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WO2025132331A1 - Composés pour le traitement d'un trouble du mouvement hypercinétique - Google Patents

Composés pour le traitement d'un trouble du mouvement hypercinétique Download PDF

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Publication number
WO2025132331A1
WO2025132331A1 PCT/EP2024/086754 EP2024086754W WO2025132331A1 WO 2025132331 A1 WO2025132331 A1 WO 2025132331A1 EP 2024086754 W EP2024086754 W EP 2024086754W WO 2025132331 A1 WO2025132331 A1 WO 2025132331A1
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acid
methyl
trifluoromethyl
compound according
compound
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Inventor
Laurent Provins
Anne MICHEL
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UCB Biopharma SRL
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UCB Biopharma SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • the invention relates to racemic and diastereoisomerically enriched 1-[[2-(methoxymethyl)- 6-(trifluoromethyl)imidazo[2, 1-b][1 ,3,4]thiadiazol-5-yl]methyl]-3-[(1 R*,2R*)-2-(trifluoromethyl)- cyclopropyl]-2H-pyrrol-5-one compounds, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals for treatment of a hyperkinetic movement disorder in a mammal.
  • Hyperkinetic movement disorders also referred to as dyskinesias are characterized by abnormal, often repetitive, involuntary movements overlapped to normal motor activity. Its 5 major types are Tremors, Chorea, Dystonia, Myoclonus and Tics. Specific disorders are Huntington’s disease chorea, tardive dyskinesia, Tourette Syndrome (and possible related hyperkinetic disorders like chorea in general, ballism, dystonia). Tics are the most common hyperkinetic disorder in children. Dystonia, stereotypies, choreoathetosis, tremors, and myoclonus also occur but are less common. Many hyperkinetic movement disorders manifest with multiple types of movements, which may include a combination of the various hyperkinesias.
  • HMDs can be itself a disease entity or a sign of another underlying neurologic condition. They can result from genetic abnormalities and neurodegenerative diseases; structural lesions; infection; drugs and toxins; or psychogenic causes. Psychiatric illnesses and corresponding long-term neuroleptic medications have been associated with HMD (i.e. tardive dyskinesia). Similarly, antiparkinsonian drug therapy can be responsible for the development of chorea and dystonia after several years of treatment (i.e. L-Dopa-induced dyskinesia. However, in many cases they have no clear cause and are thus identified as idiopathic.
  • Tremor especially essential tremor (ET) is the most frequent type of HMD seen in clinical practice.
  • Huntington’s Disease is the most frequent cause of chorea with a worldwide prevalence of 5- 14/100,000 people. Anywhere from 2-50 children/million develop early-onset dystonia and 30-7,000 adults/m il lion develop late-onset dystonia.
  • Adult-onset focal dystonia is by far the most frequent form of isolated dystonia.
  • Focal dystonia is approximately tenfold more common than generalized dystonia. Cervical dystonia is the most frequently documented focal dystonia.
  • Tardive dyskinesia represents a group of delayed-onset persistent iatrogenic movement disorders which is consecutive to exposure to dopamine receptor-blocking agents (DRBA -“neuroleptics”).
  • DRBA dopamine receptor-blocking agents
  • the overall prevalence rates of tardive dyskinesia are close to 30% for patients treated with DRBA.
  • the prevalence in general population is about 180/100,000.
  • Basal ganglia are a complex network of nuclei in the forebrain which play critical roles in motor control (facilitation of smooth voluntary movements).
  • BG consist in a group of subcortical nuclei: globus pallidus, caudate nucleus, putamen, substantia nigra and subthalamic nucleus and, any damage/disorganization may lead to motor and cognitive disabilities. Movements are regulated by two distinct pathways that process signals through the basal ganglia: the direct and the indirect pathway, with dopamine facilitating the motor loop in these two pathways. These pathways have opposite effects on thalamus.
  • Stimulation of the direct pathway induces excitation of thalamic neurons (which in turn make excitatory connections onto cortical neurons).
