SA07280317B1 - Combination Preparations Comprising SLV308 and L-DOPA - Google Patents

Abstract

Abstract: The present invention relates to the use of a combination preparation of SLV308 or N-oxide thereof, or pharmaceutically acceptable salts of such compounds: N-oxide of SLV308 SLV308 and L-DOPA, for concomitant, independent, or sequential use, in the treatment of disorders requiring restoration of dopaminergic function particularly Parkinson's disease and restless legs syndrome.

Description

D 7 Combination preparations comprising 51/1308 and L-DOPA 817308 and L-DOPA for a full description BACKGROUND The invention Ja) relates to the use of a synthesis preparation of 517308, N-aie oxide or acceptable salts Pharmaceutical of these compounds: I | HNO HN A ST - CH, L - IH N—CH, 7 ON NS —_ ARS 0 ° oxide — N from SLV308 SLV308 DOPA -.1; 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. Jia constant trembling of the hands and feet; body movement that becomes harder and slower; laps; canals; mask-like facial expressions; Label has been observed throughout human history. And in Yo in YAYY James Parkinson described this group of | The symptoms were referred to as "Parkinson's" and shortly after this timing the disease was named after the physician who first described it. The cause of Parkinson's disease involves the destruction of neurons in the substantia nigra; The part of the brain responsible for muscle movement. The vas deferens 77850 triggers striatal dopamine in YEAY

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Parkinson's disease results in major symptoms ued in Jalally akinesia and bradykinesia (1966,<©1007106). Patients suffer from initiation problems and unsteadiness in position

Specific and lack of consistency. The current pharmacological treatment of Parkinson's disease is based on restoring dopaminergic function (Blanding, 2000; 11606, 2000) © Dopamine does not cross the blood-brain barrier, and therefore it cannot be used in the treatment of Parkinson's disease. The direct precursor of L-DOPA is used. (cycling {ped isoform of ;;-dihydroxyphenylalanine; Lad is referred to as levodoya) in place of dopamine; Because it enters the brain, where the carboxylate group is removed from it to turn into dopamine. However, levodopa is also decarboxylated in peripheral tissues. Therefore, only a small part of the levodopa that is given to the patient travels to the brain. Carbidopa inhibits the decarboxylation of peripheral levodopa but itself cannot cross the blood-brain barrier; It also has no effect on the metabolism of levododia in the brain. The combination of carbidopa and levodopa is the most effective treatment for the symptoms of Parkinson's disease. However; Some limitations appear within two to five years of starting treatment. When the disease progresses; The benefit from each Vo dose becomes shorter (LSBU) and some patients swing unpredictably between being able to move and not being able to move ("on and off"). are associated with elevated plasma concentrations of levodopa and often include unusual involuntary movements, ie, dyskinesia.Periods of 'HAY' are associated with decreased plasma levodopa and episodes of bradykinesia (Jankovic, 1993; Rascol, 2000). This has encouraged

Prescribing clinicians to delay initiation of treatment with 1-0078 as fay treatment first with dopaminergic adjuvant agents. However; The use of all dopamine receptor cofactors (Jie, apomorphine, bromocriptine, lisuride, pergolide, pramipexole, or ropinirole) also has limitations. they lead to imbalances of movement; and induce psychotic-like symptoms including hallucinations, orthostatic hypotension, somnolence, and other side effects (1999) (Lozano, 1998, Bennett, and it has been suggested that these symptoms can be overcome by using partial cofactors of the dopamine receptor Dos (i.e., compounds that do not activate dopamine 5:5 receptors to the maximum) (2002 <72::::2). Hypothetically, these compounds would be able to activate Das 0 dopamine receptors when the dopaminergic tone is low; They are able to counteract hyperactivation of the dopamine 12 receptor when the dopaminergic tone is elevated, resulting in 'stabilization of dopaminergic transmission in the brain' (Jenner, 2002). Cua Jalal adjuvant M,5-117 represented by tandospirone reduces dyskinesia in VO patients with Parkinson's disease treated with L-DOPA (Kannari, 2002) and extrapyramidal side effects induced by haloperidol in protozoa (1998). 0 (Christoffersen, and very recently it has been suggested that sarzotan, an S-HT 1a cofactor, and the dopamine receptor ligand can relieve symptoms of motor impairment (2001)-(Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, and the presence of cofactor 4 S-HT could be beneficial for the therapeutic effects of a partial acceptor yo cofactor - (Johnston, 2003) Dy YEAY

<a, Various combination preparations containing M1008 and one or more other enzyme inhibitors have appeared. Well-known combinations include [L-DOPA carpidoa (as Mtl/Ls) (Sinemet®), [DOPA benzrazide (as “Madopar®”) and [Lean / T-DOPA entacapone (as” Stalevo®, (Jost, aa Bang (2005) Possible Use of Catecholamine-0-methyl Heals Inhibitors

(COMT) © as tolcapone and waitacapone; As adjunctive therapy to L-DOAP, these compounds help increase the half-life of L-DOAP 1 jell in plasma without significantly increasing Cone.

