BRPI0713695A2 - combined preparation, use thereof, and pharmaceutical composition - Google Patents

Abstract

COMBINED PREPARATION, USE OF THE SAME, AND PHARMACEUTICAL COMPOSITION. The invention relates to the use of a combined preparation of SLV308 or its N-oxide, or pharmacologically acceptable salts of compounds (I), (II). and L-DOPA, for simultaneous, separate or sequential use in the treatment of disorders that require recovery of dopaminergic function, in particular Parkinson's disease and restless legs syndrome.

Description

"COMBINED PREPARATION, USE OF THE SAME, AND PHARMACEUTICAL COMPOSITION"

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SUMMARY: TECHNICAL FIELD OF THE INVENTION

The invention relates to the use of a combined preparation of SLV308 or its N-oxide, or pharmacologically acceptable salts of the compounds:

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SLV308 SLV308 N-OXidO

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. BACKGROUND OF THE INVENTION

Constant tremors in the hands and legs, body movements that gradually become more difficult, slower and weaker, and mask-like facial expressions are symptoms that have been observed throughout human history. In 1817 James Parkinson described this set of symptoms as "paralysis agitans" and soon after the disease was named after the physician 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 with muscle movement. Loss of around 80% of striatal dopamine in Parkinson's disease results in cardinal symptoms of akinesia, stiffness and bradykinesia (Hornykiewicz, 1966). Patients have problems early in the movement and present postural instability and loss of coordination.

Current pharmacotherapy for Parkinson's disease is based on recovery of dopaminergic function (Blandini, 2000; LledO, 2000). Dopamine does not cross the blood brain barrier and therefore cannot be used to treat Parkinson's disease, its immediate precursor, L-DOPA (the levorotatory enantiomer of 3,4-dihydroxyphenylalanine, also referred to as levodopa). because it penetrates the brain where dopamine is decarboxylated. But levodopa is decarboxylated in peripheral tissues as well. Thus, only a small portion of administered levodopa is transported to the brain. Carbidopa inhibits the decarboxylation of peripheral levodopa, but cannot itself cross the blood brain barrier and has no effect on levodopa metabolism in the brain. The combination of carbidopa and levodopa is considered the most effective treatment for Parkinson's disease symptoms. However, certain limitations become apparent two to five years after initiation of therapy. As the disease progresses, the benefit of each dose becomes smaller ("the weakening effect") and some patients fluctuate unpredictably between mobility and immobility ("the active-inactive effect"). "Active" periods are usually associated with high plasma levodopa concentrations and often include abnormal involuntary movements, ie dyskinesias. "Inactive" periods were correlated with low plasma levodopa and bradykinetic episodes (Jankovic, 1993; Rascol, 2000). This suggested that doctors delay starting L-DOPA treatment by prior treatment with dopaminergic agonists.

However, the use of complete dopamine receptor agonists, such as apomorphine, bromocriptine, lisuride, pergolide, pramipexole or ropinirole, also has its limitations: They initiate dyskinesias, induce psychotic symptoms including hallucinations, orthostatic hypotension, drowsiness and other side effects. (Lozano, 1998; Bennett, 1999). It has been suggested that this may overlap using partial dopamine D2 / 3 receptor agonists (i.e. compounds that do not maximally stimulate dopamine D2 / 3 receptors) (Jenner 2002). Such compounds would hypothetically be able to stimulate dopamine D273 receptors when dopaminergic tone is low, although they may counteract excessive stimulation of the dopamine D2 receptor when dopaminergic tone is high, thus resulting in "stabilization" of dopaminergic transmission in the dopamine. brain (Jenner, 2002).

5-HT 1A receptor agonists may alleviate induction of dyskinesia, as the 5-HT 1A receptor tandospirone agonist reduced dyskinesia in Parkinson's disease patients treated with L-DOPA (Kannari, 2002) and haloperidol-induced extrapyramidal side effects. primates (Christoffersen, 1998). More recently it has been suggested that sarizotan, a 5-HT 1A receptor agonist and dopamine receptor ligand, may alleviate dyskinetic symptoms (Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, 2001). The presence of 5-HT 1A receptor agonist may be beneficial to the therapeutic effects of a partial D2 / 3 receptor agonist (Johnston, 2003).