  • Stimulation of the indirect pathway induces inhibition of thalamic neurons (rendering them unable to excite motor cortex neurons).
  • the normal functioning of the basal ganglia involves a balance between the activity of these two pathways.
  • the “direct pathway selectively facilitates certain motor (or cognitive) programs in the cerebral cortex that are adaptive for the present task, whereas the “indirect pathway” simultaneously inhibits the execution of competing motor programs.
  • Basal ganglia dysfunction may result in a wide range of neurological conditions which involved control and movement disorders and cognitive deficits: Tourette syndrome, obsessive compulsive disorder, addiction, Parkinson’s disease, Huntington’s disease, dystonia, hemiballismus.
  • tremors are associated with brainstem, cerebellum or thalamic lesion. Chorea and ballism have been linked to lesions in the subthalamic nucleus. Dystonia is primarily associated with dysfunction of the putamen or globus pallidus. Tics can also involve inflammation or degeneration of the basal ganglia in rare cases. Tardive dyskinesia has been traditionally attributed to hypersensitivity and upregulation of dopamine D2 receptors in the motor striatum due to chronic dopamine receptor blockade.
  • Certain focal or multifocal movement disorders can be targeted with botulinum toxin injections to reduce activity in antagonist muscles with some success. More severe or generalized HMDs may require neuromodulation with intrathecal baclofen or deep brain stimulation (DBS).
  • DBS deep brain stimulation
  • relaxation therapies e.g. yoga, biofeedback
  • aggravating stimuli e.g. caffeine, stressors
  • VMAT-2 Reversible vesicular monoamine transporter-2 (VMAT-2) inhibitors, which block a transporter that packages monoamines (e.g. dopamine, noradrenalin, serotonin and histamine) into presynaptic vesicles for release into the synaptic cleft, have been tested for the treatment of tardive dyskinesia.
  • This transporter is widely distributed into the brain with some regional specificity which corresponds to monoaminergic brain regions.
  • Tetrabenazine was the first VMAT-2 inhibitors approved. Then, deutetrabenazine and valbenazine were consecutively developed and, they exhibit an improved pharmacokinetic and pharmacodynamic profile than tetrabenazine. These two recent molecules are FDA approved for both tardive dyskinesia and Huntington’s disease chorea.
  • Medications that block or lessen dopamine are also used for the management of tics in Tourette syndrome, with Aripiprazole, Haloperidol and Pimozide as the only pharmacological treatments approved by FDA.
  • Trihexyphenidyl can be used to treat tremor and dystonia but is poorly tolerated. Pramipexole, beta-blockers, anti-epileptics and benzodiazepines have been used to treat tremors and myoclonus with mixed success. Botulinum toxin injections are useful for focal and multifocal dystonia. Generalized dystonia may benefit from intrathecal baclofen therapy. DBS has shown benefit for multiple HMDs especially essential tremor, tremor due to Parkinson’s disease and primary generalized dystonia.
  • Drug addiction is a chronic and relapsing psychiatric disorder, characterized by compulsive seeking and taking of the drug despite the negative consequences, craving, and feeling of a negative state when the drug is withdrawn.
  • phases of active and excessive consumption of the drug phases of more controlled use, phases of abstinence and episode of relapse.
  • phases of active and excessive consumption of the drug phases of more controlled use, phases of abstinence and episode of relapse.
  • These different stages in the process are associated with various behavioral and neurobiological mechanisms: (1) binge & intoxication, (2) withdrawal/negative affect and (3) preoccupation/anticipation.
  • the dopaminergic system and basal ganglia are highly involved in the drug addiction process.
  • Dopamine is a neurotransmitter which plays an important role in addiction by contributing to pleasurable sensations, reinforcing behaviors and triggering craving.
  • the limbic sector of the basal ganglia i.e. nucleus accumbens, ventral pallidum and ventral tegmental are) are highly suggested to play a central role in reward learning and addiction process.
