefit from each dose becomes shorter (the wearing off effect " ) and some patients oscillate unpredictably between being able to move and not being able to move ("on-off effect"). The "On" periods are usually associated with elevated plasma concentrations of Levodoya high plasma levodopa concentrations 0 and often include unusual involuntary movements; any; imbalance Periods of 'no effect' are associated with a decrease in the plasma level of levodopa

os — _ and with bouts of bradykinesia : ‎lay Jankovic, 1993; Rascol, 2000 has encouraged treating physicians to delay initiation of treatment with L-DOPA as fay treatment first with dopaminergic agents function sae lus. However; using the entire dopamine receptor cofactors apomorphine Jie or bromocryptine 8 or lisuride or pergolide or pramipexol or ropinirole; It has limits too. They lead to dal dysfunction and induce psychotic-like symptoms, including Gls somnolence. 5 orthostatic hypotension hallucinations Other side effects: (Lozano, 1998; Bennett, 1999) It has been suggested that these symptoms can be overcome with adjuvant agents. partial to the M dopamine receptor (meaning compounds that do not activate the Dy; dopamine receptors 0 to all) (2002) (Jenner) Hypothetically, these compounds would be able to activate the Dy; dopamine receptors when the tone is dopaminergic function is low; while being able to counteract excessive activation of the D; dopamine receptor when the tone is high dopaminergic function; resulting in "stability of dopaminergic transmission in the brain (2002) (Jenner, YO receptor cofactors M:5-111 may help to reduce the appearance of imbalances, as the Jalal cofactor M,5-111 represented in tandospirone reduces imbalances in patients with Parkinson's disease who are treated with ( Kannari, 2002) L-DOPA and extrapyramidal side effects induced by haloperidol in 0 (Christoffersen, 1998) primates and more recently faa have been suggested that sarzotan; It is a cofactor of M:5-111 and the dopamine receptor ligand can 0.00 relieve motor dysfunction (2001). Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, Y.O.

A - The presence of the cofactor M:5-117 could be beneficial for the therapeutic effects that are determined by the partial cofactor of the receptor and (Johnston, Cling 2003) Various combination preparations have appeared that include L-DOPA and one or more of Other enzyme inhibitors. (Stalevo®, (Jost, 2005). Recently, entacapone tolcapone (Jia catecholamine-O-methyltransferase (COMT) enzyme inhibitors have been recommended as adjunctive therapy to 011 (1-0). These compounds help increase The half-life of L-DOAP J in plasma does not significantly increase Cn and accordingly decreases the Ye taper to effect but tends to increase the intensity of side effects at maximum dose including maximal dose-induced motor impairment. Tolcapone appears to cause significant hepatic toxicity in a small proportion in patients Another strategy aimed at slowing down dopamine metabolism is when monoamine-binding reductase-B (MAO-B) inhibitors are used in combination with of ¥).L-DOPA Administration of MAO to patients is associated with a number of debilitating side effects, which limits its use. These Ve effects include; eg nausea, dizziness, lightheadedness, fainting, abdominal pain, confusion, hallucinations, dry mouth, vivid dreams Pads vivid dreams Movement dyskinesias and headache .headache There are combination preparations des consist in that they exist in the form of different dose combinations, and that during the period of disease it is sale what is Ye there is a need to use doses Great for LDOAP to keep symptoms under control

Co - +

And combination preparations that are in the form of tablets that contain specific amounts of lial are considered

easy to use; But at the same time, it provides limited flexibility. And as an illustration of the fact that combinations

Firmware is not always useful; For example; MAO-B inhibitor use can be mentioned

Selective complementation of selegiline in the treatment of Parkinson's disease. By the early stage of the disease; may be done

© Giving selegiline as monotherapy: the compound will slow down its metabolism

Dopamine is endogenous enough to keep symptoms within loaded limits. And in stages

late for the disease; The use of L-DOPA may become necessary. And when L-DOPA starts to work

diminishes_gradually the first dal of this is usually represented by the use of an enzyme inhibitor

Carbidopa Jie decarboxylase (see above); And when that becomes not enough laf the cure

0 Co-administration of selegiline will help restore the effectiveness of L-DOPA by reducing L-DOPA

breakdown of dopamine generated by L-DOPA and so on; In practical application, L-DOPA selegiline is given in the form of independent preparations that may be administered simultaneously or sequentially.

Victims severely affected by restless legs syndrome (RLS) also called EKBOM syndrome (EKBOM)

They are apparently unable to remain seated or even to stand. become the activities

need to maintain motor rest 5 limited cognitive stimulation limited

Mia ¢ cognitive stimulation when traveling and riding in a vehicle (car; plane; train etc.) or

attend meetings; or lectures; or films and plays; Or any other hard Ssh time consuming activities

If not impossible. And as a result of the torture caused by these feelings that become more severe during (Jal).

RLS patients find sleep impossible; In addition to the negative impact on their quality of life.

0 and the insistence on Al that increases during rest periods; It can be completely dissipated by motion; Jie walking.

