OA18597A

OA18597A - Brain-penetrant chromone oxime derivative for the therapy of levodopa-induced dyskinesia.

Info

Publication number: OA18597A
Application number: OA1201800073
Authority: OA
Inventors: Delphine CHARVIN; François CONQUET
Original assignee: Prexton Therapeutics Sa
Priority date: 2015-10-05
Filing date: 2016-08-26
Publication date: 2018-12-28

Abstract

The present invention provides a chromone oxime derivative of formula (I),

Description

The présent invention provides a chromone oxîme dérivative of formula (I), as described and defined further below, which is a modulator of nervous system receptors sensitive to the neuroexcitatory amino acid glutamate and présents an advantageously high brain exposure upon oral administration, for the treatment or prévention of levodopa-induced dyskinesia. The présent invention also provides an improved therapy of Parkinson’s disease, using the chromone oxîme dérivative of formula (I) in combination with levodopa.

It is known that glutamate is involved in numerous nervous fonctions. Important rôles are therefore attributed to glutamatergic receptors, In particular as regards the conduction of nerve impulse, synaptic plasticity, the development ofthe nervous system, leaming and memory.

Glutamate is also the main endogenous neurotoxin, being responsible for the neuronal death observed after ischemia, hypoxia, epileptic fits or traumatisms of the brain. Therefore glutamate receptors are cleariy considered to be involved in various disorders of the nervous system and neurodegene'rative diseases.

The glutamatergic system includes glutamate receptors and transporters as well as enzymes of glutamate metabolism. Two main types of glutamatergic receptors hâve been characterized: ionotropic (iGluRs) and metabotropic (mGluRs) receptors. lonotropîc glutamate receptors hâve been identifïed based on their pharmacology and subsequently through molecular biology. The iGluR family includes the NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-525 methyl-4-îsoxazole propionic acid) and the kainate receptor subfamilies, so named for the chemical agonist that selectively bînds to the subfamily members. iGluRs are voltage-gated ion channels that allow cation influx upon glutamate blndîng. They are directly responsible for the génération of action potentiels, they initiate neuroplastic changes in the CNS and are responsible for many diseases, including chronic pain. Metabotropic glutamate receptors are a 30 family of seven transmembrane domain G-protein-coupled receptors (GPCR). So far, eïght mGluR subtypes hâve been identifïed (mGluR1-mGluR8) and classified into three groups (l-lll) based upon sequence homology, transduction mechanism and pharmacological profile. mGluRs belong to family 3 ofthe GPCR superfamily, and as such, theyare characterized bya large extracellular amino terminal domain where the glutamate binding site Is located. mGluRs 35 are localized throughout the nervous system (central and peripheral) and hâve been shown to

play a rôle In homeostasis In many organ Systems. They hâve been found to play an Important rôle In particular in the Induction of the long-term potentiation (LTP) and the long-term dépréssion (LTD) of synaptic transmission, In the régulation of baroceptive reflexes, spatial leaming, motor leaming, postural and kinetic Intégration, and are considered to be Involved in acute or chronic degenerative diseases such as Parkinson’s disease, levodopa-induced dyskinesia, Alzheimer’s disease, Amyotrophie Latéral Sclerosls, spinocerebellar ataxia, epilepsy or Huntington's disease, as well as neuropsychiatrie disorders such as anxiety, dépréssion, autism spectrum disorder, post-traumatic stress disorder and schizophrenia.

Thus, It has been clearly demonstrated that glutamatergic pathways are Involved in the physiopathology of a number of neuronal damages and Injuries. Many nervous system disorders Including epilepsy and chronic or acute degenerative processes such as for example Alzheimer’s disease, Huntington's disease, Parkinson’s disease and Amyotrophie Latéral Sclerosis (Mattson MP., Neuromolecular Med., 3(2), 65-94, 2003), but also AIDS-induced dementia, multiple sclerosis, spinal muscular atrophy, retinopathy, stroke, Ischemia, hypoxia, hypoglycaemia and various traumatic brain Injuries, Involve neuronal cell death caused by Imbalanced levels of glutamate. It has also been shown that drug-lnduced neurotoxicity, for example neurotoxic effects of methamphetamine (METH) on striata! dopaminergic neurons, could actually be medîated by over-stimulation of the glutamate receptors (Stephans SE and

Yamamoto BK, Synapse 17(3), 203-9, 1994). Antidepressant and anxiolytic-like effects of compounds acting on glutamate hâve also been observed on mice, suggesting that glutamatergic transmission Is Implicated in the pathophysiology of affective disorders such as dépréssion, bipolar disorder, schizophrenia, anxiety, Autism Spectrum Disorders and other neurodevelopmental disorders (Palucha A et al., Pharmacol.Ther. 115(1), 116-47, 2007; Cryan

JF et al., Eur. J. Neurosc. 17(11), 2409-17, 2003; Conn PJ et al., Trends Pharmacol. Sci. 30(1), 25-31, 2009; Numberger Jl et al., JAMA Psychiatry 71:657-664, 2014; Narayanan B et al., Transi Psychiatry 5:e588, 2015; Chiocchettl AG et al., J.Neural Transm. 121(9):1081-106, 2014; Soto D. et al., Commun Integr. Biol. 7(1):e27887, 2014). Consequently, any compound able to modulate glutamatergic signalllng or function would constitute a promising therapeutic compound for many disorders of the nervous System.

Moreover, compounds modulatlng glutamate level or signalling may be of great therapeutic value for diseases and/or disorders not directly medîated by glutamate levels and/or glutamate receptors malfunctionlng, but which could be affected by modification of glutamate levels or 35 slgnaling.

The amino acid L-glutamate (referred to herein simply as glutamate) Is the major excitatory

neurotransmitter in the mammalian central and peripheral nervous system (CNS and PNS, respectively). It participâtes in ail fonctions of the nervous system and affects nervous system development at ail stages, from neuron migration, différentiation and death to the formation and élimination of synapses. Glutamate is ubiquitously distributed at high concentrations in the nervous system and Is involved in virtually ail physiological fonctions, such as leamlng and memory, motor control, development of synaptic plasticity, sensory perception, vision, respiration and régulation of cardiovascular fonction (Meldrum, 2000). Abnormalitles in the glutamatergic system are known to incur neurotoxicity and other deleterious effects on neurotransmission, neuroenergetics, and cell vlability. Accordingly, a considérable number of studies hâve been conducted to investigate the potentïal association between the glutamatergic system and neurological or psychiatrie disorders.

Glutamate opérâtes through two classes of receptors (Brâuner-Osbome H et al., J. Med. Chem. 43(14), 2609-45, 2000). The first class of glutamate receptors Is directly coupled to the 15 opening of cation channels in the cellular membrane of the neurons. Therefore they are called ionotropic glutamate receptors (iGiuRs). The IGluRs are dlvided Into three subtypes, which are named according to their sélective agonists: N-methyl-D-aspartate (NMDA), a-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainate (KA). The second class of glutamate receptors consiste of G-protein-coupled receptors (GPCRs) called metabotropic 20 glutamate receptors (mGluRs). These mGluRs are localized both pre- and post-synaptically.

They are coupled to multiple second messenger Systems and their rôle is to regulate the activity of the Ionie channels or enzymes producing second messengers via G-proteins binding the GTP (Conn PJ and Pin JP., Annu. Rev. Pharmacol. Toxicol., 37, 205-37, 1997). Although they are generally not directly involved in rapid synaptic transmission, the mGluRs modulate 25 the efficacy of the synapses by regulating either the post-synaptic channels and their receptors, or the pre-synaptic release or recapture of glutamate. Therefore, mGluRs play an Important rôle in a variety of physiological processes such as long-term potentiation (LTP) and tong-term dépréssion (LTD) of synaptic transmission, régulation of baroreceptive reflexes, spatial leamlng, motor leaming, and postural and klnetic Intégration.

To date, eight mGluRs hâve been cloned and classified ln three groups according to their sequence homologies, pharmacological properties and signal transduction mechanlsms. Group I includes mGluRI and mGluRS, group II mGluR2 and mGluR3 and group III mGluR4, mGluR6, mGiuR7 and mGluR8 (Pin JP and Acher F., Curr. Drug Targets CNS Neurol. Disord., 35 1(3), 297-317,2002; Schoepp DD et al, Neuropharmacology, 38(10), 1431-76,1999).

mGluR ligands/modulators can be classified in two families depending on their site of

Interaction with the receptor (see BrAuner-Osbome H et al., J. Med. Chem. 43(14), 2609-45, 2000 for review). The first family consists in orthosteric ligands (or compétitive ligands) able to interact with the glutamate bînding-site of the mGluRs, which is localized in the large extracellular N-terminal part of the receptor (about 560 amino acids). Examples of orthosteric ligands are S-DHPG or LY-367385 for group I mGluRs, LY-354740 or (2R-4R)-APDC for group

Il mGluRs and ACPT-I or L-AP4 for group III mGluRs. The second family of mGluRs ligands consists in allosteric ligands/modulators that interact with a different site from the extracellular active site of the receptor (see Bridges TM et al., ACS Chem Biol, 3(9), 530-41, 2008 for review). Their action results in a modulation of the effects induced by the endogenous ligand 10 glutamate. Examples of such allosteric modulators are Ro-674853, MPEP or JNJ16259685 for group I mGluRs and CBiPES, LY181837 or LY487379 for group II mGluRs.

Examples of allosteric modulators were described for the mGluR subtype 4 (mGluR4). PHCCC, MPEP and SIB1893 (Maj M et al., Neumpharmacology, 45(7), 895-903, 2003;

Mathiesen JM et al., Br. J. Pharmacol. 138(6), 1026-30, 2003) were the first ones described in 2003. More recently, more potent positive allosteric modulators were reported in the literature (Niswender CM et al., Mol. Pharmacol. 74(5), 1345-58, 2008; Niswender CM et al., Bioorg.

Med. Chem. Lett 18(20), 5626-30, 2008; Williams R et al., Bioorg. Med. Chem. Lett. 19(3), 962-6, 2009; Engers DW et al., J. Med. Chem. May 27 2009) and in two patent publications 20 describing families of amido and heteroaromatic compounds (WO 2009/010454 and WO 2009/010455).

Numerous studies hâve already described the potential applications of mGluR modulators in neuroprotection (see Bruno V et al., J. Cereb. Blood Flow Metab., 21(9), 1013-33, 2001 for 25 review). For instance, antagonist compounds of group I mGluRs showed interesting results in animal modeis foranxiety and post-ischemic neuronal injury (Piic A et al., Neumpharmacology, 43(2), 181-7, 2002; Meii E et al., Pharmacol. Biochem. Behav., 73(2), 439-46, 2002), agonists of group II mGluRs showed good results in animal modeis for Parkinson and anxiety (Konieczny J et al., Naunyn-Schmlederbergs Arch. Pharmacol., 358(4), 500-2,1998).

Group III mGluR modulators showed positive results in several animal modeis of schizophrénie (Palucha-Poniewiera A et al., Neumpharmacology, 55(4), 517-24, 2008) and chronic pain (Goudet C et al„ Pain, 137(1), 112-24, 2008; Zhang HM et al., Neumscience, 158(2), 875-84, 2009).

Group III mGluR were also shown to exert the excitotoxic actions of homocystéine and homocysteic acid contributing to the neuronal pathology and immunosenescence that occur in

Alzheimer Disease (Boldyrev AA and Johnson P, J. Alzheimers Dis. 11(2), 219-28, 2007).

Moreover, group lll mGluR modulators showed promislng results In animal models of Parktnson’s disease and neurodegeneration (Conn PJ et al., Nat. Rev. Neuroscience, 6(10),

787-98, 2005 for review; Vemon AC et al., J. Pharmacol. Exp. Ther., 320(1), 397-409, 2007;

Lopez S et al., Neuropharmacology, 55(4), 483-90, 2008; Vemon AC et al., Neuroreport, 19(4), 475-8, 2008; Williams CJ et al., J. Neurochem., 129(1), 4-20, 2014 for review). It was further demonstrated with sélective ligands that the mGluR subtype Involved In these antiparkinsonian and neuroprotective effects was mGluR4 (Marino MJ et al., Proc. Natl. Acad. Sel, USA

100(23), 13668-73, 2003; Battaglia G et al., J. Neuroscl. 26(27), 7222-9, 2006; Niswender CM et al., Moi. Pharmacol. 74(5), 1345-58, 2008). A combination treatment using a spécifie mGluR4 positive allosteric modulator, Lu AF21934, and L-DOPA was furthermore examined in hemiparkinsonian rats (Bennouar KE et al. Neuropharmacology. 2013;66:158-69).

mGluR4 modulators were also shown to exert anxiolytic activity (Stachowicz K et al., Eur. J. Pharmacol., 498(1-3), 153-6, 2004) and anti-depressive actions (Palucha A et al., Neuropharmacology 46(2), 151-9,2004; Klak K et al., Amino Acids 32(2), 169-72,2006).

