Use of dopamine d3 partial agonists for treating central nervous system disorders

Abstract

To provide the use of D3 partial agonists, in particular D3 partial agonists / D2 antagonists, for treating or inhibiting restless leg syndrome (RLS) and binge eating disorder.SOLUTION: According to the present invention, there is provided a pharmaceutical composition comprising the compound BP1.4979, which is N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-methoxypropanamide, or a pharmaceutically acceptable salt thereof, or its hydrates or hydrated salts, or the polymorphic crystalline structures thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Restless legs syndrome (RLS, or Willis-Ekbom Disease WED) is a sleep-related movement disorder with a population prevalence of 9.4%–15%. It most commonly manifests while the patient is lying down, with an urge to move the legs. This is associated with paresthesia in the limbs that decreases during movement and a circadian pattern that peaks at night.

[0002] This is a disabling central nervous system (CNS) disorder, and evidence supports the use of dopaminergic medications. Interestingly, hypothalamic dopamine has a circadian rhythm, with lowest concentrations observed at night, when RLS occurs (Carlsson et al., Psychopathology of affective disorders, 75-85, 1980). Furthermore, first-line treatment for RLS includes full dopamine D2 / D3 agonists: the first evidence that dopamine receptor stimulation is beneficial in RLS was a study of five patients showing that treatment with L-dopa plus benserazide, an indirect full dopamine agonist already known to compensate for dopamine deficiency in Parkinson's disease patients, completely eliminated RLS symptoms in these five patients (Akpinar, S. Arch. Neurol., 1982, 39(11), 739). Furthermore, treatment with bromocriptine, a direct full dopamine agonist, showed similar effects. Hening et al. (Sleep vol.27, 3, 2004, 560-583) also reported dopaminergic treatment of RLS with D2 receptor agonists.

[0003] Since then, several D2 / D3 dopamine agonists used as antiparkinsonian drugs have been developed and are currently used to treat RLS: pramipexole, ropinirole, and rotigotine (Clemens et al., Advances in Pharmacology, 2019, 84, 79). All dopamine agonists currently used to treat RLS are full agonists at both D3 and D2 receptors.

[0004] Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease share common cellular and molecular pathological mechanisms involving abnormal misfolded protein or peptide aggregation and deposition.

[0005] Parkinson's disease, Huntington's disease, and Alzheimer's disease are degenerative diseases caused by the accumulation of toxic proteins, such as parkin, huntingtin, and beta-amyloid, in central nervous system (CNS) neurons. These proteins can be removed by various cellular processes, of which autophagy is a very effective one (Wang et al. International Journal of Molecular Sciences, 2018, 19, 1422-0067).

[0006] Autophagy is a major pathway for the degradation of aggregated cellular proteins and dysfunctional organelles. Recent studies have demonstrated that upregulation of autophagy can reduce the levels of these toxic proteins and is beneficial in the context of various models of aging and neurodegenerative diseases. Understanding the signaling pathways involved in regulating autophagy is essential for the development of new therapeutics.

[0007] Autophagy is not fully effective in the diseases cited above, and stimulating it pharmacologically would be of obvious benefit. In this context, several authors have reported that activation of dopamine D2 and D3 receptors with pramipexole and quinpirole can promote autophagy activation in several cell lines, including primary neurons (Luis-Ravelo et al. Experimental Neurology, 2018, 299, 137-147; Wang et al. Autophagy, 2015, 11, 2057-2073).

[0008] In particular, autophagy was shown to be enhanced by the full D3 / D2 agonist pramipexole, and its effect was blocked by a pure D3 receptor antagonist, indicating that full stimulation of D3 receptors stimulates autophagy and thereby prevents neuronal degeneration, but the effects of partial D3 receptor agonists were not disclosed (Wang et al. 2018 (as above); Barroso-Chinea et al. Autophagy, 2019, 1-17).

[0009] Long-term treatment of these diseases is necessary. Several problems have been reported in the long-term management of this disease, including loss of efficacy over time and several side effects associated with D2 and / or D3 full agonists.