However, “as soon as the movement stops”; Symptoms return with a higher intensity. If a patient with RLS is forced to

Co

EV

remains lying down; the symptoms will go on Jie ell) what happens to a spring loaded and sooner or Sal the legs will move involuntarily; The symptoms immediately subside. Balanced or semi-balanced movements of the legs can be observed if the patient tries to remain supine (Pollmacher 1993), and these movements are referred to as dyskinesia during wakefulness (Hening, 1986) (DWA) or more commonly © legs It is called periodic limb movements - during wakefulness (PLMW) and clinically the disease can be diagnosed as RLS (13) Four diagnostic criteria are met: (1) presence of a sense of urgency to move the limbs (sale) legs ); (Y) restlessness to decrease these sensations; (7) at rest; symptoms return or become Toul from what they were; and (£) the observed daily change in the onset or severity of RLS symptoms i.e. symptoms become Toul in the evening and overnight (Allen, 2001) 0 Current treatments for RLS have varied and become a kind of torment with undesirable side effects.Therapies have included administration of dopamine and other dopaminergic function agents, benzodiazepines + opioids, and anticonvulsant agents. In cases where RLS results from secondary Alls; Jie pregnancy; or end-stage renal disease; treatment with erythropoietin” or iron deficiency; Treatment with a conventional iron supplement can reduce or eliminate symptoms, at least in some cases (Allen, 2001). It is more challenging to treat. In general, dopaminergic agents Jie function levodopa provide initial treatment lad but with continued use; Symptoms can be tolerated and relieved in about 7880 RLS (Allen, 1996) patients, and this complication is common laf 0 for dopamine cofactors (Earley 1996). Opium »and antispasmodic agents are not as regular in action

_A —

dopaminergic function (Chesson, 1999; Hening, 1 999). Despite the difference in their treatment approach; A percentage ranging from 15 to 7780 patients find that all medications are insufficient due to their adverse adverse effects and limited therapeutic benefit.

0 j Loo _ AH 5 EN {he 5 1 JAN NS 0 N-oxide 8 from bifeprunox bifeprunox 127090 DU reveals: 7-[4-([1 ,1'-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone now known as cbifeprunox binds to D-like receptors; Dopamine and PM receptors,5-111. It is considered a partial cofactor at D-dopamine receptors and a partial cofactor at serotonin 5-111 Ye receptors: (International Application: 200359 WO 97/36893; Van Vliet, 2000; Feenstra, 2001, 2002; Hesselink, 2002). (Mealy, 2004 and in International Application 0017/0771 EY; it was revealed that in vivo bifeprunox (N-oxide) rapidly converts to the parent compound; thus acting as a “Sl drug”. 0 General Description of the invention The present invention aims to develop an effective treatment (L-DOPA Jie), but without its side effects: specifically 6 7

without its hallmark of gg and no effect 'causing immobility during 'impact' periods; and significant developments in bradykinesia during "no-effect" periods. amazingly; In studies of monkeys treated with MPTP in an animal model that includes a predicted value for Parkinson's disease, combined treatment with L-DOPA© and bifeprunox reduced JB from maximal locomotor activity. Comparison of Lay observed after administration of L-DOPA alone so that hyperactivity was not observed.cal has the period of activity 'period of effect' following administration of L-DOPA given in combination with bifeprunox bifeprunox. The invention is in combination preparations comprising bifeprunox or N-oxide thereof; or its salts; hydrates s; and its pharmaceutically acceptable solutes; (L-DOPA and optionally the enzyme decarboxylase and/ Optionally, a COMT inhibitor and/or, optionally, a MAO-B inhibitor for simultaneous, independent, or sequential use in the treatment of disorders requiring restoration of dopaminergic function, specifically Parkinson's disease and restless syndrome legs.” The invention relates to the use of bifeprunox or cas N-oxide “a real PRP drug; in cases in which L-DOPA causes impairment; or it can be predicted that it may cause impairment. VO and in such cases; The specific pharmacological effects of the compound; alee (Jia) as a partial cofactor on dopamine y D receptors; dopamine and 0 as well as its full cofactor on serotonin receptors M:5-111; leads to the prevention of motor dysfunction without reducing the therapeutic effect, especially L-DOPA. The present invention relates to pharmaceutical formulations, which include:

- N = its solutes hydrates s of it; or its salts N-oxide or “bifeprunox bifeprunox | (1) Pharmacologically acceptable; and: in mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. 1-008 (() Another feature of the present invention relates to combinations of fractions comprising: hydrates s of or salts of N -oxide or “bifeprunox bifeprunox container containing –1 © and its pharmaceutically acceptable solutes; optionally in mixture with a pharmaceutically acceptable adjuvant, diluent or carrier and optionally with an acceptable adjuvant, diluent or carrier (L -DOPA container containing - “and: LY aa to a patient <L-DOPA bifeprunox ye Instructions for the sequential, independent or simultaneous administration of each —F Ve in need of this treatment. According to another feature of the invention; A method for manufacturing an assembly of parts as previously defined ' (as defined above; with component A) (1) above is presented, wherein this method involves combining the component with 0 as defined above ¢ such that The two components are suitable to give each other the following: (1) and (1) the combination of the two components 0 providing them as independent formulas (i.e., each separately from the other), where they are then combined 1 - To use them together in a combination therapy ¢ or to present them together as separate components of a 'combination package' for their use Lagan =

Yo.