  • Several highly addictive drugs, including cocaine, amphetamine, nicotine, opioids are thought to work by increasing the efficacy of the dopamine signaling in the mesocortical pathway.
  • “Drug sensitization” is developing when repeated exposure to drug use causes hypersensitivity to drugs and other stimuli associated with them. This hypersensitivity in turn causes an increased craving for drugs, triggering an exaggerated interest for these ones.
  • Levetiracetam or (S)-(-)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide is a laevorotatory compound, disclosed in the European patent No. EP-162036 as being a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system.
  • Levetiracetam has the following structure: Levetiracetam has been approved and is marketed as Keppra®, in many countries including the European Union and the United States for the treatment of various forms of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (Gower et al., Eur. J. Pharmacol. 222, 193-203 (1992)).
  • Levetiracetam has also be considered as a potential alternative therapy for Tourette syndrome (Martinez-Granero et al. Neuropsychiatric Dis and Treat. 6, 309-316 (2010)).
  • One randomized placebo-controlled double-blind study (Awaad et al. J Pediatr Neurol. 7, 257-263 (2009)), including 24 children aged 6-18 years old with TS and associated diagnoses of epilepsy or headache, received Levetiracetam (Lev) (500 to 1250 mg/day) or placebo in a randomized sequence over 8 weeks. Over twelve patients how received Lev, nine of them showed improvement in tics, two were lost to follow-up, and one patient with comorbidities (ADHD and OCD) discontinued Lev because of aggressiveness.
  • ADHD and OCD comorbidities
  • levetiracetam belongs to a chemical group of molecules referred to as racetams.
  • racetam-type drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements.
  • Piracetam appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia.
  • Imidazothiadiazole pyrrolidone compounds are disclosed in WO 2011/047860.
  • pyrrole-5-one compounds are disclosed for the treatment of epilepsy;
  • the present invention relates to compounds, compositions and methods for the treatment of a hyperkinetic movement disorder in a mammal.
  • a first aspect of the present invention is a compound of formula (I) in racemic form or in an enriched diastereomeric purity as well as its pharmaceutically acceptable salts and metabolites.
  • a specific embodiment is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thia- diazol-5-yl]methyl]-3-[(1 R,2R)-2-(trifluoro-methyl)cyclopropyl]-2H-pyrrol-5-one, in one embodiment in a diastereomeric excess of at least 90% (d.e), preferably at least 94% (d.e), more preferably at least, and most preferably at least 98% (d.e).
  • Another specific embodiment is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1- b][1 ,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoro-methyl)cyclopropyl]-2H-pyrrol-5-one (enantiomer 2), in one embodiment in a diastereomeric excess of at least 90% (d.e), preferably at least 94% (d.e), more preferably at least, and most preferably at least 98% (d.e).
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • compositions for the treatment of a hyperkinetic movement disorder as well as drug addiction and drug use disorders.
  • Such compositions typically contain the active pharmaceutical ingredient and a pharmaceutically acceptable excipient.
  • compositions which can release the active substance in a controlled manner are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
  • these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diaminetetraacetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diaminetetraacetic acid, buffers such as acetates, citrates or phosphat
  • Examples of such therapeutic agents that may be used in pharmaceuticals compositions may be but not limited to quetiapine fumarate, aripiprazole, risperidone/paliperidone, olanzapine, cariprazine HCI, lurasidone HCI, ziprasidone HCI, haloperidol/droperidol, clozapine, quetiapine fumarate extended release, but also iloperidone, flunarizine and cinnarizine, loxapine, asenapine, pimozide, molindone, lithium, chlorpromazine, triflupromazine, thioridazine, mesoridazine, trifluoperazine, prochlorperazine, perphenazine, fluphenazine, perazine, metoclopramide, tiapride, sulpiride, clebopride, remoxipride, veralipride, amis
  • the compound according to the present invention induces significant dopamine reduction in the striatum (main structure from the Basal Ganglia) without affecting other monoamines levels (i.e. serotonin and norepinephrine) in the rest of the brain like the cortex and prefrontal cortex. It is believed that reduction of dopamine, in any assay aiming at measuring dopamine levels in the striatum, is predictive and suitable for identifying any potential effect addressing HMD or psychostimulants used disorder. Inhibition of the hyperdopaminergic function is considered to be related with antihyperkinetic movement effect and, with the treatment of addiction to psychostimulants and to psychostimulant used disorders (Koch et al. Pharm & Therapeutics, 212 (2020); Alvers et al. Psychopharmacology, 224 (2012)).