Recently, an mGluR4 positive allosteric modulator, VU0155041, was shown to alleviate autistic-like syndrome in Mu opioid receptor null mice, a novel animal model of Autism Spectrum Disorders (Becker JA et al., Neuropsychopharmacology 39(9):2049-60, 2014). Therefore, mGluR4 modulators hâve a potential rôle for the treatment of ASD.

In addition, mGluR4 were also shown to be involved in glucagon sécrétion inhibition (Uehara 25 S., Diabètes 53(4), 998-1006, 2004). Therefore, orthosteric or positive allosteric modulators of mGluR4 hâve potential for the treatment of type 2 diabètes through its hypoglycémie effect.

Moreover, mGluR4 was shown to be expressed in prostate cancer cell-line (Pesslmissis N et al., Anticancer Res. 29(1), 371-7, 2009) or colorectal carcinoma (Chang HJ et al., CIL Cancer 30 Res. 11(9), 3288-95, 2005) and its activation with PHCCC was shown to inhibit growth of medulloblastomas (lacovelli L et al., J. Neuroscl. 26(32) 8388-97, 2006). mGluR4 modulators may therefore hâve also potential rôle for the treatment of cancers.

Finally, receptors of the umaml taste expressed in taste tissues were shown to be variants of the mGluR4 receptor (Eschle BK., Neurosclence, 155(2), 522-9, 2008). As a conséquence, mGluR4 modulators may also be useful as taste agents, flavour agents, flavour enhancing agents or food additives.

Chromone-derived core structures for pharmaceutically active compounds were described In the patent application WO 2004/092154. In the latter application, they are disclosed as Inhibitors of protein kinases.

EP-A-0 787 723 relates to spécifie cyclopropachromencarboxylic acid dérivatives which are said to hâve mGluR antagonistic activity.

A new class of ligands of metabotropic glutamate receptors is described in WO 2011/051478.

The chromone oxime dérivatives provided in this document are highly potent modulators of mGluRs, particularly positive allosteric modulators of mGluR4, and can advantageously be used as pharmaceuticals, in particular in the treatment or prévention of acute and chronic neurological and/or psychiatrie disorders.

Recently, it has surprisingiy been found that a novel chromone oxime dérivative from the class of compounds described in WO 2011/051478 does not only show potent activity as a positive allosteric modulator of mGluRs but also has highly advantageous pharmacokinetic properties (unpublished European patent application EP 14 18 2468.0). In particular, this novel compound of formula (I), as shown further below, has been found to exhibit an improved brain exposure after oral administration as compared to the compounds taught in WO 2011/051478, which makes it highly suitable as a médicament against neurological disorders, including Parkinson's disease.

The treatment of Parkinson's disease (PD) has been revolutionized by the development of 25 levodopa (l.e., L-3,4-dihydroxyphenylalanine; also referred to as L-DOPA), which is the gold standard for treating Parkinson's disease since 1956 and provides benefit to virtualîy ail PD patients. Even today, it is still the drug of choice, particularly In advanced stages of PD.

HO.

ΌΗ

Hi (levodopa)

A major drawback of levodopa therapy, however, Is the development of levodopa-induced dyskinesia (also referred to as L-DOPA-induced dyskinesia or LID), which results as a side effect of levodopa treatment, particularly after chronic administration of levodopa, and

constitues a severe disability for the affected patients (Thanvi B et al„ Postgrad Med J. 2007;83(980):384-8; Fahn S. Ann Neurol. 2000;47(4 Suppl 1):S2-11; Brotchie JM et al. J Neural Transm. 2005;112(3):359-91 ; and Fox SH & Brotchie JM (eds.), Levodopa-induced Dyskinesia in Parkinson’s Disease, Springer London, 2014). Levodopa-induced dyskinesia occurs in more than 50% of PD patients after 5 to 10 years of treatment with levodopa (Obeso JA et al. Neurology. 2000;55(11 Suppl 4):S13-23) and affects almost ail PD patients treated with levodopa at some point during the disease course (Rascol O et al. Mov Disord. 2015;30(11):1451-60). Although various attempts hâve been made to manage levodopainduced dyskinesia (Del Sorbo F et al. J Neurol. 2008;255 Suppl 4:32-41; Tambasco N et al., Parklnsons Dis. 2012;2012:745947; Thanvi B et al., loc. cit.; and Rascol O et al., loc. cit.), this disorder still proves devastating for many patients receiving levodopa therapy. Therefore, and since 86% of PD patients worldwide are currently under levodopa treatment, there is still an urgent and unmet clinical need for novel and improved thérapies of levodopa-induced dyskinesia.

In the context of the présent invention, it was surprisingly found that the compound of formula (I), as described and defined below, is highfy effective in the prévention and/or treatment of levodopa-induced dyskinesia, as also demonstrated in an MPTP monkey model (see Examples 3 and 5). The présent invention thus solves the problem of providing novel and 20 effective means for the therapeutic intervention in levodopa-induced dyskinesia. Moreover, the invention also solves the problem of providing an improved therapy of Parkinson’s disease, having a particularly advantageous side effect profile (see Examples 3 and 4). The compound of formula (l) according to the présent Invention furthermore shows highly bénéficiai pharmacokinetic properties, particularly in terms of brain pénétration (see Example 2).

The présent invention thus provides a compound of the following formula (I):

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, for use In the treatment or prévention of levodopa-induced dyskinesia. The invention further relates to a pharmaceutical

composition comprising the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof In combination with a pharmaceutically acceptable excipient for use In the treatment or prévention of levodopa-induced dyskinesia. The compound of formula (I) is also referred to as ΡΧΤ00233Γ in this spécification.

Accordingly, the Invention relates to the compound 6-(3-morpholin-4-yl-propyl)-2(thieno[3,2-c]pyridin-6-yl)-4H’^chromen-4-one oxime or a pharmaceutically acceptable sait, solvaté or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in 10 the treatment or prévention of levodopa-induced dyskinesia.

The présent Invention afso relates to the use of the compound of formula (I) or a pharmaceuticafly acceptable sait, solvaté or prodrug thereof for the préparation of a médicament for the treatment or prévention of levodopa-induced dyskinesia. Moreover, the 15 invention provides a method of treating or preventing levodopa-induced dyskinesia, the method comprising administering the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, to a subject in need thereof (preferably a mammal, and more preferably a human). The Invention 20 further relates to the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prévention of levodopa-induced dyskinesia by exerting antidyskinetic activity.

Furthermore, the présent Invention relates to the treatment or prévention of Parkinson’s disease, using the compound of formula (I) in combination with levodopa. This cotherapeutic approach is particularly advantageous as it allows to prevent or reduce levodopa-induced dyskinesia that occurs as a side effect of fevodopa treatment, as afso demonstrated in Example 5. The combined administration of the compound of formula (I) with levodopa further 30 allows to administer iower doses of levodopa while obtaining a comparable antiparkinsonian effect as with hlgher doses of levodopa alone (see Example 3), which also contributes to the advantageously improved side effect profile of this therapeutic combination, including the suppression or réduction of levodopa-induced dyskinesia. Yet, the compound of formula (I) does not only allow to administer reduced doses of levodopa but also exerts a potent 35 antidyskinetic effect itself (see Example 5), which renders this compound highly advantageous for the treatment or prévention of Parkinson’s disease in combination with fevodopa.

The présent invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, for use In the treatment or prévention of Parklnson’s disease, wherein said compound Is to be administered in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof. Llkewlse, the 5 invention relates to a pharmaceutical composition comprising the compound of formula (1) or a pharmaceutically acceptable sait, solvaté or prodrug thereof In combination with a pharmaceutically acceptable excipient for use In the treatment or prévention of Parklnson’s disease, wherein said pharmaceutical composition is to be administered In combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

The invention further relates to levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof for use in the treatment or prévention of Parkinson's disease, wherein said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof is to be administered In combination with the compound of formula (I) according to the présent 15 Invention or a pharmaceutically acceptable sait, solvaté or prodrug thereof. The invention also relates to a pharmaceutical composition comprising levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof, and a pharmaceutically acceptable excipient, for use in the treatment or prévention of Parkinson’s disease, wherein the pharmaceutical composition is to be administered in combination with the compound of formula (I) or a pharmaceutically 20 acceptable sait, solvaté or prodrug thereof.

Moreover, the présent invention provides a pharmaceutical composition for use in the treatment or prévention of Parkinson's disease, wherein the pharmaceutical composition comprises: (i) a compound of formula (l) or a pharmaceutically acceptable sait, solvaté or 25 prodrug thereof; (ii) levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof; and (iii) a pharmaceutically acceptable excipient.

The présent invention furthermore relates to the use of the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof for the préparation of a 30 médicament for the treatment or prévention of Parkinson’s disease, wherein said médicament

Is to be administered In combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof. The Invention also relates to the use of levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof for the préparation of a médicament for the treatment or prévention of Parkinson’s disease, wherein said médicament 35 Is to be administered In combination with the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof. Moreover, the invention provides a method of treating or preventing Parkinson's disease, the method comprising the administration of the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof to a subject in need thereof (preferably a mammal, and more preferably a human).

The compound of formula (I) according to the présent invention has been found to substantially retain the potent therapeutic activity of the structurally related compound according to Example 127 of WO 2011/051478 while, unexpectedly, showing considerably Improved pharmacokinetic properties and, In particular, a greatly improved brain exposure, as also demonstrated in Example 2.

Compound of formula (I) (PXT002331)

Potency on mGluR4: pECso = 7.12 Brain AUC(Wnf) ( h*ng/g ) <i □ mg/kg p o > = 2713 Brain/plasma ratio <t-i sm = 6.5

Example 127 of WO 2011/051478 (“PXT001858')

Potency on mGluR4: pEC» = 7.44

Brain AUC(wnf) (h*ng/g) (10 mg/kg po> = 838

Brain/plasma ratio a-ι en> = 2.0

These improved pharmacokinetic properties render the compound of formula (I) highly advantageous as a pharmaceutical, particularly as a brain pénétrant pharmaceutical. In accordance with this advantageous pharmacokinetic profile, the compound of formula (I) has further been demonstrated to show potent anti-parkinsonian efficacy In an MPTP-macaque model of Parkinson's disease, particularly at doses lower than or equal to 25 mg/kg by oral administration, as detailed in Example 3.

In accordance with the présent invention, the compound of formula (I) Is useful as a brain pénétrant modulator of mGluRs of the nervous system, particularly as a brain pénétrant positive allosteric modulator of mGluR4.

Levodopa-induced dyskinesia is a recognized and distinct pathological condition that is caused by long exposure to levodopa. Dyskinesia can occur at peak effect of levodopa, at the beginning and end of dose or between doses of levodopa. PD patients are particularly prone to develop this condition since levodopa is used primarily to treat Parkinson’s disease and is

taken by most PD patients. Patients suffering from levodopa-induced dyskinesia may show a variety of uncontrolled movements, particulariy choreic, dystonie, athetoid and/or ballistic movements. Several different types of levodopa-induced dyskinesia hâve been described in PD patients, which are classified on the basis of their appearance In relation to the PD patients on-off cycle (see, e.g., Fox SH & Brotchie JM (eds.), Levodopa-induced Dyskinesia in Parkinson's Disease, Springer London, 2014). The présent invention particulariy relates to the treatment or prévention of levodopa-induced dyskinesia in patients/subjects suffering from Parkinson's disease, including specifically each one of on-period levodopa-induced dyskinesia (e.g., peak-dose levodopa-induced dyskinesia, or square-wave levodopa-induced dyskinesia), 10 off-period levodopa-induced dyskinesia, and diphasîc levodopa-induced dyskinesia.

The scope of the invention embraces ali pharmaceutically acceptable sait forms of the compound of formula (I) which may be formed, e.g., by protonation of an atom carrying an électron lone pair which is susceptible to protonation, such as an amino group, with an 15 inorganic or organic acid, or as a sait of a hydroxy group with a physiologically acceptable cation as they are well known in the art. Exemplary base addition salts comprise, for example, alkali métal salts such as sodium or potassium salts; alkaline-earth métal salts such as calcium or magnésium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine 20 salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as Ν,Ν-dibenzylethylenediamine salts, benetamîne salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quatemary ammonium salts such as tétraméthylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriéthylammonium salts, benzyltributylammonium salts, 25 methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Exemplary acid addition salts comprise, for example, minerai acid salts such as hydrochloride, hydrobromlde, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, 30 propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate salts; sulfonate salts such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid 35 salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compound of formula (I) include a hydrochloride sait, a hydrobromide sait, a mesylate sait, a sulfate sait, a tartrate sait, a fumarate sait, an acetate sait, a citrate sait, and a phosphate sait.