, Another feature of the invention is also related to ways to treat a patient suffering from; Or susceptible to a condition in which the restoration of dopaminergic function is required or desirable. This method includes giving the patient a therapeutically effective total amount of: cbifeprunox bifeprunox =) © or aie N-oxide or its salts hydrates s and its solubles of acceptable Lats and optionally in mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in association with: 1-00 and optionally in mixture with a pharmaceutically acceptable adjuvant or diluent or Alla.Another Lad feature of the invention relates to the use of pharmaceutical formulations which Comprising: bifeprunox bifeprunox or N-oxide _ thereof; or its salts Pharmaceutical Acceptable hydrates and solutes: 00 0M"1-00; optionally in mixture with an acceptable adjuvant, diluent, or carrier LV ans Manufacture A drug for the treatment of Alla in which restoration of dopaminergic function is required or desirable Examples of decarboxylase inhibitors are carbidopa benserazide Abily catechol-amine-O-methyl transferase (COMT) inhibitors are: entacapone + and ctolcapone s <nitecapone \o monoamine oxidase-B (MAO-B) inhibitors include: deprenyl desmethyldeprenyl 1 (-)-deprenyl (selegiline), and phenelzine (nardil), 5 N-propargyl-1-(R)-aminoindan (rasagaline), and

- 17

tranyl-cypromine (parnate) 003466 f

,. procarbazine § furazolidone, isocarboxazid, pargyline, methyclothiazide

To further describe Dla, some of the quantitative expressions described in this document are not consistent with the term "about". Please indicate that whether or not the term "about" is used explicitly

© Each quantity shown herein refers to the actual stated value; It also indicates the ratio

The approximation from this specified value that Way is derived for normal skill in the domain; Including the approximate percentage resulting from experimental and/or standard conditions for this specified value.

Throughout this document and its claims; The term 'includes' and its derivatives are not intended to exclude additions, components, integers, or other steps.

0 The term 'combination' as used herein includes a product that contains specified ingredients in predetermined amounts or proportions as well as any product that results, either directly or indirectly, from the mixing of specified ingredients in specified quantities. For pharmaceutical formulations, it includes This term includes a compound comprising one or more active ingredients; an optional carrier comprising inert components; and any product resulting, directly or indirectly, from the combination, complication or agglomeration of any

VO two or more components; or from the separation of one or more components; or from other types of reactions that take place in one or more components. and in general; Pharmaceutical compositions are prepared by systematically and closely combining the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, forming the product into the desired formulation. The pharmaceutical composition includes a sufficient amount of the active compound to produce the desired effect when the disease progresses.

0 and so on; The pharmaceutical compositions covered by the present invention include any prepared composition

Yo..

Co-gel by mixing a compound covered by the present invention and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means that the carrier, diluent, or excipient must be in harmony with the other components of the formulation and not harm those who receive it. tablet or injection fluid; as well as Jie and other medicines to be physically mixed into a single preparation Bifeprunox© in dosage forms of L-DOPA; and Bifeprunox for treatment sets; It includes 1 term "separate parts"; with instructions for use; and optionally with other means of facilitating adherence to giving the correct compounds; Combinations shall be marked or with graphics. Simultaneous drug therapy The contents of the "treatment kit parts" can be given either simultaneously or at different time intervals The administration of treatment either simultaneously or sequentially depends on the other properties of the drugs used, such as onset and length of action, levels Plasma; by a specialist.It is preferable that the dose range from mg/kg.The typical daily dose will vary from active ingredients 01 mg/kg to 1.1 VO Relevant indications of the disease; Jie's age and vary in a wide range and will It depends on various factors and the weight and gender (male / female) of the patient, and it can be determined by a specialist doctor.In general, the 0001 to 1.1 doses given orally and by injection will range from Total Active Ingredients.. Gags mg and the expression “therapeutic effective amount” as used herein refers to a quantity of a therapeutic agent Vo

Co - vg - can be treated by giving the patient a formula of the invention. And that Ula is used to treat the quantity is the amount sufficient to produce a therapeutic or analgesic response and mitigate the disease; It can be monitored on a reported JU treatment in an animal or human tissue system. The effect may include; The seriousness of the condition to be treated, and according to what is recommended by the physician (the therapist (or researcher) or the veterinarian; or the physician specialized in the treatment; or any other specialist); which you choose to give. Combinations and over therapies; or it is useful to specify an exact effective quantity; a priori. The term “pharmaceutically acceptable salt” refers to such salts; which are based on sound medical opinion; suitable for use in human and lower animal tissues without causing excessive toxicity, irritation, anaphylactic response, etc. and are compatible with respect to a reasonable benefit/risk ratio. Pharmaceutical acceptable salts are well known in this field. It can be prepared on site at the last compounds of the invention; or separately by reacting with dilly segregation bases or non-toxic, pharmaceutically acceptable acids; Including organic or inorganic bases and organic or inorganic acids. Pharmaceutically acceptable salts may be obtained using procedures 0 by mixing one of the standard special compounds (JU) well known in the art; for example, an inorganic acid or an organic acid. Jie of the invention with a suitable acid;

Bifeprunox “given in combination with” includes the administration of those corresponding formulations containing and/or independently and/or concomitantly” during the course of treatment for the given condition; ml (L-DOPA) and where may Whether this condition is acute or chronic, the expression should preferably include giving both forms (and optionally 0

Yo.