Recently, different combined preparations containing L-DOPA and one or more other enzyme inhibitors have been introduced. Well-known are the combinations L-DOPA / carbidopa (eg Sinemet®), L-DOP A / benserazide (eg Madopar®) and L-DOPA / carbidopa / entacapone (eg Stalevo®) (Jost, 2005 )). More recently, atecolamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjunctive therapy to L-DOPA. These compounds extend the plasma half-life of L-DOPA without significantly increasing Cmax. Thus, they decrease the duration of the weakening but tend to increase the intensity of peak dose side effects including peak dose dyskinesias. Tolcapone appears to induce significant liver toxicity in a small percentage of patients. Another strategy aimed at lowering dopamine metabolism is the use of monoamine oxidase-B (MAO-B) inhibitors in combination with L-DOPA. Administration of ΜΑΟ inhibitors, however, is associated with numerous 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. Characteristics for the combined preparations are that they exist in many different dose combinations, because during the course of the disease usually higher doses of L-DOPA are required to keep the symptoms under control. Combined tablet preparations containing fixed amounts of medications are easy to use but also offer limited flexibility. An illustration of the fact that fixed combinations are not universally used is, for example, the use of the selective MAO-B selegiline inhibitor in the treatment of Parkinson's disease. In the early stage of the disease, selegiline may be given as monotherapy: the compound will decrease endogenous dopamine metabolism sufficiently to keep symptoms within tolerable limits. In late stages of the disease, the use of L-DOPA may become necessary. When the effectiveness of L-DOPA begins to weaken, usually the first solution to the problem is the use of a carbidopa decarboxylase inhibitor (see above) and also when it becomes insufficient, selegiline co-therapy will restore the efficacy of L-DOPA reducing dopamine arrest generated from L-DOPA. Thus, in practice, L-DOPA and selegiline are administered in separate preparations which may be given simultaneously or sequentially.

Victims seriously affected by restless leg syndrome (RLS; also known as Ekbom syndrome) are virtually unable to remain seated or even still. Activities that require motor rest and limited cognitive stimulation, such as transportation (car, plane, train, etc.) or following longer meetings, conferences, cinemas, or other performances, become difficult, if not impossible. Tortured by these severe feelings at night, RLS patients find that sleeping is virtually impossible, adding to the diminishing quality of their lives. The impulse to move, which increases in rest periods, can be completely dissipated by movement, such as walking. However, once the movement stops, the symptoms return with greater intensity. If an RLS patient is forced to remain in position, symptoms will continue to appear like a loaded spring and eventually the legs will involuntarily move, relieving symptoms immediately. Rhythmic or semi-rhythmic movements of the legs are observed if the patient tends to remain in the same position (Pollmacher, 1993). These movements are referred to as dyskinesias-while-awake (DWA) (Hening, 1986) or more commonly, periodic limbic movements while awake (PLMW). Clinically, RLS is indicated when four diagnostic criteria are met: (1) a sensation of an impulse to move the limbs (usually the legs); (2) motor rest reduces sensations; (3) when at rest, symptoms return or worsen; and (4) marked circadian variation in the occurrence or severity of RLS symptoms; that is, symptoms get worse at dusk and at night (Allen, 2001).

Current treatments for RLS are varied and plagued with undesirable side effects. Therapies included the administration of dopamine agonists, other dopaminergic agents, benzodiazepines, opiates and anticonvulsants. In cases where RLS results from a secondary condition, such as pregnancy, end-stage renal disease, erythropoietin treatment, or iron deficiency, removal of the condition, such as birth or traditional iron supplementation treatment, may reduce or eliminate symptoms. at least in some cases (Allen, 2001). However, RLS resulting from non-secondary conditions ("idiopathic" RLS) presents a better treatment challenge. Dopaminergic agents such as levodopa usually provide effective initial treatment, but with continued use, increased tolerance and symptom occurs in about 80% of RLS patients (Allen, 1996); This complication is also common for dopamine agonists (Earley, 1996). The other alternatives, benzodiazepines, opiates and anticonvulsants are not as uniformly effective as dopaminergic agents (Chesson51999; Hening, 1999). Despite the change in their treatment regimens, 15-20% of patients found that all medications were inappropriate due to adverse effects and limited treatment benefit.

