Compounds for treatment and prevention of central nervous system diseases

Abstract

The present invention relates to the use of a pharmaceutical composition for the preparation of a medicament for the treatment and / or prevention of central nervous system diseases, wherein the pharmaceutical composition comprises a compound of formula (I) or any salt, derivative, isotope or mixture thereof and at least one pharmaceutically acceptable excipient.

Description

[0001] This application is a divisional application of the patent application for the invention with the application date of December 31, 2020, the application number of 202080096672.0, and the invention name of “Compounds for the treatment and prevention of central nervous system diseases”. TECHNICAL FIELD

[0002] The present invention relates to pharmaceutical compositions of 4-piperidinecarboxylate derivatives. In particular, the present invention relates to pharmaceutical compositions comprising 4-piperidinecarboxylate derivatives and at least one pharmaceutically acceptable excipient, for the treatment and / or prevention of brain diseases. BACKGROUND

[0003] Human brain functions are essentially supported by synaptic activities, which are the result of the joint action of neurotransmitter systems and other biological targets. The complex structural organization of neurons and their neurotransmitter systems, particularly their presence in scattered anatomical regions, allows the running and control of all the basic activities within the human body.

[0004] Brain diseases are the result of a deficiency or a significant loss of synaptic activities caused by unknown or known factors, including but not limited to developmental disorders, genetic mutations of biological targets, tumors, toxic substances, neurodegenerative processes affecting the brain structure, inflammatory reactions, aging, or brain damage due to traumatic events. The main consequence of brain diseases is a functional disorder, which, due to particular compensatory mechanisms, leads to an overexcitation or loss of neurotransmission activities.

[0005] The main feature of brain diseases and related syndromes is an imbalance of synaptic activities. Epilepsy is characterized by an imbalance of excitatory and inhibitory activities of neurotransmitter systems, which leads to difficulties in concentration, fragmented memory, and disorders of excitatory activities. Epilepsy is caused by genetic and non-genetic causes, such as brain damage and tumors. Parkinson’s disease is characterized by a massive loss of dopaminergic systems, which leads to an imbalance of the function of some brain regions and neurotransmitters that control motor functions and thus to severe motor disorders. Other neurological diseases are associated with neurotransmitter disorders, such as schizophrenia, psychotic disorders, attention deficits, obsessive-compulsive disorders caused by significant dopaminergic hyperactivity, or Alzheimer’s disease and cognitive disorders, which have been shown to be the result of an incorrect hyperactivity caused by defects in neurodegenerative processes. Inflammation caused by different factors, such as toxic substances or viral infections, can severely affect brain function and be associated with neurodegenerative diseases or be a key factor in neurodegenerative diseases. Chronic inflammation can lead to tissue damage and eventually to tissue destruction and is often caused by inappropriate immune responses. Inflammation in the nervous system (“neuroinflammation”), especially over long periods of time, can be particularly harmful. While inflammation itself can not cause the disease, it plays an important role in the pathogenesis of diseases of the entire central nervous system.

[0006] These consequences are devastating for the life of the patient and although some active drugs have been discovered and developed for the treatment of these brain diseases, such as levodopa or dopamine agonist therapies (for Parkinson's disease), gamma-aminobutyric acid modulators, etc. (for epilepsy), these drugs are only partially effective, or completely ineffective for at least a significant part of the patient population, or are associated with important side effects, which remain a major unsolved problem for the patient.

[0007] Furthermore, many brain diseases and syndromes, associated or not with major brain diseases, remain today problematic, such as multiple system atrophy, restless leg syndrome, dystonia, infantile epilepsy syndrome, muscular dystrophy.

[0008] There is a huge unmet medical need in the treatment of human brain diseases. The present invention provides a new therapeutic approach for the treatment of the above-mentioned diseases characterized by a pathological dysregulation of synaptic activity or neurodegenerative processes. SUMMARY

[0009] The present invention relates to a pharmaceutical composition for the treatment and / or prevention of a central nervous system disease, comprising a compound of formula (I) or a salt, derivative, isotope or mixture thereof and at least one pharmaceutically acceptable excipient,

[0010]

[0011] wherein R1, R2and R 11 are independently of each other C1-C3alkyl; R3, R4, R5, R6, R7, R8, R9and R 10 are independently of each other selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy and C1-C3thioalkyl; and A is a 5- or 6-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms, which 5- or 6-membered aromatic ring is unsubstituted or substituted by 1, 2, 3 or 4 groups, each group being independently selected from halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy and C1-C3thioalkyl.