— mg \ — frequently) so that the administration is at frequent intervals so that there is a beneficial effect on the patient» i.e. a greater effect; during the course of treatment of the particular condition; Lee if each of the two formulations were given (and optionally more frequently) alone 6 in the absence of form A (say) during the same treatment period. The determination of whether a combination provides a greater beneficial effect for; and during the entire treatment period will depend on a particular case on the condition to be treated or prevented but a person skilled in the art can routinely determine this. Accordingly the expression 'in combination with' implies that one of the two formulas will be given (and optionally frequently) before and/or after and/or at the same time as the other. When used in this context, the expressions 'given simultaneously' and 'given at the same time' include administration of independent doses of L-DOPA bifeprunox at 8 00 hour intervals, such as ve An hour; or 18 hours; or 11 hours; or 7 hours; or ? hours; or 2 hours” or an hour or 00 minutes between each other. The term ‘wie’ as used in This document refers to any treatment of an intrusive organism that favors a human condition or disease and includes: (1) inhibiting the disease or condition - i.e. stopping its progression; (7) mitigating the disease or condition - i.e. making the condition recede or (3) stopping Gabel Disease © and as used herein; The term "medical treatment" includes preventive, diagnostic, and therapeutic regimens performed both in the body and externally on humans or other And organisms. The term 'patient' as used herein refers to an organism, preferably a mammal and preferably a human, who is the object of treatment, observation, or experiment. Brief Explanation of Drawings Yo.

- 1)

L mg/kg” by mouth) alone or in combination with bifeprunox (demonstrates the effect of Fig. 1: mg/kg; orally) on locomotor activity in young American monkeys 0.2) — DOPA

LMPTP known handler with

L mg/kg” by mouth) alone or in combination with A) bifeprunox Figure 7: Shows the effect of (.50 mg/kg; by mouth) on locomotor activity in young American monkeys - 0008 ©

Known MPTP processed with hours at 1 mg/kg; (oral) during £) bifeprunox Fig. no.: Showing effect of known rhesus monkeys treated with 10017. * of >00+ compared with vector (Mann Whitney) vector - mg/kg; Oral) alone or in combination A; OR (bifeprunox i fig.: denotes 0 v mg/kg; oral) on locomotor activity “on impact” during L—DOPA V0) with a comparison of ...# > p * MPTP hours in known young American monkeys treated with a vector — vector mg/kg; orally) (Mann Whitney) alone or in combination 4 (bifeprunox Fig. ©: showing the effect of ( 5./a mg/kg; orally) on the disability value in monkeys of 1. - DOPA with 0

Known MPTP processed with mg/kg; Oral) alone or in combination with A) bifeprunox Fig. 6: Shows the effect of (.5 mg/kg; orally) on disability value in known primates 1. - 008

MPTP treated with mg/kg; by mouth) alone or in combination A or 4 ( bifeprunox Fig. 7: showing the effect of 01

Co : 117 - - with (V.0) L - DOPA mg/kg; oral) on total disability values within 1 hour in known American monkeys treated with 14017. * M > 0.05 compared with vector-vector (Mann Whitney). Figure tA showing the effect of bifeprunox (4 or 4 mg/kg; orally) alone or in combination with L-DOPA (V.0) mg/kg; Effect etal on total disability values within Vv hours in known American monkeys treated with >0.5 pF MPTP compared with vector (Mann Whitney) Jil. Examples 0 Treatment with the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) leads to dopaminergic depletion in the caudate-cortex (part of the brain) and to Parkinsonian-like behavior in primates. HUMAN AND HUMAN: (Lange, 1992; Langston, 1984; Langston, 1 986). Example No. 1: Interaction between L-DOPA bifeprunox 0 Animals: A well-known young American monkey (Callithrix) was used. jacchus = 1” aged between ? and © years; © female and 1 male); in this study; she was previously treated with MPTP (Y (mg/kg daily subcutaneous injection) and showed fixed motor defects. These animals responding to treatment with als L-DOPA were simply not responsive to the test compound.They were laboratory-conditioned to show dyskinesia even though some of the motor impairments were present.You.

0 a.m. - 1 p.m. Drug treatment: Bifeprunox was suspended in sucrose 700 and administered by feeding through a gastric fistula with a volume of [de 1 kg. and dissolved: 1-0"NH L-3,4-Dihydroxyphenylalanine (L-dopa) methylester (Sigma Chemical Co,

UK) kg. [de 1 and fed by gastric fistula with a volume of 701 sucrose in a © 7 specific 7 pag of sucrose in p (Merck Sharp and Dohme, UK) carbidopa and suspended mg/kg via Y) domperidone ml/kg and administered directly into the animal's mouth. ?aly was dissolved in a volume of 01 minutes in a period of bifeprunox and was administered before sucrose LY + in (Sigma, UK 1000 mg / kg) orally in the form of the free base (Alt) bifeprunox kg., [de mg/kg of L-DOPA (V.0) alone or in combination with Lal or with a vector (+7 sucrose) 0 mg/kg VY. ¢ carbidopa Oral route as the free base; where it was given in combination with (1 = n) MPTP orally) to animals treated with L-DOPA or its carrier before administration of bifeprunox to animals treated with bifeprunox. Min. Vo was given L-DOPA a minute before carbidopa was given. Domperidone 01 was given 00 times before bifeprunoxs Uae) by 01 minutes. Behavioral study: in all studies; Animals were acclimated individually to behavioral study cages for an hour prior to treatment. Therefore, the animals were placed in activity study cages (04,07 Ve x cm) equipped with a transparent perspex door so that they could be observed clearly. Each cage was fitted with two infrared emitters each lie on a horizontally oriented photocell and its detectors were arranged to allow maximum motion assessment. The locomotor activity was evaluated in the form of Yo.

