JP2009539941A - Combination preparation comprising SLV308 and L-DOPA - Google Patents

Abstract

[Chemical 1]

The present invention relates to SLV308 or its N-oxide, or their compounds (I) for simultaneous, separate or sequential use in the treatment of diseases requiring restoration of dopaminergic function, in particular Parkinson's disease and restless leg syndrome. , (II) pharmacologically acceptable salts and the use of L-DOPA combination preparations.

Description

Table of Contents Page Title of Invention 1
Table of contents 1
Summary: Technical Field of Invention 1
Background of the Invention 2
Detailed Description of the Invention 5
Definition 7
Example 10
Example 1: Pharmacological method 10
Example 2: Pharmacological test results 12
Example 3: Pharmaceutical formulation 13
Description of FIGS. 1-7 15
Reference 16
Claim 19
Summary 20
Drawings 1-7 21

SUMMARY: TECHNICAL FIELD OF THE INVENTION The present invention relates to SLV308 for simultaneous, separate or sequential use in the treatment of diseases requiring restoration of dopaminergic function, particularly Parkinson's disease and restless leg syndrome. Or an N-oxide thereof, or a pharmaceutically acceptable salt of such a compound:

And the use of L-DOPA combination formulations.

Conventional technology

BACKGROUND OF THE INVENTION Continuous tremors in the limbs, body movements that become increasingly stiff, slow and weak, and masked facial expressions are symptoms that have been observed throughout human history. In 1817, James Parkinson described this group of symptoms as “paralsis agitans” and was immediately named after the physician who first described the disease in detail. The pathological cause of Parkinson's disease involves the destruction of substantia nigra neurons in the part of the brain that is involved in muscle movement. In Parkinson's disease, about 80% of the loss of striatal dopamine results in important symptoms of inability to move, stiffness and slow movement (Horykiewicz, 1966). Patients have problems starting to exercise and exhibit postural instability and loss of coordination.

  Current pharmacotherapy for Parkinson's disease is based on restoration of dopaminergic function (Blandini, 2000; Lledo, 2000). Since dopamine does not cross the blood brain barrier, it cannot be used to treat Parkinson's disease; instead, its immediate precursor, L-DOPA (a levorotatory enantiomer of 3,4-dihydroxyphenylalanine, also called levodopa) Is used because it passes through the brain where it is decarboxylated to dopamine. However, levodopa is also decarboxylated in peripheral tissues. That is, only a small portion of the 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 symptoms of Parkinson's disease. Nevertheless, certain limitations become apparent within 2 to 5 years of starting treatment. As the disease progresses, the benefits from each medication are shortened ("the wearing off effect") and some patients can predict between mobility and immobility Some people (and “on-off effect”. The “on” period usually accompanies high plasma levodopa concentrations and often results in abnormal involuntary movements, ie dyskinetic syndromes. The “off” period correlates with low plasma levodopa and slow motion episodes (Jankovic, 1993; Rascol, 2000), which allows clinicians to start L-DOPA treatment by prior treatment with dopaminergic agonists Will be delayed.

However, the use of full dopamine receptor agonists such as apomorphine, bromocriptine, lisuride, pergolide, pramipexol or ropinirole also has its limitations: they induce dyskinetic syndromes and hallucination-like psychology Induces symptoms, orthostatic hypotension, somnolence and other side effects (Lozano, 1998: Bennett, 1999). It has been suggested that this can be overcome by using partial dopamine D _2/3 receptor agonists (ie compounds that do not maximally stimulate dopamine D _2/3 receptors) (Jenner 2002). Such compounds can stimulate dopamine D _2/3 receptors when dopaminergic tones are low, but excessive dopamine D ₂ receptor stimulation when dopaminergic tones are high. It was speculated that this could lead to “stabilization” of dopaminergic transmission in the brain (Jenner 2002).

5-HT _1A receptor agonists are induced by haloperidol in Parkinson's disease dyskinetic syndrome (Kannari, 2002) and primates in Parkinson's disease patients treated with L-DOPA by the 5-HT _1A receptor agonist tandospirone The reduction of extrapyramidal side effects (Christoffersen, 1998) can improve the induction of dyskinetic syndromes. More recently, it has been suggested that sarizotan, 5-HT _1A receptor agonists and dopamine receptor ligands could improve dyskinetic symptoms (Olanow, 2004; Bara-Jimenez, 2005; Bibibiani, 2001). The presence of 5-HT _1A receptor agonists could be beneficial for the therapeutic effects of partial D _2/3 receptor agonists (Johnston, 2003).