[0012] In one embodiment, A is selected from phenyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, diazyl and triazyl; preferably is phenyl.

[0013] In one embodiment, the compound of formula (I) has the formula (II):

[0014]

[0015] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 are as defined above in formula (I); R 12 , R 13 , R 15 and R 16 are independently of each other selected from the group consisting of hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl; and R 14 is C1-C3 alkyl.

[0016] In one embodiment, R1is methyl. In one embodiment, R2is methyl. In one embodiment, R 11 is ethyl. In one embodiment, R3, R4, R5, R6, R7, R8, R9and R 10 are independently of each other selected from the group consisting of hydrogen and C1-C3 alkyl, and are preferably hydrogen. In one embodiment, R 12 , R 13 , R 15 and R 16 are independently of each other selected from the group consisting of hydrogen and C1-C3 alkyl, are preferably hydrogen, and R 14 is C1-C3 alkyl, preferably methyl.

[0017] In one embodiment, the central nervous system disease is a movement disorder, a mood disorder, a neurological disease, a neurodegenerative disease or an inflammatory disease caused by a disease-causing agent or pathogen (neuroinflammation).

[0018] In one embodiment, the movement disorder is selected from the group consisting of Parkinson's disease, Huntington's disease, a muscle disorder, multiple system atrophy, inherited and non-inherited dystonia including functional dystonia, restless leg syndrome, cerebellar dysfunction and a drug-induced movement disorder. In one embodiment, the movement disorder is Parkinson's disease.

[0019] In one embodiment, the movement disorder is selected from the group consisting of a psychotic disorder, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety, panic disorder, Tourette syndrome, obsessive-compulsive disorder and an attention deficit disorder including attention deficit hyperactivity disorder. In one embodiment, the mood disorder is anxiety.

[0020] In one embodiment, the neurological disease is selected from epilepsy, Alzheimer's disease (AD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD), or hyperactivity, agnosia, amyotrophic lateral sclerosis (ALS), ataxia including Friedreich's ataxia, spongiform leukoencephalopathy, dementia, neuropathic pain, migraine, headache, and tension headache. In one embodiment, the neurological disease is epilepsy.

[0021] In one embodiment, the neurodegenerative disease of the nervous system is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy. In one embodiment, the neurodegenerative disease of the nervous system is Alzheimer's disease.

[0022] In one embodiment, the inflammatory disease caused by a pathogenic agent or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neurological disease, SARS-CoV-2-induced neurological disease, neuronal destruction, infection or damage of oligodendrocytes, infection or damage of astrocytes, infection or damage of neurons, and neuronal apoptosis. In one embodiment, the inflammatory disease caused by a pathogenic agent or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neurological disease, SARS-CoV-2-induced neurological disease, and infection or damage of oligodendrocytes.

[0023] In one embodiment, the use of the application also comprises the administration of another therapeutic agent for the treatment and / or prevention of a disease of the central nervous system. In one embodiment, the pharmaceutical composition also comprises another therapeutic agent for the treatment and / or prevention of a disease of the central nervous system.

[0024] In one embodiment, the pharmaceutical composition is in a form suitable for oral administration. In one embodiment, the pharmaceutical composition is in the form of a film.

[0025] Definitions

[0026] In the present application, the following terms have the following meanings:

[0027] - "about" before a number means plus or minus 10% of the value of the number.

[0028] - "alkoxy" means a group of the formula -O-alkyl.

[0029] - "alkyl" refers to any saturated straight-chain or branched hydrocarbon chain having 1 to 12 carbon atoms; preferably having 1 to 6 carbon atoms; more preferably having 1 to 3 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and its isomers (e.g., n-pentyl or isopentyl), or hexyl and its isomers (e.g., n-hexyl or isohexyl). Preferably, the alkyl group is ethyl or methyl; more preferably methyl.

