US20200171042A1

US20200171042A1 - Brain-penetrant chromone oxime derivative for the therapy of levodopa-induced dyskinesia

Info

Publication number: US20200171042A1
Application number: US16/709,988
Authority: US
Inventors: Delphine CHARVIN; François CONQUET
Original assignee: Prexton Therapeutics SA
Current assignee: Prexton Therapeutics SA
Priority date: 2015-08-27
Filing date: 2019-12-11
Publication date: 2020-06-04
Also published as: ZA201801642B; HRP20192250T1; KR20180041234A; DOP2018000060A; LT3341380T; ES2764490T3; RS59651B1; US10532057B2; CA2995313A1; EP3341380A1; HUE047531T2; AU2016313138A1; MX2018002255A; MA42700B1; PH12018500430A1; US20180271874A1; PL3341380T3; ME03591B; CN108349993A; WO2017032874A1

Abstract

The present invention provides a chromone oxime derivative of formula (I), which is a modulator of nervous system receptors sensitive to the neuroexcitatory amino acid glutamate and presents an advantageously high brain exposure upon oral administration, for the treatment or prevention of levodopa-induced dyskinesia. The present invention also provides an improved therapy of Parkinson's disease, using the chromone oxime derivative of formula (I) in combination with levodopa.

Description

The present invention provides a chromone oxime derivative 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 presents an advantageously high brain exposure upon oral administration, for the treatment or prevention of levodopa-induced dyskinesia. The present invention also provides an improved therapy of Parkinson's disease, using the chromone oxime derivative of formula (I) in combination with levodopa.
It is known that glutamate is involved in numerous nervous functions. Important roles are therefore attributed to glutamatergic receptors, in particular as regards the conduction of nerve impulse, synaptic plasticity, the development of the nervous system, learning 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 clearly considered to be involved in various disorders of the nervous system and neurodegenerative diseases.
The glutamatergic system includes glutamate receptors and transporters as well as enzymes of glutamate metabolism. Two main types of glutamatergic receptors have been characterized: ionotropic (iGluRs) and metabotropic (mGluRs) receptors. Ionotropic glutamate receptors have been identified based on their pharmacology and subsequently through molecular biology. The iGluR family includes the NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and the kainate receptor subfamilies, so named for the chemical agonist that selectively binds to the subfamily members. iGluRs are voltage-gated ion channels that allow cation influx upon glutamate binding. They are directly responsible for the generation of action potentials, they initiate neuroplastic changes in the CNS and are responsible for many diseases, including chronic pain. Metabotropic glutamate receptors are a family of seven transmembrane domain G-protein-coupled receptors (GPCR). So far, eight mGluR subtypes have been identified (mGluR1-mGluR8) and classified into three groups (I-III) based upon sequence homology, transduction mechanism and pharmacological profile. mGluRs belong to family 3 of the GPCR superfamily, and as such, they are characterized by a large extracellular amino terminal domain where the glutamate binding site is located. mGluRs are localized throughout the nervous system (central and peripheral) and have been shown to play a role in homeostasis in many organ systems. They have been found to play an important role in particular in the induction of the long-term potentiation (LTP) and the long-term depression (LTD) of synaptic transmission, in the regulation of baroceptive reflexes, spatial learning, motor learning, postural and kinetic integration, and are considered to be involved in acute or chronic degenerative diseases such as Parkinson's disease, levodopa-induced dyskinesia, Alzheimer's disease, Amyotrophic Lateral Sclerosis, spinocerebellar ataxia, epilepsy or Huntington's disease, as well as neuropsychiatric disorders such as anxiety, depression, 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 Amyotrophic Lateral Sclerosis (Mattson M P., 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-induced neurotoxicity, for example neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons, could actually be mediated by over-stimulation of the glutamate receptors (Stephans S E and Yamamoto B K, Synapse 17(3), 203-9, 1994). Antidepressant and anxiolytic-like effects of compounds acting on glutamate have also been observed on mice, suggesting that glutamatergic transmission is implicated in the pathophysiology of affective disorders such as depression, bipolar disorder, schizophrenia, anxiety, Autism Spectrum Disorders and other neurodevelopmental disorders (Palucha A et al., Pharmacol. Ther. 115(1), 116-47, 2007; Cryan J F et al., Eur. J. Neurosc. 17(11), 2409-17, 2003; Conn P J et al., Trends Pharmacol. Sci. 30(1), 25-31, 2009; Nurnberger J I et al., JAMA Psychiatry 71:657-664, 2014; Narayanan B et al., Transl Psychiatry 5:e588, 2015; Chiocchetti A G 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 signalling or function would constitute a promising therapeutic compound for many disorders of the nervous system.
Moreover, compounds modulating glutamate level or signalling may be of great therapeutic value for diseases and/or disorders not directly mediated by glutamate levels and/or glutamate receptors malfunctioning, but which could be affected by modification of glutamate levels or signaling.
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 participates in all functions of the nervous system and affects nervous system development at all stages, from neuron migration, differentiation and death to the formation and elimination of synapses. Glutamate is ubiquitously distributed at high concentrations in the nervous system and is involved in virtually all physiological functions, such as learning and memory, motor control, development of synaptic plasticity, sensory perception, vision, respiration and regulation of cardiovascular function (Meldrum, 2000). Abnormalities in the glutamatergic system are known to incur neurotoxicity and other deleterious effects on neurotransmission, neuroenergetics, and cell viability. Accordingly, a considerable number of studies have been conducted to investigate the potential association between the glutamatergic system and neurological or psychiatric disorders.
Glutamate operates through two classes of receptors (Bräuner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000). The first class of glutamate receptors is directly coupled to the opening of cation channels in the cellular membrane of the neurons. Therefore they are called ionotropic glutamate receptors (iGluRs). The iGluRs are divided into three subtypes, which are named according to their selective agonists: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainate (KA). The second class of glutamate receptors consists of G-protein-coupled receptors (GPCRs) called metabotropic glutamate receptors (mGluRs). These mGluRs are localized both pre- and post-synaptically. They are coupled to multiple second messenger systems and their role is to regulate the activity of the ionic channels or enzymes producing second messengers via G-proteins binding the GTP (Conn P J and Pin J P., Annu. Rev. Pharmacol. Toxicol., 37, 205-37, 1997). Although they are generally not directly involved in rapid synaptic transmission, the mGluRs modulate 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 role in a variety of physiological processes such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, regulation of baroreceptive reflexes, spatial learning, motor learning, and postural and kinetic integration.