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SLV308, 7- [4-methyl-1-piperazinyl] -2 (3H) -benzoxazolone monohydrochloride, binds to dopamine D2-type receptors and 5-ΗΤ1Α receptors · It is a partial dopamine D2 / 3 receptor agonist and a complete serotonin 5-HT 1A receptor agonist. In cloned human dopamine D 1 receptors SLV308 acted as a potent but partial D2 receptor agonist (pEC50 = 8.0 and pA2 = 8.4) with a 50% efficacy in forskolin-stimulated cAMP accumulation. In recombinant human dopamine D3 receptors, SLV308 acted as a partial agonist in [35S] GTPγS binding induction (67% of dopamine), had a higher degree of potency compared to quinpirol (pEC50 = 9.2) and antagonized the induction of [35S] GTPγS binding dopamine (pA2 = 9.0). SLV308 acted as a complete 5-HT1A receptor agonist in phoscoline-induced cAMP accumulation in cloned human 5-HT1A receptors (pEC50 = 6.3) similar to the 5-HT1A 8-OH-DPAT receptor agonist. In SLV308 rat striatal slices concentration-attenuated attenuated phoscoline stimulated accumulation of cAMP as expected for a dopamine D2 / 3 receptor agonist. SLV308 antagonized the inhibitory effect of quinpirol on K +-stimulated [3H] dopamma release (pA2 = 8.5) from rat striatal slices. In the same paradigm the terguride partial D2 agonist demonstrated a greater degree of antagonism in the presence of quinpirol (pA2 = 10.3) similar to the haloperidol D2 antagonist (pA2 = 9.3) but less than SLV308 (pA2 = 8.5). In conclusion, SLV308 combines high potency partial antagonism in dopamine D2 / 3 receptors (acting as a dopamine stabilizer) with low potency 5-HT1A receptor agonism and complete efficacy. (WO 00/29397; Feenstra, 2001; Johnston, 2001a, b; Hesse / ink, 2001, 2003, McCreary, 2001, 2006; Wolf, 2003). WO 2007/023141 has described that in vivo SLV308 N-oxide is rapidly converted to SLV308, thus functioning as a "prodrug".

DETAILED DESCRIPTION OF THE INVENTION

The aim of the present invention was to develop a treatment as effective as L-DOPA, but without its side effects: In particular without its characteristic "go-back" effect, causing dyskinesias during "active" periods and bradykinetic episodes during "inactive" period. .

Surprisingly, in studies on MPTP-treated physicians, an animal model with predictable value for Parkinson's disease, it was observed that combined treatment with L-DOPA and SLV308 reduced peak locomotor activity observed after L-DOPA alone, so that hyperactivity was not observed. Duration of activity "idle" time) after L-DOPA was longer by co-administration of SLV308.

The subject matter of the invention are combined preparations of SLV308 or its N-oxide, or pharmacologically acceptable salts, hydrates or solvates thereof and L-DOPA and optionally a decarboxylase inhibitor and / or optionally a COMT inhibitor, and or, optionally, a MAO-B inhibitor for simultaneous, separate or sequential use in the therapy of disorders requiring recovery of dopaminergic function, in particular Parkinson's disease and "Restless Leg Syndrome".

The invention relates to the use of SLV308 or its N-oxide, a true "prodrug" in cases where an L-DOPA induces dyskinesias, or may be predicted to induce dyskinesias. In such cases, compound-specific pharmacological activities, viz. Partial agonism at dopamine-D2 and dopamine-D3 receptors, as well as serotonin 5-HT1A full agonism receptors, result in blockade of dyskinesias without reduction of the effect. L-DOPA therapy.

The present invention relates to pharmaceutical formulations comprising:

(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates or solvates thereof, and:

(ii) L-DOPA, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

A further aspect of the present invention relates to part kits comprising: (i) a vessel containing SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates or solvates thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:

(ii) a vessel containing L-DOPA, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:

(iii) instructions for sequential, separate or simultaneous administration of SLV308 and L-DOPA to a patient in need thereof.