Thus, they do shorten the tapering period of effect but tend to increase the intensity of the side effects of the maximum dose, including the motor impairment resulting from the maximum dose. Tolcapone appears to cause significant hepatotoxicity in small patients. There is another strategy aimed at

0 Slowing of dopamine metabolism when monoamine-oxidase-B (MAO-B) inhibitors are used in combination with L-DOPA. However; Administration of MAO to patients is associated with a number of debilitating side effects, which limits its use. These effects include; For example (Jha) nausea, vertigo, mild retching, syncope, abdominal pain, confusion, delirium, dry call, vivid dreams, dyskinesia, and headache. A feature of combination preparations is that they exist in the form of

0 different dosage combinations; During the course of the disease, higher doses of L-DOAP are usually necessary to keep symptoms under control. and combination preparations

They are in the form of tablets containing specific amounts of drugs; It is easy to use; but it is in

At the same time, it provides limited flexibility. As an illustration of the fact that fixed combinations are not always useful; For example; The use of a selective MAO-B inhibitor complemented by selegenin can be mentioned

0 in the treatment of Parkinson's disease. In the early stage of the disease; Selignin may be given as YEAY

1 - Monotherapy: The compound will slow endogenous dopamine metabolism enough to keep symptoms in check. In the late stages of the disease; The use of 1707/8 can become necessary. Ladies The effectiveness of L-DOPA gradually begins to wane; The first solution to this problem is usually a carbidopa Jie decarboxylase inhibitor (see above); And when this becomes not enough laf, combined treatment with selegnin will help restore the effectiveness of L-DOPA by reducing the breakdown of dopamine generated by L-1-0017/8. Thus, in practice, L-DOPA and Selenin are given as independent preparations that may be administered concomitantly or sequentially.

Severely affected victims appear to have Restless Leg Syndrome (RLS) (also called Syndrome 868014); ge 0 outwardly unable to remain seated or even to stand. activities that need to maintain motor stillness and limited cognitive alertness; Nie when moving, taking a vehicle (car, train, etc.) or attending meetings; or lectures; or films and plays; or

Any activities that take Ssh time are difficult, if not impossible. As a result of the torture caused by these feelings, which become more severe during the night; RLS patients find sleep impossible; Plus 0 on the negative impact on their quality of life. insistence on movement; which increases during rest periods; It can be completely dissipated by motion; Jie walking. However; Once the movement stops; Symptoms return with a higher intensity. if a patient with RLS is forced to remain supine; The symptoms will continue to grow (Jie what happens to a loaded spring and sooner or Sal) the legs will move (Anh) and the symptoms will immediately subside. Balanced or semi-balanced movements of the legs can be observed if patient 0 tries to remain supine (201756860, 1993). These movements are referred to as dyskinesia - during - YEAY ov o -

Alert (Hering, 1986) (DWA) or in the form of SST commonly called; Periodic limb movements - during wakefulness (014177). Clinically speaking; RES can be diagnosed if four diagnostic criteria are met: (1) a sense of urgency to move limbs (usually the legs); (7) restless movement to reduce these sensations; (7) when resting; symptoms return or become worse from what they were; and (£) the observed daily change in the onset or severity of RLS symptoms i.e. eof symptoms

Toul in the evening and at night (Allen 2001). Current treatments for RES have varied and become a kind of torment with unwanted side effects. Treatments have included the administration of dopamine cofactors and other dopaminergic cofactors. OEM, benzodiazepines, opiate preparations, antispasmodic agents, and in cases where RLS results from a secondary condition, pregnancy Bia, end-stage renal disease, erythropoietin therapy, or iron deficiency; Resolution of the condition; Jia delivery of the newborn; treatment with a conventional iron supplement; can reduce or eliminate symptoms; in at least some cases (dllen, 2001). However, RLS caused by conditions not secondary to RLS (‘automatic’); is more challenging to treat. Dopaminergic agents such as levodopa generally provide effective initial treatment; VO but with continued use can be tolerated and symptoms can be relieved in up to 7850 ¢ patients (Allen, 1996) RLS This complication is also common for dopamine cofactors (Earley, 1996) as for alternatives (ay od) benzodiazepines and opiate formulations; And anticonvulsant agents are not as regular in effect as dopaminergic agents (Chesson, 1999). (Hening, 1999). Despite the difference in their approach to treatment, the ratio ranges from 11 to 771