To date, eight mGluRs have been cloned and classified in three groups according to their sequence homologies, pharmacological properties and signal transduction mechanisms. Group I includes mGluR1 and mGluR5, group II mGluR2 and mGluR3 and group III mGluR4, mGluR6, mGluR7 and mGluR8 (Pin J P and Acher F., Curr. Drug Targets CNS Neurol. Disord., 1(3), 297-317, 2002; Schoepp D D 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 Bräuner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000 for review). The first family consists in orthosteric ligands (or competitive ligands) able to interact with the glutamate binding-site of the mGluRs, which is localized in the large extra-cellular 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 II 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 T M 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 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., Neuropharmacology, 45(7), 895-903, 2003; Mathiesen J M 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 C M et al., Mol. Pharmacol. 74(5), 1345-58, 2008; Niswender C M 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 D W et al., J. Med. Chem. May 27, 2009) and in two patent publications describing families of amino and heteroaromatic compounds (WO 2009/010454 and WO 2009/010455).
Numerous studies have 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 review). For instance, antagonist compounds of group I mGluRs showed interesting results in animal models for anxiety and post-ischemic neuronal injury (Pilc A et al., Neuropharmacology, 43(2), 181-7, 2002; Meli E et al., Pharmacol. Biochem. Behav., 73(2), 439-46, 2002), agonists of group II mGluRs showed good results in animal models for Parkinson and anxiety (Konieczny J et al., Naunyn-Schmiederbergs Arch. Pharmacol., 358(4), 500-2, 1998).
Group III mGluR modulators showed positive results in several animal models of schizophrenia (Palucha-Poniewiera A et al., Neuropharmacology, 55(4), 517-24, 2008) and chronic pain (Goudet C et al., Pain, 137(1), 112-24, 2008; Zhang H M et al., Neuroscience, 158(2), 875-84, 2009).
Group III mGluR were also shown to exert the excitotoxic actions of homocysteine and homocysteic acid contributing to the neuronal pathology and immunosenescence that occur in Alzheimer Disease (Boldyrev A A and Johnson P, J. Alzheimers Dis. 11(2), 219-28, 2007).
Moreover, group III mGluR modulators showed promising results in animal models of Parkinson's disease and neurodegeneration (Conn P J et al., Nat. Rev. Neuroscience, 6(10), 787-98, 2005 for review; Vernon A C et al., J. Pharmacol. Exp. Ther., 320(1), 397-409, 2007; Lopez S et al., Neuropharmacology, 55(4), 483-90, 2008; Vernon A C et al., Neuroreport, 19(4), 475-8, 2008; Williams C J et al., J. Neurochem., 129(1), 4-20, 2014 for review). It was further demonstrated with selective ligands that the mGluR subtype involved in these antiparkinsonian and neuroprotective effects was mGluR4 (Marino M J et al., Proc. Natl. Acad. Sci. USA 100(23), 13668-73, 2003; Battaglia G et al., J. Neurosci. 26(27), 7222-9, 2006; Niswender C M et al., Mol. Pharmacol. 74(5), 1345-58, 2008). A combination treatment using a specific mGluR4 positive allosteric modulator, Lu AF21934, and L-DOPA was furthermore examined in hemiparkinsonian rats (Bennouar K E 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 opiod receptor null mice, a novel animal model of Autism Spectrum Disorders (Becker J A et al., Neuropsychopharmacology 39(9):2049-60, 2014). Therefore, mGluR4 modulators have a potential role for the treatment of ASD.
In addition, mGluR4 were also shown to be involved in glucagon secretion inhibition (Uehara S., Diabetes 53(4), 998-1006, 2004). Therefore, orthosteric or positive allosteric modulators of mGluR4 have potential for the treatment of type 2 diabetes through its hypoglycemic effect.
Moreover, mGluR4 was shown to be expressed in prostate cancer cell-line (Pessimissis N et al., Anticancer Res. 29(1), 371-7, 2009) or colorectal carcinoma (Chang H J et al., Cli. Cancer Res. 11(9), 3288-95, 2005) and its activation with PHCCC was shown to inhibit growth of medulloblastomas (Iacovelli L et al., J. Neurosci. 26(32) 8388-97, 2006). mGluR4 modulators may therefore have also potential role for the treatment of cancers.
Finally, receptors of the umami taste expressed in taste tissues were shown to be variants of the mGluR4 receptor (Eschle B K., Neuroscience, 155(2), 522-9, 2008). As a consequence, 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 specific cyclopropachromencarboxylic acid derivatives which are said to have mGluR antagonistic activity.
A new class of ligands of metabotropic glutamate receptors is described in WO 2011/051478. The chromone oxime derivatives 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 prevention of acute and chronic neurological and/or psychiatric disorders.
Recently, it has surprisingly been found that a novel chromone oxime derivative 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 medicament against neurological disorders, including Parkinson's disease.
The treatment of Parkinson's disease (PD) has been revolutionized by the development of levodopa (i.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 virtually all PD patients. Even today, it is still the drug of choice, particularly in advanced stages of PD.
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 constitutes 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 J M et al. J Neural Transm. 2005; 112(3):359-91; and Fox S H & Brotchie J M (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 J A et al. Neurology. 2000; 55 (11 Suppl 4):S13-23) and affects almost all 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 have been made to manage levodopa-induced dyskinesia (Del Sorbo F et al. J Neurol. 2008; 255 Suppl 4:32-41; Tambasco N et al., Parkinsons 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 therapies of levodopa-induced dyskinesia.
In the context of the present invention, it was surprisingly found that the compound of formula (I), as described and defined below, is highly effective in the prevention and/or treatment of levodopa-induced dyskinesia, as also demonstrated in an MPTP monkey model (see Examples 3 and 5). The present invention thus solves the problem of providing novel and 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 (I) according to the present invention furthermore shows highly beneficial pharmacokinetic properties, particularly in terms of brain penetration (see Example 2).
The present invention thus provides a compound of the following formula (I):
or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention of levodopa-induced dyskinesia. The invention further relates to a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in combination with a pharmaceutically acceptable excipient for use in the treatment or prevention of levodopa-induced dyskinesia. The compound of formula (I) is also referred to as “PXT002331” in this specification.
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 salt, solvate 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 prevention of levodopa-induced dyskinesia.
The present invention also relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment or prevention of levodopa-induced dyskinesia. Moreover, the invention provides a method of treating or preventing levodopa-induced dyskinesia, the method comprising administering the compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 further relates to the compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 prevention of levodopa-induced dyskinesia by exerting antidyskinetic activity.
Furthermore, the present invention relates to the treatment or prevention 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 levodopa treatment, as also demonstrated in Example 5. The combined administration of the compound of formula (I) with levodopa further allows to administer lower doses of levodopa while obtaining a comparable antiparkinsonian effect as with higher 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 reduction 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 antidyskinetic effect itself (see Example 5), which renders this compound highly advantageous for the treatment or prevention of Parkinson's disease in combination with levodopa.