According to a further aspect of the invention, there is provided a method of preparing a parts kit as defined herein, which method comprises placing a component (i) as defined above in association with a component (ii) of the form defined above, thus yielding the two components suitable for administration together. Placing the two components in association with each other includes which components (i) and (ii) can be:

(i) provided as separate formulations (ie independently of one another), which are subsequently put together for use in conjunction with each other and combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use together in combination therapy.

Still another aspect of the invention relates to methods for treating a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is necessary or desired, which method comprises administering to the patient a total therapeutically effective amount. in:

(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates or solvates thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; together with:

(ii) L-DOPA, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Still another aspect of the invention relates to the use of pharmaceutical formulations comprising:

(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates or solvates thereof, and:

(ii) L-DOPA, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in the manufacture of a medicament for the treatment of a condition in which recovery of dopaminergic function is required or desired.

DEFINITIONS

Examples of decarboxylase inhibitors are carbidopa and benserazide. Examples of catecholamine-O-methyl transferase (COMT) inhibitors are: entacapone, nitecapone and tolcapone and monoamine oxidase-B (MAO-B) inhibitors include: deprenyl, (-) - deprenyl (selegiline), desmetildeprenil, N-propargil -1- (R) -aminoindan (rasagaline), phenelzine (nardyl), tranylcypromin (parnate), CGP3466, furazolidone, isocarboxazid, pargillin, methyclothiazide and procarbazine. To provide a more concise description, some of the quantitative expressions given here are not qualified by the term "about". It is understood that whether the term "about" is used explicitly or not, each amount given herein means referring to the actual given value and is also meant to refer to the approximation to such a given value that would reasonably be inferred from including approximations by virtue of the experimental and / or measurement conditions for that given value.

Throughout the description and claims of this specification the word "comprises" and variations of the word, such as "comprising" and "understood" are not intended to exclude other additives, components, integers or steps.

The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from the combination of specified ingredients in specified amounts. With respect to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any of two or more of the ingredients, or dissociation of one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by placing the active ingredient uniformly and intimately in association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes sufficient active object compound to produce the desired effect upon the progress or condition of the diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In the context of this patent application, the term "combined preparation" encompasses both true combinations, meaning SLV308 and other physically combined medicaments in a preparation such as a tablet or injection fluid, as well as "kit-parts", comprising SLV308. and L-DOPA in separate dosage forms, together with instructions for use, optionally with additional devices for compliance with the administration of component compounds, for example, labels or drawings. With true combinations, pharmacotherapy by definition is simultaneous. The contents of the "kit of parts" can be administered both simultaneously and at different time intervals. The therapy being both concomitant and sequential will depend on the characteristics of the other drugs used, onset and duration of action, plasma levels, clearance, etc., as well as the disease, its stage and individual patient characteristics.

The dose of the composition to be administered will depend on the relevant indication, age, weight and gender of the patient and may be determined by a physician. The dosage will preferably be in the range of 0.01 mg / kg to 10 mg / kg. The typical daily dose of active ingredients varies over a wide range and will depend on a number of factors, such as the relevant indication, route of administration, age, weight and gender of the patient and may be determined by a physician. Overall, oral and parenteral dosages will be in the range 0.1 to 1,000 mg per day of total active ingredients.

The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent for treating a condition treatable by administering a composition of the invention. The amount is sufficient to provide a detectable or relieving therapeutic response in an animal or human tissue system. The effect may include, for example, treating the conditions listed herein. The precise effective amount for a subject will depend on the subject's size and height, the nature and extent of the condition being treated, recommendations of the treating physician (researchers, veterinarians, doctors or other doctors) and the therapy, or combination of therapies, selected for administration. Thus, it is not used to specify an exact effective amount in advance.

The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of medical judgment, suitable for use in contact with lower human and animal tissues without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They may be prepared in situ when finally isolating and purifying the compounds of the invention, or separately reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable strong acid, for example an inorganic acid or an organic acid.