Some patients find that all medications are insufficient due to their adverse effects and limited therapeutic benefit. 0 0 HIN A, (IAM) —CH, IH) 2 nm “ma /— nm” oxide nitrate — N from SLV308 SLV308 © and <SLV308 mono hydrochloride = [4-methyl -1- Piperazinil] (HY) Y = — benzoxazolone” binds to Dy dopamine-like receptors and M,5-111 receptors. It is a partial cofactor at M dopamine receptors and a full cofactor at serotonin 5-HT a receptors and at cloned human Dy dopamine receptors; 517308 acts as a potent but Lisa cofactor to the Dy receptor (W150m = “A” and pA; = 8.4) with an potency of 78500 upon forskolin-induced cAMP assembly. at doamine and human receptors resulting from genetic recombination; 8 acts as a partial cofactor in inducing [PSIGTPYS] binding (771 of its induction of dopamine); It has a greater potency compared to quinpirol (pECso) = 1.7) and acts as a dopamine pA-binding antagonist;) [PSIGTPYS = 3) and 51.7308 acts as a full cofactor of the 5-HTia receptor on forskolin-induced cAMP pool In human S-HTa receptor clone 0 (mO286m=1.1) analogous to the cofactor of the receptor m5-1111-8-OH-DPAT and in slices taken from rat striatum, the concentration of 51.7308 degrades the cAMP pool. Induced by forskolin independently; as expressed in relation to a receptor cofactor

Dopamine 5:. 81,7308 acts as an antagonist to the inhibitory effect of quinpirole on dopamine release [PH] induced by KF (pA = #.8) from slices taken from rat striatum. and in the same form; The use of the partial cofactor, Dy receptor, showed greater antagonism in the presence of quinpirole (0011 = pAy) similar to the receptor antagonist halopyridol (3.Y = pA;) Dy but less than 517308 (significant = 8.5). . Conclusion; 81,7308 combines being a high potency partial cofactor at the dopamine receptors (acting as a dopamine stabilizer) with a low potency full cofactor of the serotonin receptor M:5-111. (Intl 00/29397 Feenstra, WO Johnston, 200195: Hessellink, 2001, 2003, McCreary, 2001, 200664 3:2001). And in the international application 023141/2007 cWO it was revealed that in vivo the oxide, Ne from

SLV308 0 rapidly converts to SLV308 and thus functions as a “prodrug”. General Description of the Invention The present invention aims to develop an effective treatment (L-DOPA Jie) but without its side effects: namely, without its distinguishing feature of “having lack of affect”; causing movement imbalances during periods of “with effect”; and significant developments in bradykinesia during periods of “without effect.”

MPTP Amazingly enough; In studies of young monkeys treated with 1-0 in an animal model including a predicted value for Parkinson's disease; It was found that the combined treatment with “observed after Lay of maximal value of locomotor activity compared to JB may SLV308 and DOPA alone” so that hyperactivity was not observed. The period of activity (period of effect) of L-DOPA was increased by administration of SLV308 by administration of it in combination with L-DOPA after administration of SLV308.

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— Ne The subject matter of the invention is synthetic preparations comprising 81.7308 or lial (L-DOPA) enzyme inhibitor oxide or its salts; its hydrates; pharmaceutically acceptable solutes; and casa 1 for use (MAO-B). Optionally a gf and/or COMT decarboxylase inhibitor and/or optionally a simultaneous, independent or sequential inhibitor in the treatment of disorders requiring restoring dopaminergic function, specifically Parkinson's disease and restless legs syndrome. © thereof; a real 'prodrug'; in cases where N and the invention relates to the use of 5117308 or oxide in motor impairment; or it can be predicted that it may cause motor impairment. L-DOPA is induced as a partial adjuvant alee these cases; the specific pharmacological effects of the compound, such as;

L- serotonin 1 5-1 3 lead to inhibition | For motor impairment without reducing the therapeutic effect, especially Ye .DOPA : of the current invention in pharmaceutical formulations; Including 1 related to 817308; or oxide 11 thereof; or its pharmaceutically acceptable salts, hydrates and solutes; and: (i) in mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. L-DOPA(Y) Another feature of the present invention relates to combinations of fractions comprising: 0 or its salts, hydrates and solutes of acceptable cate N A vessel containing 81.7308; or (1) pharmaceutical oxide; optionally in mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and:

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11 - Y) and E) contain L-DOPA and optionally with a commercially acceptable adjuvant, diluent, or carrier and: ( ) Instructions for the sequential, independent, or simultaneous administration of both SLV308 and “(L- DOPA for a patient in need of this treatment. As previously defined candle so that the two components are suitable for giving with each other. It includes combining the two components; This includes the following components (1) and () Y: (1) provided as independent formulations (i.e., each separately from the other), where they are then combined (Ve) for use in combination with each other in combination therapy; OR (Y) THEY ARE PACKAGED AND PROVIDED TOGETHER AS INDEPENDENT INGREDIENTS OF A 'COMBINATION PACKAGE' FOR. Another feature of the invention relates to methods of treating a patient suffering from, or at risk of developing, a condition in which restoration of dopaminergic function is desired or desired; this method includes administration of 0 Patient A therapeutically effective (Alen) amount of: 0 (8) or casa N oxide or its salts, hydrates and solutes for pharmaceutically acceptable and optionally in mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; jointly Hon