Po - ya - minutes and for 10 of them JS times the light beam is cut off due to the movement of animals; At intervals of 220 minutes for animals in cages, the activity was evaluated for 10 hours. An adjustment period of 1 duration was allowed during which a baseline for the activity was established; before giving her the drug. The cut-off value for 'having an effect' was defined as 3 times the activity at baseline in the treated young monkeys and hyperactivity was defined as ¥ times the normal activity in the MPTP monkeys using © in which activity is about The 'presence of the effect' object is the time period in minutes that the and/or vector and/or bifeprunox threshold value of the 'presence of the effect'. The animals were treated with and after treatment with the drug; The animals' locomotor activity and immobility were assessed as DOPA as described below for up to 6 hours after administration. And the animals used were hours on any day of A in the study placed in the mechanized activity cages for a period not exceeding 0 of the study; She was allowed three days to recover between treatments with the drug to ensure recovery considerations, and locomotor activity, motor deficits, and the presence of motor impairment were evaluated as follows: 0 suitable for the animal

Luby Motor Activity Assessment: In all studies; The animals were acclimatized separately in cages, and then the animals were treated with drugs. bifeprunox + behavior for 1 hour prior to treatment with the appropriate Parkinson's disease (LAL) + antibody; YO hours were evaluated using motorized activity cages and disability rates by an observer who did not know anything about

Les the cure. Locomotor activity “during impact” was defined as the time period during which 100 animals exhibited activity of more than ? Examples of basic motor activity or a motor activity whose value was already greater than this value. Last minutes 01 Disability and motor impairment values: The motor impairment and disability were assessed before; or during the Ve

Yo.

every yo-minute period after administration of bifeprunox for up to 7 hours after treatment with the drug. The following disability score values were used: Disability scores: Disability was assessed for animals and its value was determined as follows: alertness, cognition (normal = sleepy yellow = ¢) Y reaction (normal = 0; low = 1; slow = oF absent = ?); Inspection's movements (present = 0; low = oO) absent = 1); perception and eye movements (normal = 0 unusual = 1); sale status = 0 trunk non O + 0 gale limbs abnormal + ON tail unusual + 0 significantly abnormal = 4); balance/symmetry (gale) = zero; acquired - unbalanced A = oF times spontaneous fall = 3 ?); beep (gale) = zero; low = 1 absent = ?); Mobility (normal = 0; bradykinetic or hyperkinetic = 0; Y = immobile or severely hyperkinetic (Ye = immobile) and quiescence was noted if present. Disability “during the effect period” was defined as the period The time the animals exhibited disability values equal to or less than 1 (threshold effect value). Statistical analysis and data: Data were presented as mean locomotor activity (counts/yo-min) or disability values (value in 10 minutes/0’min) for 1 hour of the experiment; OR total 0 locomotor activity (0 counts/”© min) or total disability score (total value over 17 μm). Data were analyzed using a Kruskall Wallis ANOVA. and post-hoc Man-Whitney [lial] as needed. Data were corrected for multiple comparisons using the equation: plausible probability = ae fo comparisons; Lo = a dua A separate group of those animals used in the study were treated with the vector 0 was used in the statistical comparison. You.

1 oxy - EXAMPLE 7: Effects of bifeprunox in contrast to values of locomotor deficits induced by L-DOPA. Locomotor activity: assisted (V.0) L-DOPA mg/kg; Oral) plus carbidopa VY. 5 (mg/kg; orally before L-DOPA bVe min)_ increased locomotor activity compared to the vector (Figs. 1 and ?£575) immediately after administration. The activity peaked (average © 1177 The range of counts ranged from 877 to 17484 per ye minutes) within 10 to 181 minutes after administration of /1-000. The average activity duration ranged from 1880 to 170 minutes (Fig. 4) The total locomotor activity and locomotor activity “during the effect period” were greater than the vector-treated animals (M Jil 205 from Mann Whitney). Bifeprunox (£ mg/kg orally) helped to increase locomotor activity. compared to administration of the vector Ye (Fig. 1 and *) immediately after administration.The activity peaked (mean TAO (mean range of counts from ©011 to VAY per ye min) within 10 to VAL minutes after administration The mean 5% persistence of activity (during the effect) was from 740 to 0 minutes (Fig. p) less than VO (Mann Whitney 0266). Initial treatment with bifeprunox (§ mg/kg oral) helped; 0 minutes before using L-DOPA (V.0 mg/pas oral) in addition to VY.0) carbidopa mg/kg; Oral; Voy min before use (L-DOPA) increased locomotor activity compared to baseline activity (Fig. 1 and *) immediately after administration. Activity reached its peak (mean VOAY count range from 907 to 771 every 0?min) within 01 to VAL Te minutes after administration.The average duration of activity (during ctl) was from 790 to 70 Yo.

yy - minute; The ¢ profile is slightly longer than that observed after administration of L-DOPA alone and bifeprunox. Locomotor activity tended to be increased compared to the use of L-DOPA alone and bifeprunox (; mg/kg oral) alone (Figures ? and and 4).