"Administration in conjunction with" includes that respective formulations comprising SLV308 and L-DOPA are administered sequentially, separately and / or simultaneously during the course of treatment of the relevant condition, the condition of which may be acute or chronic. Preferably, the term includes that the two formulations are administered (optionally repeatedly) sufficiently close in time that there is a beneficial effect for the patient, i.e. greater during the course of treatment of the relevant condition, that if both formulations were administered (optionally repeatedly) alone, in the absence of the other formulation, during the same course of treatment. Determining whether a combination provides a better beneficial effect on the course of treatment and during it a particular condition will depend on the condition to be treated or prevented, but can be routinely achieved by one of skill in the art. Thus, the term "in conjunction with" includes that either of the two formulations may be administered (optionally repeatedly) before, after and / or at the same time as administration with the other component. When used in this context, the terms "concurrently administered" and "concurrently administered" include that individual doses of SLV308 and L-DOPA are administered within 48 hours, for example 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes of each other.

The term "treatment" as used herein refers to any treatment of a mammalian, preferably human, condition or disease and includes: (1) inhibiting the disease or condition, i.e. stopping its development, (2) alleviating the disease or condition, that is, causing the condition to regress or (3) stop the symptoms of the disease.

As used herein, the term "medical therapy" is intended to include prophylactic, diagnostic and therapeutic regimens performed in vivo or ex vivo in humans or other mammals.

The term "subject" as used herein refers to an animal, preferably a mammal, above all preferably a human who has been the object of the treatment, observation or experiment.

EXAMPLES

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

EXAMPLE 1: Interaction between SLV308 and L-DOPA at Therapeutically Relevant Doses

Animals: Common adult male and female tamarins (Callithrix jacchus; n = 6, weighing 320-450 g, 2-3 years old) were used in this study. Animals were housed alone or in pairs under standard conditions at a temperature of 24 ± 20 ° C and 50% relative humidity, employing a 12-hour light-dark cycle with free access to food and water. All experimental work was performed according to the Animals (Scientific Procedures Act) 1986, project license nr PPL 70/4986.

MPTP administration: d (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride; Research Biochemical International, UK) was dissolved in .9% sterile saline solution and administered by subcutaneous injection ( sc) (Pearce, 1998). To induce complete injury, MPTP (2.0 mg / kg, sc) was administered once daily for 5 consecutive days. During treatment with MPTP and for the next six to eight weeks, animals were manually fed on a tamarin jelly diet until they had recovered sufficiently to feed themselves and their body weights had stabilized. All animals were determined responsive to L-DOPA administration prior to use. The test began only when the animals had recovered from the acute effects of MPTP treatment. This study was 70 days after the start of MPTP treatment.

Medicines: SLV308 was dissolved in 10% sucrose and given in a volume of 2 mL / kg and administered by oral gavage. Doses are expressed as mg / kg free base. Methyl L-DOPA ester (Sigma, UK) was dissolved in 10% sucrose and given in a volume of 2 mL / kg and administered by oral gavage. Carbidopa (Merck Sharp and Dohme, UK) was suspended in 10% sucrose and given in a volume of 2 mL / kg and administered directly into the animal's mouth. Domperidone (Sigma, UK) was suspended in 10% sucrose and given in a volume of 2 mL / kg and administered directly into the animal's mouth. Doses were based on a previous study with SLV308 in which it was observed that the optimal effect of SLV308 on locomotor activity and destability score was 0.26 mg / kg, po. Doses of L-DOPA were chosen to reflect a moderate and high dose of L-DOPA (7.5 and 12.5 mg / kg, po respectively).

Procedure: On the day of the experiment, animals were weighed, treated with domperidone (2 mg / kg, po) directly in the mouth and after 60 minutes were treated with either SLV308 (0.26 mg / kg, po) or oral gavage vehicle. . After 30 minutes, carbidopa (12.5 mg / kg, po) was administered and 30 minutes later L-DOPA (7.5 or 12.5 mg / kg, po) or its vehicle was administered. A modified Latin square design was employed with a one week washout period between treatments. Animals were estimated for locomotor activity and disability as described below.