Recently, various combination formulations have been introduced that contain L-DOPA and one or more other enzyme inhibitors. Well known are L-DOPA / carbidopa (eg, Sinemet ™), L-DOPA / benserazide (eg, Madopapar ™) and L-DOPA / carbidopa / entacapone (eg, Stalevo ™) (eg Jost, 2005) More recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjuvant therapies for L-DOPA. , Prolong the plasma half-life of L-DOPA without significantly increasing C _max , ie, they reduce the period of time when the effect is gradually abolished, but increase the peak-dose side effect effects including dyskinetic syndromes at peak doses. Tolcapone appears to induce significant hepatotoxicity in relatively few patients Another approach aimed at slowing dopamine metabolism is monoamine oxidase-B in combination with L-DOPA. (MAO-B) inhibitors, but administration of MAO inhibitors is accompanied by a number of debilitating side effects that limit their use, such as nausea, dizziness, dizziness in the head, fainting, There are abdominal pain, confusion, hallucinations, dry mouth, vivid dreams, dyskinetic syndrome and headaches.The characteristics of the combination formulation are usually higher doses of L-DOPA during the course of the disease to keep the symptoms under control Is that they exist in many different dose combinations.The combination formulation in tablet form containing a fixed amount of drug is At the same time, they are limited in flexibility, a specific example of the fact that a fixed combination is not always useful is, for example, selegrin, a selective MAO-B inhibitor in the treatment of Parkinson's disease In the early stages of the disease, selegrin may be given as a monotherapy: this compound will reduce the metabolism of endogenous dopamine enough to maintain symptoms within acceptable limits. Later in the disease, the use of L-DOPA may be necessary, and once L-DOPA begins to weaken, the first solution to the problem is usually decarboxylase inhibitor-like carbidopa (above Combination therapy with selegrin reduces the degradation of dopamine produced from L-DOPA. To preserve the effectiveness of L-DOPA by Succoth. Thus, in practice, L-DOPA and seregulin are administered in separate formulations that can be given simultaneously or sequentially.

  Patients with severe restless legs syndrome (RLS, also known as Ebohm syndrome) can hardly sit or stand still. It is not possible to participate in activities that require the movement to remain stationary and with limited cognitive stimuli, such as transport (cars, airplanes, trains, etc.) or longer meetings, lectures, movies or other performances It will be difficult if not. The pain caused by these sensations that become more serious at night makes RLS patients almost impossible to sleep and their quality of life falls. The desire to move as the rest period increases can be completely diverged by exercises such as walking. But once you stop exercising, your symptoms will get stronger and return. If the RLS patient is forced to lie down, the symptoms continue to grow like a loaded spring, eventually moving the legs involuntarily, and the symptoms are immediately relieved. Leg rhythmic or semi-rhythmic movements are observed when the patient attempts to remain lying (Pollmacher, 1993). These movements are referred to as dyskinesia-while-awake (DWA) (Hening, 1986), or more commonly, periodic limb movements during awakening (PLMW). Clinically, RLS is indicated when four diagnostic criteria are met: (1) craving to move the limb (usually the leg); (2) constant movement to reduce sensation; (3) resting Symptoms return or worsen; and (4) significant circadian variability in the occurrence or severity of RLS symptoms; ie symptoms worsen in the evening and night (Allen, 2001).

Current treatments for RLS are diversified and suffer from undesirable side effects. Treatment included administration of dopamine agonists, other dopamine agonists, benzodiazepines, opiates and antispasmodics. If RLS results from pregnancy, end-stage renal disease, secondary conditions such as erythropoietin treatment, or iron deficiency, elimination of conditions such as birth or treatment with conventional iron supplementation is at least a symptom in some cases Can be reduced or eliminated (Allen, 2001). However, RLS that does not arise from secondary conditions (“sudden RLS”) presents a greater challenge to treatment. Dopamine agonists such as levodopa generally provide an effective initial treatment, but subsequent use results in increased tolerance and increased symptoms in about 80% of RLS patients (Allen, 1996); this complication is a dopamine agonist (Earley, 1996). Other options, benzodiazepines, opiates and antispasmodics, are not as effective as dopamine agonists (Chesson, 1999; Henning, 1999). Despite changes in their treatment plan, 15-20% of patients find that all medications are inadequate due to side effects and treatment benefit limitations.