A particularly preferred pharmaceutically acceptable sait of the compound of formula (I) is a hydrochloride sait. Accordingly, it Is preferred that the compound of formula (I) is in the form of a hydrochloride sait, a hydrobromide sait, a mesylate sait, a sulfate sait, a tartrate sait, a fumarate sait, an acetate sait, a citrate sait, or a phosphate sait. More preferably, the compound of formula (I) is in the form of a hydrochloride sait. Even more preferably, the compound of formula (I) is in the form of a blshydrochloride monohydrate sait (i.e,, · 2 HCl • H₂O).

Moreover, the scope of the invention embraces solid forms of the compound of the formula (I) 10 in any solvated form, including e.g. solvatés with water, for example hydrates, or with organic solvents such as, e.g., methanol, éthanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph. It is to be understood that such solvatés of the compound of the formula (I) also include solvatés of a pharmaceutically acceptable sait ofthe compound ofthe formula (I).

Furthermore, the présent Invention embraces all possible Isomers, Including configuratlonal or conformational Isomers, of the compound of formula (I), either In admixture or in pure or substantially pure form. In particular, the compound of formula (I) may hâve the (E)-configuration or the (Z)-configuration at the oxime group (=N-OH) as shown below, and the 20 présent invention embraces the (E)-isomer of the compound of formula (I), the (Z)-isomer of the compound of formula (I), and mixtures of the (E)-lsomer and the (Z)-lsomer of the compound of formula (I).

(E)-isomer of the compound of formula (I)

It is preferred that the compound of formula (I) Is the (E)-isomer, which is particularly advantageous in terms of Its activity. Accordingly, it Is preferred that at least 70 mol-%, more preferably at least 80 mol-%, even more preferably at least 90 mol-%, even more preferably at least 95 mol-%, êven more preferably at least 98 mol-%, and yet even more preferably at least 99 mol-% ofthe compound of formula (I) Is présent in the form ofthe (E)-isomer. Likewise, it is preferred that at least 70 mol-%, more preferably at least 80 mol-%, even more preferably at

least 90 mol-%, even more preferably at least 95 mol-%, even more preferably at least 98 mol-%, and yet even more preferably at least 99 mol-% of the compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof which is contained in the pharmaceutical composition of the présent Invention Is In the form of the (E)-isomer, I.e., has the (E)-configuration at the oxime group comprised In the compound of formula (l).

Pharmaceutically acceptable prodrugs of the compound of the formula (I) are dérivatives which hâve chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compound of the formula (I) which is pharmaceutically active in 10 vivo. Prodrugs of the compound of the formula (I) may be formed în a conventional manner with a functional group of the compound, such as a hydroxy group. The prodrug derivatîve form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organisai (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Such prodrugs include, e.g., an acyloxy dérivative prepared by reacting the 15 hydroxyl group of the compound of formula (I) with a suitable acylhalide or a suitable acid anhydride. An especialîy preferred acyloxy derivatîve as a prodrug is -OC(=O)-CH3, -OC(=O)-C₂H_S, -OC(=O)-C₃H7, -OC(=O)-(tert-butyl), -OC(=O)-Ci5H₃i, -OC(=O)CH₂CH₂COONa, -O(C=O)-CH(NH₂)CH₃ or -OC(=O)-CH2-N(CH₃)₂. Accordingly, the pharmaceutically acceptable prodrug may be a compound of formula (I), wherein the oxime 20 -OH group is In the form of an O-acyl-oxime (or acyloxy derivatîve) such as, e.g., -OC(=O)CH₃. -OC(=O)-C₂H₅, -OC(=O)-C₃H7, -OC(=O)-(tert-butyl), -OC(=O)-Ci_SH₃i, -OC(=O)CH₂CH₂COONa, -O(C=O)-CH(NH₂)CH₃ or-OC(=O)-CHî-N(CH₃)2. The oxime -OH group of the compound of formula (I) may also be In the form of an O-alkyl-oxime such as, e.g., -O-CH₃, -O-C₂H₅₁ -O-C3H7 or -O-(tert-butyl). The oxime -OH group of the compound of formula (I) may 25 also be in the form of an O-dialkylphosphinyloxy such as -0-P(=0)-[O-(CH₃)₂], -0-P(=0)-[0(CrCsh], -0-P(=0)-[0-(C₃-C7)₂] or -O-P(=0)-ÎO-(tert-butyl)2] or in the form of an O-phosphoric acid -O-P(=0)-(0H)₂ or in the form of an O-sulfuric acid -O-SOrOH. Thus, the pharmaceutically acceptable prodrug according to the présent invention is preferably a compound of formula (I), wherein the oxime -OH group is in the form of an O-acyl-oxime 30 group, an O-alkyl-oxime group, an O-dialkylphosphinyloxy group, an O-phosphoric acid group, or an O-sulfuric acid group.

The scope of the présent invention further embraces ail pharmaceutically acceptable sait forms of levodopa, which may be formed, e.g., by protonation of the amino group comprised in 35 levodopa with an Inorganic or organic acid, or as a sait of the carboxylic acid group and/or of one or both of the hydroxy groups comprised In levodopa with a physiologlcalîy acceptable cation. Exemplary base addition salts comprise, for example, alkali métal salts such as sodium

or potassium salts; alkaline-earth métal salts such as calcium or magnésium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamïne salts; aralkyl amine salts such as N,N-dibenzylethylenediamine 5 salts, benetamine salts; heterocyclic aromatic amine salts such as pyridine salts, plcoline salts, quinoline salts or Isoqulnoline salts; quatemary ammonium salts such as tétraméthylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriéthylammonium salts, benzyltributylammonium salts, methyltrloctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts.

Exemplary acid addition salts comprise, for example, minerai acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropîonate, 15 undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, sallcylate or ascorbate salts; sulfonate salts such as methanesulfonate, ethanesuffonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesuffonate, 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid salts such as aspartate or glutamate salts. A preferred pharmaceutically acceptable sait of levodopa is levodopa hydrochloride (e.g., as described in WO 2007/011701).

The scope of the invention also embraces solid forms of levodopa in any solvated form, Including e.g. solvatés with water, for example hydrates, or with organic solvents such as, e.g., methanol, éthanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, 25 respectively; or In the form of any polymorph. It is to be understood that such solvatés also include solvatés of a pharmaceutically acceptable sait of levodopa.

Pharmaceutically acceptable prodrugs of levodopa are known in the art and are described, e.g., in Di Stefano A et al. Curr Pharm Des. 2011;17(32):3482-93, Di Stefano A et al. 30 Molécules. 2008;13(1 ):46-68, Karaman R. Chem Biol Drug Des. 2011 ;78(5):853-63, and the référencés cited therein. Typically, prodrugs of levodopa are chemïcally modified forms of this active agent, which must undergo enzymatic and/or chemical transformation In vivo In order to release the active agent levodopa, whereby an enhanced absorption and a prolongée! pharmacological activity as compared to directly administered levodopa may be achieved. In 35 particular, pharmaceutically acceptable prodrugs of levodopa include those wherein the carboxy group of levodopa is in the form of an ester, wherein the amino group of levodopa is in the form of an amide, wherein one or both of the hydroxy groups of levodopa Is/are in the form

of an ester, and any combinations thereof (including also any combinations of the spécifie prodrug groups mentioned in the following), as well as pharmaceutically acceptable salts and solvatés of such prodrugs. For example, the 3-hydroxy group and/or the 4-hydroxy group of levodopa may be In the form of a group -0-C0-(Cm alkyl), -O-CO-(C₂_e alkenyl), -0-C0-(Cm alkylene)-aryl, or -0-C0-(Cm alkylene)-heteroaryl, such as, e.g., -O-CO-CHj, -O-CO-CH2CH3, -O-CO-CH(CH₃)₂, -O-C0-C(CH₃)₃, -O-CO-CH₂C(CH₃)₃, -O-CO-CH₂CH(CH₃)₂, -O-COC(CH₃)2CH₂CH₃, -O-CO-(n-butyl), -O-CO-hexenyl, -O-CO-phenyl, -O-CO-benzyl, or -O-COCH₂CH2-phenyl. The carboxy group of levodopa may be In the form of a group -COO-(Ci_e alkyl), -COO-(C₂-e alkenyl), -C00-(Cm alkylene)-aryl, or -COO-(C<m alkylenej-heteroaryl, such as, e.g., -COO-CH₃, -COO-CH₂CH₃₁ -COO-CH(CH₃)₂, -COO-C(CH₃)₃, -COO-CH2C(CH₃)₃, -COO-CH₂CH(CH₃)_2i -COO-C(CH₃)₂CH₂CH₃, -COO-(n-butyl), -COO-hexenyl, -COO-phenyl, -COO-benzyl, or -COO-CH₂CH2-phenyl. The amino group of levodopa may be in the form of a group -NH-C0-(Cn alkyl), such as, e.g., -NH-CO-CH₃ or -NH-CO-CH2CH₃. Moreover, the carboxy group and/or the amino group of levodopa may also be in the form of an amide formed with an amino acid, with a dipeptide or with a tripeptide (e.g., the carboxy group of levodopa may form an amide with an amino group of an amino acid, of a dipeptide or of a tripeptide, and/or the amino group of levodopa may form an amide with a carboxy group of an amino acid, of a dipeptide or of a tripeptide). Glycosyi dérivatives of levodopa can also be used. Fùrthermore, any one of the prodrugs referred to in Di Stefano A et al. Cuit Pharm Des. 2011 ;17(32):3482-93, Di Stefano A et al. Molécules. 2008;13(1):46-68, or Karaman R. Chem Biol Drug Des. 2011 ;78(5):853-63, or a pharmaceutically acceptable sait or solvaté thereof can also be used as a pharmaceutically acceptable prodrug of levodopa in accordance with the présent invention. It is partlcularly prefened that the pharmaceutically acceptable prodrug of levodopa Is selected from melevodopa, etilevodopa, XP21279, and pharmaceutically acceptable salts and solvatés thereof.

The compound of formula (I), optionally In combination with levodopa, may be administered per se or may be formulated as a médicament. Within the scope of the présent invention are pharmaceutical compositions comprising as an active Ingrédient the compound of the formula 30 (I) as defined herein above. The pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, dislntegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, or antioxidants.

The pharmaceutical compositions can be formulated by techniques known to the person skilled 35 in the art, such as the techniques published in Remlngton’s Pharmaceutical Sciences, 20*” Edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parentéral, such as intramuscular, intravenous, subeutaneous, intradermal, intraarterial, rectal,

nasal, topical, aérosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, émulsions, suspensions, syrups, élixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewlng tablets and effervescent tablets.

Dosage forms for parentéral administration include solutions, émulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parentéral administration. Dosage forms for rectal and vaginal administration Include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and Insufflation, for example by a metered inhaler. Dosage forms for topical 10 administration include creams, gels, ointments, salves, patches and transdermal delivery

Systems.

The compound of formula (I) according to the Invention or the above described pharmaceutical compositions comprising the compound of formula (I) may be administered to a subject by any 15 convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g. as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, Intranasal, ocular, buccal, and sublingual), parentéral (e. g., using Injection techniques or infusion techniques, and including, for example, by injection, e.g. subcutaneous, intradermal, intramuscular, intravenous, intraarterial, 20 intracardiac, intrathecal, Intraspinal, intracapsular, subcapsular, intraorbltal, intraperitoneal, Intratracheal, subcuticular, intraarticular, subarachnoid, or intrastemal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by Inhalation or Insufflation therapy using, e.g., an aérosol, e.g. through mouth or nose), gastrointestinal, Intrauterine, Intraocular, subcutaneous, ophthalmic (Including intravitreal or intracameral), 25 rectal, and vaginal. It Is particularly preferred that the compound of formula (I) according to the présent Invention or the pharmaceutical compositions of the invention are to be administered orally.

If said compound or pharmaceutical compositions are administered parenterally, then 30 examples of such administration Include one or more of: intravenously, Intraarterially, Intraperitoneally, Intrathecally, intraventricularly, întraurethrally, Intrastemally, intracranially, Intramuscularly or subcutaneously administering the compound or the pharmaceutical compositions, and/or by using infusion techniques. For parentéral administration, the compound is best used in the form of a stérile aqueous solution which may contain other 35 substances, for example, enough salts or glucose to make the solution isotonie with blood. The aqueous solutions should be sultably buffered (preferably to a pH of from 3 to 9), if necessary. The préparation of suitable parentéral formulations under stérile conditions is readily

accomplished by standard pharmaceutical techniques well known to those skilled In the art.