[0010] Nausea and vomiting are common adverse events resulting from D2 receptor stimulation by D2 agonists, and currently used D2 / D3 full dopamine agonists promote the loss of behavioral control that leads to disorders such as gambling or hypersexuality. Furthermore, potentiation, i.e., the exacerbation of symptoms after long-term use of these drugs, presumably due to D2 or D3 receptor overstimulation, is a serious drawback of currently used dopamine D2 / D3 full agonists.

[0011] Therefore, there remains a need to provide an effective treatment for disorders of the central nervous system (CNS) that is free from the above-mentioned side effects.

[0012] WO2007 / 148208 discloses D3 receptor ligands that may be antagonists, inverse agonists, partial agonists, or full agonists. Di Ciano et al. (Neuropsychopharmacology 44, 1284-1290, 2019) disclosed that one of the compounds disclosed therein (BP1.4979) is a D3 partial agonist that also has D2 antagonist properties.

[0013] This compound, which has D3 partial agonist activity and D2 antagonist activity, was surprisingly discovered to be a partial D3 agonist but fully active against disorders of the central nervous system (CNS). Indeed, it had not been suggested that a partial agonist of the D3 receptor would be as effective as a full D3 agonist in treating these diseases. Summary of the Invention

[0014] According to a first object, the present invention relates to a compound of the formula:

[0015] [ka] N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl] Ethyl}cyclohexyl)-3-methoxypropanamide

[0016] or a pharmaceutically acceptable salt thereof, a hydrate or hydrated salt thereof, or a polymorphic crystalline structure thereof, which is used in the prevention or treatment of disorders of the central nervous system (CNS).

[0017] According to one embodiment, the disorder is selected from restless legs syndrome, essential tremor, binge eating disorder, and a neurodegenerative disease.

[0018] According to one embodiment, the disorder is restless legs syndrome (RLS). According to one embodiment, the disorder is essential tremor. According to one embodiment, the disorder is binge eating disorder. According to one embodiment, the disorder is a neurodegenerative disease.

[0019] According to one embodiment, the neurodegenerative disease is selected from Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD). BP1.4979 is a D3 partial agonist and D2 antagonist. The structure and preparation method of BP1.4979 are disclosed in WO2007 / 148208.

[0020] It was found to be a potent and selective, but partial, D3 receptor agonist: it exhibits activity at cloned human dopamine D3 receptors with a dissociation constant of 1.2 nM and an intrinsic activity of 30% as assessed by functional assays (i.e., mitogenesis). In contrast, it exhibits a K value of only 661 nM at human D2 receptors, where it behaves as a pure antagonist. In addition, it is inactive at 160 other receptors, channels, or enzymes.

[0021] Despite its D3 partial agonist profile, it was surprisingly found to be as potent as dopamine itself or a full dopamine D3 agonist. Thus, the activity of D3 partial agonists is unexpected, especially as it is as potent as a full D3 agonist.

[0022] Furthermore, D3 partial agonists are less prone to side effects associated with D3 full agonists (especially potentiation).

[0023] D2 antagonists are also antiemetic and therefore do not have the side effects of nausea and vomiting reported for D2 agonists and used to treat RLS.

[0024] Furthermore, the selectivity of D3 receptors over D2 receptors is highly unexpected, since D2 and D3 receptors are highly homologous proteins, with 78% sequence identity within the transmembrane domain. Therefore, obtaining compounds selective for D3 over D2 receptors is notoriously difficult (Chien et al., Science, 330, 1091 (2010)).

[0025] As far as RLS is concerned, BP1.4979 was found to be as effective in RLS as dopamine itself or a full dopamine agonist.

[0026] The activity of the D3 partial agonist / D2 antagonist was highly unexpected, as activity in RLS was likely achieved only by selectively fully stimulating the D3 receptor. -High prevalence of inhibitory D3 receptors in the sensory processing region of the spinal cord (dorsal horn), which is the gateway for sensory processing involved in the involuntary limb movements that occur during sleep in RLS; -Nonselective dopamine agonists act as D3 receptor agonists at lower concentrations than D2 receptors and are effective in RLS at relatively low doses compared to those used for the treatment of Parkinson's disease (presumably via stimulation of D2 receptors in the latter indication); -D3 receptor knockout animals exhibit some of the symptoms of RLS.