SLV308,7- [4- methyl-1-piperazinyl] -2 (3H) - benz oxazolone monohydrochloride, it binds to the dopamine _{D 2} like receptors and _{5-HT 1A} receptor. It is a partial agonist at the dopamine D _2/3 receptor and a full agonist at the serotonin 5-HT _1A receptor. In cloned human dopamine D _{2, L} receptors, SLV308 is acted as an effective agent for the cAMP accumulation forskolin stimulated acted as partial D ₂ receptor agonist with 50% efficacy (PEC ₅₀ = 8.0 and pA ₂ = 8.4). In human recombinant dopamine _{D 3} receptors, SLV308 acts as a partial agonist in the induction of ^[35 S] ^GTPγS binding (67% of dopamine), altitude compared to quinpirole _{(quinpirole) (pEC} 50 = 9.2) And antagonized dopamine induction of [ ³⁵ S] GTPγS binding (pA ₂ = 9.0). SLV308 acts as a complete 5-HT _1A receptor agonist for forskolin-induced cAMP accumulation at the cloned human 5-HT _1A receptor, similar to 5-OH _1A receptor agonist 8-OH-DPAT (PEC ₅₀ = 6.3). As expected for dopamine D _2/3 receptor agonists, SLV308 attenuated forskolin-stimulated cAMP accumulation in a concentration-dependent manner in rat striatum slices. SLV308 antagonizes the inhibitory effect of quinpirole on the release of [ ³ H] dopamine stimulated by K ⁺ from rat striatum slices (pA ₂ = 8.5). In this same paradigm, the partial D ₂ agonist terguride, like the D ₂ antagonist haloperidol (pA ₂ = 9.3), exhibited a higher degree of antagonism in the presence of quinpirole (pA _2). = 10.3), lower than SLV308 (pA ₂ = 8.5). In summary, SLV308 has a highly effective partial activity at the dopamine D _2/3 receptor (acts as a dopamine stabilizer) and a low potency serotonin 5-HT _1A receptor activity at full potency. (Patent Document 1; Feenstra, 2001; Johnston, 2001 ^{a, b} ; Hesselink, 2001, 2003, McCreary, 2001, 2006; Wolf, 2003). US Pat. No. 6,057,059 discloses that the N-oxide of SLV308 is rapidly converted to SLV308 in vivo, ie, functions as a “prodrug”.

References

International Publication No. 00/29397 Pamphlet International Publication No. 2007/023141 Pamphlet

DETAILED DESCRIPTION OF THE INVENTION The goal of the present invention is as effective as L-DOPA, but without its side effects, especially motor abnormalities during the “on” period and slow movements during the “off” period. It was to develop a treatment without its characteristic “on-off effect” that causes the episode.

  Surprisingly, a study involving marmoset treated with MPTP, an animal model with predictive value for Parkinson's disease, showed that treatment combining L-DOPA and SLV308 was observed after treatment with L-DOPA alone. It was found that hyperactivity was not observed because the peak motor activity was reduced. The duration of activity (“on” time) after L-DOPA was increased by co-administration of SLV308.

  The subject of the present invention is SLV308 or its N-oxide, or its use for simultaneous, separate or sequential use in the treatment of diseases requiring restoration of dopaminergic function, in particular Parkinson's disease and "restless leg syndrome" Pharmacologically acceptable salts, hydrates and solvates, and L-DOPA, and optionally decarboxylase inhibitors and / or optionally COMT inhibitors and / or optionally MAO-B inhibitors in combination formulations is there.

The present invention relates to the use of SLV308 or its N-oxide, the use of a true “prodrug” where L-DOPA induces a dyskinetic syndrome or can be assumed to induce a dyskinetic syndrome. In such a case, the specific pharmacological activity of the compound, i.e. partial agonism on dopamine _{D 2} and dopamine _{D 3} receptors (agonism), as well as full agonism for the serotonin _{5-HT 1A} receptor, L -Provides block of dyskinetic syndromes without diminishing the therapeutic effect of DOPA.