Said compound or pharmaceutical compositions can also be administered orally In the form of tablets, capsules, ovules, élixirs, solutions or suspensions, which may contain flavoring or 5 coloring agents, for immédiate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The pérorai administration of the compound or pharmaceutical composition according to the Invention Is particularly preferred.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, 10 calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC). sucrose, gelatin and acacia. Additionally, lubricating agents such as magnésium stéarate, stearlc acid, glyceryl 15 behenate and talc may be Included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients In this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or élixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as 20 water, éthanol, propylene glycol and glycerin, and combinations thereof.

Altematively, said compound or pharmaceutical compositions can be administered In the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compound of the présent Invention may also 25 be dermally or transdermally administered, for example, by the use of a skin patch.

Said compound or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions In Isotonie, pH adjusted, stérile saline, or, preferably, as solutions in 30 isotonie, pH adjusted, stérile saline, optionally in combination with a preservative such as a benzylalkonîum chloride. Altematively, they may be formulated in an ointment such as petrolatum.

For topical application to the skin. said compound or pharmaceutical compositions can be 35 formulated as a suitable ointment containing the active compound suspended or dissolved In, for example, a mixture with one or more of the following: minerai oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Altematively, they can be formulated

as a suitable lotion or cream, suspended or dissolved ln, for example, a mixture of one or more of the following: minerai oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

Typically, a physîcian will détermine the actual dosage which will be most suitable for an Individual subject. The spécifie dose level and frequency of dosage for any particular Individual subject may be varied and will dépend upon a variety of factors Including the activity of the spécifie compound employed, the metabolic stability and length of action of that compound, the âge, body weight, general health, sex, diet, mode and time of administration, rate of excrétion, 10 drug combination, the severity of the particular condition, and the Individual subject undergolng therapy.

A proposed, yet non-limiting dose of the compound of formula (!) for administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, 15 of the active ingrédient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose will dépend on the route of administration. A further, particularly preferred dose of the compound of formula (I) for pérorai administration to a mammal (such as a human) Is about 1 to about 25 mg/kg bodyweight (e.g., 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, or 25 mg/kg), which dose may be administered, e.g., 1, 2, 3 or 4 20 times per day (preferably twice per day). Even more preferably, the compound of formula (I) is to be administered to a subject (e.g., a mammal, preferably a human) twice a day at a dose, per each administration, of 2 to 25 mg/kg bodyweight. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the âge and weight of the patient/subject as well as the severity of the condition to be treated. The précisé dose and 25 route of administration will ultimately be at the discrétion of the attendant physician or veterinarian.

The compound of formula (I) according to the invention can be administered in monotherapy for the treatment or prévention of levodopa-induced dyskinesia (e.g., without concomitantly 30 administering any further therapeutic agents against levodopa-induced dyskinesia). However, for the treatment or prévention of levodopa-induced dyskinesia, the compound of formula (I) can also be administered in combination with one or more other therapeutic agents. When the compound of formula (I) Is used for the treatment or prévention of levodopa-induced dyskinesia in combination with a second therapeutic agent active against this same condition, 35 the dose of each compound may differ from that when the corresponding compound Is used alone. The combination of the compound of formula (I) with one or more other therapeutic agents may comprise the simultaneous/concomitant administration of the compound of formula

(I) and the other therapeutic agent(s) (either In a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequentiat/separate administration of the compound of formula (I) and the other therapeutic agent(s).

The subject in which levodopa-induced dyskinesia Is to be treated or prevented in accordance with the invention typically continues taking levodopa, e.g., before, concurrently with, or after the administration of the compound of formula (I). The présent invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities In combination 10 with a pharmaceutically acceptable excipient, for use in the treatment or prévention of levodopa-induced dyskinesia in a subject (preferably a human) that Is taking levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof. The invention likewise relates to the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities In combination 15 with a pharmaceutically acceptable excipient, for use in the treatment or prévention of levodopa-induced dyskinesia, wherein said compound is to be administered in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof. The compound of formula (I) (or the pharmaceutically acceptable sait, solvaté or prodrug thereof) and levodopa (or the pharmaceutically acceptable sait, solvaté or prodrug thereof) can be 20 administered simultaneously/concomitantly, either in a single pharmaceutical formulation or in separate pharmaceutical formulations, or they can be administered sequentially. It Is preferred that the compound of formula (I) and levodopa are administered simultaneously, or that the compound of formula (I) Is administered first, followed by the administration of levodopa. The compound of formula (I) and levodopa may be administered by any convenient route, as 25 described above, and are preferably both administered orally.

As described above, the présent invention relates, in particular, to the treatment or prévention of Parkinson’s disease, using the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof in combination with levodopa or a pharmaceutically acceptable 30 sait, solvaté or prodrug thereof. The invention thus relates to the compound of formula (I) for use In the treatment or prévention of Parkinson’s disease, wherein the compound of formula (I) Is to be administered In combination with levodopa. The compound of formula (I) (or the pharmaceutically acceptable sait, solvaté or prodrug thereof) and levodopa (or the pharmaceutically acceptable sait, solvaté or prodrug thereof) can be administered 35 simultaneously/concomitantly or sequentially. In the case of sequential administration, the compound of formula (I) may be administered first, followed by the administration of levodopa (e.g., at least about 5 min'after the first administration, preferably about 5 min to about 3 hours

after the first administration, more preferably about 10 min to about 1 hour after the first administration). Levodopa may also be administered first, followed by the administration of the compound of formula (I) (e.g., at least about 5 min after the first administration, preferably about 5 min to about 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration). In the case of slmultaneous administration, the compound of formula (I) and levodopa may be administered in the same pharmaceutical composition or In two différént/separate pharmaceutical compositions. They may also be provided In two different/separatecompartments ofthe same pharmaceutical dosage form. It Is preferred that the compound of formula (I) and levodopa are administered simultaneously, or that the compound of formula (I) is administered first, followed by the administration of levodopa. The compound of formula (I) and levodopa may be administered by any convenlent route, as described above, and are preferably both administered orally.

The présent Invention also relates to the treatment or prévention of Parkinson’s disease, using 15 the compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof

In combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof, wherein the compound of formula (I) and levodopa are to be administered In combination with one or more further therapeutic agents, preferably In combination with a levodopa decarboxylase Inhibitor and/or a catechol-O-methyl transferase (COMT) inhibitor.

The administration of the compound of formula (I) and levodopa in combination with a levodopa decarboxylase inhibitor (also referred as ‘L-DOPA decarboxylase inhibitor” or “DDC Inhibitor”) Is advantageous as It prevents or reduces an undesired peripheral décarboxylation of levodopa by L-DOPA decarboxylase, I.e. a décarboxylation of levodopa before It crosses the 25 blood-brain barrier in the patients body. The enzyme L-DOPA decarboxylase (also referred to as “DOPA decarboxylase, aromatic L-amino acid decarboxylase, “tryptophan decarboxylase, or 5-hydroxytryptophan decarboxylase; EC number: 4.1.1.28) Is a lyase that catalyzes the décarboxylation of levodopa (L-DOPA) to dopamine and CO₂. Since levodopa Is able to cross the blood-brain barrier, while dopamine is not, the peripheral décarboxylation of 30 levodopa results in the formation of dopamine that will not reach the brain, which decreases the effectiveness of levodopa treatment. The combined administration of a levodopa decarboxylase inhibitor thus allows a greater proportion of exogenously administered levodopa to reach the brain and exert its bénéficiai therapeutic effect.

The levodopa decarboxylase inhibitor to be administered In combination with levodopa and the compound of formula (I) is preferably a peripheral levodopa decarboxylase inhibitor, I.e., a levodopa decarboxylase Inhibitor that cannot cross the blood-brain barrier. Such levodopa

decarboxylase inhibitors are known in the art (see, e.g., ‘Dopa decarboxylase inhibitors, Br Med J. 1974; 4(5939):250-1) and include, e.g., carbidopa, benserazide (also referred to as ‘serazide or ‘Ro 4-4602), α-methyldopa (also referred to as methyldopa or L-a-methyl-3,4dihydroxyphenylalanine), a-difluoromethyldopa (also referred to as difluromethyldopa or “DFMD), as well as pharmaceutically acceptable salts and solvatés thereof. More preferably, the levodopa decarboxylase inhibitor is carbidopa, benserazide, or a pharmaceutically acceptable sait or soivate thereof (such as, e.g., carbidopa monohydrate or benserazide hydrochloride). Even more preferably, the levodopa decarboxylase inhibitor Is carbidopa or a pharmaceutically acceptable sait or soivate thereof.

The administration of the compound of formula (I) and levodopa In combination with a catecho!-O-methyl transferase inhibitor (COMT inhibitor) is advantageous as the inhibition of the enzyme catechol-O-methyl transferase (COMT; EC number: 2.1.1.6) prevents the méthylation of levodopa into 3-methoxy-4-hydroxy-L-phenylalanine. This, in tum, results in an 15 enhanced bioavailability and a prolonged therapeutic effect of levodopa. The COMT inhibitor is preferably selected from entacapone, tolcapone, nitecapone, opicapone, as well as pharmaceutically acceptable salts and solvatés thereof. More preferably, the COMT Inhibitor is entacapone, tolcapone, opicapone, or a pharmaceutically acceptable sait or soivate thereof. Even more preferably, the COMT inhibitor is entacapone or a pharmaceutically acceptable sait 20 or soivate thereof.

It is particularly preferred that the compound of formula (I) (or a pharmaceutically acceptable sait, soivate or prodrug thereof) and levodopa (or a pharmaceutically acceptable sait, soivate or prodrug thereof) are administered in combination with both a levodopa decarboxylase 25 inhibitor (preferably carbidopa) and a COMT Inhibitor (preferably entacapone).

The (i) compound of formula (I) (or a pharmaceutically acceptable sait, soivate or prodrug thereof) and (ii) levodopa (or a pharmaceuticaily acceptable sait, soivate or prodrug thereof), together with (iii) a levodopa decarboxylase inhibitor and/or (iv) a COMT inhibitor, may be 30 administered simultaneously/concomitantly or may be administered sequentially in any suitable order. In the case of sequential administration, for example, the compound of formula (I) may be administered first, followed by the administration of a single pharmaceutical composition comprising levodopa In combination with a levodopa decarboxylase inhibitor and/or a COMT inhibitor (e.g., at least about 5 min after the first administration, preferably about 5 min to about 35 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration). Altematively, a corresponding pharmaceutical composition comprising levodopa in combination with a levodopa decarboxylase inhibitor and/or a COMT Inhibitor may

be administered first, followed by the administration of the compound of formula (I) (e.g.. at least about 5 min after the first administration, preferably about 5 min to about 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration), ln the case of simultaneous administration, the compound of formula (I) and levodopa as well 5 as the levodopa decarboxylase inhibitor and/or the COMT inhibitor may be administered in the same pharmaceutical composition or in two or more different/separate pharmaceutical compositions. Administration is preferably simultaneous or the compound of formula (I) is administered first. Thus, it is preferred that the compound of formula (I) and a pharmaceutical composition comprising levodopa in combination with a levodopa decarboxylase inhibitor 10 and/or a COMT inhibitor are administered simultaneously, or that the compound of formula (I) is administered first, followed by the administration of a pharmaceutical composition comprising levodopa in combination with a levodopa decarboxylase inhibitor and/or a COMT inhibitor.

Pharmaceutical combination formulations of levodopa that are known in the art can also be used, e.g., a combined pharmaceutical formulation of levodopa and carbidopa (such as the extended-release carbidopa-levodopa formulation IPX066; see, e.g., Hauser RA. Expert Rev Neumther. 2012;12(2):133-40), a combined pharmaceutical formulation of levodopa and benserazide (such as a formulation comprising levodopa and benserazide hydrochloride in a ratio of levodopa to benserazide of about 4:1; e.g., Madopar*), or a combined pharmaceutical formulation of levodopa, carbidopa and entacapone (such as Stalevo®; see, e.g., Seeberger LC et al. Expert Rev Neurother. 2009;9(7):929-40).

The compound of formula (I) and levodopa may also be administered in combination with one 25 or more further therapeutic agents, other than or in addition to the levodopa decarboxylase inhibitors and the COMT inhibitors that hâve been described above. Such further therapeutic agents include, in particular, further antiparkinson drugs like, e.g., droxidopa, apomorphine, pramipexole, aplindore, bromocriptine, cabergoline, ciladopa, dihydroergocryptine, lisuride, pardoprunox, pergolide, piribedil, ropïnirole, rotigotine, ladostigil, lazabemide, mofegiline, pargyline, rasagiline, selegiline, benzatropine, bîperiden, bomaprine, chlorphenoxamine, cycrimine, dexetimide, dimenhydrinate, diphenhydramine, etanautine, etybenzatropine, mazaticol, metixene, orphenadrine, phenglutarimide, piroheptine, procyclidine, profenamine, trihexyphenîdyl, tropatepine, amantadine, budipine, memantine, methylxanthines, rimantadine, UWA-101, safinamide, and pharmaceutically acceptable saits and solvatés of any of these 35 agents.