[0027] Therefore, based on these observations, activity in RLS was predicted to depend on affinity for the D3 receptor, with full D3 agonists expected to have greater activity than partial D3 agonists. Furthermore, partial agonists may also act as antagonists, thereby adversely affecting their activity in RLS.

[0028] Thus, the activity of BP1.4979 was highly unexpected. Similarly, PD, AD and HD are chronic diseases in which sustained activity at the D3 receptor is desirable.

[0029] As mentioned above, full D3 receptor agonists promote autophagy and reduce the aggregation of toxic proteins such as parkin, huntingtin, and beta-amyloid, but this effect is blocked by D3 receptor antagonists. Because partial D3 agonists exhibit activity with a much lower maximal effect than full agonists, the efficacy of partial agonists such as BP1.4979 in these conditions was largely unpredictable.

[0030] Advantageously, as a partial agonist, BP1.4979 is less likely to induce receptor desensitization than a full agonist.

[0031] Essential tremor is a medical condition characterized by involuntary rhythmic contractions and relaxations. It can be an action (intention) tremor, which intensifies when attempting to use the affected muscles during voluntary movements such as eating or writing, or a postural tremor that exhibits persistent muscle tone. This means that it differs from resting tremors such as those in Parkinson's disease, which do not correlate with movement.

[0032] Binge eating disorder (BED) has been introduced as a new disorder in the DSM-V (American Psychiatric Association. (2013). Feeding and eating disorders. In Diagnostic and statistical manual of mental disorders (5th ed.)). BED is characterized by repeated episodes of binge eating in the absence of regular compensatory behaviors such as vomiting or laxative abuse. Associated features include eating until uncomfortably full, eating when not physically hungry, eating alone, and feelings of depression and guilt. BED is associated with increased psychopathology, including depression and personality disorders.

[0033] Currently, medication is provided using lisdexamfetamine, which acts by releasing dopamine in the central nervous system, thus behaving like a full dopaminergic agonist.

[0034] As used herein: An "antagonist" refers to a ligand that can bind to a receptor but does not activate the physiological response of said receptor.

[0035] "Agonist" defines a ligand that is capable of binding to a receptor and eliciting a physiological response of said receptor.

[0036] The term "full agonist" refers to an agonist that binds to and activates a receptor with the maximal response that the agonist is capable of eliciting at the receptor.

[0037] The term "partial agonist" refers to an agonist that also binds to and activates a given receptor, but has only partial efficacy at the receptor compared to a full agonist, even at maximal receptor occupancy.

[0038] The potency of an agonist defines the amount of agonist required to elicit a desired response: it is inversely proportional to the half-maximal effective concentration (EC50), i.e., the concentration of the agonist that elicits a response halfway between baseline and maximum after a specific exposure time.

[0039] Typically, a D3 full agonist elicits 100% efficacy (or intrinsic activity) relative to a reference full agonist for that D3 receptor.

[0040] Typically, a partial agonist according to the present invention will elicit less than 100% efficacy (or intrinsic activity) relative to a reference full agonist for the D3 receptor, generally comprising 10-90%, particularly 20-80%.

[0041] The reference full agonist for the D3 receptor is generally selected from endogenous agonists such as dopamine, or may be selected from known reference full agonists such as quinelorane or 7-OHDPAT.

[0042] The intrinsic activity of a compound against a receptor can be measured by in vitro tests such as mitogenesis (Chio et al., Mol. Pharmacol, 45: 51-60, 1994), gene receptor assays (Fitzgerald et al., Anal. Biochem. 275: 54-61, 1999), or calcium flux (Moreland et al., Biochem. Pharmacol. 68:761-772, 2004).