The present invention is:
(I) SLV308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, and:
(Ii) L-DOPA in a mixture with pharmaceutically acceptable auxiliary substances, diluents or carriers
It relates to a pharmaceutical formulation comprising

Further aspects of the invention are:
(I) SLV308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, optionally in a mixture with pharmaceutically acceptable auxiliary substances, diluents or carriers. A container containing, and;
(Ii) a container comprising L-DOPA, optionally in a mixture with a pharmaceutically acceptable auxiliary substance, diluent or carrier; and
(Iii) instructions for sequential, separate or simultaneous administration of SLV308 and L-DOPA to the patient in need;
To a kit part comprising

In accordance with a further aspect of the invention, there is provided a method of making a part of a kit as defined herein, wherein the method is to combine component (i) as defined above with component (ii) as defined above, ie two components. Making them suitable for administration in a junction with each other. To associate the two components with each other, components (i) and (ii) include:
(I) provided as separate formulations (ie, independent of each other) and subsequently combined for use in conjunction with each other in combination therapy; or (ii) for use in conjunction with each other in combination therapy Packaged together and presented as separate components in a “combination pack”.

In yet another aspect of the present invention, a method for treating a patient suffering from or suspected of having a condition in which restoration of dopaminergic function is necessary or desired, the method is a therapeutically effective total amount of:
(I) SLV308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, optionally in a mixture with pharmaceutically acceptable auxiliary substances, diluents or carriers. ;
(Ii) administering L-DOPA, optionally in combination with a mixture with pharmaceutically acceptable auxiliary substances, diluents or carriers.

Yet another aspect of the present invention is in the manufacture of a medicament for treating a condition in which restoration of dopaminergic function is necessary or desired:
(I) SLV308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof; and (ii) pharmaceutically acceptable auxiliary substances, diluents or It relates to the use of a pharmaceutical formulation comprising a mixture with a carrier.

Definitions Examples of decarboxylase inhibitors are carbidopa and benserazide. Examples of catecholamine-O-methyltransferase (COMT) inhibitors are entacapone, nitecapone, and tolcapone, and examples of monoamine oxidase B (MAO-B) inhibitors include deprenyl, (-)- Deprenyl (selegiline), desmethyl deprenyl, N-propargyl-1- (R) -aminoindan (rasagaline), phenelzine (nardil), tranylcypromine (parnate), CGP3466, furazolidone, isocarbox There are isocaboxazid, pargyline, methyclothiazide and procarbazine.

  To provide a more concise description, some of the quantitative expressions given herein are not limited by the term “about”. Whether or not the term “about” is expressly used, each quantity given herein is meant to refer to the value actually given, and as such experiments and / or It is also understood to mean an approximation of a predetermined value as reasonably inferred based on ordinary techniques in the art, including approximation by measurement conditions.

  Throughout the description and claims, the term “comprise” and variations of this term, such as “comprising” and “comprises” It is not intended to exclude adducts, ingredients, integers or steps.

As used herein, the term “composition” refers to a product comprising a specified component in a predetermined amount or ratio, as well as any that arises directly or indirectly from combining a specific component in a specific amount. Of products. In the context of pharmaceutical compositions, this term refers to a complex comprising a product comprising one or more active ingredients, and any carrier comprising an inert ingredient, and any combination of two or more ingredients. Or any product resulting directly or indirectly from aggregation, from dissociation of one or more components, or from other types of reactions or interactions of one or more components. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product into the desired formulation. . The pharmaceutical composition includes a compound of interest that is sufficiently active to produce the desired effect on disease progression or condition. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means 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 application, the term “combination formulation” includes both essential combinations of SLV 308 and other drugs physically combined into one formulation, such as a tablet or infusion fluid, as well as separately. Means comprising SLV308 and L-DOPA in the dosage form together with instructions for use, optionally further promoting compliance for administration of the component compounds, eg "kit part" comprising labels and drawings means. With an essential combination, pharmacotherapy is by definition concurrent. The contents of the “kit parts” can be administered either simultaneously or at different time intervals. Either simultaneous or sequential treatment will depend on the characteristics of the other drugs used, characteristics such as duration of occurrence and action, plasma levels, clearance, etc., and the characteristics of the disease, its stage and individual patient.

  The dose of the composition to be administered depends on the patient's symptoms, age, weight and sex involved and can be determined by a physician. The dosage is preferably in the range of 0.01 mg / kg to 10 mg / kg. Typical daily doses of active ingredients vary widely and depend on various factors such as relevant signs, route of administration, patient age, weight and gender and can be determined by a physician. In general, oral and parenteral dosages result in all active ingredients in the range of 0.1 to 1,000 mg per day.