The present invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention of Parkinson's disease, wherein said compound is to be administered in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof. Likewise, the invention relates to a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in combination with a pharmaceutically acceptable excipient for use in the treatment or prevention of Parkinson's disease, wherein said pharmaceutical composition is to be administered in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof.
The invention further relates to levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in the treatment or prevention of Parkinson's disease, wherein said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof is to be administered in combination with the compound of formula (I) according to the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof. The invention also relates to a pharmaceutical composition comprising levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient, for use in the treatment or prevention of Parkinson's disease, wherein the pharmaceutical composition is to be administered in combination with the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Moreover, the present invention provides a pharmaceutical composition for use in the treatment or prevention of Parkinson's disease, wherein the pharmaceutical composition comprises: (i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; (ii) levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof; and (iii) a pharmaceutically acceptable excipient.
The present invention furthermore relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment or prevention of Parkinson's disease, wherein said medicament is to be administered in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof. The invention also relates to the use of levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment or prevention of Parkinson's disease, wherein said medicament is to be administered in combination with the compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 salt, solvate or prodrug thereof in combination with levodopa or a pharmaceutically acceptable salt, solvate 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 present 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.
These improved pharmacokinetic properties render the compound of formula (I) highly advantageous as a pharmaceutical, particularly as a brain penetrant 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 present invention, the compound of formula (I) is useful as a brain penetrant modulator of mGluRs of the nervous system, particularly as a brain penetrant 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, particularly choreic, dystonic, athetoid and/or ballistic movements. Several different types of levodopa-induced dyskinesia have been described in PD patients, which are classified on the basis of their appearance in relation to the PD patient's on-off cycle (see, e.g., Fox S H & Brotchie J M (eds.), Levodopa-Induced Dyskinesia in Parkinson's Disease, Springer London, 2014). The present invention particularly relates to the treatment or prevention 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), off-period levodopa-induced dyskinesia, and diphasic levodopa-induced dyskinesia.
The scope of the invention embraces all pharmaceutically acceptable salt forms of the compound of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt 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 metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benetamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Exemplary acid addition salts comprise, for example, mineral 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, 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 salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compound of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I) is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt. More preferably, the compound of formula (I) is in the form of a hydrochloride salt. Even more preferably, the compound of formula (I) is in the form of a bishydrochloride monohydrate salt (i.e., ⋅2 HCl⋅H₂O).
Moreover, the scope of the invention embraces solid forms of the compound of the formula (I) in any solvated form, including e.g. solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol 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 solvates of the compound of the formula (I) also include solvates of a pharmaceutically acceptable salt of the compound of the formula (I).
Furthermore, the present invention embraces all possible isomers, including configurational 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 have the (E)-configuration or the (Z)-configuration at the oxime group (═N—OH) as shown below, and the present 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)-isomer and the (Z)-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-%, even more preferably at least 98 mol-%, and yet even more preferably at least 99 mol-% of the compound of formula (I) is present in the form of the (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 salt, solvate or prodrug thereof which is contained in the pharmaceutical composition of the present 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 (I).
Pharmaceutically acceptable prodrugs of the compound of the formula (I) are derivatives which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compound of the formula (I) which is pharmaceutically active in vivo. Prodrugs of the compound of the formula (I) may be formed in a conventional manner with a functional group of the compound, such as a hydroxy group. The prodrug derivative form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Such prodrugs include, e.g., an acyloxy derivative prepared by reacting the hydroxyl group of the compound of formula (I) with a suitable acylhalide or a suitable acid anhydride. An especially preferred acyloxy derivative as a prodrug is —OC(═O)—CH₃, —OC(═O)—C₂H₅, —OC(═O)—C₃H₇, —OC(═O)-(tert-butyl), —OC(═O)—C₁₅H₃₁, —OC(═O)—CH₂CH₂COONa, —O(C═O)—CH(NH₂)CH₃or —OC(═O)—CH₂—N(CH₃)₂. Accordingly, the pharmaceutically acceptable prodrug may be a compound of formula (I), wherein the oxime —OH group is in the form of an O-aryl-oxime (or acyloxy derivative) such as, e.g., —OC(═O)—CH₃, —OC(═O)—C₂H₅, —OC(═O)—C₃H₇, —OC(═O)-(tert-butyl), —OC(═O)—C₁₅H₃₁, —OC(═O)—CH₂CH₂COONa, —O(C═O)—CH(NH₂)CH₃or —OC(═O)—CH₂—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—C₂H₅, —O—C₃H₇or —O—(tert-butyl). The oxime —OH group of the compound of formula (I) may also be in the form of an O-dialkylphosphinyloxy such as —O—P(═O)—[O—(CH₃)₂], —O—P(═O)—[O—(C2-C₅)₂], —O—P(═O)—[O—(C₃-C₇)₂] or —O—P(═O)—[O-(tert-butyl)₂] or in the form of an O-phosphoric acid —O—P(═O)—(OH)₂or in the form of an O-sulfuric acid —O—SO₂—OH. Thus, the pharmaceutically acceptable prodrug according to the present invention is preferably a compound of formula (I), wherein the oxime —OH group is in the form of an O-acyl-oxime 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 present invention further embraces all pharmaceutically acceptable salt forms of levodopa, which may be formed, e.g., by protonation of the amino group comprised in levodopa with an inorganic or organic acid, or as a salt of the carboxylic acid group and/or of one or both of the hydroxy groups comprised in levodopa with a physiologically acceptable cation. Exemplary base addition salts comprise, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benetamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Exemplary acid addition salts comprise, for example, mineral 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, 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 salts such as aspartate or glutamate salts. A preferred pharmaceutically acceptable salt 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. solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol 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 solvates also include solvates of a pharmaceutically acceptable salt 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. Molecules. 