[0043] "Ligand" refers to the ability of a compound to bind to and form a complex with dopaminergic D2 and / or D3 receptors.

[0044] The term "affinity" exemplifies the intermolecular driving force between a ligand (compound) and a receptor. In particular, high affinity ligand binding means that a relatively low concentration of ligand is sufficient to maximally occupy the ligand-binding sites of the D2 and / or D3 receptors, whereas low affinity binding means that a relatively high concentration of ligand is required before the binding sites are maximally occupied.

[0045] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, which are modified by making acid or base salts thereof. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propanoic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, and maleic acid. Further addition salts include ammonium salts such as tromethamine, meglumine, and epolamine, and metal salts such as sodium, potassium, calcium, zinc, or magnesium. The hydrochloride and oxalate salts are preferred.

[0046] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two.Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is incorporated herein by reference.

[0047] The activity of a compound in RLS can be predicted by its efficacy in a relevant animal model. Animal models predicting RLS are described by Ondo WG et al. (Movement Disorders, 2000, 15, 154-158) and Clemens S et al. (J. Neurosci. 2004, 24, 11337-11345).

[0048] In particular, the present invention provides in vivo assays that predict activity in RLS, such as in rodents. The present invention discloses a method for predicting the activity of a test compound in RLS, comprising running the compound in an electrophysiological model of monosynaptic spinal reflexes in rats.

[0049] More particularly, an in vivo screening method for identifying drug candidates for treating RLS is disclosed, the method comprising conducting an in vivo assay comprising: Conducting electrophysiological models of monosynaptic spinal reflexes in rodents using test and control compounds; comparing the measured response of the test compound with the measured response of a control compound at a given concentration of the test; If the activity of the test compound is greater than the activity of the test compound, then selecting said test compound.

[0050] According to one embodiment, the model includes: -Stimulating the sensitive root and recording the resulting motor root action potential. - Apply control or test compound to the dorsal horn -Evaluation of the inhibition of monosynaptic reflexes by control and test compounds.

[0051] According to one embodiment, the measured response is an inhibition of synaptic transmission.

[0052] More specifically, the responses measured in this test reflect inhibitory modulatory inputs in the descending hypothalamic-dorsal spinal dopaminergic neuronal pathway that appear to be deficient in RLS, resulting in exaggerated reflexes in this disease.

[0053] According to one embodiment, the reference compound is a full dopamine D2 / D3 receptor agonist, such as dopamine or pramipexole (currently used in RLS), or the D3 receptor full agonist 7-OHDPAT.

[0054] According to one embodiment, the test compound is a D3 partial agonist.

[0055] The activity of BP1.4979 (a partial D3 agonist) in RLS was shown to be equivalent to that of rotigotine (a mixed D2 and D3 full agonist) in a double-blind vs. placebo clinical trial, and the study reported no side effects (nausea and vomiting) commonly associated with current treatments.

[0056] According to a further object, the present invention relates to a method for treating and / or preventing RLS in a patient in need thereof, comprising administering to said patient a D3 partial agonist as defined above.

[0057] The activity of BP1.4979 (a partial D3 agonist) for binge eating disorder has been demonstrated using a rodent model of the disease, namely sucrose binge eating in rats.

[0058] The activity of BP1.4979 (a partial D3 agonist) on excessive food intake in relation to binge eating disorders has been measured in a clinical trial in relation to smoking cessation. Upon smoking cessation, smoking volunteers receiving BP1.4979 gained less weight than smoking volunteers receiving placebo. This was dose-dependent, indicating that this effect is related to the compound.

[0059] According to a further object, the present invention relates to a method for the treatment and / or prevention of binge eating disorder in a patient in need thereof, comprising administering to said patient a D3 partial agonist as defined above.

[0060] According to yet another object, the present invention relates to a method for treating and / or preventing the above-mentioned disorders of the central nervous system (CNS) in a patient in need thereof, which method comprises administering to said patient a D3 partial agonist as defined.