  • a QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. This spectrometer is equipped with an ESI source and an LIPLC Acquity with diode array detector (200 to 400 nm). Data is acquired in a full MS scan from m/z 70 to 800 in positive/negative modes with an acidic elution. The reverse phase separation is carried out at 45 °C on a Waters Acquity LIPLC HSS T3 1.8 pm (2.1x50 mm) column for acidic elution. Gradient elution is done with H2O/ACN/TFA (95/5/0.05%) (solvent A) and ACN (solvent B).
  • NMR spectra were recorded on a BRLIKER AVANCEIII 400 MHz-Ultrashield NMR Spectrometer fitted with a Windows 7 Professional workstation running Topspin 3.2 software and a 5 mm Double Resonance Broadband Probe (PABBI 1 H/ 19 F-BB Z-GRD Z82021/0075) or a 1 mm Triple Resonance Probe (PATXI 1 H/ D- 13 C/ 15 N Z-GRD Z868301/004).
  • PABBI 1 H/ 19 F-BB Z-GRD Z82021/0075 a 5 mm Double Resonance Broadband Probe
  • PATXI 1 H/ D- 13 C/ 15 N Z-GRD Z868301/004 1 mm Triple Resonance Probe
  • Chemical shifts are referenced to signals deriving from residual protons of the deuterated solvents (DMSO-cfe, MeOH-ck or CDCI3). Chemical shifts are given in parts per million (ppm) and coupling constants (J) in Hertz (Hz). Spin multiplicities are given as broad (br), singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m).
  • mice Male Sprague Dawley rats (Janvier, France) were housed in groups of 2 rats per cage and could habituate to the new environment for at least one week before experimentation. Animals were housed in a temperature (20-21 °C) and humidity regulated (-40%) environment, with a 12: 12 light/dark cycle (light on at 06:00 AM). All animals had free access to standard pellet food and water. The weight of the rats was ⁇ 300g at the time of drug testing. Additional enrichment was provided (red cylinders). Animal health was monitored daily by the animal care staff and by the experimenters on the day of experimentation.
  • the compound was administered as a suspension formulated in a vehicle solution containing 1% (w/v) methylcellulose (400 cps), 0.1 % (w/v) Silicone antifoam 1510 US and 0.1 % (w/v) Tween80 in water.
  • Rats were sacrificed 45 min post-administration; blood was collected from the heart and brains were rapidly removed. Plasma was obtained through centrifugation at 3000g for 15 min at 4°C. Striatum, cortex and prefrontal cortex (PFC) were carefully dissected (on ice). All samples were stored at -80°C until analysis.
  • DA Dopamine
  • NE Norepinephrine
  • 5-HT serotonin
  • tissue samples were homogenized in 1/20 (v/v) EDAT 0.3 nM/HCIC>4 0.05N and centrifuged at 150000 rpm at 4°C for 15 minutes. 10pL of the supernatant were injected in an HPLC.
  • the HPLC System used was a Thermo Scientific Vanquish LIHPLC (Ultra high performance (pressure) liquid chromatography) system coupled to a Thermo Scientific Q Exactive Plus high-resolution mass spectrometer.
  • the software used was Themo Scientific Xcalibur.
  • the autosampler temperature was set to 15°c.
  • the analytical UPLC columns was a Waters Acquity HSS T3, 1.8 pm, 100x2.1mm ID operated at 40°c. Flow rate was 0.4 ml/min. Analyses were performed in a gradient mode with a run cycle time of 12 min.