[0030] - "Aryl" refers to a polyunsaturated aromatic hydrocarbon group containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 5 or 6 carbon atoms, the group having a single ring (i.e., phenyl) or fused polycyclic aromatic rings (i.e., naphthyl) or covalently linked polycyclic aromatic rings, wherein at least one ring is an aromatic ring. The aromatic ring may optionally contain one or two additional rings (cycloalkyl, heterocyclic or heteroaryl) fused with it. Examples of aryl groups are phenyl, biphenyl, biphenylene, 5-tetrahydronaphthalene or 6-tetrahydronaphthalene, naphth-1-yl or naphth-2-yl, 4-indenyl, 5-indenyl, 6-indenyl or 7-indenyl, 1-acenaphthyl, 2-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl, 3-dihydroacenaphthyl, 4-dihydroacenaphthyl or 5-dihydroacenaphthyl, 1-pentenyl or 2-pentenyl, 4-indenyl or 5-indenyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-pyrene, 2-pyrene, 3-pyrene, 4-pyrene or 5-pyrene.

[0031] - "Aromatic ring" refers to the collective term for aryl and heteroaryl groups.

[0032] - "Halogenated alkyl" refers to the alkyl group defined above, wherein at least one hydrogen atom is replaced by a halogen atom selected from fluorine, chlorine, bromine and iodine. Preferably, each halogen atom in the halogenated alkyl group is fluorine, that is, the halogenated alkyl group is "fluoroalkyl".

[0033] - "Heteroaryl" refers to an aromatic ring or aromatic ring system containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 4 or 5 carbon atoms, having one or two rings fused together or covalently linked, wherein at least one ring is an aromatic ring, and wherein one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatomium can optionally be quaternized. Such a ring can be fused with aryl, cycloalkyl, heteroaryl, or heterocyclic rings. Examples of heterocyclic groups are furanyl, phenylthio, pyrazolyl, imidazolyl, etc. azole group, iso Azolyl, thiazolyl, isothiazolyl, triazolyl oxadiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl or thieno[3,2-b]furyl.

[0034] -“pharmaceutically acceptable” used in connection with ingredients of a composition refers to the fact that the ingredients of the pharmaceutical composition are compatible with each other and with the subject to which the pharmaceutical composition is administered for use.

[0035] -“pharmaceutically acceptable excipient” refers to an excipient or carrier that does not produce an adverse, allergic or other untoward reaction when administered to a subject, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as the US Food and Drug Administration (FDA) office or the European Medicines Agency (EMA).

[0036] -“pharmaceutical composition” refers to a composition comprising at least one pharmaceutically active ingredient and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is for therapeutic use and is related to health. In particular, the pharmaceutical composition can be suitable for the treatment of a disease selected from eating disorders, for example obesity.

[0037] -“solvate” refers to a molecular complex comprising the compound of the present application and a stoichiometric or sub-stoichiometric amount of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term “hydrate” refers to the case where the solvent is water.

[0038] -“subject” refers to a warm-blooded animal, preferably a mammal, more preferably a human. Preferably, the subject is a patient, i.e. a subject awaiting, undergoing or becoming the target of a medical procedure. For example, the subject can be treated for an eating disorder, for example obesity.

[0039] -“thioalkyl” refers to a group of the formula -S-alkyl.

[0040] -“therapeutic agent”, “active drug” and “pharmaceutically active agent” are synonymous and refer to a compound for therapeutic use and related to health. In particular, the therapeutic agent can be suitable for the treatment of an eating disorder, for example obesity.

[0041] "treatment" or "treating" or "amelioration" refer to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder in an individual in need thereof. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in whom the disease is to be prevented. An individual whose disease or pathology is successfully "treated" will exhibit one or more of the following: a reduction in the number of pathogenic cells; a reduction in the percentage of total cells that are pathogenic; some degree of alleviation in one or more symptoms associated with the particular disease or disorder; a reduction in morbidity and / or mortality; and / or an improvement in quality of life indicators. The above parameters for assessing successful treatment and amelioration of a disease are readily measurable by routine procedures familiar to a physician. For example, the disease can be selected from the group consisting of eating disorders, e.g., obesity.