[0061] Identifying subjects in need of treatment for the diseases and conditions described herein is within the ability and knowledge of one of ordinary skill in the art, who can readily identify subjects in need of such treatment through the use of clinical tests, physical examination, genetic testing and medical / family history.

[0062] According to one embodiment, the recommended dose of BP1.4979 may be 10-100 mg, preferably 10-15 mg, administered twice daily. However, alternative therapeutically effective amounts of BP1.4979 can be readily determined by the attending physician, as one of ordinary skill in the art, by using conventional techniques and observing results obtained under similar circumstances. Determining a therapeutically effective amount may involve considerations including, but not limited to, the subject's species; its size, age, and general health; the specific disease involved; the extent or severity of disease involvement; the individual subject's response; the specific compound administered; the method of administration; the bioavailability characteristics of the administered formulation; the selected administration regimen; the use of concomitant medications; and other relevant circumstances. The amount of BP1.4979 required to achieve the desired biological effect will vary depending on many factors, including the dose of the administered drug, the chemical properties (e.g., hydrophobicity) of the compound used, the potency of the compound, the type of disease, the patient's disease state, and the route of administration.

[0063] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal or human, as appropriate.

[0064] As used herein, "pharmaceutically acceptable carrier" includes any diluent, adjuvant, excipient, or vehicle, such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, vehicles, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art, and except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0065] In the context of the present invention, the term "treatment" or "treating" as used herein means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. "Therapeutically effective amount" means an amount of a compound / agent according to the present invention effective to produce a desired therapeutic effect. According to the present invention, the term "patient" or "patient in need thereof" refers to a human or non-human mammal suffering from or likely to suffer from a neuropsychological disorder. Preferably, the patient is a human.

[0066] Typically, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing 0.1-10% w / v compound for parenteral administration. Typical dosage ranges are 1 g / kg to 0.1 g / kg body weight / day, with a preferred dosage range of 0.01 mg / kg to 10 mg / kg body weight / day. Preferred daily doses for adults include 5, 50, 100, and 200 mg, as well as equivalent doses in human children. The preferred dosage of a given drug will likely depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological potency of the selected compound, the compound's excipient formulation, and its route of administration.

[0067] The compounds of the present invention can be administered in unit dosage form, and the term "unit dosage" refers to a single dosage that can be administered to a patient, can be easily handled, packaged, and remains as a physically and chemically stable unit dosage containing the active compound itself, or as a pharmaceutically acceptable composition, as described below. Thus, a typical daily dose range is 0.01 to 10 mg / kg body weight. As a general guide, a unit dose for humans ranges from 1 mg to 100 mg per day. Preferably, the unit dosage range is 1 to 500 mg per day, 1 to 4 times per day, and more preferably 10 mg to 300 mg twice per day. The compounds provided herein can be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable excipients. Such compositions can be prepared for oral administration, particularly in the form of tablets or capsules; parenteral administration, particularly in the form of liquid solutions, suspensions, or emulsions; intranasal administration, particularly in the form of powders, nasal drops, or aerosols; or cutaneous administration, e.g., via a topical or transdermal patch.

[0068] The compositions can be conveniently administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical arts, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Oral compositions generally include an inert diluent carrier or an edible carrier.

[0069] Tablets, pills, powders, capsules, troches, and the like may contain one or more of the following ingredients, or compounds of a similar nature: binders, such as microcrystalline cellulose or gum tragacanth; diluents, such as starch or lactose; disintegrants, such as starch and cellulose derivatives; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint or methyl salicylate. Capsules can be in the form of hard or soft capsules and are generally made from gelatin blends, optionally blended with plasticizers and starch capsules. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as sugar, shellac, or enteric coatings. Other oral dosage forms, such as syrups or elixirs, may contain sweeteners, preservatives, dyes, colorings, and flavoring agents. Additionally, the active compounds may be incorporated into fast dissolution, modified release, or sustained release preparations and formulations, wherein such sustained release preparations are preferably bimodal.