2008; 13(1):46-68, Karaman R. Chem Biol Drug Des. 2011; 78(5):853-63, and the references cited therein. Typically, prodrugs of levodopa are chemically 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 prolonged pharmacological activity as compared to directly administered levodopa may be achieved. In 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 specific prodrug groups mentioned in the following), as well as pharmaceutically acceptable salts and solvates 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 —O—CO—(C_1-6alkyl), —O—CO—(C_2-6alkenyl), —O—CO—(C_0-4alkylene)-aryl, or —O—CO—(C_0-4alkylene)-heteroaryl, such as, e.g., —O—CO—CH₃, —O—CO—CH₂CH₃, —O—CO—CH(CH₃)₂, —O—CO—C(CH₃)₃, —O—CO—CH—CH₂C(CH₃)₃, —O—CO—CH₂CH(CH₃)₂, —O—CO—C(CH₃)₂CH₂CH₃, —O—CO—(n-butyl), —O—CO-hexenyl, —O—CO-phenyl, —O—CO-benzyl, or —O—CO—CH₂CH₂-phenyl. The carboxy group of levodopa may be in the form of a group —COO—(C_1-6alkyl), —COO—(C_2-6alkenyl), —COO—(C_0-4alkylene)-aryl, or —COO—(C_0-4alkylene)-heteroaryl, such as, e.g., —COO—CH₃, —COO—CH₂CH₃, —COO—CH(CH₃)₂, —COO—C(CH₃)₃, —COO—CH₂C(CH₃)₃, —COO—CH₂CH(CH₃)₂, —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—CO—(C_1-6alkyl), such as, e.g., —NH—CO—CH₃or —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). Glycosyl derivatives of levodopa can also be used. Furthermore, any one of the prodrugs referred to in Di Stefano A et al. Curr Pharm Des. 2011; 17(32)3487-93, Di Stefano A et al Molecules. 2008; 13(1):46-68, or Karaman R. Chem Biol Drug Des. 2011; 78(5):853-63, or a pharmaceutically acceptable salt or solvate thereof can also be used as a pharmaceutically acceptable prodrug of levodopa in accordance with the present invention. It is particularly preferred that the pharmaceutically acceptable prodrug of levodopa is selected from melevodopa, etilevodopa, XP21279, and pharmaceutically acceptable salts and solvates thereof.
The compound of formula (I), optionally in combination with levodopa, may be administered per se or may be formulated as a medicament. Within the scope of the present invention are pharmaceutical compositions comprising as an active ingredient the compound of the formula (I) as defined herein above. The pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, or antioxidants.
The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20^thEdition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral 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 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 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), parenteral (e. g., using injection techniques or infusion techniques, and including, for example, by injection, e.g. subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g. through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, and vaginal. It is particularly preferred that the compound of formula (I) according to the present invention or the pharmaceutical compositions of the invention are to be administered orally.
If said compound or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compound or the pharmaceutical compositions, and/or by using infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile 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, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The peroral 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, 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 magnesium stearate, stearic acid, glyceryl 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 elixirs, 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 water, ethanol, propylene glycol and glycerin, and combinations thereof.
Alternatively, 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 present invention may also 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 isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum,
For topical application to the skin, said compound or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
A proposed, yet non-limiting dose of the compound of formula (I) 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, of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. A further, particularly preferred dose of the compound of formula (I) for peroral 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 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 age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
The compound of formula (I) according to the invention can be administered in monotherapy for the treatment or prevention of levodopa-induced dyskinesia (e.g., without concomitantly administering any further therapeutic agents against levodopa-induced dyskinesia). However, for the treatment or prevention 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 prevention of levodopa-induced dyskinesia in combination with a second therapeutic agent active against this same condition, 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 sequential/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 present invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 prevention of levodopa-induced dyskinesia in a subject (preferably a human) that is taking levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof. The invention likewise relates to the compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 prevention of levodopa-induced dyskinesia, wherein said compound is to be administered in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of formula (I) (or the pharmaceutically acceptable salt, solvate or prodrug thereof) and levodopa (or the pharmaceutically acceptable salt, solvate or prodrug thereof) can be 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 described above, and are preferably both administered orally.
As described above, the present invention relates, in particular, to the treatment or prevention of Parkinson's disease, using the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof. The invention thus relates to the compound of formula (I) for use in the treatment or prevention 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 salt, solvate or prodrug thereof) and levodopa (or the pharmaceutically acceptable salt, solvate or prodrug thereof) can be administered 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 simultaneous administration, the compound of formula (I) and levodopa may be administered in the same pharmaceutical composition or in two different/separate pharmaceutical compositions. They may also be provided in two different/separate compartments of the 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 convenient route, as described above, and are preferably both administered orally.
The present invention also relates to the treatment or prevention of Parkinson's disease, using the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in combination with levodopa or a pharmaceutically acceptable salt, solvate 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 decarboxylation of levodopa by L-DOPA decarboxylase, i.e. a decarboxylation of levodopa before it crosses the blood-brain barrier in the patient's 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 decarboxylation of levodopa (L-DOPA) to dopamine and CO₂. Since levodopa is able to cross the blood-brain barrier, while dopamine is not, the peripheral decarboxylation of 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 beneficial 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-α-methyl-3,4-dihydroxyphenylalanine), α-difluoromethyldopa (also referred to as “difluromethyldopa” or “DFMD”), as well as pharmaceutically acceptable salts and solvates thereof. More preferably, the levodopa decarboxylase inhibitor is carbidopa, benserazide, or a pharmaceutically acceptable salt or solvate thereof (such as, e.g., carbidopa monohydrate or benserazide hydrochloride). Even more preferably, the levodopa decarboxylase inhibitor is carbidopa or a pharmaceutically acceptable salt or solvate thereof.