Initial treatment with A) bifeprunox mg/kg orally helped; before 10

© min of L-DOPA (V.2 mg/pas orally) plus VY.0) carbidopa mg/pas orally; 0 minutes prior to using L-DOPA increased locomotor activity compared to baseline activity (formal ? and ©) immediately after administration. Activity reached its peak (mean OY count range from 409 to 147). every 30 minutes) within 01 to

470 minutes after administration. The mean duration of activity (during effect) ranged from 700 to 0

0 minutes; Figure 4) Sl is shorter than bifeprunox by itself. The total locomotor activity and the duration of the activity were not different when compared using (A) bifeprunox mg/kg via L-DOPAj (V.0) (pill).

mg/kg; oral) plus carbidopa (1Y.0) mg/kg; Oral; before

0 minutes of L-DOPA alone (Figures Y, F, and 4).

Motor deficits: assisted L-DOPA (V.0) mg/kg; orally) in addition to carbidopa

(1.0) 0 mg/kg; administered 0 minutes before L-DOPA reduced deficit values compared to the vector (Figures © and 3 nor As) immediately after administration (m less of 0 + 0. compared to the vector-treated control group” ail (Mann Whitney) Disability values reached their peak (median oF value range from AY ;) within 0 to Vor min (median Vo minutes)

After L-DOPA was given, this effect lasted for 11 minutes/17 minutes for L-DOPA.

0 "during ape effect".

Yo.

a yy - - “5:180000”; ( ) M less than 0 + 0 compared to the vector-treated control group (Mann Whitney) Disability values reached their peak (medium value; range of values ? to ;) within 0 to YE minutes (mean yo min) © after administration This effect lasted for 701 min/£Y min ‘during the effect period’. (Fig. A) bifeprunox mg/kg helped Oral route) reduced the disability values compared to administration of the vector (formal + and ) immediately after administration (p) less than 0.050 compared to the control group that was treated with the vector” (Mann Whitney). It was treated with the vector (Fig. 7).The deficiency values reached their peak (median value of the range of values from 0 .from ? to #) within 0 to 1001 minutes after administration.This effect lasted for 770 min/0 min “during effect” and was longer than vector treatment (Fig. A). Initial treatment with bifeprunox helped; mg/kg orally); Te minutes before using L-DOPA (V.0) mg/kg; oral) plus carbidopa (1Y.0) mg/kg; Oral; Minutes before Yo of using (L-DOPA) reduced the deficit values during the study period (Fig. 0 (Tg) and the deficit values reached their peak (average oF ranges from Y to ;) within 10 to YE minutes after administration.The mean duration of activity (during effect) was 0/7750 + LEY and duration of activity tended to be increased compared to use of bifeprunox alone (Fig. A Initial treatment with A) bifeprunox mg/kg orally) 0 10 minutes prior to L-DOPA (V.0 mg/kg orally) plus its dexamethasone helped 1Y.0) Yo.

Cov - mg/kg”; Oral; 701 4883 patients accepted the use of L-DOPA to reduce disability values during the study period (Figs 1 and 7). The disability values reached their peak (mean 7; range from ? to ce in Within 10 to 101 minutes after administration, the mean duration of activity (during effect) was 0/1765 -£Y and total locomotor activity and duration of activity were not different when compared with A) bifeprunox mg/kg by mouth) or [ane V.0) L-DOPA kg; by (pd) plus carbidopa (VY.0) mg/kg; Oral; 0 minutes prior to administration of L-DOPA (Fig. A (Conclusion: L-DOPA V2.2 mg/kg; oral) increased locomotor activity and decreased disability values in Known young American monkeys treated with MPTP and bifeprunox Ve (£ and + mg/kg orally) also helped to increase locomotor activity and reduce disability values. When given in combination with L-DOPA, bifeprunox (£ and A mg/kg orally) tended to increase total locomotor activity and locomotor activity “on the effect” compared to the use of L-DOPA alone. . Example No.: Pharmaceutical preparations 0 The types of pharmaceutical preparations that can be used include; For example but not limited to; contains tablets, chewable tablets, capsules (including microcapsules), solutions, solutions for injection, ointments (creams and gels), suppositories, and other types disclosed in this application or which may become apparent to a person skilled in the field from the description and from general information in the field. the use of oral formulations; injection into a vein or under the skin; or by force; or via the Ye bronchi; or in the nose; or by lung; or transdermal; or buccal; or rectally; Yo

Co — Yo —

or by non-enteric route” or by other methods of administration. The pharmaceutical formulation contains at least one preparation of the invention in mixture with an adjuvant, a diluent and/or a carrier

Pharmacologically acceptable. It is appropriate that the total amount of active ingredients range from about 7,001

(w/w) to about 4 7 (w/w) in formula; It is suitable from 0.8 7 to Lou

© (w/w); Preferably from 1 7 to YO 72 (w/w). The molar ratio may range from bifeprunox (or N-oxide thereof) to 10/8 - 1. of 10:0001 (dea to about Vere tp) and from

appropriate to range from 0:0 to 1:700; Preferably 1:90 to cov).