Furthermore, the compound of formula (I) can also be radio-labeled by canying out its

synthesis (e.g., as described in Example 1) using precursors comprising at least one atom which is a radioisotope. Preferably, radioisotopes of carbon atoms, hydrogen atoms, sulfur atoms, or iodine atoms are employed, such as, e.g., ¹⁴C, ³H, ^{25 * * * * 30 * * * * 35}S, or ^12!l. Compounds labeled with ³H (tritium) can also be prepared by subjecting the compound of formula (I) to a hydrogen exchange reaction such as, e.g,, a platinum-catalyzed exchange reaction In tritiated acetic acid (Le., acetic acid comprising ³H Instead of Ή), an acid-catalyzed exchange reaction in tritiated trifluoroacetic acid, or a heterogeneous-catalyzed exchange reaction with tritium gas. For a person skilled in the field of synthetic chemistry, various further ways for radio-labeling the compound of formula (I) or preparing radio-labeled dérivatives of this compound are readily 10 apparent. Fluorescent labels can also be bound to the compound of formula (I) following methods known In the art.

The subject or patient to be treated In accordance with the présent invention may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a 15 hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a macaque, a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human. In the context of this invention, it is particularly envlsaged that animais are to be treated which are economically, agronomicaliy or scientifically important. Scientifically 20 important organisms include, but are not limited to, mice, rats, macaques, marmosets, dogs and rabbits. Non-limiting examples of agronomicaliy important animais are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animais. Preferably, the subject/patient is a mammal; more preferably, the subject/patient is a human.

The term “treatment of a disorder or disease as used herein is well known in the art.

“Treatment of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed In a patient/subject. A patlent/subject suspected of suffering from a disorder or disease typically shows spécifie clinical and/or pathological symptoms which a skilied person can easily attribute to a spécifie pathological condition (I.e., diagnose a disorder or disease).

The “treatment of a disorder or disease may, for example, lead to a hait in the progression of the disorder or disease (e.g., no détérioration of symptoms) or a delay in the progression of the disorder or disease (in case the hait in progression is of a transient nature only). The “treatment of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complété response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the “treatment of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, for example, lead to a

hait In the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complété response may be followed by a relapse. It is to be understood that a subject/patient may expérience a broad range of responses to a treatment (e.g., the exemplary responses as described herein above).

Treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complété response and eventually to heallng of the disorder or disease) and palliative treatment (including symptomatic relief).

Also the term ‘prévention’ or prophylaxie’ of a disorder or disease as used herein is well known In the art. For example, a patient/subject suspected of being prône to suffer from a disorder or disease as defined herein may, in particular, benefit from a prevention/prophylaxis of the disorder or disease. Said subject/patient may hâve a susceptibility or prédisposition for a disorder or disease, including but not limited to hereditary prédisposition. Such a prédisposition 15 can be determined by standard assays, using, for example, genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the présent Invention has not been diagnosed or cannot be diagnosed in said patient/subject (for example, said patient/subject does not show any clinical or pathological symptoms). Thus, the term “prévention or “prophylaxie comprises the use of compound of the présent invention 20 before any clinicai and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physicien. The terms prophylaxis and prévention are used herein interchangeably.

As used herein, the term alkyl refers to a monovalent saturated acyclic (i.e., non-cyclic) 25 hydrocarbon group (i.e., a group consisting of carbon atoms and hydrogen atoms) which may be linear or branched. Accordingly, an alkyl group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “Cm alkyi dénotés an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyi groups are methyl, ethyl, propyi (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl).

The term alkenyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “Cm alkenyl dénotés an alkenyl group having 2 to 6 carbon atoms. Preferred exemplary alkenyl groups are 35 ethenyl, propenyi (e.g., prop-1-en-1-yi, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl). pentenyl, or pentadienyi (e.g., isoprenyl).

The term alkylene refera to an alkanediyl group, I.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A 'Cm alkylene dénotés an alkylene group having 1 to 4 carbon atoms, and the term ‘C« alkylene* indicates that a covalent bond (corresponding to the option “Co alkylene*) or a Cm alkylene is présent. Preferred exemplary alkylene groups are methylene (-CHr), ethylene (e.g., -CH2-CH2- or -CH(-CH₃)-), propylene (e.g., -CH2-CH2CHî-, -CHt-CHrCHs)-, -CH2-CH(-CH₃)-, or -CH(-CH₃)-CH2-), or butylène (e.g., -CH2-CH2-CH2CH_r).

The term aryl refera to an aromatic hydrocarbon ring group, including monocyclic aromatic 10 rings as well as bridged ring and/or fused ring Systems containing at least one aromatic ring (e.g., ring Systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring Systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). Aryl* may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1,2dihydronaphthyl), tetralinyl (I.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), 15 anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refera to phenyl or naphthyl, and most preferably refera to phenyl.

The term “heteroaryl* refera to an aromatic ring group, Including monocyclic aromatic rings as 20 well as bridged ring and/or fused ring Systems containing at least one aromatic ring (e.g., ring

Systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring Systems composed of two or three rings, wherein at least one of these bridged rings Is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and 25 N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if présent) and/or one or more N ring atoms (if présent) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) 30 and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl* may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thîanthrenyl, furyl (i.e., furanyl), benzofuranyl, 35 isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyi, 3-pyridyl, or 4-pyridyl),

pyrazinyi, pyrimidinyi, pyridazinyl, indolyl (e.g., 3H-lndolyl), isoindolyî, indazofyl, indolizinyî, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quînoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothîazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5oxadiazolyl (Le., furazanyl), or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thîadiazolyl, 1,2,5thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5a]pyrimidin-3-yl), 1,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl. benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,310 triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl,

H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridînyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2ajpyridinyl), quinazolinyl, thienopyridinyl, tetrahydrathienopyridinyl (e.g., 4,5,6,7- tetrahydrothleno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms frf présent) and/or one or more N ring atoms (if présent) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if présent) and/or one or more N ring atoms (if présent) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, the term “heteroaryl particulariy preferably refers to pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyi.

The term “amino acid or “amino acid residue refers to any one of the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) but also to non-proteinogenic and/or non-standard α-amino acids (such as, e.g., omithine, citrulline, homolysine, pyrrolysine, 4-hydroxypraline, norvaline, norleucine, terieucine (tert-leucine), or an alanine or glycine that is substituted at the side chain with a cyclic group like, e.g., cydopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyciohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-aianine), γ-amino acids (e.g., γ-aminobutyric acid) and δ-amino acids.

Unless defined otherwise, it is preferred that an “amino acid is selected from a-amino acids, more preferably from the 20 standard proteinogenic α-amino acids (which can be présent as the L-isomer or the D-isomer, and are preferably présent as the L-isomer).

The terms “dipeptide and “tripeptide refer to an oligomer of two and three amino acids, respectlvely, wherein the amino acids are linked via amide bonds that are formed between an amino group (preferably an α-amino group) of one amino acid and a carboxyl group (preferably an α-carboxyl group) of another amino acid.

In this spécification, a number of documents including patent applications and sclentific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, ail referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by 15 reference.

The reference in this spécification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the 20 common general knowledge in the technical field to which the présent spécification relates.

Moreover, any référencés to the unpublished European patent application EP 14 18 2468.0 or to the compound of formula (i) in the Introductory part of this spécification are not and should not be understood as acknowledgment or admission or any form of suggestion that the said application, the compound of formula (i) or any related information are known in the art or 25 belong to the state of the art accessible to a skilled person.

The invention is also described by the following illustrative figures. The appended figures show:

Figure 1: PXT002331 and PXT001858 brain exposure after oral administration in rats (10 mg/kg).

Figure 2: PXT002331 and PXT001858 plasma concentration after oral administration In rats (10 mg/kg).

Figure 3: PXT002331 and PXT001858 brain levei after oral administration in rats (10 mg/kg).

Figure 4: PXT002331 and PXT001858 brain/plasma ratio after oral administration in rats (10 mg/kg).

Figure 5: Evaluation ofthe antl-parkinsonian efficacy of PXT002331 in the 1-methyl-4-phenyl5 1,2,3,6-tetrahydropyridine (MPTP) macaque model of Parkinson’s disease (see Example 3).

(A) PXT002331 as a stand-alone treatment; oral administration twice a day during 4 days, assessment of parklnsonian scores at day 4; data are mean + s.e.m. over 2 hours observation (n = 7 ; 1 of the 8 monkeys initially used was excluded); Veh » vehicle; LD opt = L-dopa optimal dose*; * = P < 0.05 vs Veh; *** = P < 0.001 vs Veh; statistical analysis: Friedman 10 followed by Dunn’s. (B) Combined treatment using PXT002331 (25 mg/kg) + low dose of Ldopa (4-9 mg/kg) - parkinsonism time course; oral administration twice a day during 4 days, assessment at day #4; L-dopa optimal dose (“LDopf): 19 mg/kg on average; L-dopa suboptimal dose (“LDso*): 7 mg/kg on average; combined administration of L-dopa (suboptimal dose) and PXT002331: twice a day/4 days. The table présents statistical analyses of the 15 effects of the combined treatment (LDso+25mg/kg PXT002331) over 135 min following administration of levodopa. Two-way repeated measures ANOVA followed by Bonferroni’s multiple comparison. Statistical slgnificance was assigned when P < 0.05. (C) Combined treatment using PXT002331 + low dose of L-dopa - différence ln parkinsonlan score for monkeys treated with low dose of L-dopa and PXT002331 In comparison to low dose of 20 L-dopa alone, and ln comparison to optimal dose of L-dopa; assessment at day 4, between 1 and 2 h after L-dopa administration (i.e., 2 and 3 h after PXT002331 administration); ail monkeys treated with PXT002331 + L-dopa showed an improvement in parkinsonlan score.

(D) Combined treatment using PXT002331 + low dose of L-dopa - dose-response évaluation for different doses of PXT002331; assessment of parkinsonlan scores at day 4; Veh = 25 vehicle; low LD = low dose of L-dopa; “LD opt = optimal dose of L-dopa; * = P < 0.05 vs low

LD; statistical analysis: non-parametric one-way repeated, measures ANOVA (Friedman's test), followed by Dunn’s multiple comparison; N = 7. (E) Computerized locomotor activity ln the chronic low doses of MPTP (CLD MPTP) macaque model of eariy-stage PD for PXT002331 in combination with L-dopa (low dose or optimal dose) upon oral administration; * 30 = P < 0.05 vs vehicle; ** = P < 0.01 vs vehicle; *** = P < 0.001 vs vehicle; statistical analysis:

Friedman followed by Dunnett’s; N = 5 (6 monkeys/1 excluded). (F) Combined treatment using PXT002331 + optimal dose of L-dopa in eariy-stage PD monkey model - disability score and dyskinesia score, (G) Robustnessofthe effects of PXT002331 inthe MPTPmacaque model of eariy stage PD. Total locomotor activity (LMA) of each individual CLD MPTP-lesioned 35 macaque before and after addition of PXT002331 at 25 mg/kg to the optimal dose of L-DOPA (LDopt). Notably, ail animais Included In this study did respond to the treatment with PXT002331 (N = 5).

Figure 6: Cognitive performance of CLD MPTP monkeys in the Variable Delayed Response (VDR) task in presence or absence of PXT002331 (see Example 4). Percentages (A) and iatencies (B) of correct responses in the global VDR task foliowing administration of 5 PXT002331 at 25 mg/kg alone or in combination with L-DOPA (33, 66, 100: 33%, 66% and

100% of the optimal dose of L-DOPA, respectively) among CLD MPTP-iesloned macaques. Data are expressed as means of group (bar) and Individuai performance (symboi; N=4; 40 trials each) and analyzed using Friedman tests followed by Dunn's multiple comparison tests.

Figure 7: Positive effect of PXT002331 In cognitive performance of the most cognitiveiy impaired CLD MPTP monkey (see Example 4). Percentages of omissions (A, B) and of correct responses (C, D) per delay in the VDR task following administration of optimal dose of L-DOPA alone (A, C) or In combination with PXT002331 at 25 mg/kg (B, D) among CLD MPTP-lesioned macaques. Data are expressed as means of group (bar) and individuai performance (symboi; N=4; 8 trials per delay). Notably, the performances of one animal are Improved by the treatment with PXT002331, both in the attentional component (at short duration delays) and In the memory component (long duration delays) of the task. Dr-D5: delays 1 to 5, respectively.