VY — (L-DOPA 0) and optionally in mixture with an adjuvant, diluent, or acceptable carrier (Ala). A further feature of the invention relates to the use of pharmaceutical formulations comprising: 8 0; or cae N oxide or its salts, hydrates and pharmacologically acceptable solutes; and: (L-DOPA M ° and optionally in mixture with an adjuvant, diluent, or carrier acceptable (LV aa) in the manufacture of a drug for the treatment of aura in which restoration of dopaminergic function is desired or desirable. Definitions) All decarboxylase inhibitors These are carbidopa and benzrazide Examples of cathyolamine-0,0-methyltransferase (COMT) inhibitors are entacapone, niticapon, and tolcapone Monoamine-oxidase-B (MAO-B) inhibitors include: Diprebnyl f (-)-diprepnyl (Celegene)” and des fis Diprepnyl” and 17 = propargyl (R)-1-aminoindane (Rasalgine); phenelzine (Nardil); tranyl-cypromine (Parnate)”; and 0073466 ; furazolidone ; isocarboxazid ; pargiline ; Please note that whether or not the term 'about' is used explicitly al no each quantity shown in this document refers to the actual specified value; It also stands for the YEAY ratio

#1” is deduced according to normal skill in the field; Including Ally's approximation of this specified value The approximate percentage resulting from experimental and/or standard instances of this specified value. Throughout this document and its claims; The term 'includes' and its derivatives are not intended to exclude additives, ingredients, integers, or other steps. The term 'combination' as used herein includes a product that includes specified ingredients © as well as any product that produces - either directly or indirectly - from Bans (Bans) in specified amounts or proportions in relation to pharmaceutical formulations; this term Lads includes the mixing of specified components in specified quantities. A compound comprising one or more active ingredients and an optional carrier comprising on inert ingredients; as well as any product that results, directly or indirectly, from the combination, complexation, or agglomeration of any two or more ingredients; from the separation of one or more ingredients; or from other types of reactions. In general, pharmaceutical compositions are prepared by systematically and closely combining the active ingredient with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, forming the product into the desired form. The pharmaceutical composition includes a sufficient amount of the active compound to produce the desired effect when the disease condition progresses. Thus, the pharmaceutical compositions dealt with in the present invention include any composition prepared 0 by mixing a compound covered by the present invention and a pharmaceutically acceptable carrier. The expression "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.

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In the context of this request; The term 'combination preparation' includes two correct combinations, which means 8 and other drugs that are physically mixed in a Jie daly preparation, tablet or injection fluid; and the term 'therapeutic kit parts'; It contains SLV308 and L-DOPA in separate dosage forms; with instructions for use; and optionally with other means of facilitating compliance with the administration of the compounds that make up the medicine; Jia with a sign or graphics. And with the right combinations.; Drug treatment is concomitant. The contents of the 'therapeutic kit parts' can be administered either simultaneously or at different time intervals. Administration of treatment either simultaneously or sequentially depends on the properties of the other drugs used; ie onset and length of action; plasma levels and purification; etc.

On the disease and what stage it is ed and the patient's prescriptions. 0 The dose of the formulation to be administered will depend on the indications of the disease; the age, weight and gender (male/female) of the patient; It can be determined by a specialist. Preferably, the dose ranges from 100 mg/kg to 10 mg/kg. The typical daily dose of active ingredients will vary and vary over a wide range and will depend on various factors Jie the indications relevant to the disease; age, weight, and gender (male/female) (compa), which can be determined by a medical professional. In general; YO doses given orally and by injection will range from 1.1 to 10001

mg per day of total active ingredients.

The expression "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent used to treat a condition that can be treated by administration to the patient of a composition of the invention. And that amount is the amount sufficient to produce a therapeutic or analgesic and mitigating response to the disease »; 0 can be detected in an animal or human tissue system. And il for example JU may include the remedy mentioned YEAY

“ve been mentioned in this application. The exact amount effective for a patient will depend on the patient's size and general health; Depending on its nature and the severity of the condition to be treated, and on what the attending physician (or researcher), veterinarian, or treating physician recommends; or any other specialist); therefore, it is not useful to carry out the treatments; or treatment combinations; which you choose to administer. ey determine the exact effective amount in advance. © The term “pharmaceutical acceptable salt” refers to such salts; which are based on sound medical opinion; are suitable for use in human and lower animal tissues without causing excessive toxicity, irritation, allergic response, etc. and are compatible with respect to a reasonable benefit/risk ratio. Pharmaceutical acceptable salts are well known in this the field. It can be prepared on site

Separation and final purification of the compounds of the invention” or separately by reacting them with non-toxic, pharmaceutically acceptable bases or acids; Including organic or inorganic bases and organic or inorganic acids. Pharmacologically acceptable salts can be obtained using standard procedures well known in the art; (JE) by mixing a compound of the invention with a suitable acid, such as an inorganic acid or an organic acid.