Preparations of the invention may be formulated into forms suitable for administration; using known processes using adjuvants such as solid, liquid or powdered components; like materials

0 Filling and expanding agents, liquid or solid, known at the pharmaceutical level; solvents; and emulsifying agents. lubricants; flavoring agents; colouring agents; and/or Regulatory Substances. Commonly used auxiliaries include magnesium carbonate, titanium dioxide, sucrose saccharose s lactose, sorbitol, mannitol, and other sugars or other sugar alcohols called alcohols.

00, talc 6, lactoprotein, gelatin, starch, amylopectin ¢, cellulose and its derivatives; And vegetable and animal oils Jie fish liver oil

sunflower, peanut, sesame, polyethylene glycol, and solvents such as purified water; mono- or polyhydric alcohols such as glycerol; As well as with the use of loosening agents and lubricating agents such as

Yo cmagnesium stearate, calcium stearate, sodium stearyl fumarate; And polyethylene glycol waxes YO.

- glycol waxes. The mixture may then be processed and formed into granules or pressed into tablets. Active ingredients can be mixed separately Blane with other inactive ingredients; before mixing them together to form a formula. Active ingredients can also be mixed with each other; before mixing it with other inactive © ingredients to form a formula. Soft gelatin capsules may be prepared using capsules containing a mixture of the active ingredients of the invention and vegetable oil; fat” or any other suitable carrier for the formation of soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients along with the powdered Vo solid ingredients such as lactose or sucrose; csorbitol or mannitol; or potato starch; or cornstarch; or amylopectin or cellulose derivatives; or gelatin. Dosage units suitable for rectal administration can be prepared (1) in the form of suppositories containing the active substance mixed with a natural fat base; (7) in the form of a gelatin capsule for rectal administration containing the active substance mixed with vegetable oil or paraffin oil. or other vehicle (Ye) suitable for a gelatin capsule for rectal administration; (?) in a pre-formulated Aa microenema; or (©;) in a dry microenema formulation that is reconstituted in a suitable solvent immediately prior to administration. Liquid preparations may be prepared as syrups, elixirs, concentrated drops or suspensions Jie solutions or suspensions containing the active ingredients the remainder consisting of, for example, Ye sugar or sugar alcohols and a mixture of ethanol, water and glycerol glycerol and propylene

, 1h except -

propylene glycol and polyethylene glycol, if desired; These liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine, carboxymethyl cellulose jie, or other thickening agents. Liquid formulations may also be prepared in the form of a reformulated dry powder

© in a suitable solvent before use. Solutions suitable for parenteral administration may be prepared as a solution of the formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffers. Solutions suitable for parenteral administration may also be prepared in the form of a dry preparation that is reformulated in a suitable solvent before use.

1 comprising one container or shawl and according to the present invention; Formulations and combinations of more packed with one or more ingredients of a pharmaceutical composition according to the invention are also presented for use in medical treatment. Such containers may be accompanied by various written materials such as instructions for use; or a note formulated according to instructions. The government agency regulating the manufacture, use or sale of pharmaceutical products, and this note reflects the approval of that authority to manufacture, use or sell Ve pharmaceutical products intended for administration to humans or in the veterinary field.The formulas of the present invention are used in the manufacture of medicines for use In the treatment of a condition for which it is required or desirable; and medical treatment methods comprising the administration of a therapeutically effective total dopaminergic function-restoring amount of at least one of the preparations of the invention in a patient suffering from, or at risk of developing, a condition It is desired or desirable to restore 0

. dopaminergic function Yo.

the reviewer

Allen and Earley 'Augmentation of the restless leg syndrome with carbidopa/levodopa'.

Sleep 19: 205-213, 1996.

Allen and Earley, Restless leg syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol 18: 128-147, 2001 ©

Bara-Jimenez W et al. 2005. Effects of serotonin (5-HT) agonist in advanced

Parkinson's disease. Movement Disorders 20: 932-936;

Bennett and Piercey, pramipexole - a new dopamine agonist for the treatment of

Parkinson's disease. J Neurol Sci 163: 25-31, 1999. 01

Bibbiani et al., 2001. Serotonin 5-111 agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57: 1829-1834;

Blandini et al., 'Functional changes of the basal ganglia circuitry in Parkinson's disease',. Prog Neurobiol 62, 63-88, 2000.

Chesson et al (1999) Practice parameters for the treatment of restless leg syndrome and Vo periodic limb movement disorder. An American Academy of Sleep Medicine Report.

Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 22: 961-968;

Yo.

— Y q —

Christoffersen and Meltzer, 1998. Reversal of haloperidol-induced extrapyramidal side effects in cebus monkeys by 8-hydroxy-2-(di-n-propylamino)tetralin and its enantiomers.

Neuropsychopharmacology 18:399-402).

Earley and Allen (1996) Pergolide and carbidopa/levodopa treatment of the restless leg syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep©19:801-810.

Feenstra et al., 2001, “New 1-aryl-4-(Biarylmethylene)piperazines as potential atypical anti-psychotic agents with mixed dopamine 102- receptor- and serotonin 5-111 a receptor affinities”, Bioorg. Med. Chem. Lett., 11, 2345-2349,

Feenstra et al., 2002, “New approaches in antipsychotics: design and synthesis of ligands 01 binding to dopamine-D; and serotonin 5-111 receptors, clinical candidates DU 127090 and SLV313”, Drugs of the Future 2002, 27 (Suppl. A).