Estimation of locomotor activity: Animals were placed individually in activity cages (50 χ 60 χ 70 cm) fitted with a clear perspex door to allow clear visibility for observation. Each cage was equipped with 8 horizontally oriented infrared photocell emitters and their corresponding detectors arranged to allow maximum movement estimation. Locomotor activity was estimated as the number of light beam interruptions caused by movement of animals accumulated at 10-minute intervals for up to 7 hours. Animals were naturally acclimated for a period of 60 minutes in activity cages during which baseline activity was estimated prior to drug administration. The "active" threshold was defined as 3-fold baseline activity in MPTP-treated monkeys. Hyperactivity was defined as 3-fold normal activity in original tamarins. "Active" time was the amount of time in minutes that activity was above the "active" threshold.

Deficiency Rate: The animals were monitored by a mirror on one side by experienced observers, treated for treatment and classified for the degree of motor dysfunction. Motor dysfunction was rated on a disability rate scale; vigilance (normal = 0, reduced = 1, sleeping = 2); check (present = 0, reduced = 1, absent = .2); posture (normal = 0, abnormal trunk +1, abnormal tail + 1, abnormal limbs + 1, flexed = 4); equilibrium (normal = 0, worst = 1, unstable = 2, spontaneously falls = 3); reaction to stimuli (normal = 0, reduced = 1, slow = 2, absent = 3); vocalization (normal = 0, reduced = 1, absent = 2); mortality (normal = 0, bradykinesia or hyperkinesia = 1, aquinesia or severe hyperkinesia = 2). These values have been summed to give a maximum score of 18.

Analysis and statistics: Total locomotor activity counts and total disability scores were analyzed for treatment effect using the Friedman Test (SPSS, Version 10) followed by Wicoxon or Mann-Whitney post-hoc tests to determine individual differences. The significance level was adjusted to 5%. EXAMPLE 2: Effects of SLV308 on L-DOPA-induced Reversals of Motor Disabilities

Spontaneous locomotor activity: SLV308 (0.26 mg / kg, po) increased locomotor activity within 30 minutes of administration (Figure 1). Peak activity was seen 180 minutes after treatment and locomotor activity and lasted for the observation period d 7 hours. L-DOPA (7.5 and 12.5 mg / kg, po) produced an immediate increase in locomotor activity that peaked 60-90 minutes after administration (Figures 1 and 2). The duration of the activity was 150-240 minutes. Peak activity after L-DOPA (7.5 and 12.5 mg / kg, po) was higher than the view after following SLV308 (0.26 mg / kg, po) alone. After pretreatment with SLV308 (0.26 mg / kg, po), the peak and duration of activity after L-DOPA (7.5 mg / kg, po) were similar to those seen after SLV308 (0.26 mg / kg, po) alone (Figure 1). Combination treatment with L-DOPA (7.5 mg / kg, po) plus SLV308 (0.26 mg / kg, po) reduced peak locomotor activity after L-DOPA (7.5 mg / kg, po) alone at a level similar to that seen after SLV308 (0.26 mg / kg, po) alone, such that hyperactivity was not observed (Figure 1). SLV308 (0.26 mg / kg, po) did not reduce, but did not increase, peak activity seen after L-DOPA (12.5 mg / kg, po). However, the duration of activity ("active" time) after L-DOPA (7.5 and 12.5 mg / kg, po) was longer by co-administration of SLV308 (0.26 mg / kg, po), reflecting the duration of SLV308 activity (Figure 3). Total locomotor activity was higher after all treatments compared to a vehicle-treated group (Figure 4), although no other differences were observed.

Motor deficiency: L-DOPA (7.5 and 12.5mg / kg po) produced an immediate reversal of peak deficiency and 90 minutes after administration, with a score of 2.5 (Figures 5 and 6). The duration of this effect was 150 and 180 minutes for L-DOPA at 7.5 and 12.5 mg / kg po, respectively. SLV308 (0.26 mg / kg po) reduced deficiency scores immediately after administration (Figure 5). A maximum improvement in disability (score 3) was maintained from 1 to 7 hours after administration. After pretreatment with SLV308 (0.26 mg / kg po) followed by L-DOPA (7.5 and 12.5 mg / kg po), the duration of disability reversal was similar to that seen after SLV308 (0, 26 mg / kg po) alone (median activity duration: 420 min, 420 min and 390 min respectively). Total deficiency scores were reduced within 7 hours after administration of SLV308 (0.26 mg / kg po) administered alone or in combination with L-DOPA (7.5 mg / kg or 12.5 po) (Figure 7). . The addition of SLV308 (0.26 mg / kg po) to L-DOPA (7.5 mg / kg po) caused an increase in total deficiency score compared to L-DOPA (7.5 mg / kg po) alone. (Figure 7).