SLV308 and the term "give together with" includes giving those corresponding forms having 0s in succession; and/or independently and/or simultaneously” during the course of treatment of the particular condition; (L-DOPA) and where this condition may be acute or chronic. Preferably, the expression includes giving the two forms (and optionally repeatedly) so that Administer at such close intervals that there is a beneficial effect on if each formulation of the given Lae is administered; Ad) the patient; any greater effect; during the treatment period

0 both formulas (and optionally frequently) by themselves in the absence of the other formula” during the same period

11 - — Therapeutic. It will depend on whether a combination provides a greater beneficial effect in terms of; During the entire treatment period; specific case; On the condition to be treated or prevented, but the person experienced in the field can determine this routinely. Thus, the expression 'ba in conjunction with implies that Uae) & one of the two forms will be given (and optionally repeatedly) before, after, and/or at the same time as the giving of the other. When used in this context, my expression ' given simultaneously and 'at the same time' includes administration of independent doses of SLV308 and L-DOPA at intervals of A hour; or 71 hours; or ? hours; or 2 hours; or an hour; or Vo minutes; in between. The term 'treatment' as used herein refers to any treatment of a mammal; preferably a human 0 condition or disease It includes: (1) inhibiting the disease or condition—that is, stopping its progression; (Y) relieving the disease or condition—that is, making the condition regress; or (7) stopping the symptoms of the disease. As used in this Adsl includes The term “medical treatment” means preventive, diagnostic, and therapeutic regimens performed in vivo and ex vivo on humans or other mammals. “Gage” as used herein; denotes (IS preferably Mammal 0 and preferably Human He is the target of the treatment, observation, or experiment. oral) on activity (all) following treatment with V.0) 1, - DOPA mg/kg; (oral) in known infected monkeys (MPTP = 1) (n). Dots represent the average amount of total locomotor activity in YEAY.

17 - - time intervals of vo min to 1 hour. The arrow indicates: 1 to the treatment with 51.7308; The arrow indicates ?: treatment with DOPA - .a. The symbols refer to the following; Empty boxes indicate the carrier group; filled squares indicate L-DOPA at 1.5 mg/kg; via endl) and the empty triangle indicates 81/7308 at 0.71 mg/kg; Oral; join, © Filled circles indicate a use of 81.7308 followed by IL-DOPA at 1.9 mg/kg; Oral. Figure ?: showing the effect of 517308 (.771 mg/kg; oral) on locomotor activity following treatment with 1Y.0 - 1.00-8 mg/kg; orally) in known young American monkeys with MPTP (« = 1). The dots express the mean amount of total motor activity in Ve over time periods of 30 4880 for 1 hour. Arrow 1: indicates treatment with SLV308 and arrow ?: indicates treatment with DOPA - .1. The symbols refer to the following; Empty boxes indicate the carrier group; The black triangles indicate IL-DOPA at fama 1Y.0 kg; Oral; Empty triangles indicate SLV308 at 0.776 mg/kg; Oral; Empty circles indicate the use of 5817308 followed by L-DOPA at a rate of VY.0 mg/pas for oral VO. The dashed lines indicate: the squiggly line indicates the ASN value “of impact”; The non-zigzag Jad denotes the threshold value for hyperactivity. Columns indicating error have been omitted for graphic clarity. Figure iF showing the effect of 817308 (+1 mg/kg; oral) on locomotor activity in the “effect” period following treatment with L-DOPA (V.0) and 0.1Y mg/kg; Oral). 0 and the bars represent the mean total counts within + hours after 51,7308 oral YEAY administration

- 18' mg/kg; Oral; = 1). The columns express the mean of the total time "effect 1) - (p's < 0.001, Friedman Test) in hours. There was an increase in the time "effect" after treatment - (Wilcoxon Test) alone L —- DOPA significant difference Comparison using eX < pH (mg / kg; oral) on the amount of activity +.YT) 817308 Figure No. 4;: Shows the effect of oral (pas mg / 1Y .0 and V.0) 1. - 00 cumulative post-treatment with Shall © Oral SLV308 1 hours after administration The bars represent the mean of the total counts during and there was a clear increase in counts After (n = 1 by mouth; aa mg/.77) a significant difference compared to using ooo > m (p's <0.001, Kruskall Wallis) treatment is considered to be mg/kg. SLV308 (+.YT) and Figure 10 demonstrates the effect of the (Mann Whitney Test) vector Sub pal mg/V.© (L-DOPA by mouth) on motor deficits adjustable using 0 and the independent points express the amount of (n = 1) MPTP (oral) in known infected American monkeys 1 hours after 1 minute treatment and for 71 days the average total disability over time periods up to treatment using 81,7308; The arrow ?: points to :1 and the arrow indicates .1. - DOPA using and the symbols indicate the following; Blank boxes indicate group JL - DOPA treatment with mg/kg; Oral) VO indicates 1. - DOPA transporter; filled squares indicate 0 mg/kg; Oral); filled circles denote 517308) +.Y1; empty triangle denotes mg/kg; Oral). And the columns that L - DOPA (V.0) were omitted, followed by the use of 8 to indicate the error for the purpose of clarity of the drawing. mg/kg; (oral) in primates (V1Y.0) 1. - DOPA adjustable with 0

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AS The independent points express the amount of the average total disability. (1 =n) MPTP known to be infected hours after treatment with 00 (1--]1. denotes 1 minute and for ©0 in time intervals of

L-DOPA Arrow: indicates treatment with ¢SLV308 indicates treatment with: 1 arrow and symbols indicate the following; Empty boxes indicate the carrier group; filled squares indicate 51.7308 kg; Oral) Empty triangles indicate [ana VY.0) 1. - DOPA to ©

L - by mouth); Filled circles indicate use of 51.7308 followed by (pas mg/kg 0.77 (mg/kg; oral). Columns indicating error have been omitted for 1.100 graphic clarity. mouth) on motor deficits + V1) 5117308 Figure 1: showing the effect of mg/kg; Oral). It expresses 17.5 and (0) L-DOPA cumulative (V.0) after treatment with 0.