Figure 8: Effects of co-administration of PXT002331 (25 mg/kg) and L-DOPA on dyskinesia of MPTP-macaque models of earty and of advanced stages of PD (see Example 4). In the model of earty stage of PD, the highest dyskinesia score observed over a 4-hour period post-L-DOPA administration was noticed (left half of the figure, left Y axis). In the model of advanced stage of PD, each dot represents individuai mean dyskinesia scores measured over a 2-hour period post-L-DOPA administration (right half of the figure, right Y axis).

Figure 9: Effect of the combined treatment with PXT002331 and L-DOPA on dyskinesia of MPTP-macaque model of L-DOPA-induced dyskinesia (LID) (see Example 5). (A) Mean dyskinesia score of MPTP macaques over 2 hours and (B) corresponding locomotor activity.

Veh: vehicle, High LD: high dose of L-DOPA (11-25 mg/kg), Low LD: low dose of L-DOPA (4-10 mg/kg),, PXT(-30min): administration of PXT002331 30 min before L-DOPA, PXT(0min): administrations of PXT002331 and L-DOPA at the same time; Day 1: acute administration of the combined treatment with PXT002331 (25 mg/kg) and levodopa (low dose); Day 8: effect measured at day 8 of the sub-chronic treatment (administration of PXT002331 twice daily for 8 consecutive days). * P<0.05, ** P<0.01 when compared to low LD (non-parametric one-way RM ANOVA (Friedman's test) followed by Dunn's multiple comparison).

Figure 10: Robustness of the effects of PXT002331 in the MPTP macaque model of L-DOPAinduced dyskinesia (see Example 5). Dyskinesia score of each individual MPTP-lesioned macaque before and after addition of PXT002331 at 25 mg/kg at day 1 (A) and at day 8 (B) of a sub-chronic treatment. * P<0.05, ** P<0.01 when compared to L-DOPA (non-parametric one-way RM ANOVA (Friedman's test) followed by Dunn's multiple comparison). Notably, ail dyskinetic animais did respond to the treatment with PXT002331 (N=4). Two monkeys did not présent dyskinesia (score=0) both in absence and in presence of PXT002331.

The invention will now be described by reference to the following examples which are merely 10 lilustrative and are not to be construed as a limitation of the scope of the présent invention.

EXAMPLES

Example 1: Préparation of the compound of formula (I)

1) General synthetic route

The compound of formula (I) according to the invention (I.e., PXT002331) can be prepared from readily available starting materials by several synthetic approaches, using solution-phase 20 or solid-phase chemistry protocols, or mixed solution and solid phase protocols. For example, the compound of formula (I) can be prepared using the synthetic schemes depicted below.

The commercially available bromo acetophenone I Is reacted with commercial thleno[3,2-c]pyridine methyl ester II in a solvent such as tetrahydrofuran (THF) and in the presence of a weak base like potassium tert-butoxîde (tBuOK) to yield the intermediate diketone III. This procedure Is known as Baker Venkataraman rearrangement (Baker, W., J.Chem.Soc, 1933,1381).

The intermediate diketone III Is then cyclized under acidic conditions in the presence of a strong dehydrating agent like sulfuric acid (H2SO4) in refluxing acetic acid (AcOH) to yield the chromone IV.

Advanced Intennedlate

Introduction of the oxime may be obtained by reacting the dérivative IV with hydroxyl amine hydrochloride (HONH2, HCl) In pyridine or éthanol under microwave conditions to yield directly 5 the chromone oxime advanced intermediate that would lead to PXT002331 In a couple of reaction steps. This advanced intermediate leading to PXT002331 can be also obtained by using a two-step procedure as depicted above using fert-butyl hydroxylamine hydrochloride (tBuONH₂, HCl) In éthanol followed in a subséquent step by deprotection of the fert-butyl group under acidic conditions like hydrochloric acid (HCl) In a mixture of polar solvent such as THF 10 and acetic acid.

Introduction of the alkylene side chain is obtained by a palladium catalyzed cross-coupling 15 reaction such as Neglshl cross-coupling using a commercially available zinc reagent and appropriate ligand/palladium catalytic System. Subséquent functionalization followed by standard reductive amination using weak reducing agents such as triacetoxy borohydride yield advanced intermediate VII in good yields. Final deprotection of the oxime protecting group under acidic conditions lead to the compound of formula (I), l.e. PXT002331.

2) Synthesis of the compound of formula (I)

The commercially available starting matériels used in the following experimental description were purchased from Aldrich, Sigma, ACROS or ABCR unless otherwise reported.

The compounds described in the following hâve been named according to the standards used in the program AutoNom vl .0.1.1 (MDL Information Systems, Inc.).

¹H NMR analyses were carried out using BRUKER NMR, model DPX-400 MHz FT-NMR. Resldual signal of deuterated solvent was used as internai reference. Chemical shifts (δ) are 10 reported in ppm in relative to the résiduel solvent signal (δ « 2.50 for ¹H NMR In DMSO-de, and

7.26 in CDCb). s (singlet), d (doublet), t (triplet), q (quadruplet), br (broad). Some compounds in the experimental part exist as mixture of E/Z Isomers In different ratios. E/Z isomer ratio was well determined for the final compound PXT002331.

The MS data provided herein below were obtained as followed: Mass spectrum: LC/MS Waters ZMD (ESI).

HPLC analyses were obtained as followed using a Waters X-bridgeTM C8 50 mm x 4.6 mm column at a flow of 2 mL/min; 8 min gradient HzOlCHaCNrTFA from 100:0:0.1 % to 0:100:0.05 20 % with UV détection (254 nm).

The mass directed préparative HPLC purifications were performed with a mass directed auto purification Fraction lynx from Waters equipped with a Sunfire Prep C18 OBD column 19x100 mm 5 pm, unless otherwise reported. Ail purifications were performed with a gradient of 25 ACN/HjO or ACN/HjO/HCOOH (0.1 %).

The compound of formula (I) was prepared as shown in the following reaction scheme:

Reaction Schéma

S HCl/THF

tί^(0,Bl,, N(OtBu)

	Ίοΐ	F 1	β Mofphdln· N«BH(OAc),	Xi
	7	s-/	DCU’MeOH	e	I

Steps 1 and 2:6-Bromo-2-(thieno[3.2-c]pyridin-6-yl)-4H-chromen-4-one (3)

To a suspension of potassium tert-butoxide (156.0 g, 1.39 mol, 3.0 eq) In THF (500 mL) at O’C was added a solution of 5-bromo-2-hydroxyacetophenone (100.0 g, 0.47 mol, 1 eq) in THF (500 mL). The reaction mixture was stirred vigorously for 10 minutes. A solution of 10 thienopyridine ester (98 g, 0.51 mol, 1.1 eq) in THF (1.0 L) was added to the reaction mixture.

The resulting reddish suspension was refluxed for 1 h, at which time LC/MS analysis indicated completion of the reaction. The reaction mixture was cooled to room température (RT) to give a thick orange suspension and poured Into ice water (5.0 L). The aqueous layer was neutralized by addition of an aqueous HCl solution (1.5 N) under vigorous stirring. The resulting yellow solid was collected by filtration, washed with water and dried under suction. The crude mass was again further dried overnight under pressure at 45°C for 16 h, which yielded 156 g of a yellow solid.

The yellow solid (156 g) was then suspended at RT in glacial acetic acid (1.0 L) and concentrated H2SO4 (10 mL). This mixture was heated at 110°C for 2 hours. The reaction mixture tumed into a brown suspension. After confirming completion of the reaction (by LC/MS), the crude mass was suspended In ice water (2.0 L) and neutralized by addition of an aqueous NaOH solution (1 N). The precipitated beige solid obtained was collected by filtration, washed with water and dried under suction. The material was further dried one night at 50°C under high vacuum to yield 140.0 g of the title compound as a beige solid.

Yield: 83%.

LC/MS: Mass found (m/z, M+1, 358.0), Area 94.78%.

¹H NMR (DMSO-de, 400MHz) δ 9.32 (s, 1H), 9.06 (s, 1H), 8.15 (m, 2H), 8.06 (m, 1H), 7.84 (d, J 5.4 Hz, 1H), 7.77 (d, J 5.4 Hz, 1H), 7.32 (s, 1H).

Step 3:6-Bromo-2-(thieno[3₁2-c]pyridin-6’yl)-4H-chromen-4-one O-fert-birtyl-oxime (4)

In a sealed tube, a suspension of 6-bromo-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one (20.0 g, 56 mmol, 1 eq) and O-tert-butyl hydroxylamine hydrochloride (14.0 g, 112 mmol, 2 eq) in anhydrous EtOH (300 mL) was heated at 115°C for 20 hours. After confirming the reaction completion by TLC, the reaction mixture was filtered and the yellow solid washed twice with cold EtOH (50 mL) and dried under vacuum to yield 20 g of the title compound as a yellow solid.

Yield: 83%.

LC/MS: Mass found (m/z, M+1,429.0), Area 97.83%.

¹H NMR (DMSO-de, 400MHz) δ 9.25 (s, 1H), 8.78 (s, 1H), 8.05 (m, 2H), 7.71 (m, 2H), 7.59 (s, 1H), 7.48 (s, 1H), 1.40 (s, 9H).

Step 4: 6-(2-(1,3]Dloxolan-2-y1-ethyl)-2-(thieno[3,2-c]pyridin-6-y1)-4H-chromen-4-one O-tertbutyl-oxime (5)

To a degassed solution of 6-bromo-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tertbutyl-oxime (100.0 g, 233 mmol, 1 eq) and 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl (4.9 g, 11.6 mmol, 0.05 eq) In anhydrous THF (500 mL) was added palladium (11) acetate (2.6 g, 11.6 mmol, 0.05 eq) followed by 2-(1,3-dioxolan-2-yl)ethylzinc bromide solution (0.5 M in THF, 652 mL, 362 mmol, 1.5 eq). The reaction mixture was heated at 100°C for 14 hours. After confirming completion of the reaction by LC/MS, the reaction mixture was quenched with water (20 mL) and concentrated under vacuum. The resultîng crude yellow oil was purified by chromatography on silica gel using cyclohexane/ethyl acetate (80/20) as eluent to afford 85 g of the title compound as a yellow solid.

Yield: 82%

HPLC: 93.00% (254 nm), RT: 2.50 min.

LC/MS: Mass found (m/z, M+1,451.0), Area 93.96%.

¹H NMR (DMSO-d_e, 400MHz) δ 9.27 (s, 1H), 8.77 (s, 1H), 8.05 (d, J 5.4 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J 5.4 Hz, 1H), 7.62 (s, 1H), 7.43 (m, 2H), 4.85 (m, 1H), 3.93 (m, 2H), 3.80 (m, 2H), 2.75 (m. 2H), 1.90 (s, 2H), 1.39 (s, 9H).

Step 5: 3-(4-tert-Butoxyimino-2-(thleno[3.2-c]pyridin-6-yl)-4H-chromen-6-y1)-propionaldehyde (6)

To a solution of 6-(2-(1,3]dioxolan-2-yl-ethyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one

O-fert-butyl-oxIme (100.0 g, 222 mmol, 1 eq) in THF (1.0 L) was slowly added an aqueous solution of HCl (3 N, 1.0 L). The resulting yellow mixture was stirred at room température for 24 hours to give a thick yellow émulsion. After completion of the reaction (LC/MS), the reaction mixture was neutralized by addition of an aqueous saturated solution of NaHCOs and extracted with CH2CI2 (2 x 5.0 L). The combined organic extracts were washed with brine (2.0 L), dried 10 over magnésium sulfate, filtered and concentrated under vacuum to yield 89 g of the title compound as a yellow solid. The resulting yellow solid was taken crude to the next step without further purification.

Yield: 92%

LC/MS: Mass found (m/z, M+1,407.3), Area 91%.

’H NMR (CDCh, 400MHz) δ 9.79 (s, 1H), 9.09 (s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.67 (s. 1H), 7.52 (d, J 5.4 Hz, 1H), 7.43 (d, J 5.4 Hz, 1H), 7.17 (m, 2H), 2.93 (m, 2H). 2.77 (s, 2H), 1.37 (s, 20 9H).