Conclusion: These data confirm that both L-DOPA (7.5 and 12.5 mg / kg, po) and SLV308 (0.26 mg / kg, po) reverse MPTP-induced akinesia and deficiency. Both high and low doses of L-DOPA had short action durations and produced periods of hyperactivity. The duration of SLV308 activity was considerably longer than for L-DOPA, but hyperactivity was not observed. When given in combination, SLV308 pretreatment prevented hyperactivity after L-DOPA. No such interaction between SLV308 and L-DOPA was observed in deficiency scores, since the effect of the combination of SLV308 and L-DOPA resembles the effect of SLV308 alone.

EXAMPLE 3: PHARMACEUTICAL PREPARATIONS

Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions and other types described or apparent to one of the art. in specification technology and general knowledge in technology. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other routes of administration. The pharmaceutical formulation contains at least one preparation of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The total amount of suitable active ingredients is in the range from about 0.1% (w / w) to about 95% (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 SLV308 (or its N-oxide) and L-DOPA may be in the range of about 1,000: 1 to about 1: 1,000, suitably falls in the range of 300: 1 to 1: 300 and preferably 50: 1 to 1:50.

The preparations of the invention may be provided in forms suitable for administration by usual procedures using auxiliary substances such as liquids or solids, powdered ingredients such as pharmaceutically customary liquids or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorants , dyes and / or buffer substances. Commonly 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 fish liver oil, sunflower, walnut kernel or castor oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols, such as glycerol, as well as with disintegrating agents and lubricating agents, such as such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture was then granulated or compressed into tablets.

The active ingredients may be separately premixed with the other non-active ingredients before being mixed to form a formulation. The active ingredients may also be mixed together before being mixed with the non-active ingredients to form a formulation.

Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable carrier for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients together with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives or gelatin. Rectal administration dosage units may be prepared (i) in the form of suppositories containing the active substance in admixture with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in admixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a ready-to-use micro enema; or (iv) as a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations may be prepared in the form of syrups, elixirs, drops or concentrated suspensions, for example solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol. propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared as a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent prior to use.

Also provided in accordance with the present invention are formulations and "part kits" comprising one or more containers loaded with one or more of the ingredients of a pharmaceutical composition of the invention for use in medical therapy. Associated with such containers may be various written materials, such as instructions for use, or a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical products, the notices of which reflect approval by the manufacture, use, or sale agency. for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for use in treating a condition in which recovery of dopaminergic function is required or desired and methods of medical treatment or comprising administering a total therapeutically effective amount of at least one preparation of invention to a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired.

LEGENDS FOR FIGURES 1-7

Figure 1: The effect of SLV308 (0.26 mg / kg po) on locomotor activity after treatment with L-DOPA (7.5 mg / kg po) on injured common MPTP doctors (n = 6). Points represent median counts of total locomotor activity at 30-minute intervals for 7 hours. Arrow 1: SLV308 treatment, Arrow 2 L-DOPA treatment. Symbols: vehicle group open squares, loaded squares L-DOPA 7.5 mg / kg po, open triangle SLV308 0.26 mg / kg po and filled circles SLV308 followed by L-DOPA 7.5 mg / kg po.

Figure 2: The effect of SLV308 (0.26 mg / kg, po) on locomotor activity following treatment with L-DOPA (12.5 mg / kg, po) on MPTP-injured common physicians (n = 6). Points represent median counts of total locomotor activity at 30-minute intervals for 7 hours. Arrow 1: SLV308 treatment, Arrow 2 L-DOPA treatment Symbols: vehicle group empty squares, filled squares (black): L-DOPA 12.5 mg / kg po, 0.26 mg / kg po empty triangles and circles SLV308 followed by L-DOPA 12.5 mg / kg po. Dotted lines: Continuous-threshold line "active", Discontinuous-threshold line of hyperactivity. Error bars are omitted for clarity.