The administration of the compound of formula (I) and levodopa in combination with a catechol-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 methylation of levodopa into 3-methoxy-4-hydroxy-L-phenylalanine. This, in turn, results in an 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 solvates thereof. More preferably, the COMT inhibitor is entacapone, tolcapone, opicapone, or a pharmaceutically acceptable salt or solvate thereof. Even more preferably, the COMT inhibitor is entacapone or a pharmaceutically acceptable salt or solvate thereof.
It is particularly preferred that the compound of formula (I) (or a pharmaceutically acceptable salt, solvate or prodrug thereof) and levodopa (or a pharmaceutically acceptable salt, solvate or prodrug thereof) are administered in combination with both a levodopa decarboxylase inhibitor (preferably carbidopa) and a COMT inhibitor (preferably entacapone).
The (i) compound of formula (I) (or a pharmaceutically acceptable salt, solvate or prodrug thereof) and (ii) levodopa (or a pharmaceutically acceptable salt, solvate or prodrug thereof), together with (iii) a levodopa decarboxylase inhibitor and/or (iv) a COMT inhibitor, may be 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 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration). Alternatively, 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). In the case of simultaneous administration, the compound of formula (I) and levodopa as well 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 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 R A. Expert Rev Neurother. 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 L C 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 or more further therapeutic agents, other than or in addition to the levodopa decarboxylase inhibitors and the COMT inhibitors that have 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, ropinirole, rotigotine, ladostigil, lazabemide, mofegiline, pargyline, rasagiline, selegiline, benzatropine, biperiden, bornaprine, chlorphenoxamine, cycrimine, dexetimide, dimenhydrinate, diphenhydramine, etanautine, etybenzatropine, mazaticol, metixene, orphenadrine, phenglutarimide, piroheptine, procyclidine, profenamine, trihexyphenidyl, tropatepine, amantadine, budipine, memantine, methylxanthines, rimantadine, UWA-101, safinamide, and pharmaceutically acceptable salts and solvates of any of these agents.
Furthermore, the compound of formula (I) can also be radio-labeled by carrying out its synthesis (e.g., as described in Example 1) using precursors comprising at least one atom which is a radioisotope. Preferably, radioinotopes of carbon atoms, hydrogen atoms, sulfur atoms, or iodine atoms are employed, such as, e.g., ¹⁴C, ³H, ³⁵S, or ¹²⁵I. 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 (i.e., acetic acid comprising ³H instead of ¹H), 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 derivatives of this compound are readily 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 present invention may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a 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 envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, macaques, marmosets, dogs and rabbits. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. 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 patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt 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 complete 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 halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience 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 complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
Also the term “prevention” or “prophylaxis” of a disorder or disease as used herein is well known in the art. For example, a patient/subject suspected of being prone 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 have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition 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 present 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 “prevention” or “prophylaxis” comprises the use of compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician. The terms “prophylaxis” and “prevention” are used herein interchangeably.
As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) 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 “C_1-6alkyl” denotes an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (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 “C_2-6alkenyl” denotes an alkenyl group having 2 to 6 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, 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 pentadienyl (e.g., isoprenyl).
The term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C_1-4alkylene” denotes an alkylene group having 1 to 4 carbon atoms, and the term “C_0-4alkylene” indicates that a covalent bond (corresponding to the option “C₀alkylene”) or a C_1-4alkylene is present. Preferred exemplary alkylene groups are methylene (—CH₂—), ethylene (e.g., —CH₂—CH₂— or —CH(—CH₃)—), propylene (e.g., —CH₂—CH₂—CH₂—, —CH(—CH₂—CH₃)—, —CH₂—CH(—CH₃)—, or —CH(—CH₃)—CH₂—), or butylene (e.g., —CH₂—CH₂—CH₂—CH₂—).
The term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic 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., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), 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 refers to phenyl or naphthyl, and most preferably refers to phenyl.
The term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic 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), 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 N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) 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) 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, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromenyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl), or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[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 (if present) and/or one or more N ring atoms (if present) 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 present and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, the term “heteroaryl” particularly preferably refers to pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.
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, Gln, Gly, His, Ile, 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., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, norvaline, norleucine, terleucine (tert-leucine), or an alanine or glycine that is substituted at the side chain with a cyclic group like, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), 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 α-amino acids, more preferably from the 20 standard proteinogenic α-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably present as the L-isomer).
The terms “dipeptide” and “tripeptide” refer to an oligomer of two and three amino acids, respectively, 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 specification, a number of documents including patent applications and scientific 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, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.
The reference in this specification 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 common general knowledge in the technical field to which the present specification relates. Moreover, any references to the unpublished European patent application EP 14 18 2468.0 or to the compound of formula (I) in the introductory part of this specification 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 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:

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

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

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

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

FIG. 5: Evaluation of the anti-parkinsonian efficacy of PXT002331 in the 1-methyl-4-phenyl-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 parkinsonian 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 followed by Dunn's. (B) Combined treatment using PXT002331 (25 mg/kg)+low dose of L-dopa (4-9 mg/kg)—parkinsonism time course; oral administration twice a day during 4 days, assessment at day #4; L-dopa optimal dose (“LDopt”): 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 presents statistical analyses of the effects of the combined treatment (LDso+25 mg/kg PXT002331) over 135 min following administration of levodopa. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison. Statistical significance was assigned when P<0.05. (C) Combined treatment using PXT002331+low dose of L-dopa—difference in parkinsonian score for monkeys treated with low dose of L-dopa and PXT002331 in comparison to low dose of L-dopa alone, and in 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); all monkeys treated with PXT002331+L-dopa showed an improvement in parkinsonian score. (D) Combined treatment using PXT002331+low dose of L-dopa—dose-response evaluation for different doses of PXT002331; assessment of parkinsonian scores at day 4; “Veh”=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 in the chronic low doses of MPTP (CLD MPTP) macaque model of early-stage PD for PXT002331 in combination with L-dopa (low dose or optimal dose) upon oral administration; *=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 early-stage PD monkey model—disability score and dyskinesia score. (G) Robustness of the effects of PXT002331 in the MPTP macaque model of early stage PD. Total locomotor activity (LMA) of each individual CLD MPTP-lesioned macaque before and after addition of PXT002331 at 25 mg/kg to the optimal dose of L-DOPA (LDopt). Notably, all animals included in this study did respond to the treatment with PXT002331 (N=5).

FIG. 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 latencies (B) of correct responses in the global VDR task following administration of 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-lesioned macaques. Data are expressed as means of group (bar) and individual performance (symbol; N=4; 40 trials each) and analyzed using Friedman tests followed by Dunn's multiple comparison tests.

FIG. 7: Positive effect of PXT002331 in cognitive performance of the most cognitively 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 individual performance (symbol; 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. “D1”-“D5”: delays 1 to 5, respectively.

FIG. 8: Effects of co-administration of PXT002331 (25 mg/kg) and L-DOPA on dyskinesia of MPTP-macaque models of early and of advanced stages of PD (see Example 4). In the model of early 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 individual mean dyskinesia scores measured over a 2-hour period post-L-DOPA administration (right half of the figure, right Y axis).

FIG. 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 (−30 min): administration of PXT002331 30 min before L-DOPA, PXT (0 min): 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).

FIG. 10: Robustness of the effects of PXT002331 in the MPTP macaque model of L-DOPA-induced 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, all dyskinetic animals did respond to the treatment with PXT002331 (N=4). Two monkeys did not present 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 illustrative and are not to be construed as a limitation of the scope of the present invention.

EXAMPLES

Example 1

Preparation 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 starting materials by several synthetic approaches, using solution-phase 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 thieno[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-butoxide (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.
Introduction of the oxime may be obtained by reacting the derivative IV with hydroxyl amine hydrochloride (HONH₂, HCl) in pyridine or ethanol under microwave conditions to yield directly 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 tert-butyl hydroxylamine hydrochloride (tBuONH₂, HCl) in ethanol followed in a subsequent step by deprotection of the tent-butyl group under acidic conditions like hydrochloric acid (HCl) in a mixture of polar solvent such as THF and acetic acid.
Introduction of the alkylene side chain is obtained by a palladium catalyzed cross-coupling reaction such as Negishi cross-coupling using a commercially available zinc reagent and appropriate ligand/palladium catalytic system. Subsequent 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), i.e. PXT002331.

2) Synthesis of the Compound of Formula (I)

The commercially available starting materials used in the following experimental description were purchased from Aldrich, Sigma, ACROS or ABCR unless otherwise reported.
The compounds described in the following have been named according to the standards used in the program AutoNom v1.0.1.1 (MDL Information Systems, Inc.).
¹H NMR analyses were carried out using BRUKER NMR, model DPX-400 MHz FT-NMR. Residual signal of deuterated solvent was used as internal reference. Chemical shifts (δ) are reported in ppm in relative to the residual solvent signal (δ=2.50 for ¹H NMR in DMSO-d₆, and 7.26 in CDCl₃). 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-bridge™ C8 50 mm×4.6 mm column at a flow of 2 mL/min; 8 min gradient H₂O:CH₃CN:TFA from 100:0:0.1% to 0:100:0.05% with UV detection (254 nm).
The mass directed preparative HPLC purifications were performed with a mass directed auto purification Fraction lynx from Waters equipped with a Sunfire Prep C18 OBD column 19×100 mm 5 μm, unless otherwise reported. All purifications were performed with a gradient of ACN/H₂O or ACN/H₂O/HCOOH (0.1%).
The compound of formula (I) was prepared as shown in the following reaction scheme:

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 0° 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 thienopyridine ester (98 g, 0.51 mol, 1.1 eq) in THE (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 temperature (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 turned 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-d₆, 400 MHz) 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[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl-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-d₆, 400 MHz) 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]Dioxolan-2-yl-ethyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl-oxime (5)
To a degassed solution of 6-bromo-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl-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 (II) 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 resulting 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-d₆, 400 MHz) 67 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-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-6-yl)-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-tert-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 temperature for 24 hours to give a thick yellow emulsion. After completion of the reaction (LC/MS), the reaction mixture was neutralized by addition of an aqueous saturated solution of NaHCO₃and extracted with CH₂Cl₂(2×5.0 L). The combined organic extracts were washed with brine (2.0 L), dried over magnesium 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%.
¹H NMR (CDCl₃, 400 MHz) 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, 9H).
Step 6: 6-(3-Morpholin-4-yl-propyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl oxime (7)
To a mixture of 3-(4-tert-butoxyimino-(2-thieno[3,2-c]pyridin-6-yl)-4H-chromen-6-yl)-propionaldehyde (100.0 g, 246 mmol, 1 eq), morpholine (50 mL, 492 mmol, 2 eq) in CH₂Cl₂(1.0 L) and Methanol (500 mL) was added sodium triacetoxyborohydride (104 g, 492 mmol, 2 eq) under N₂atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by LC/MS, the mixture was neutralized by addition of an aqueous saturated solution of NaHCO₃and extracted with CH₂Cl₂(2×5.0 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%.
¹H NMR (DMSO-d₆, 400 MHz) 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, 1H), 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-Morpholin-4-yl-propyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one oxime
To a stirred solution of 6-(3-morpholin-4-yl-propyl)-2-(thieno[3,2-c]pyridin-6-yl)-4H-chromen-4-one O-tert-butyl oxime (10.0 g, 21 mmol, 1 eq) in acetic acid (100 mL) was added a solution of dioxane-HCl (4 M, 150 mL, 3 eq) at room temperature under inert atmosphere. The reaction mixture was heated at 80° C. 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), Et₂O (2×50 mL) to afford 8 g of a yellow solid as a HCl salt.
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%.
¹H NMR (DMSO, 400 MHz) 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

Biological Evaluation of the Compound of Formula (I)

The compound of formula (I) according to the invention (i.e., PXT002331) was tested for its agonistic 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 have a potency of pEC₅₀=7.12 (corresponding to an EC₅₀of about 0.076 μM), which is comparable to that of the compound of Example 127 of WO 2011/051478 (i.e., “PXT001858”) which has a pEC₅₀of 7.44 (corresponding to an EC₅₀of about 0.036 μM).
The in vitro ADME profile of PXT002331 was also very similar with reference to phase I metabolic stability: CL (h/r): 55/101 μl/min/mg protein and intestinal absorption: CaCo-2 (A-B, pgp): 4.11 .10-6 cm/s, no efflux.
In both cases, i.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 salt.
However, despite very similar physico-chemical properties 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 Pharmacokinetics Evaluation:

PXT002331 and PXT001858 were administered per os (p.o.) at 10 mg/kg to male Sprague-Dawley 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 samples (200 μl) 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° C. The plasma (supernatant) was separated in another tube and stored at −80° C. until analysis. Two groups of 3 animals were used for each route of administration: in one group, blood samples were collected to determine the kinetics of plasma exposure over a 24-hour period, and in the second group, blood and brain were collected at one terminal time point (0.5, 1.0, 1.5, 2.0, 4.0 hours) to determine the kinetics of brain exposure and brain/plasma ratio.

Compound Analysis:

The respective parent compound (free base) was analysed in plasma samples 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 2.0 at T=1.5 h; see FIG. 4) leading to a 3-fold improvement in the brain AUC when compared to PXT001858. A posteriori, one potential hypothesis might rely on the difference 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 glucuronidation as compared to PXT001858 (see table below). Nonetheless, this difference 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 FIGS. 1 to 4.

TABLE 1

PK parameters of PXT002331 and PXT001858 after
oral administration in rats at 10 mg/kg.

	Brain/Plasma	Cmax
Oral PK	ratio	(Brain)	Plasma AUC	Brain AUC
10 mpk	(T = 1.5 h)	(ng/G tissue)	inf(h*ng/ml)	inf(h*ng/g)

PXT002331	6.5	818	432	2713
PXT001858	2.0	521	394	838

TABLE 2

PXT002331 and PXT001858 in vitro glucuronidation
(peak area) in rat liver microsomes.

	Time (min)	0	5	15	30	60

PXT002331	0	0	0	0	0
PXT001858	0	164	353	798	2 556

PXT002331 and PXT001858 in vitro glucuronidation

(peak area) in rat intestinal microsomes.

Time (min)	0	5	15	30	60

PXT002331	0	2 492	4 724	8 369	16 897
PXT001858	0	13 840	30 396	68 072	14 8307

These results demonstrate that the compound of formula (I) according to the present invention, i.e. PXT002331, has highly advantageous pharmacokinetic properties and shows a considerably 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 prevention of neurological and/or psychiatric disorders.

Example 3

In Vivo Evaluation of the Compound of Formula (I) in an MPTP Monkey Model of Parkinson's Disease