[0042] The term "individual" refers to a vertebrate, preferably a mammal, more preferably a human. Examples of individuals include humans, non-human primates, dogs, cats, mice, rats, horses, cows, sheep, and transgenic species thereof. In one embodiment, the individual can be a "patient" who is awaiting medical care, or is receiving medical care, or was / is the target of a medical procedure, or whose development of a disease is being monitored, i.e., a warm-blooded animal, more preferably a human.

[0043] In one embodiment, the individual is an adult (e.g., a human subject who is older than 18 years of age). In another embodiment, the individual is a child (e.g., a human subject who is younger than 18 years of age). In one embodiment, the individual is a male or male gender. In another embodiment, the individual is a female or female gender. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 is a graph showing the distance moved by zebrafish larvae treated with vehicle (control, open circles), pentylazole at a concentration of 10 mM (black circles).

[0045] Figure 2 is a graph showing the distance moved by zebrafish larvae treated with pentylazole at a concentration of 10 mM (black circles) or treated with pentylazole at a concentration of 10 mM in combination with Cmpdl at a concentration of 100 μΜ (inverted white triangles) or treated with Cmpdl at a concentration of 100 μΜ (open circles).

[0046] Figure 3 is a graph showing the distance moved by zebrafish larvae treated with vehicle (control, open circles), apomorphine at a concentration of 75 μΜ (black circles).

[0047] Figure 4 Figure 5 is a graph showing the distance moved by zebrafish larvae treated with apomorphine at a concentration of 75 mM (black circles) or with a combination of apomorphine at a concentration of 75 mM and Cmpdl at a concentration of 100 mM (inverted white triangles).

[0048] Figure 5 Figure 6 is a graph showing the distance moved by zebrafish larvae treated with vehicle (control, open circles) or Cmpdl at a concentration of 100 mM (inverted black triangles).

[0049] Figure 6 Figure 7 is a graph showing the cumulative distance moved by zebrafish larvae treated with vehicle (control, dotted line), pentetrazole at a concentration of 10 mM (solid line) over 2 min, 22 min and 60 min. The area of the response to pentetrazole relative to the response to control is indicated by the connecting lines and background pattern. One-way ANOVA with Tukey's method for multiple comparisons, control vs PTZ (pentetrazole) ***P<0.001, **P<0.003.

[0050] Figure 7 Figure 8 is a graph showing the cumulative distance moved by zebrafish larvae treated with pentetrazole at a concentration of 10 mM (solid line), a combination of pentetrazole at a concentration of 10 mM and Cmpdl at a concentration of 100 mM (dotted line) or Cmpdl at a concentration of 100 mM (dotted thin line) over 2 min, 4 min, 10 min and 20 min. The area of the response to pentetrazole treatment relative to treatment with Cmpdl alone or Cmpdl in combination with pentetrazole is indicated by the connecting lines and background pattern. One-way ANOVA with Tukey's method for multiple comparisons, Cmpdl + PTZ vs PTZ **P<0.002; Cmpdl vs PTZ ***P<0.0001.

[0051] Figure 8 Figure 9 is a graph showing the cumulative distance moved by zebrafish larvae treated with vehicle (control, solid line), apomorphine at a concentration of 55 mM (thin line) over 2 min, 4 min, 10 min and 20 min. The area of the response to apomorphine relative to control is indicated by the connecting lines. One-way ANOVA with Tukey's method for multiple comparisons, control vs APO (apomorphine) ***P<0.0003; **P<0.022.

[0052] Figure 9is a graph showing the cumulative distance moved by zebrafish larvae treated with apomorphine at a concentration of 55 mM (solid line) or with a combination of apomorphine at a concentration of 55 mM and Cmpdl at a concentration of 65 mM (dotted line) over 2 min, 22 min and 60 min. The area of the response with apomorphine treatment versus the response with Cmpdl and apomorphine combination treatment is indicated by the connecting line and the background pattern. One-way ANOVA with Tukey's method for multiple comparisons, Cmpdl + APO vs APO ** P<0.0046; Cmpdl vs APO * P<0.06.