[0070] Preferred formulations include pharmaceutical compositions in which the compounds of the present invention are formulated for oral or parenteral administration, or more preferably, pharmaceutical compositions in which the compounds of the present invention are formulated as tablets. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc, in any combination. It is also an aspect of the present disclosure that the compounds of the present invention can be incorporated into food or liquids. Liquid formulations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid compositions may also contain binders, buffers, preservatives, chelating agents, sweeteners, flavorings, and colorants. Non-aqueous solvents include alcohol, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohol and water, buffered media, and saline. In particular, biocompatible and biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients for controlling the release of active compounds. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.

[0071] Alternative modes of administration include formulations for inhalation, including dry powder, aerosol, or drop-like means. These may be, for example, aqueous solutions containing polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or oily solutions for administration in the form of nasal drops, or gels for intranasal application. Formulations for buccal administration include, for example, lozenges or pastilles, and may also contain flavoring bases such as sucrose or gum arabic, and other excipients such as glycocholate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories with a solid-based carrier such as cocoa butter and may contain salicylate. Formulations for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that can be used include petroleum jelly, lanolin, polyethylene glycol, alcohol, or combinations thereof. Formulations suitable for transdermal administration may be presented as separate patches and may be dissolved and / or dispersed in lipophilic emulsions or buffers, aqueous solutions, polymers, or adhesives. [Brief explanation of the drawings]

[0072] [Figure 1] FIG. 1 shows the effect of BP1.4979 (30 nM) on the amplitude of the ventral root response evoked by suprathreshold stimulation of the dorsal root (40 V, 50 μs), showing the average of 15 recordings each in control and BP1.4979 perfusion conditions. [Figure 2] Figure 2 shows the effect of BP1.4979 (30 nM) on the amplitude of the response of the ventral root evoked by suprathreshold stimulation of the dorsal root (40 V, 50 μs), showing the amplitude of the peak response over time. DETAILED DESCRIPTION OF THE INVENTION

[0073] The present invention is further illustrated by the following non-limiting examples. [Example]

[0074] The efficacy of BP1.4979 and three currently used dopamine agonists at human dopamine D2 and D3 receptors was evaluated in the following systems:

[0075] Mitogenic assay of D3 receptor activation Chinese hamster ovary (CHO) cells stably expressing human dopamine D3 receptors were seeded overnight in 96-well plates. The cells were then washed with serum-free medium and incubated with various concentrations of ligand for 20 hours. A tritiated thymidine pulse was added for 4 hours. The cells were then detached with trypsin / EDTA, transferred to GF / C multiscreen microplates, washed with ice-cold PBS and ethanol, and dried. 3 H]-thymidine incorporation was measured by liquid scintillation in a microbeta counter.

[0076] The results were consistent with the maximum [ 3 H]-thymidine incorporation is expressed as a percentage.

[0077] In this test, BP1.4979 behaved as a partial agonist (intrinsic activity 30%, EC500.7 nM), whereas pramipexole and ropinirole were full agonists with EC500.6 and 0.7 nM, respectively.

[0078] GTPγ at D3 dopamine receptors 35 S binding test Thawed membranes from CHO cells stably expressing the human D3 receptor were diluted to a final concentration of 5 μg / 180 μL / well in binding buffer containing 50 mM HEPES, 3 mM MgCl2, 140 mM NaCl, 4 μM GDP, pH 7.4, and distributed into 96-well polystyrene microplates. 35[S]-labeled ligand (0.2-0.3 nM) was added for an additional 30 min at room temperature. After transfer to a Millipore GF / C HTS® microplate, the reaction was stopped by filtration of the reaction mixture, followed by three 250 μl washes. Filter-bound radioactivity was measured in a Microbeta liquid scintillation counter with 70 μl of scintillation fluid.

[0079] In this test, BP1.4979 exhibits partial activity (less than 5%) that is too weak to measure, indicating that BP1.4979 is clearly not a full agonist. Pramipexole, a full agonist, inhibits GTPγ[ 35 The compounds were as efficient as dopamine, the benchmark for full agonists, in the [S] assay. Furthermore, the compounds were compared for their potency in activating human dopamine D2 receptors.