The anti-parkinsonian efficacy of the compound of formula (I) according to the present invention (i.e., PXT002331) was evaluated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of Parkinson's disease (using macaques of the species Macaca fascicularis), which reproduces most of the clinical and pathological hallmarks of Parkinson's disease and is considered a “gold standard” (see Porras G et al., Cold Spring Harb Perspect Med., 2(3):a009308, 2012 and references cited therein for a general description of the MPTP model).
The results of the studies performed in a MPTP macaque model of advanced stages of PD are summarized in FIGS. 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 parkinsonian score at administration doses of 2 to 25 mg/kg perorally (p.o.) twice a day (see FIG. 5A). In this experiment, PXT002331 was orally administered twice a day during a period of 4 days, and the parkinsonian score was assessed at day 4 over 2 hours of observation (data are mean values+standard error of the mean (s.e.m.); n=7 monkeys).
The anti-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 FIGS. 5B and 5C). In this model, levodopa methyl ester was administered sub-cutaneously together with a fixed dose of 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 parkinsonian 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 FIG. 5B, it was found that the combined administration of PXT002331 and a suboptimal dose of L-dopa gave a considerable improvement in parkinsonian 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 clinically highly 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. Remarkably, all treated monkeys showed a significant improvement in parkinsonian score, which indicates a high robustness of the anti-parkinsonian effect of PXT002331 (see FIG. 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 evaluation of the combination of PXT002331 (at doses from 2 mg/kg to 100 mg/kg) with L-dopa (low dose) are shown in FIG. 5D (the assessment of parkinsonian scores took place at day 4). It was found that PXT002331 in combination with L-dopa provides a highly potent anti-parkinsonian effect upon oral administration over a range of different doses. The optimal anti-parkinsonian efficacy was achieved with administration doses of PXT002331 of 2 mg/kg to 25 mg/kg.
A significant 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 FIG. 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 signals were collected with 24 light beams and a video track recorder in order to discriminate all 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 L-dopa was robust since each and every monkey included in the study responded to this treatment (see FIG. 5G).
As shown in FIG. 5F, it was furthermore found that increasing doses of PXT002331 in combination with L-dopa (optimal dose) provided an improvement in the disability score, 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 undesirable adverse effect that typically occurs during treatment with L-dopa.
These findings confirm that PXT002331 is highly advantageous for use in the treatment or prevention of Parkinson's disease, both in monotherapy (without the concomitant use of further antiparkinson drugs) and in cotherapy using further antiparkinson drugs such as L-dopa (levodopa). In these experiments, doses of 2 mg/kg to 25 mg/kg of PXT002331, to be orally 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 all tested MPTP macaques, which benefit from an enhanced 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 animals, in order to assess potential side effects on cognitive symptoms.
Whether global performances were considered, or each delay separately, or all the delays simultaneously, none of the treatments with PXT002331, alone or in combination with L-DOPA, induced any worsening of the cognitive performances of the animals, as also shown in FIG. 6.
In summary, none of the treatments with PXT002331 had a negative impact on cognitive performance of macaques (by contrast with L-DOPA for example). Moreover, it is noteworthy that for one out of the four animals tested, PXT002331 even had a beneficial effect on its cognitive performance in the VDR task. This animal displayed almost 100% of omissions after 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 _ofcorrect responses increased accordingly (see FIG. 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 early stage PD (see FIG. 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 FIG. 8 (right half). In these animals, even with the highest doses of L-DOPA, dyskinesia were very mild, as shown by the low mean dyskinesia score (see FIG. 8, right half). It was decided to test the effects of PXT002331 on L-DOPA-induced dyskinesia in animals in a more advanced stage, presenting more pronounced dyskinesia, as described in Example 5.

Example 5

Assessment of the Anti-Dyskinetic Efficacy of the Compound of Formula (I) in MPTP Macaque Models of L-DOPA-Induced Dyskinesia (LID)

Like PD patients, MPTP macaques experience 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 reduction of dyskinesia was observed in the presence of PXT002331 (see FIG. 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 efficacy of L-DOPA for reducing parkinsonian symptoms (tremor, posture, mobility) was maintained in association with PXT002331 dose, as shown in FIG. 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 treatment (see FIG. 10).
These results show that the compound of formula (I), i.e. PXT002331, is highly effective in the prevention or reduction of levodopa-induced dyskinesia (LID), as demonstrated in the MPTP macaque model of LID. Moreover, PXT002331 can be used either as an acute or a chronic medication against levodopa-induced dyskinesia, which renders it particularly suitable for the treatment or prevention of this pathological condition.

Claims

1-49. (canceled)

50. A method of treating or preventing levodopa-induced dyskinesia, the method comprising the administration of a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject in need thereof:

51. The method of claim 50, wherein said compound, or the pharmaceutically acceptable salt, solvate or prodrug thereof, has the (E)-configuration at the oxime group comprised in formula (I).

52. The method of claim 50, wherein said compound, or the pharmaceutically acceptable salt, solvate or prodrug thereof, is in the form of a hydrochloride salt.

53. The method of claim 50, wherein the method comprises orally administering said compound to said subject.

54. The method of claim 50, wherein said subject is a human.

55. A method of treating Parkinson's disease, the method comprising the administration of a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.

56. The method of claim 55, wherein the compound of formula (I), or the pharmaceutically acceptable salt, solvate or prodrug thereof, has the (E)-configuration at the oxime group comprised in formula (I).

57. The method of claim 55, wherein the compound of formula (I), or the pharmaceutically acceptable salt, solvate or prodrug thereof, is in the form of a hydrochloride salt.

58. The method of claim 55, wherein the method comprises the simultaneous administration of said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof.

59. The method of claim 55, wherein said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof are provided in a single pharmaceutical composition.

60. The method of claim 55, wherein said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof are provided in separate pharmaceutical compositions.

61. The method of claim 55, wherein the method comprises the sequential administration of said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof.

62. The method of claim 55, wherein the method comprises orally administering said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof to said subject.

63. The method of claim 55, wherein the method further comprises administering a levodopa decarboxylase inhibitor to said subject.

64. The method of claim 55, wherein the method further comprises administering a catechol-O-methyl transferase (COMT) inhibitor to said subject.

65. The method of claim 55, wherein the method further comprises administering a levodopa decarboxylase inhibitor and a catechol-O-methyl transferase (COMT) inhibitor to said subject.

66. The method of claim 63, wherein the levodopa decarboxylase inhibitor is selected from the group consisting of carbidopa, benserazide, α-methyldopa, α-difluoromethyldopa, and pharmaceutically acceptable salts and solvates thereof.

67. The method of claim 64, wherein the COMT inhibitor is selected from the group consisting of entacapone, tolcapone, nitecapone, opicapone, and pharmaceutically acceptable salts and solvates thereof.

68. The method of claim 55, wherein said subject is a human.