TT) columns for mean total counts within + hours after oral administration of 51.7308 kg; Oral; = 1). There was a clear decrease in disability after treatment (M [ana

Mann (Jil) is a significant difference compared to using 1-DOPA <0.0. Whitney Test -(Mann Whitney Test) oral) cans V0 Examples YEAY

Treatment with the neurotoxin (pm) of Jae-1 (MPTP) neurotoxins (sa-phenylph-tip = tetrahydropyridine) leads to dopamine depletion in the caudate-cortex (part of the brain) and to Parkinsonian-like behavior in primates and humans (Lange , 1992; Langston, 1984, Langston, 1986). (Jie © No. (Je lal) 1) between SLV308 and L-DOPA at the relevant therapeutic doses. Animals: All known adult monkeys of any species (male or female) Callithrix were used. =n Yacchus 1” She weighs between TY. and £00 can and is ? to ? Years); in this study. Animals were fixed individually or in pairs under standard conditions at a temperature of VE + 7 C and a relative humidity of 0 75 using a light-dark cycle spanning Vy Vo hours; Allow her free access to food and water. All experimental work was performed in accordance with J - Animals (Scientific Procedures Act) 1986, project license nr PPL 70/4986 given MPTP hydrochloride dissolved ( ) = methyl pphenyl — YY 7 1 tetrahydropyridine ¢ (Research Biochemical International, UK) in sterile saline 70.9 pH and administered by subcutaneous injection (Pearce, 1998) (sc). For complete infection Y) MPTP 0 mg/kg was given; (sc) once daily for © days. During treatment with MPTP for 7 to A weeks (AG), animals were hand-fed following a jelly-feeding baboons regimen until recovered enough to feed themselves and weights stabilized. All animals were shown to be responsive to L-DOPA before it was used. A procedure to test Ls was started after

The animals recovered from the acute effects of treatment with 10717. In this study; The period was days ago. Vo MPTP Initiation of treatment with kg and given by [de 1 sucrose in a volume of 701 Drugs: 817308 dissolved in the feed by gastric fistula. Doses were expressed as mg/kg; of free base. ml/kg and 1 sucrose with a volume of 701 in (Sigma, UK) L-DOPA © methyl ester dissolved in (Merck Sharp and Dohme, UK) Direct administration in the animal's mouth. Domperidone was suspended in kg and was administered directly into the animal's mouth. Doses [de 7 sucrose at a specific volume of 0 that the full effect of 51.7308 on activity led were based on a previous study using 51.7308; where it turns out

L - mg/kg; The motive doses of 1776 were selected and the fraction values were reached at an average of 1776

YY.0 5V.0) L-DOPA 0m0008 given orally to reflect a medium and large dose of 0 mg/kg; by art; respectively). Procedure: On the day of administration; animals were weighed; treated with domperidone (¥ mg/kg) in mg/kg; via +. YT) 51,7308 minutes were processed using either 1010 Mouth Directly; And after another minute; 1" Oral) or with a vector by feeding through a gastric fistula. After (mg/kg) or its vector. A YY.o square design was used for L-DOPA (or ©) L-DOPA was administered. Modified Latin 0 with 1-week compensation periods between treatments; animals were assessed for locomotor activity and disability, as described below. Locomotor activity assessment:

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- 1 o- cm) equipped with a door Ve 7 Te x 8 0) Then the animals were placed separately in cages to determine the activity A-ray transparent perspex so that they can be observed clearly. Each cage was provided with a number Each of them is a horizontally oriented optical cell, and its detectors are arranged to allow the maximum evaluation of movement.The locomotor activity was evaluated in the form of the number of times the beam was cut in hours.And it was 1 minutes and for a period of 10 Photosynthesis due to movement of animals, at intervals of ½ min for animals in activity assessment cages during which a 10 line allowed an acclimatization period of baseline duration for activity before administration of the drug. The MPTP activity at baseline in American monkeys treated with excessive use was defined as ?the same as the normal activity in simple American monkeys. activity on the cut-off value for “having effect.” 0 Determination of disability scores: Animals were observed through a one-way mirror by experienced observers; Treatment was prevented and classified in terms of the degree of motor impairment. 1 = motor impairment was assessed using a scale to determine the degree of impairment of alertness and cognition (normal = 0; low = 7); mode (normal = (ile) = sleepy = 7); Check (present = 0 low tail abnormal + 1; limbs abnormal + 1; curved < 4); 1 + 0 trunk abnormal 05 times spontaneous fall = ); response of = balance (normal = acquired yellow = 0) unbalanced?; absent = 7); sounds =o day) = low « ja = verb on alarms (normal