[0080] Calcium flux assay for D2 receptor activation / inhibition We evaluated the potential agonist properties of test compounds using HEK293 cells expressing the short isoform of human dopamine D2. Cells were loaded with Fluo-4-AM supplemented with sulfinpyrazone, plated in 96-well plates, and then introduced into the FLEX station for fluorescence measurements following calcium transients.

[0081] Responses were calculated as the maximum minus the minimum fluorescence count (Fmax-Fmin). Results are expressed as a percentage of the maximum response elicited by the reference full agonist quinelorane.

[0082] In this study, pramipexole, rotigotine, and ropinirole behaved as full agonists with EC50 values of 5.4, 0.3, and 20 nM, respectively. In contrast, BP1.4979 failed to activate the receptor at concentrations up to 1,000 nM, even completely blocking the effects of dopamine or agonists.

[0083] In summary, BP1.4979 is distinctly different from the three dopamine ligands currently used to treat RLS in that they are potent D3R and D2R full agonists, whereas BP1.4979 is a partial D3R agonist and inactive as an agonist at D2R.

[0084] Effect of BP1.4979 in a rat RLS model RLS is thought to reflect abnormal sensitivity of spinal stretch reflexes. These reflexes are inhibitoryly modulated by dopamine released in the dorsal horn from descending dopaminergic projections arising from A11 dopamine cells in the hypothalamus. Therefore, it was interesting to examine the effects of BP1.4979 on monosynaptic responses in the isolated spinal cord, an electrophysiological model of the stretch reflex, which may explain some aspects of the mechanisms involved in RLS. We analyzed electrophysiological responses, i.e., motor action potentials recorded in the ventral roots of isolated spinal cords from rat pups after dorsal root stimulation.

[0085] Using a threshold stimulus intensity (40V, 50 μs), BP1.4979 was tested at three concentrations (30, 100, and 300 nM) and responses were recorded.

[0086] The results are shown in Figures 1 and 2. At 30 nM, BP1.4979 completely inhibited synaptic transmission in these fibers, i.e., to the same extent as dopamine or full dopamine D2 / D3 receptor agonists such as pramipexole and 7-OHDPAT.

[0087] Dopamine, pramipexole, and 7-OHDPAT completely or nearly completely inhibited the monosynaptic reflex. Surprisingly, when applied at nanomolar concentrations in place of dopamine or full dopamine agonists, BP1.4979 induced inhibition of the same amplitude as the latter.

[0088] In another series of experiments, BP1.4979 dose-dependently inhibited the amplitude of postsynaptic responses measured in the ventral root of the spinal cord after supramaximal stimulation of the dorsal root, an effect that was suppressed in the presence of the dopamine DOA antagonist BP1.4096 (Example 107 of WO2007 / 148208), but had no effect by itself.

[0089] In summary, although it is a partial D3 receptor agonist and D2 receptor antagonist, distinguishing it from agents commonly used in RLS, BP1.4979 appeared unexpectedly to be fully active in this model of the disease.

[0090] Clinical Trial: Efficacy of BP1.4979 (Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Clinical Trial) in Restless Legs Syndrome A double-blind study was conducted in 29 patients. BP1.4979 was administered at a dose of 15 mg twice daily for 2 weeks and its effects were compared with placebo. BP1.4979 demonstrated significant efficacy compared with placebo in patients with RLS, using the PLMS index (regular limb movements per hour of sleep).

[0091] Periodic limb movement index was significantly reduced after treatment with BP1.4979.

[0092] This was compared with rotigotine, an existing reference compound used to treat RLS (Bogan et al. Clinical Therapeutics / Volume 36, Number 3, 2014). Wu et al. (2018), PLoS ONE 13(4): e0195473, reported the PLMS index with rotigotine.

[0093] The results show that the values obtained with BP1 (PLMS index reduction) of 4979 are similar to those reported by Wu et al. in the rotigotine group.