  As used herein, the term “therapeutically effective amount” refers to the amount of a therapeutic agent for treating a condition that can be treated by administering a composition of the invention. The amount is sufficient to produce a detectable therapeutic or ameliorative response in a tissue system, animal or human. Effects include, for example, treating the conditions listed herein. The exact effective amount for an individual is the size and health of the individual, the nature and extent of the condition being treated, the recommendation of the treating physician (researcher, veterinarian, physician or other clinician), and the therapeutic agent selected for administration Depends on the combination of therapeutic drugs. That is, it is not useful to specify a precise effective amount in advance.

  The term “pharmaceutically acceptable salt” is suitable for contact with human and lower animal tissues without undue toxicity, inflammation, allergic response, etc., within the scope of reliable medical judgment, and Refers to a salt in which a reasonable benefit / risk ratio is balanced. Pharmaceutically acceptable salts are well known in the art. They can be prepared there when the compounds of the invention are finally isolated and purified, or they can be pharmaceutically acceptable non-toxic bases or acids (inorganic or organic bases and inorganic or It can be prepared separately by reacting with an organic acid). Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing the compounds of the invention with a suitable acid, such as an inorganic or organic acid.

“Co-administered” includes that each formulation comprising SLV308 and L-DOPA is administered sequentially, separately and / or simultaneously over the course of treatment of the relevant condition, this condition being acute Or it may be chronic. Preferably the term is used to administer (and optionally repeat) the two formulations within a time that is sufficiently close so that there is a beneficial effect on the patient, and this effect will be one of the two over the course of treatment of the relevant condition. Is greater than when either formulation is administered alone (optionally repeated) in the absence of the other formulation. The determination of whether a combination provides a greater beneficial effect with respect to a particular condition and over the course of its treatment depends on the condition to be treated or prevented, but can be accomplished routinely by those skilled in the art. . That is, the term “in conjunction” includes (optionally and repeatedly) that one or the other of the two formulations can be administered before, after and / or simultaneously with the other component. As used in this context, the terms “administered simultaneously” and “administered at the same time as” mean that the individual doses of SLV308 and L-DOPA are 48 hours, for example 24 hours, Including being administered to each other within 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes.

  The term “treatment” as used herein refers to any treatment of a mammal, preferably a human condition or disease, and (1) to suppress the disease or condition, ie to halt its progression, 2) to lighten the disease or condition, ie, the regression of the condition occurs, or (3) to stop the symptoms of the disease.

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

  As used herein, the term “individual” refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experimentation.

  Treatment with neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been shown to result in depletion of dopamine in the caudate nucleus-putamen and “Parkinson-like in nonhuman and human primates. (Lange, 1992; Langston, 1984; Langston, 1986).

Example 1: Interaction between SLV308 and L-DOPA at doses relevant to treatment Animals: Common adult marmoset ( Callithrix jacchus; n = 6, 320-450 g, 2-3 ages) ) Was used in this experiment. Animals were housed alone or in pairs under standard conditions of a temperature of 24 ± 2 ° C. and 50% relative humidity, using a 12 hour light / dark cycle, and provided food and water ad libitum. All experimental work was performed on animals (Scientific Procedures Act).
(Act) 1986, project license nrPPL70 / 4986.

Administration of MPTP: (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride; Research Bao Chemical International: Research Biochemical International, UK) was dissolved in 0.9% sterile saline, And it was administered by subcutaneous (sc) injection (Pearce, 1998). In order to induce complete lesions, MPTP (2.0 mg / kg, sc) was administered once a day for 5 consecutive days. During MPTP treatment and for 6-8 weeks thereafter, the animals recovered enough to be able to eat alone, and the animals were given a marmoset jelly diet by hand until the body weight stabilized. All animals were determined to be responsive to L-DOPA administration prior to use. The study was started only when the animals recovered from the acute effects of MPTP treatment. In this experiment, this was 70 days after the start of MPTP treatment.

Drug: SLV308 was dissolved in 10% sucrose and a volume of 2 ml / kg was obtained and administered by oral gavage. The dosage is expressed in mg / kg free base. L-DOPA methyl ester (Sigma: Sigma, UK) was dissolved in 10% sucrose and a volume of 2 ml / kg was obtained and administered by oral gavage. Carbidopa (Merck Sharp and Dohme, UK) was dissolved in 10% sucrose to obtain a volume of 2 ml / kg and administered directly into the animal's mouth. Domperidone (Sigma, UK) was dissolved in 10% sucrose to obtain a volume of 2 ml / kg and administered directly into the animal's mouth. The dosage was based on prior experiments with SLV308, where the optimal effect on SLV308 motor activity and disease score was 0.26 mg / kg, po. It has been shown to be achieved. The dosage of L-DOPA was selected to reflect medium and high doses of L-DOPA (7.5 and 12.5 mg / kg, po, respectively).