Wall Mobility (normal = 0; slow ¢) Y = absent 1 = (normal = 0; low) These were aggregated (Y = hypermobile = 0; immobile or hyperactive) Vigorous in motion

AA values to give a maximum result equal to Ye

Statistical analysis and data: Total locomotor activity counts and total disability scores were analyzed to find out the effect of treatment using Friedman Test (SPSS, Version 10), followed by two Mann-Whitney post-hoc sl Wicoxon tests to determine individual differences. The level of significance was set at Jo ©Example No. ?: 51.7308 effects in contrast to locomotor deficit values induced by L-DOPA Spontaneous locomotor activity: assisted 51.7308 YT) + mg/kg; Oral) to increase locomotor activity within 30 minutes of administration (see Figure 1). The peak value of locomotor activity was observed after 1088 minutes of treatment and onset of locomotor activity; It continued throughout the observation period, which extended to 1 hour. L-DOPA (0.1 L and 17.8 mg/kg) helped; oral) produced an immediate increase in locomotor activity that peaked 01 to 80 minutes after administration (formal (V5) and the duration of sustained activity ranged from 101 to YE minutes. The peak activity value after administration of L-DOPA (°) was 17.8 mg/kg; oral) greater than that observed following administration of fama +. YY (8 kg” by mouth) alone. and after diasall treatment with SLV308 1-77 (mg/kg; oral); The peak value and duration of activity persistence after administration of DOPA-a (0 mg/ans (V.0) orally) were similar to those observed following administration of 51.7308 (©-77 mg/kg; orally) alone (Fig. 1. Combined treatment with L-DOPA (V.0) mg/kg helped; Oral) plus 517308 YT .+ mg/kg; oral) to reduce the peak value of locomotor activity following administration of L-DOPA (V.0 mg/kg); (orally) alone to a level similar to that observed after administration of Yo (517308*-T7) mg/kg; oral) alone so that hyperactivity was not observed (Fig. 1). YEAY failed

8 (0.7 mg/an orally) reduced” but did not cause an increase; The peak value of activity observed after administration of VY. ©) L-DOPA mg/kg; Oral). However; the period of sustained activity (the “effect” period) following administration of L-DOPA (V.0), 17.9 mg/kg; (oral) was increased by co-administration with 5,137,308 (00,771 mg/kg; by oral); This reflects the duration of activity of 51.7308 (Fig. L(V). Gross locomotor activity increased after all treatments compared to a vector-treated group (Fig. 4), although no other differences were observed. Motor deficits: L (V.0) -DOPA and 17.8 mg/kg; orally) to induce immediate reversal of deficits that peaked at 00 minutes after administration; with a value equal to 7.5 (Figure © and 1). 0 And this effect lasted You sad 1 minute and 181 minutes for L-DOPA when given in the amount of 1.5 and [ana VY.0 kg; Oral; Respectively. Also, 51,7308 reduced disability values immediately after administration (fig. ©). The maximum improvement in disability (V-value) was maintained between 1 and 1 hour after administration. Following initial treatment with 51.7308 (077 mg/kg) pellets of treatment with L-DOPA (0.0) and 17.0 mg/kg; orally); The duration of disability reversal, Ne, was similar to that observed after administration of 51.7308 (.1+¥) mg/kg; oral) alone (average activity duration: 4710 minutes; £4Y minutes; YA minutes, respectively). Total disability decreased within 17 hours after administration of 8117308 (0.771 mg/kg" orally) alone or in combination with 0078-1 (V.0) or 17.5 mg/kg; Oral) (form L(V) and Canad has added 51.7308 (0.77 mg/kg; oral) to 1-0078 V.0) mg/kg; Via

- ovo mg/kg; Oral (V.0) L-DOPA increased the total value of disability compared to the use of ofl (VJs alone [see mg/kg; oral], 0.1Y, and V.0) L-DOPA from IS Conclusion: These data confirm that mg/kg; Oral) reverses emerging immobility and impotence (1 1) 8 L-DOPA durations of action Both high and low doses of MPTP were shortened and resulted in periods of hyperactivity. The duration of action of 51.7308 was significantly longer, but hyperactivity was not observed. When L-DOPA was somewhat greater than that given in combination, initial treatment with 81.7308 prevented hyperactivity. ,

L- which follows giving /1-0017. No interaction was observed between 5117308 and 0m00 when calculating deficit values; As the effect of the combination of 0078-1 is similar to the effect of 0 alone. 8 Example No. 3: Pharmaceutical preparations 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 may become clear to a person skilled in the field from the description and general information in the field. . formulations to be used orally; injection into a vein or under the skin; or by force; or through the airways; or in the nose; or by lung; or transdermal; or buccal; or rectally, or by non-intestinal route; or by other methods of administration. The pharmaceutical formula contains a preparation