  • Mobile phase A was Ammonium Formate 10 mM in water & mobile phase B 100% Acetonitrile. Volume injected was 10 pl on column.
  • Compound 2 selectively decreases dopamine levels in the striatum without significantly affecting other monoamines (NE or 5-HT) in this brain region. Unexpectedly, compound 2 doesn’t modulate either DA, NE and 5-HT in different brain regions than the striatum like the cortex and prefrontal cortex.

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  • Chemical & Material Sciences (AREA)
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  • Psychology (AREA)
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  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne des composés de formule (I), un procédé de préparation de ceux-ci, des compositions pharmaceutiques les contenant et leur utilisation en tant que produits pharmaceutiques pour le traitement d'un trouble du mouvement hypercinétique.
PCT/EP2024/086754 2023-12-21 2024-12-17 Composés pour le traitement d'un trouble du mouvement hypercinétique Pending WO2025132331A1 (fr)

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EP23218981 2023-12-21
EP23218981.1 2023-12-21

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162036A1 (fr) 1984-05-15 1985-11-21 U C B, S.A. (S)-alpha-éthyl-2-oxo-1-pyrrolidineacétamide
WO2006128692A2 (fr) * 2005-06-01 2006-12-07 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidine
WO2011047860A1 (fr) 2009-10-23 2011-04-28 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidinyle imidazothiadiazole
WO2019215062A1 (fr) 2018-05-08 2019-11-14 Ucb Biopharma Sprl Dérivés de 1-imidazothiadiazolo-2h-pyrrol-5-one

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162036A1 (fr) 1984-05-15 1985-11-21 U C B, S.A. (S)-alpha-éthyl-2-oxo-1-pyrrolidineacétamide
WO2006128692A2 (fr) * 2005-06-01 2006-12-07 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidine
WO2011047860A1 (fr) 2009-10-23 2011-04-28 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidinyle imidazothiadiazole
WO2019215062A1 (fr) 2018-05-08 2019-11-14 Ucb Biopharma Sprl Dérivés de 1-imidazothiadiazolo-2h-pyrrol-5-one

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
ALVERS ET AL., PSYCHOPHARMACOLOGY, 2012, pages 224
AWAAD ET AL., J PEDIATR NEUROL., vol. 7, 2009, pages 257 - 263
BAGSHAWE, DRUG DEV. RES., vol. 34, 1995, pages 220 - 230
BERTOLINI ET AL., J. MED. CHEM., vol. 40, 1997, pages 2011 - 2016
BODOR, ADV. DRUG RES., vol. 13, 1984, pages 255 - 331
BROOKS, D.J.: "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development", NEURORX, vol. 2, no. 2, 2005, pages 226 - 236, XP025343813, DOI: 10.1602/neurorx.2.2.226
BUNDGAARD: "Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
GOWER ET AL., EUR. J. PHARMACOL., vol. 222, 1992, pages 193 - 203
KOCH ET AL., PHARM & THERAPEUTICS, vol. 212, 2020
LARSEN ET AL.: "Design and Application of Prodrugs, Drug Design and Development", 1991, HARWOOD ACADEMIC PUBLISHERS
LORENE CALVANO: "Development of a Scalable Route to a Pyrrolidone Compound via a Hydroxyfuranone", vol. 26, no. 4, 15 March 2022 (2022-03-15), US, pages 1106 - 1114, XP093165613, ISSN: 1083-6160, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.1c00350> DOI: 10.1021/acs.oprd.1c00350 *
MARTINEZ-GRANERO ET AL., NEUROPSYCHIATRIC DIS AND TREAT., vol. 6, 2010, pages 309 - 316
no. 1403586-73-1
S.M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
SHAN ET AL., J. PHARM. SCI., vol. 86, no. 7, 1997, pages 765 - 767
WOODS ET AL., J CLIN PSYCHIATRY, vol. 69, no. 4, 2008, pages 546 - 554

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