  Procedure: On the day of the experiment, animals are weighed and treated with domperidone (2 mg / kg, po) administered directly into the mouth, and 60 minutes later, SLV308 (0.26 mg / kg, po) or Treated by oral nutrition with any of the excipients. 30 minutes later, 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 used with a one week wash-out period between treatments. Animals were evaluated for motor activity and disease as described below.

  Assessment of locomotor activity: Animals were individually placed in activity cages (50 x 60 x 70 cm) with transparent perspex doors that allow clear viewing for observation. Each cage was equipped with 8 vertical infrared photovoltaic emitters and their corresponding detectors were arranged to allow maximum evaluation of motion. The locomotor activity was evaluated as the number of light blockages caused by animal movement accumulated over 7 hours at 10 minute intervals. The animals were acclimated for 60 minutes in the activity cage, during which time baseline activity was assessed, followed by drug administration. The “on” threshold was defined as 3 baseline activities in MPTP-treated marmoset. Hyperactivity was defined as 3 standard activities in naive marmoset. The “on” time was the period (in minutes) of activity above the “on” threshold.

Disease scoring; animals were monitored through a one-way mirror by an experienced observer who was not informed of the treatment and scored for the degree of motor dysfunction. Motor dysfunction was scored on a disease scoring scale: agility (normal = 0, decline = 1, blurred = 2); checking (yes = 0, decline = 1, no = 2); position (normal) = 0, abnormal trunk +1, abnormal tail +1, abnormal limb +1, flexion = 4); balance (normal = 0, disease = 1, unstable = 2, spontaneously reduced = 3); response to stimuli ( Normal = 0, Decreasing = 1, Slow = 2, None = 3); Vocalization (Normal = 0, Decreasing = 1, None = 2); Exercise (Normal = 0, Slow or Excessive Exercise = 1, Exercise Impossible or severe hyperactivity = 2). These values together gave a maximum score of 18.

  Analysis and statistics: Total motor activity counts and total disease scores were calculated using Friedman test (SPSS, version 10) followed by Wilcoxon or Mann-Whitney post-hoc test effects. Were analyzed to determine individual differences. The level of significance was set at 5%.

Example 2: Effect of SLV308 on reversal of L-DOPA-induced motor disease Natural motor activity: SLV308 (0.26 mg / kg, po) increased motor activity within 30 minutes of administration (Figure 1) . Peak activity was seen 180 minutes after treatment and motor activity persisted for a 7 hour observation period. 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 activity was 150-240 minutes. The peak activity after L-DOPA (7.5 and 12.5 mg / kg, po) was greater than that seen after 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) is after SLV308 (0.26 mg / kg, po) alone. Similar to the peak and duration seen (Figure 1). Combination treatment with SLV308 (0.26 mg / kg, po) in addition to L-DOPA (7.5 mg / kg, po) resulted in peak motor activity after L-DOPA (7.5 mg / kg, po) alone. Was reduced to the level seen after SLV308 (0.26 mg / kg, po) alone, and no hyperfunction was observed (FIG. 1). SLV308 (0.26 mg / kg, po) failed to lower but not increase the peak activity seen after L-DOPA (12.5 mg / kg, po). However, the period of activity ("on" time) after L-DOPA (7.5 and 12.5 mg / kg, po) is increased by co-administration of SLV308 (0.26 mg / kg, po) Reflects the period (Figure 3). Total locomotor activity increased with all treatments compared to the vehicle-treated group (FIG. 4), but no other differences were observed.

  Motor disease: L-DOPA (7.5 and 12.5 mg / kg, po) caused an immediate reversal of the disease, which peaked 90 minutes after administration with a score of 2.5 (Figure 5 and 6). The duration of this effect was 7.5 and 12.5 mg / kg, 150 and 180 minutes for po L-DOPA, respectively. SLV308 (0.26 mg / kg, po) lowered the disease score immediately after administration (FIG. 5). Maximum improvement in disease (score 3) was maintained for 1-7 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 disease reversal period was SLV308 (0.26 mg / kg, po) alone Similar to the period seen later (median duration of activity: 420 min, 420 min and 390 min, respectively). The overall disease score decreased over 7 hours after administration of SLV308 (0.26 mg / kg, po) administered alone or in combination with L-DOPA (7.5 and 12.5 mg / kg, po) ( FIG. 7). Addition of SLV308 (0.26 mg / kg, po) to L-DOPA (7.5 mg / kg, po) resulted in an increase in the overall disease score compared to L-DOPA (7.5 mg / kg, po) alone (FIG. 7).