Hening et al., (1986) Dyskinesias while awake and periodic movements in sleep in restless leg syndrome: treatment with opioids. Neurology 36: 1363-6

Hening et al., (1999) The treatment of restless leg syndrome and periodic limb Yo movement disorder. An American Academy of Sleep Medicine Review. Sleep 22: 970-999

Hessellink et al., 2003, DU 127090, SLV308 and SLV318: characterization of a chemically related class of partial dopamine agonists with varying degrees of 5-1111

©. : agonism, Eur. J. Neurol. 10: S1, 2151, 20038

Hesselink et al., DU 127090, SLV308 and SLV318: characterization of a chemically related class of partial dopamine agonists with varying degrees of 5-HT agonism, Eur.

J. Neurol. 10: 81, 2151, 2003.

Horfiykiewicz O (1966). Dopamine (3-hydroxytyramine) and brain function. Pharmacol

Reviews, 18, 925-964).

Jankovic, J.,” Natural course and limitations of levodopa therapy.” Neurology 43: S14-

S17, 1993.

Jenner P. Pharmacology of dopamine agonists in the treatment of Parkinson's disease.

Neurology 26: S1-8, 2002. AR

Johnston, L.C., et al., Association between Intrinsic Activity and the Antiparkinsonian

Effects of a Novel Dopamine Agonist series in the 1-methyl-4-phenyl-1 ,2,3,6- terahydropyridine Treated Primate Model of Parkinson's Disease. Eur. J. Neurol. 10: S1, 2158, 2003.

Jost, W.H. et ‘Efficacy and tolerability of Stalevo® in patients with Parkinson’s Vo disease experiencing wearing-off’, Aktuelle Neurologie, 32, Suppl. 6, 5318-5325, 2005.

Kannari et al., Tandospirone citrate, a selective 5-111 M agonist, alleviates L-DOPA induced dyskinesia in patients with Parkinson's disease. No To Shinkei 54: 133-137,

YOU ur

Lange K.W., et al. (1992). Terguride stimulates locomotor activity at 2 months but not months after MPTP-treatment of common marmosets. Eur J of Pharmacology, 212, 247-52;

Langston and Irwin (1986). MPTP: Current concepts and concepts. Clean

Neuropharmacol 9, 485-507.

Langston et al. (1984). MPTP-induced parkinsonism in humans and non-human primates-clinical and experimental aspects. Acta Neurol Scand 70, 49-54).

Lleds, p. 'Dopamine agonists: the treatment for Parkinson's disease in the XXI century? Parkinsonism Relat Disord 7, 51-58, 2000. 0

Lozano et al., New developments in understanding the etiology of Parkinson's disease and in its treatment. Curr Open Neurobiol 8: 783-90, 1998.

Mealy, N.E., et al., *Bifeprunox mesylate”, Drugs of the Future, 29(9), 938, 2004.

Olanow et al, 2004, Multicenter, open label, trial of sarizotan in Parkinson disease patients with levodopa-indicated dyskinesias (the SPLENDID Study). Clean 1

Neuropharmacol 27: 58-62;

Pearce, et al., De Novo Administration of Ropinirole and Bromocriptine Induces Less

Dyskinesia than L-DOPA in the MPTP-treated Common Marmoset. Movie Dis, Mar,

- The Name 13(2), 234-41, 1998

Pollmacher and Schulz, 'Periodic leg movements (PLM): their relationship to sleep stages. Sleep 16: 572-577, 1993

Rascol et al., A five-year study of the incidence of dyskinesia in patients with early

Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 342: © 1484-1491, 2000

Van Vliet et al., 2000, “DU 127090: a highly potent, atypical dopamine receptor ligand”,

Journal of the European College of Neuropsychopharmacology (ECNP), 1 0(3), S294, 20001770 97/36893 WO 2007/023141

Claims (1)

Claims 1-1 a pharmaceutical composition comprising (1) “a probiotic or N-oxide Y thereof: 0 i 1 ot fh _ 09 they are the > l 0 ben 2 bifeprunox bifeprunox from N-oxide $ m or pharmaceutically acceptable salts of these compounds” and DOPA (Y) - .1 or > aie pharmaceutically acceptable salts for eid or stand-alone use; or sequential” in the treatment of 7 disorders that require restoration of dopaminergic function. 1 " - the preparation according to claim No. 1, which also contains a decarboxylase inhibitor Y. 1 ?- preparation according to claim No. 1 or oY where Y also includes a COMT inhibitor 1 ;- preparation according to claim No. 1 or oY 1 or Cua (YF) also includes an MAO-B inhibitor. a 1 © - a pharmaceutical composition pursuant to any of Claims Y from 1 to ; ; For use in the manufacture of a drug for the treatment of disorders that require restoration of dopaminergic function. 1-1 pharmaceutical composition pursuant to any of the claims from 1 Y to ; ; For use in the manufacture of a drug for the treatment of Parkinson's disease —V 1 a pharmaceutical composition lah pharmaceutical composition of any of the claims Y 1 through ; ; For use in the manufacture of restless leg syndrome g al —A 1 pharmaceutical composition comprising; In addition to at least one pharmaceutically acceptable carrier and/or pharmaceutically acceptable adjuvant; YF contains a pharmacologically effective quantity of a preparation according to any of the claims 1 to £« as active ingredients ¢. Y 8 + 0