Figure 3: The effect of SLV308 (0.26 mg / kg, po) on "active" locomotor time after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). Bars represent median total counts for 6 hours after oral administration of SLV308 (0.26 mg / kg po; n = 6). Bars represent median total "active" time in hours. There was an increase in "active" time throughout treatment (p's <0.001, Friedman's test). # p <0.02. Significant difference compared to L-DOPA alone (Wilcoxon test).

Figure 4: The effect of SLV308 (0.26 mg / kg, po) on cumulative locomotor activity counts after L-DOPA treatment (7.5 and 12.5 mg / kg, po). Bars represent median total counts for 6 hours after oral administration of SLV308 (0.26 mg / kg po; n = 6). The increase in counts was significantly across treatment (p's <0.001, Kruskall Wallis). * p <0.002. Significant difference compared to vehicle (Mann Whitney test).

Figure 5: The effect of SLV308 (0.26 mg / kg, po) on reversal of motor deficiency by L-DOPA (7.5 mg / kg, po) on common MPTP monkeys (n = 6). Individual points represent the median total deficiency score at 30-minute intervals for 7 hours after L-DOPA treatment. Arrow 1: SLV308 treatment, Arrow 2 L-DOPA treatment: Symbols: vehicle group empty squares, L-DOPA loaded squares (7.5 mg / kg, po), SLV308 empty triangle (0.26 mg / kg, po ) and filled circles SLV308 followed by L-DOPA (7.5 mg / kg, po). Error bars are omitted for clarity.

Figure 6: The effect of SLV308 (0.26 mg / kg, po) on reversal of motor deficiency by L-DOPA (12.5 mg / kg, po) on common MPTP tamarins (n = 6). Individual points represent the median total deficiency score at 30-minute intervals for 7 hours after L-DOPA treatment. Arrow 1: SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: vehicle group empty squares, L-DOPA loaded squares (12.5 mg / kg, po), SLV308 empty triangles (0.2 6mg / kg, po) and SLV308 filled circles followed by L-DOPA 12.5mg / kg po. Error bars are omitted for clarity.

Figure 7: The effect of SLV308 (0.26 mg / kg po) on cumulative motor deficiency following treatment with L-DOPA (7.5 and 12.5 mg / kg po). Bars represent median total counts for 6 hours after oral administration of SLV308 (0.26 mg / kg, po; n = 6). The decrease in disability was significant throughout treatment (p <0.0005, Kruskall Wallis). * p <0.001, Significant difference compared to vehicle (Mann Whitney test). # p <0.002 compared to L-DOPA (7.5 mg / kg, po) (Mann Whitney test).

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Claims (10)

Combined preparation, characterized in that it comprises (i) SLV308 or its N-oxide: or pharmacologically acceptable salts thereof and (ii) L-DOPA or pharmacologically acceptable salts thereof for simultaneous, separate or sequential use in therapy. disorders that require recovery of dopaminergic function. Preparation according to Claim 1, characterized in that it additionally comprises a decarboxylase inhibitor. Preparation according to claim 1 or claim 2, characterized in that it further comprises a COMT inhibitor. Preparation according to any one of claims -1, 2 or 3, characterized in that it additionally comprises an MAO-B inhibitor. Use of a preparation as defined in any one of claims 1-4, characterized in that it is for the manufacture of a medicament for the treatment of disorders requiring recovery of dopaminergic function. Use according to claim 5, characterized in that said disorder is Parkinson's disease. Use according to claim 5, characterized in that said disorder is restless leg syndrome. Pharmaceutical composition, characterized in that it comprises, in addition to the pharmaceutically acceptable carrier and / or at least <p> formula </p> <p> formula </p> a pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of a preparation such as defined in any one of claims 1-4 as active ingredients. 9. A method for treating Parkinson's disease or restless leg syndrome in a human or animal patient in need of such treatment, which comprises administering to the patient simultaneously, separately or sequentially, an amount of SLV308 or its N-oxide. or a pharmacologically acceptable salt thereof and an amount of L-DOPA, wherein the amounts are effective for treatment. A method according to claim 9, characterized in that additionally an amount of a decarboxylase inhibitor and / or a COMT inhibitor and / or a MAO-B inhibitor is administered.