  Conclusion: These data indicate that both L-DOPA (7.5 and 12.5 mg / kg, po) and SLV308 (0.26 mg / kg, po) reverse MPTP-induced immobility and disease. Confirm. Both high and low doses of L-DOPA had a short duration of action and resulted in periods of hyperactivity. Although the activity period of SLV308 was significantly longer than that of L-DOPA, no hyperactivity was observed. When given in combination, SLV308 pretreatment prevented hyperfunction after L-DOPA. Such an interaction between SLV308 and L-DOPA was not observed because the effect of the combination of SLV308 and L-DOPA resembles the effect of SLV308 alone.

Example 3: Pharmaceutical formulations The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments ( Creams and gels), suppositories, suspensions, and other types disclosed herein or apparent to those skilled in the art from this specification and general knowledge in the art. The composition may be administered by oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other routes for administration. The pharmaceutical formulation comprises at least one formulation of the invention in a mixture with pharmaceutically acceptable adjuvants, diluents and / or carriers. The total amount of suitable active ingredients ranges from about 0.1 (w / w)% to about 95 (w / w)% of the formulation, suitably 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 is in the range of about 1000: 1 to about 1: 1000, suitably about 300: 1 to 1: 300, and preferably 50: 1-1: 50.

  The preparations according to the invention are auxiliary substances, for example liquid or solid powdered ingredients, such as pharmaceutically customary liquid or solid fillers and fillers, solvents, emulsifiers, lubricants, fragrances, colorants and / or buffer substances. To form suitable for administration by conventional methods. Commonly used supplements include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, fish liver oil, sunflower Animal and vegetable oils such as groundnut or sesame oil, polyethylene glycols and solvents such as sterile water and poly-alcohols such as mono- or glycerol, and disintegrants and magnesium stearate, calcium stearate, stearyl Contains lubricants such as sodium fumarate and polyethylene glycol wax.

  The active ingredient may be premixed separately from other inactive ingredients before mixing to form the formulation. The active ingredients may be mixed with each other before mixing with the non-active ingredients to form a formulation.

  Soft gelatin capsules can be prepared using capsules, vegetable oils, fats or other suitable excipients for soft gelatin capsules containing a mixture of the active ingredients of the present invention. Hard gelatin capsules can contain particles of the active ingredient. Hard gelatin capsules may also contain the active ingredient together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. The dosage unit for rectal administration is (i) a suppository form containing the active substance mixed with a neutral fat base; (ii) in a mixture with vegetable oil, paraffin oil or other excipients suitable for gelatin rectal capsules In the form of gelatin rectal capsules containing the active substance in: (iii) ready-made micro-enema form; or (iv) dry micro-enema preparation reconstituted with a suitable solvent just prior to administration.

  Liquid formulations are syrups, elixirs, concentrated drops or suspensions, such as solutions or suspensions containing the active ingredient and the remainder consisting of a mixture of, for example, sugar or sugar alcohol and ethanol, water, glycerol, propylene glycol and polyethylene glycol Can be prepared. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid formulations can also be prepared in the form of a dry powder that is reconstituted with a suitable solvent prior to use. A solution for parenteral administration can be prepared as a solution of the formulation of the present invention in a pharmaceutically acceptable solvent. These solutions may contain stabilizing components, preservatives and / or buffering components. Solutions for parenteral administration can also be prepared as dry powders that are reconstituted with a suitable solvent prior to use.

  Also provided in accordance with the present invention is a “kit part” comprising a formulation and one or more containers filled with one or more components of a pharmaceutical composition of the invention for use in dosage therapy. It is. Such container (s) may be accompanied by various documents such as instructions for use, or notices of conditions described by government agencies that regulate the manufacture, use or sale of pharmaceutical products. This notice may represent an approval by the institution of manufacture, use or sale for human or veterinary administration. The use of a formulation of the invention in the manufacture of a medicament for use in the treatment of a condition in which restoration of dopaminergic function is needed or desired, and suffering from or suffering from a condition in which restoration of dopaminergic function is needed or desired A method of medical treatment comprising administering to a suspected patient a total effective amount of at least one formulation of the invention.