+ at least one of the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent, and/or carrier. It is appropriate that the total amount of active ingredients range from about 72 000 (w/w) to about 7 58 (w/w) in the formulation; Fits from vio 7 to 50 2 (w/w); Preferably from 1 7 to yo 7 (w/w). The molar ratio may range from 51.7308© (or N oxide thereof) to 707/8 - 1. From about 1:0001 to about 1:0001 and it is appropriate to range from 1:000 to Yen. : 1 preferably from 0 : 1 to cov 1 and the preparations of the invention may be formulated into forms suitable for administration by using known processes using adjuvants such as solid, liquid or powdered components such as fillers and expanding agents known as liquid or solid “Pharmaceutical Grade Solvents, Emulsifying Agents, Lubricants, Flavoring Agents, Colorants, and/or Bulking Auxiliaries Commonly used include magnesium carbonate, titanium dioxide, lactose, sucrose, sobitol, mannitol and other sugars or sugar alcohols; talc milk protein, gelatin, starch, and amylopectin; cellulose and its derivatives; vegetable and animal oils such as cod liver, sunflower, peanut, sesame, or polyethylene glycol; solvents such as sterilized water, mono- or polyhydric alcohols such as glycerol, as well as with the use of degrading agents lubricating agents; Jie; magnesium stearate; calcium stearate; sodium stearyl fumarates; and polyethylene glycol waxes. The mixture may then be processed and formed into granules or pressed into tablets. YEAY

No - the active ingredients can be mixed separately (Als) 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; vegetable oil; or spread; 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 together with powdered solid ingredients such as lactose, sucrose, sorbitol or mannitol; or potato starch; or cornstarch” or amylopectin; or cellulose derivatives or gelatin. The dosage units suitable for rectal administration 0 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 paraffin oil or other suitable carrier for a softgel capsule for rectal administration; (V7) in the form of preformulated rectal micro-Lia; or (;) in the form of a dry rectal micro-dia reconstituted in a suitable solvent prior to Direct administration VO Liquid formulations may be prepared as syrups, elixirs, concentrated drops or suspensions, such as solutions or suspensions containing the active ingredients and the remainder consisting of, for example, sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and poly Ethylene glycol If desired, these liquid formulations may contain coloring agents, flavoring agents, preservatives, saccharin, carboxymethyl cellulose, or other thickening agents. in YEAY solvent

suitable 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 prior to use. According to the present invention; Lad provided formulations and "part combinations" comprising one or more containers filled with one or more ingredients of a pharmaceutical composition according to the invention; 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 the instructions of the government agency regulating the manufacture, use or sale of pharmaceutical products.” This note reflects the approval of that authority to manufacture, use or sell pharmaceutical products intended for administration to humans or in the veterinary field. Formulations of the present invention are used in the manufacture of medicaments for use in the treatment of a condition in which restoration of dopaminergic function is desired or desirable” and in medical treatment methods comprising the administration of a total effective ladle amount of at least one preparation of the invention to a patient suffering from; 1 is or is at risk of developing a condition in which restoration of dopaminergic function is desired or desirable. References Allen and Earley 'Augmentation of the restless leg syndrome with carbidopa/levodopa'. Sleep 19: 205-213, 1996. YEAY.

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

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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.

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

Effects of a Novel Dopamine and 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.

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WO 00/29397

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Claims (1)

Y £ —_ — Claims 1-1 Pharmaceutical Composition Incorporating Oxide - IN 51.7308 X H 0 CH, ¥ \ / Mar " : N-oxide 51-1308 + or pharmaceutically acceptable salts thereof; and ( “) 0078-1 or pharmaceutically acceptable salts thereof; + for immediate use; or separately or sequentially in the treatment of disorders requiring restoration of 2 dopamine-generating function ‎—Y 1 Pharmaceutical formulation comprising 517308 or its Oxide-17: 0 0 A ao CH ‎SNCN as NCH, d o 58 511/308 N-oxide or acceptable salts thereof (L-DOPA or pharmaceutically acceptable salts of these compounds; and (7) decarboxylase enzyme also includes a decarboxylase reductase doy fishing; for immediate use ; or separately or sequentially in the treatment of disorders requiring a Dopamine © inhibitor Restore 1 dopamine-generating function Also includes a Cua inhibitor OR ; 1 Pharmaceutical formulation according to Claim No. - * 1 COMT YEAY . To — _ 1 + - a pharmaceutical composition according to any Claim 1 or ?; or; Where ¥ also includes a MAO-B inhibitor 0 1 - a pharmaceutical formulation according to any of the claims 1 of - 7 used in the manufacture of a drug for the treatment of disorders requiring the restoration of dopamine-generating function 1 -dopaminergic function 1 - A pharmaceutical composition according to any of the protection elements of - 1, where it is used in the manufacture of a drug for the treatment of Parkinson's Disease 1 7 - A pharmaceutical composition according to any of the protection elements of - 1, where it is Use in the manufacture of a drug for the treatment of Restless Leg Syndrome (A) - a pharmaceutical composition that includes in addition to the pharmaceutically acceptable carrier and/or sale Y at least one pharmaceutically acceptable adjunct to an effective amount (re Liles is prepared according to any of the protection elements No. 1 - 4 as active ingredients.