Step 6: 6-(3-Morpholin-4-yi-propyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl oxlme (7)

To a mixture of 3-(4-tert-butoxyimino-(2-thieno[3,2-c]pyridin-6-yl)'4H-chromen-6-yl)18597 propionaldéhyde (100.0 g, 246 mmol, 1 eq), morpholine (50 mL, 492 mmol, 2 eq) in CH2CI2 (1.0 L) and Methanol (500 mL) was added sodium triacetoxyborohydride (104 g, 492 mmol, 2eq) under N₂ atmosphère. The reaction mixture was stirred at room température for 3 hours. After completion of the reaction by LC/MS, the mixture was neutralized by addition of an aqueous saturated solution of NaHCOj and extracted with CH2CI2 (2 x 5.0 L). The combined organic extracts were washed with brine (2.0 L), dried over sodium sulfate, filtered and concentrated under vacuum to afford a thick brown solid. The resulting crude brown solid was purified by chromatography on silica gel to afford 73.0 g of the title compound as a yellow solid.

Yield: 63%.

HPLC: 95.97% (254 nm).

LC/MS: Mass found (m/z, M+1,478.3), Area 96.62%.

’H NMR (DMSO-de, 400MHz) δ 9.24 (s, 1H). 8.74 (s, 1H), 8.03 (d, J 5.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J 5.4 Hz, 1 H). 7.59 (m, 1H), 7.39 (m, 2H), 3.56 (m, 4H), 2.65 (m, 2H), 2.28 (m, 6H), 1.73 (m, 2H), 1.36 (s, 9H).

Step 7:6-(3-Morpholîn-4-yl-propy1)-2-(thieno[3,2-c]pyridln-6-yl)-4H-chromen-4-one oxime

	N(OH)
0^

	u

To a stirred solution of 6-(3-morpholin-4-yl-propyl)-2-(thîeno[3,2-c]pyridin-6-yl)-4H-chromen-4one O-tert-butyl oxime (10.0 g, 21 mmol, 1 eq) in acetic acid (100 mL) was added a solution of dîoxane-HCI (4 M, 150 mL, 3 eq) at room température under inert atmosphère. The reaction mixture was heated at 80^eC for 14 hours (LC/MS monitoring indicated 100% conversion). The organic solvents were concentrated under vacuum where a solid mass started to precipitate. The yellow solid was filtered off, washed with dioxane (200 mL), EtzO (2 x 50 mL) to afford 8 g of a yellow solid as a HCl sait.

Yield: 90%

HPLC purity: 98.44% (254 nm). E/Z ratio = 97.54 % /1.75%.

LC/MS: Mass found (m/z, M+, 422.3), Area 97.3%.

’H NMR (DMSO, 400MHz) δ 11.06 (brs, 1H), 10.72 (brs, 1H), 9.28 (s, 1H), 8.80 (s, 1H), 8.07 (d, J 5.4 Hz, 1H), 7.76-7,70 (m, 3H), 7.47-7.41 (m, 2H), 3.95 (m, 2H), 3.80 (m, 2H), 3.42, (m, 2H), 3.08 (m, 4H), 2.71 (m, 2H), 2.10 (m, 2H).

Example 2: Blologlcal évaluation of the compound of formula (I)

The compound of formula (I) according to the Invention (i.e., PXT002331) was tested for its agonistlc and/or positive allosteric modulator activity on human mGluR4 using the calcium assay described in Example 171 of WO 2011/051478. PXT002331 was found to hâve a potency of pECso = 7.12 (corresponding to an EC50 of about 0.076 pM), which Is comparable to that of the compoud of Example 127 of WO 2011/051478 (i.e., PXT001858) which has a pECw of 7.44 (corresponding to an EC50 of about 0.036 pM).

cLogP4.18

rr 0·^	,OH
	'S
	y
	PXTOO2331 pEC50 = 7.12 cLogP4.91	s-^

PSA 95

PSA 105

The in vitro ADME profile of PXT002331 was also very similar with reference to phase I metabolic stability: CL (h/r): 55/101 pl/min/mg protein and Intestinal absorption: CaCo-2 (A-B, pgp): 4.11 .10-6 cm/s, noefflux.

In both cases, l.e. PXT002331 and PXT001858, plasma protein binding was high with less than 1% of free fraction and compounds do not suffer from a lack of solubility (s > 10 mg/ml In water) as hydrochloride sait.

However, despite very similar physico-chemical propertîes and ADME profiles, PXT002331

was found to show an unexpected, highly advantageous oral in vivo PK profile when compared to PXT001858, as described In the following.

In vivo pharmacokînetics évaluation:

PXT002331 and ΡΧΤ001Θ58 were administered per os (p.o.) at 10 mg/kg to male SpragueDawley rats. Volume of administration was 10 ml/kg. In parallel, PXT002331 was also administered intravenously (i.v.) at 1 mg/kg, with a volume of administration of 2 ml/kg. Blood sampies (200 pi) were collected at time ranging from 15 minutes to 24 hours for the p.o.

administration and from 5 minutes to 24 hours for the I.v. administration In ice-cold tubes containing 0.2% K2EDTA. Tubes were centrifuged at 10,000 rpm for 5 minutes at 4^eC. The plasma (supematant) was separated In another tube and stored at -80*C until analysis. Two groups of 3 animais were used for each route of administration: in one group, blood sampies were collected to détermine the kinetics of plasma exposure over a 24-hour period, and in the 15 second group, blood and brain were collected at one terminal time point (0.5,1.0,1.5, 2.0, 4.0 hours) to détermine the kinetics of brain exposure and brain/plasma ratio.

Compound analysis:

The respective parent compound (free base) was analysed in plasma sampies and in brain homogenate using a LC-MS/MS method. Concentrations are expressed in ng/ml of plasma or in ng/g of brain tissue,

Results:

At 10 mg/kg, using the same vehicle (Tween-80 / Ethanol / 30% HPBCD (2/10/88)), PXT002331 showed a comparable plasma exposure than PXT001858 as reflected by its AUC (1,1-fold) and Cmax (0.7-fold). Oral bioavailability of PXT002331 in this experiment was 39%. Despite their similar oral absorption, PXT002331 has a higher brain/plasma ratio (6.5 versus 30 2.0 at T=1.5 h; see Figure 4) ieading to a 3-fold Improvement in the brain AUC when compared to ΡΧΤ00185Θ. A posteriori, one potential hypothesls might rely on the différence of phase II conjugation in the intestine and liver during oral absorption. When both compounds were assayed in vitro in the presence of UGT (UDP-Glucuronosyl transferase), PXT002331 showed a much lower level of glucuronldation as compared to ΡΧΤ001Θ5Θ (see table below). 35 Nonetheless, this différence observed In vitro cannot by itself explain the unexpected advantageous PK results obtained with PXT002331. The results obtained in these experiments are furthermore summarized In Tables 1 to 3 below and in Figures 1 to 4.

Oral PK 10mpk	Brain/Plasma ratio (T=1.5 h)	Cmax (Brain) (ng/G tissue)	Piasma AUC inf(h*ng/ml)	Brain AUC lnf(h*ng/g)
PXT002331	6.5	818	432	2713
PXT001858	2.0	521	394	838

Table 1: PK parameters of PXT002331 and PXT001858 after oral administration in rats at mg/kg.

Time (min)	0	5
PXT002331	0	0
PXT001858	0	164

15	30	60
0	0	0
353	798	2 556

Table 2: PXT002331 and PXT001858 in vitro glucuronidation (peak area) In rat liver microsomes.

Time (min)	5	15	30	60
PXT002331	2 492	4 724	8 369	16 897
PXT001858	13 840	30 396	68 072	14 8307

Table 3: PXT002331 and PXT001858 In vitro glucuronidation (peak area) in rat Intestinal microsomes.

These résulte demonstrate that the compound of formula (I) according to the présent Invention,

I.e. PXT002331, has highly advantageous pharmacokinetic properties and shows a considérably improved brain exposure as compared to the compound of Example 127 of WO 2011/051478 (PXT001858). These properties render the compound of formula (I) particularly suitable as a therapeutic agent, e.g., for the treatment or prévention of neurologicai and/or psychiatrie disorders.

Example 3: In vivo évaluation of the compound of formula (I) In an MPTP monkey mode! of Parkinson’s disease

The anti-parkinsonian efticacy of the compound of formula (I) according to the présent invention (I.e., PXT002331) was evaluated In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque mode! of Parkinson’s disease (using macaques of the species Macaca fasdeuiaris), which reproduces most of the clinical and pathological hallmarks of Parkinson’s disease and Is considered a “gold standard (see Porras G et al., Coid Spring Harb Perspect

Med._t 2(3):a009308, 2012 and référencés cited therein for a general description of the MPTP model).

The results of the studîes performed in a MPTP macaque model of advanced stages of PD are 5 summarized in Figures 5A to 5G. In particular, it was found that PXT002331 as a stand-alone treatment shows potent anti-parkinsonian activity in MPTP-treated macaques, with an optimal improvement of the parkinsonlan score at administration doses of 2 to 25 mg/kg perorally (p.o.) twice a day (see Figure 5A). In this experiment, PXT002331 was orally administered twlce a day during a period of 4 days, and the parkinsonlan score was assessed at day 4 over 2 hours 10 of observation (data are mean values + standard errer of the mean (s.e.m.); n = 7 monkeys).

The antl-parkinsonian efficacy of PXT002331 (25 mg/kg) was further evaluated in combination with low (suboptimal) doses of L-dopa (levodopa; 4-9 mg/kg) (see Figures 5B and 5C). In this model, levodopa methyl ester was administered sub-cutaneousfy together with a fixed dose of 15 benserazide (50 mg total), a peripherally-acting levodopa decarboxylase inhibitor. Doses of

PXT002331 were orally administered twice a day during 4 days, and assessment of parkinsonlan scores took place at day 4 (between 1 and 2 h after L-dopa administration, i.e., between 2 and 3 h after PXT002331 administration). As also shown in Figure 5B, it was found that the combined administration of PXT002331 and a suboptimal dose of L-dopa gave a 20 considérable improvement in parkinsonlan score as compared to the administration of L-dopa (suboptimal dose) alone. These data furthermore point to an increase of the on'-time achieved by PXT002331 in combination with L-dopa, which is a cllnically hlghly relevant advantage, as also reflected by the fact that “on-time* Is an endpoint for the assessment of clinical efficacy in phase 3 in Parkinson's disease patients. Remarkabfy, ail treated monkeys 25 showed a signifîcant improvement in parkinsonlan score, which indicates a high robustness of the anti-parklnsonlan effect of PXT002331 (see Figure 5C). These results confirm that PXT002331 can advantageously be used as an add-on treatment together with L-dopa (levodopa).

The results of a dose-response évaluation of the combination of PXT002331 (at doses from 2 mg/kg to 100 mg/kg) with L-dopa (low dose) are shown in Figure 5D (the assessment of parkinsonian scores took place at day 4). It was found that PXT002331 in combination with L-dopa provides a hlghly potent anti-parklnsonian effect upon oral administration over a range of different doses. The optimal anti-parkinsonian efficacy was achieved with administration 35 doses of PXT002331 of 2 mg/kg to 25 mg/kg.

A slgnificant improvement in locomotor activity could further be demonstrated for PXT002331

(25 mg/kg) administered orally in combination with either a low dose of L-dopa or an optimal dose of L-dopa, as also shown in Figure 5E (early stage PD monkey model; N = 5). In this model, levodopa was administered orally as Madopar which contains benserazide hydrochloride (4:1 ratio of levodopa:benserazide), a peripherally-acting levodopa decarboxylase inhibitor. In this experiment, each monkey was equipped with a detector of movements and signais were collected with 24 light beams and a video track recorder In order to descriminate ail types of movements. The movements of each monkey were quantified every 5 min using computer-based activity monitors. Total values are presented over 4 hours. The advantageous effect on locomotor activity achieved by PXT002331 in combination with 10 L-dopa was robust since each and every monkey included in the study responded to this treatment (see Figure 5G).

As shown in Figure 5F, it was fùrthermore found that increasing doses of PXT002331 In combination with L-dopa (optimal dose) provided an improvement in the disability score, 15 without inducing dyskinesia. A particularly advantageous improvement in the disability score could be achieved using 25 mg/kg PXT002331 In combination with L-dopa (optimal dose). Moreover, none of the tested combinations of PXT002331 (at doses from 25 mg/kg to 100 mg/kg) with an optimal (high) dose of L-dopa resulted In any induction of dyskinesia, which is an undesîrable adverse effect that typically occurs during treatment with L-dopa.

'

These findings confirm that PXT002331 Is highly advantageous for use in the treatment or prévention of Parkinson’s disease, both in monotherapy (without the concomitant use of further antiparkinson drugs) and in cotherapy using further antlparkinson drugs such as L-dopa (levodopa). In these experiments, doses of 2 mg/kg to 25 mg/kg of PXT002331, to be orally 25 administered, were found to be particularly efficacious.