Effect of SLV308 (0.26 mg / kg, po) on motor activity after treatment with L-DOPA (7.5 mg / kg, po) in common marmoset (n = 6) lesioned with MPTP . The dots represent the median total motor activity count at 30 minute intervals over 7 hours. Arrow 1: SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: white square excipient group, black square L-DOPA 7.5 mg / kg po, white triangle SLV308 0.26 mg / kg po, and black circle SLV308 followed by L-DOPA 7.5 mg / kg po. Effect of SLV308 (0.26 mg / kg, po) on locomotor activity following treatment with L-DOPA (12.5 mg / kg, po) in MPTP-lesioned marmoset (n = 6). The dots represent the median total motor activity count at 30 minute intervals over 7 hours. Arrow 1: SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: white square excipient group, black square L-DOPA 12.5 mg / kg po, white triangle SLV308 0.26 mg / kg po, and black circle SLV308 followed by L-DOPA 12.5 mg / kg po. Dashed line: broken line— “on” threshold, solid line—hyperfunction threshold. Error bars are omitted for clarity. Effect of SLV308 (0.26 mg / kg, po) on exercise “on” time after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). Bars represent the median total count over 6 hours after oral administration of SLV308 (0.26 mg / kg, po; n = 6). The bar represents the median of all “on” times in hours. There was an increase in “on” time across treatments (p ′s <0.001, Friedman test). #P <0.02, significant difference compared to L-DOPA alone (Wilcoxon test). Effect of SLV308 (0.26 mg / kg, po) on cumulative motor activity count after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). Bars represent the median total count over 6 hours after oral administration of SLV308 (0.26 mg / kg, po; n = 6). The increase in count was significant across treatments (p's <0.001, Kruskal Wallis). ^* P <0.002, significant difference compared to vehicle (Mann-Whitney test). Effect of SLV308 (0.26 mg / kg, po) on motor disease reversal by L-DOPA (7.5 mg / kg, po) in MPTP common marmoset (n = 6). Individual points represent the median total disease score at 30 minute intervals over 7 hours after treatment with L-DOPA. Arrow 1: SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: white square excipient group, black square L-DOPA (7.5 mg / kg, po), white triangle SLV308 (0.26 mg / kg, po), and black circle SLV308 followed by L-DOPA (7.5 mg / Kg, po). Error bars are omitted for clarity. Effect of SLV308 (0.26 mg / kg, po) on motor disease reversal by L-DOPA (12.5 mg / kg, po) in MPTP common marmoset (n = 6). Individual points represent the median total disease score at 30 minute intervals over 7 hours after treatment with L-DOPA. Arrow 1: SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: white square excipient group, black square L-DOPA (12.5 mg / kg, po), white triangle SLV308 (0.26 mg / kg, po), and black circle SLV308 followed by L-DOPA 12.5 mg / kg po. Error bars are omitted for clarity. Effect of SLV308 (0.26 mg / kg, po) on cumulative motor disease after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). Bars represent the median total count over 6 hours after oral administration of SLV308 (0.26 mg / kg, po; n = 6). Disease reduction was significant across treatments (p <0.0005, Kruskal 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).

Claims (10)

For simultaneous, separate or sequential use in the treatment of diseases requiring restoration of dopaminergic function:
(I) SLV308 or its N-oxide
Or a combination preparation comprising a pharmacologically acceptable salt of these compounds and (ii) L-DOPA or a pharmacologically acceptable salt thereof.   The preparation according to claim 1, further comprising a decarboxylase inhibitor.   The preparation according to claim 1 or 2, further comprising a COMT inhibitor.   The preparation according to any one of claims 1, 2 and 3, further comprising a MAO-B inhibitor.   Use of the preparation according to any one of claims 1 to 4 for producing a medicament for treating a disease requiring restoration of dopaminergic function.   Use according to claim 5, wherein the disease is Parkinson's disease.   6. Use according to claim 5, wherein the disease is restless leg syndrome.   In addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of the formulation according to any one of claims 1 to 4 as an active ingredient A pharmaceutical composition comprising   In human or animal patients in need of treatment for Parkinson's disease or restless leg syndrome, a certain amount of SLV308 or its N-oxide or a pharmaceutically acceptable salt thereof and a certain amount of L-DOPA are simultaneously and separately Or a method of treating Parkinson's disease or restless leg syndrome, comprising administering to a patient sequentially, the amount being effective for treatment.   10. The method of claim 9, further comprising administering an amount of decarboxylase inhibitor and / or COMT inhibitor and / or MAO-B inhibitor.