[0094] This is quite surprising as it indicates that BP1.4979 is effective as a D3R and D2R full agonist in RLS pathology.

[0095] Furthermore, no patients reported nausea-related symptoms and no vomiting episodes. The lack of these side effects commonly observed with pramipexole, ropinirole, and rotigotine significantly improved the benefit / risk ratio of treating RLS with BP1.4979.

[0096] In conclusion, clinical trials confirm the interest of D3R partial agonists in RLS.

[0097] Activity of BP1.4979 in rodent models of binge eating disorder Female Sprague-Dawley rats (225–250 g) were fed a 10% sucrose solution and experimental chow for 12 hours, followed by a 12-hour daily fast for over three weeks (i.e., daily intermittent sucrose and chow). Control animals received sucrose solution and experimental chow ad libitum. Following this regimen, these rats receiving intermittent feeding developed hyperphagia and entered a state resembling drug addiction in several aspects: increased daily sucrose intake, withdrawal behavior, craving, and cross-sensitization (N.M. Avena, P. Rada, and B.G. Hoebel, “Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake.” Neurosci Biobehav Rev. 2008;32(1):20–39). On the experimental day, rats were intraperitoneally administered 0.3 and 1 mg / kg BP1.4979 or vehicle (n=8 per group) 30 min before sucrose reintroduction, followed by measurement of intake.

[0098] Lack of weight gain during smoking cessation by volunteers receiving BP1.4979 In a double-blind clinical trial, healthy smokers had to quit smoking while receiving either placebo (n=55) or BP1.4979 3 mg (n=52), 10 mg (n=53), or 15 mg (n=58) once daily.

[0099] After 12 weeks, volunteers receiving placebo gained 1.0 kg, while those receiving BP1.4979 gained less weight: 0.9 kg (0.5 kg) in the 3 mg (respectively 10 mg) group and 0.0 kg in the 15 mg group.

[0100] A similar trend was observed 12 weeks after treatment ended: Compared to pre-treatment weight, volunteers receiving placebo gained 2.3 kg, while those receiving BP1.4979 gained 2.0 kg, 1.4 kg, and 0.2 kg less in the 3 mg, 10 mg, and 15 mg groups, respectively.

Claims

1. Formula for treating or preventing restless leg syndrome (RLS): 【Chemistry 1】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising the compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure, to be administered in doses selected from 10 to 15 mg as B.I.D (twice daily).

2. Formula for treating or preventing binge eating disorder: 【Chemistry 2】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising the compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure.

3. The pharmaceutical composition according to claim 2, administered in a dose selected from 1 mg to 100 mg per day.

4. The pharmaceutical composition according to claim 2, administered in a dose selected from 10 to 15 mg as B.I.D (twice daily).

5. A formula for treating or preventing restless leg syndrome (RLS): 【Transformation 3】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure, which is administered twice daily at a dose of 10 to 300 mg of the compound.

6. A formula for treating or preventing RLS: 【Chemistry 4】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising the compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure, wherein the compound is administered twice daily in a dose of 10 to 100 mg.

7. A formula for treating or preventing RLS: 【Transformation 5】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising the compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure, wherein the compound is administered in a daily dose of 50 to 100 mg.

8. A formula for treating or preventing essential tremor: 【Transformation 6】 N-(4-{2-[4-(3-cyanophenyl)piperazine-1-yl] Ethyl cyclohexyl)-3-methoxypropanamide A pharmaceutical composition comprising the compound BP1.4979 represented by , or a pharmaceutically acceptable salt thereof, its hydrate or hydrated salt, or its polymorphic crystalline structure.

9. The pharmaceutical composition according to claim 8, wherein the compound is administered twice a day in a dose containing 10 to 100 mg.

10. The pharmaceutical composition according to claim 8, administered in a daily dose containing 50 to 100 mg of the compound.

11. A pharmaceutical composition for use according to any one of claims 8 to 10, wherein the compound is administered in a dose selected from 10 to 15 mg in a B.I.D (twice daily) manner.

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