Example 4: Assessment of the side effects of the compound of formula (I) In MPTP macaque models of Parkinson’s disease

Adverse events and side effects of PXT002331 were analyzed during each study performed in macaques (see Example 3).

General behavior

PXT002331 alone or with L-DOPA never Induced any apparent adverse change In behavior (neither circling, nor excitement, lethargy, sleepiness, etc.). Thus, these treatments, even at

high doses, are well tolerated by ail tested MPTP macaques, which benefit from an enhaneed anti-parkinsonian response, without any apparent adverse effect.

Cognitive performance

Monkeys that receive chronic low doses of MPTP administration (CLD MPTP macaque model) develop cognitive impairment, as measured in the Variable Delayed Response (VDR) task. It was therefore decided to evaluate the cognitive impact of PXT002331 in these animais, In order to assess potential side effects on cognitive symptoms.

Whether global performances were considered, or each delay separately, or ail the delays simultaneously, none of the treatments with PXT002331, alone or in combination with L-DOPA, in duce d any worsentng of the cognitive performances of the animais, as also shown in Figure 6.

In summary, none of the treatments with PXT002331 had a négative impact on cognitive performance of macaques (by contrast with L-DOPA for example). Moreover, it Is noteworthy that for one out of the four animais tested, PXT002331 even had a bénéficiai effect on its cognitive performance in the VDR task. This animal displayed almost 100% of omissions after 20 administration of an optimal dose of L-DOPA (worse cognitive performance). Its omission rate decreased by half when PXT002331 (25 mg/kg) was added to the optimal dose of L-DOPA treatment and its percentage of correct responses increased accordingly (see Figure 7).

Dyskinesia

Administration of PXT002331 alone or in combination with L-DOPA never induced dyskinesia.

Indeed, following administration of PXT002331 alone or in combination with any doses of L-DOPA tested, there was no induction of dyskinesia in the CLD MPTP macaques. It has to be noted that even L-DOPA alone did not induce dyskinesia in this model of earty stage PD (see 30 Figure 8, left half).

In the model of more advanced stages of PD, PXT002331 alone did not induce dyskinesia at any of the doses tested. Dyskinesia were weak or absent at sub-optimal doses of L-DOPA and were not increased by PXT002331 treatment (at any dose tested), as also shown in Figure 8 35 (right half). In these animais, even with the highest doses of L-DOPA, dyskinesia were very mild, as shown by the low mean dyskinesia score (see Figure 8, right half). It was decided to test the effects of PXT002331 on L-DOPA-induced dyskinesia in animais in a more advanced stage, presenting more pronounced dyskinesia, as described in Example 5.

Example 5: Assessment of the antl-dysklnetlc efflcacy of the compound of formula (I) In MPTP macaque modela of L-DOPA-Induced dyskinesia (LID)

Like PD patients, MPTP macaques expérience side effects of their long-term L-DOPA therapy, including L-DOPA-induced dyskinesia (LID). This was the case with the MPTP macaques that were at an advanced stage of parkinsonism used in this experiment. PXT002331 was tested in these monkeys, using the dose of 25 mg/kg in combination with L-DOPA.

Notably, a clear réduction of dyskinesia was observed in the presence of PXT002331 (see Figure 9A). This was observed for both the administration of PXT002331 30 min before or at the same time as L-DOPA. Moreover, this was observed as early as day 1, which corresponds to an acute administration of PXT002331, and is maintained after a sub-chronic treatment (twice daily for 8 consecutive days). Importantly, the efflcacy of L-DOPA for reducing parkinsonian symptoms (tremor, posture, mobility) was maintained in association with PXT002331 dose, as shown in Figure 9B.

As with the anti-parkinsonian effect measured in Examples 3 and 4, it has to be noted that the anti-dyskinetic effect of PXT002331 was very robust since, again, each and every dyskinetic monkey included in the study responded to this treatment (see Figure 10).

These results show that the compound of formula (I), I.e. PXT002331, is highly effective in the prévention or réduction of levodopa-lnduced dyskinesia (LID), as demonstrated in the MPTP macaque model of LID. Moreover, PXT002331 can be used either as an acute or a chronic médication against levodopa-lnduced dyskinesia, which rentiers It particularfy suitable for the treatment or prévention of this pathological condition.

Claims

1. A compound of the following formula (I):

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, 10 for use in the treatment or prévention of levodopa-induced dyskinesia. 2. The compound for use according to claim 1, wherein said compound has the (E)-configuration at the oxime group comprised In formula (I). 15 3. The compound for use according to claim 1 or 2, wherein said compound is in the form of a hydrochloride sait. 20 4. A pharmaceutical composition comprising a compound as defined in any one of daims 1 to 3 and a pharmaceutically acceptable excipient for use in the treatment or prévention of levodopa-induced dyskinesia. 5. The compound for use according to any one of daims 1 to 3 or the pharmaceutical composition for use according to claim 4, wherein said compound or said pharmaceutical composition is to be administered orally.

A compound of the following formula (I):

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, for use In the treatment or prévention of Parkinsoris disease,

10 wherein said compound is to be administered in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

7. The compound for use according to claim 6, wherein the compound of formula (I) has the (E)-configuration at the oxime group comprised In formula (I).

8. The compound for use according to claim 6 or 7, wherein the compound of formula (I) Is In the form of a hydrochloride sait.

9. A pharmaceutical composition comprising a compound of formula (I) or a

2 0 pharmaceutically acceptable sait, solvaté or prodrug thereof as defined in any one of claims 6 to 8, and a pharmaceutically acceptable excipient, for use in the treatment or prévention of Parkinson’s disease, wherein the pharmaceutical composition is to be administered in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

10. Levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof for use In the treatment or prévention of Parkinson’s disease, wherein said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof is to be administered in combination with a compound of the following formula (I):

_r or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

11. The levodopa for use according to claim 10, wherein the compound of formula (I) has the (E)-configuration atthe oxime group comprised in formula (I).

12. The levodopa for use according to claim 10 or 11, wherein the compound of formula

10 (I) is in the form of a hydrochloride sait.

13. A pharmaceutical composition comprising levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof, and a pharmaceutically acceptable excipient, for use in the treatment or prévention of Parkinson’s disease, wherein the pharmaceutical

15 composition is to be administered in combination with a compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof as defined in any one of claims 10to 12.

14. The compound for use according to any one of claims 6 to 8 or the levodopa for use

20 according to any one of claims 10 to 12 or the pharmaceutical composition for use according to claim 9 or 13, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered slmultaneously.

15. The compound for use according to claim 14 or the levodopa for use according to claim 14 or the pharmaceutical composition for use according to claim 14, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug

3 0 thereof are provided in a single pharmaceutical composition.

16.

The compound for use according to claim 14 or the levodopa for use according to claim

14 or the pharmaceutical composition for use according to claim 14, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are provided in separate pharmaceutical compositions.

17. The compound for use according to any one of daims 6 to 8 or the levodopa for use according to any one of daims 10 to 12 or the pharmaceutical composition for use according to claim 9 or 13, wherein said compound of formula (I) or the r

pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered sequentially.

18. The compound for use according to any one of daims 6 to 8 and 14 to 17 or the levodopa for use according to any one of daims 10 to 12 and 14 to 17 or the pharmaceutical composition for use according to any one of daims 9 and 13 to 17, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered orally.

19. A pharmaceutical composition for use in the treatment or prévention of Parkinson’s disease, wherein the pharmaceutical composition comprises:

- a compound of the following formula (I)

N(OH) cr T T 1 n Tl s— (l)

or a pharmaceutically acceptable sait, solvaté or prodrug thereof;

- levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof; and

- a pharmaceutically acceptable excipient.

20. The pharmaceutical composition for use according to claim 19, wherein the compound of formula (I) has the (E)-configuration at the oxime group comprised in formula (I).

21. The pharmaceutical composition for use according to claim 19 or 20, wherein the compound of formula (I) is in the form of a hydrochloride sait.

22. The pharmaceutical composition for use according to any one of daims 19 to 21, wherein said pharmaceutical composition is to be administered orally.

23. The compound for use according to any one of daims 6 to 8 and 14 to 18 or the levodopa for use according to any one of daims 10 to 12 and 14 to 18 or the t f pharmaceutical composition for use according to any one of daims 9 and 13 to 22, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered ln combination with a levodopa decarboxylase inhibitor and/or a catechol-O-methyl transferase (COMT) inhibitor.

24. The compound for use according to claim 23 or the levodopa for use according to claim 23 or the pharmaceutical composition for use according to claim 23, wherein both a levodopa decarboxylase inhibitor and a COMT Inhibitor are to be administered.

25. The compound for use according to claim 23 or 24 or the levodopa for use according to claim 23 or 24 or the pharmaceutical composition for use according to claim 23 or 24, wherein the levodopa decarboxylase inhibitor is carbidopa, benserazide, a-methyldopa, α-difluoromethyldopa, or a pharmaceutically acceptable sait or solvaté of any one of these agents.

26. The compound for use according to any one of daims 23 to 25 or the levodopa for use according to any one of daims 23 to 25 or the pharmaceutical composition for use according to any one of daims 23 to 25, wherein the COMT inhibitor is entacapone, tolcapone, nltecapone, opicapone, or a pharmaceutically acceptable sait or solvaté of any one of these agents.

27. The compound for use according to any one of daims 1 to 3, 5 to 8,14 to 18 and 23 to 26 or the levodopa for use according to any one of daims 10 to 12,14 to 18 and 23 to 26 or the pharmaceutical composition for use according to any one of daims 4,5,9 and 13 to 26, wherein the subject to be treated is a human.

28. Use of a compound of the following formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, for the préparation of a médicament for the treatment or prévention of levodopa-lnduced dyskinesia.

29. The use of claim 28, wherein said compound has the (E)-configuration at the oxime

10 group comprised in formula (I).

30. The use of claim 28 or 29, wherein said compound is in the form of a hydrochloride sait.

15 31. The use of any one of claims 28 to 30, wherein said médicament is for oral administration.

32. Use of a compound of the following formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof, for the préparation of a médicament for the treatment or prévention of Parkinson’s disease, wherein said médicament Is to be administered in combination with levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

33. Use of levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof for the préparation of a médicament for the treatment or prévention of Parkinson’s disease, wherein said médicament ts to be administered ln combination with a 5 compound of the following formula (I)

10 or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

34. The use of claim 32 or 33, wherein the compound of formula (I) has the (E)-configuration at the oxime group comprised ln formula (I).

15 35. The use of any one of daims 32 to 34, wherein the compound of formula (I) is in the form of a hydrochloride sait.

36. The use of any one of daims 32 to 35, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the

20 pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered simultaneously.

37. The use of claim 36, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically

25 acceptable sait, solvaté or prodrug thereof are provided ln a single médicament.

38. The use of claim 36, wherein said compound of formula (1) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are provided in separate médicaments.

39. The use of any one of daims 32 to 35, wherein said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof are to be administered sequentially.

40. The use of any one of claims 32 to 39, wherein the medicament(s) comprising said compound of formula (I) or the pharmaceutically acceptable sait, solvaté or prodrug thereof and said levodopa or the pharmaceutically acceptable sait, solvaté or prodrug thereof is/are for oral administration.

41. Use of a first compound and a second compound for the préparation of a médicament for the treatment or prévention of Parkinson’s disease, wherein said first compound is a compound of the following formula (I)

N(OH) cr m O s—!/ (D

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, and wherein said second compound is levodopa or a pharmaceutically acceptable sait, solvaté or prodrug thereof.

42. The use of claim 41, wherein the compound of formula (I) has the (E)-configuration at the oxime group comprised in formula (I).

43. The use of claim 41 or 42, wherein the compound of formula (I) is in the form of a hydrochloride sait.

44. The use of any one of claims 41 to 43, wherein said médicament is for oral administration.

45. The use of any one of claims 32 to 44, wherein said medicament(s) is/are to be administered in combination with a levodopa decarboxylase inhibitor and/or a catechol18597

O-methyl transferase (COMT) ïnhibitor. R 46. The use of claim 45, wherein said medicament(s) is/are to be administered in combination with a levodopa decarboxylase inhibitor and with a COMT inhibitor. □ 47. The use of claim 45 or 46, wherein the levodopa decarboxylase inhibitor is carbidopa, benserazide, α-methyldopa, α-difluoromethyldopa, or a pharmaceutically acceptable sait or solvaté of any one of these agents. 10 48/ The use of any one of claims 45 to 47, wherein the COMT inhibitor is entacapone, tolcapone, nitecapone, opicapone, or a pharmaceutically acceptable sait or solvaté of any one of these agents. 49. The use of any one of claims 28 to 48, wherein said medicament(s) is/are for 15 administration to a human.