[0053] Figure 10 is a graph showing the cumulative distance moved by zebrafish larvae treated with vehicle (control, dotted line) or Cmpdl at a concentration of 100 mM (solid line) over 2 min, 22 min and 60 min. The area of the response with vehicle treatment versus the response with Cmpdl treatment is indicated by the connecting line. DETAILED DESCRIPTION

[0054] The present application relates to a pharmaceutical composition comprising a compound of formula (I), or a salt, derivative, isotope or mixture thereof and at least one pharmaceutically acceptable excipient,

[0055]

[0056] wherein:

[0057] - R1, R2 and R 11 are independently of each other C1-C3 alkyl,

[0058] - R3, R4, R5, R6, R7, R8, R9 and R 10 are independently of each other selected from the group consisting of hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl, and

[0059] - A is a 5- or 6-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms, the 5- or 6-membered aromatic ring being unsubstituted (i.e. not substituted) or substituted by 1, 2, 3 or 4 groups, each group being independently selected from the group consisting of halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl.

[0060] As it comprises a piperidine moiety substituted in position 4 by a formate group (COOR 11 ), the above-mentioned compound of formula (I) qualifies as a "4-piperidine formate derivative" in the sense of the present application.

[0061] In one embodiment, A is a 5- or 6-membered aromatic ring selected from phenyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, diazyl (i.e., pyrazinyl, pyrimidinyl, or pyridazinyl), and triazyl, unsubstituted or substituted as defined above for formula (I). In one embodiment, A is phenyl, unsubstituted or substituted as defined above for formula (I). In one embodiment, A is 4-alkylphenyl, i.e., phenyl substituted at least at the 4 position with an alkyl group, e.g., a C1-C3 alkyl group.

[0062] In one embodiment, the compound of formula (I) has formula (II):

[0063]

[0064] wherein:

[0065] -R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 are as defined above for formula (I),

[0066] -R 12 , R 13 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl, and

[0067] -R 14 is C1-C3 alkyl.

[0068] In one embodiment, R1is selected from the group consisting of methyl, ethyl, and propyl. In one embodiment, R1is methyl.

[0069] In one embodiment, R2is selected from the group consisting of methyl, ethyl, and propyl. In one embodiment, R2is methyl.

[0070] In one embodiment, R 11 is selected from the group consisting of methyl, ethyl, and propyl. In one embodiment, R 11 is ethyl.

[0071] In one embodiment, R3, R4, R5, R6, R7, R8, R9, and R 10 are each independently selected from the group consisting of hydrogen and C1-C3 alkyl. In one embodiment, R4, R6, R8, and R 10 are hydrogen. In one embodiment, R3, R4, R5, R6, R7, R8, R9, and R 10 are hydrogen.

[0072] In one embodiment, R 12 , R 13 , R 15 and R 16 are independently of each other selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl. In one embodiment, R 12 , R 13 , R 15 and R 16 are independently of each other selected from the group consisting of hydrogen and C1-C3 alkyl. In one embodiment, R 12 , R 13 , R 15 and R 16 are hydrogen.

[0073] In one embodiment, R 14 is C1-C3 alkyl. In one embodiment, R 14 is selected from the group consisting of methyl, ethyl and propyl. In one embodiment, R 14 is methyl.

[0074] In one preferred embodiment, the compound of formula (I) is ethyl 1-(N-(methylsulfonyl)-N-(p-tolyl)alaninyl)piperidine-4-carboxylate of formula (1) (hereinafter denoted by "Compound 1" or "Cmpd 1"):

[0075]

[0076] Compound 1 was synthesized using Professional 15.0 naming (PerkinElmer).

[0077] According to one embodiment, at least one pharmaceutically acceptable excipient is clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

[0078] In particular, the pharmaceutical composition of the present application can optionally comprise inactive substances normally used in pharmaceutical formulations, such as co-solvents, lipid vehicles, antioxidants, surfactants, humectants, emulsifiers, buffers, pH adjusters, preservatives (or conserving agents), isotonic agents, stabilizers, granulating or binding agents, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, bulking agents, release agents, sweeteners, flavoring agents, and the like.

[0079] In a preferred embodiment, the pharmaceutical composition of the application comprises one or more than one pharmaceutically acceptable cosolvent. Preferably the cosolvent is selected from the group consisting of caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, isosorbide dimethyl ether and mixtures thereof. In a particular embodiment, the pharmaceutical composition of the application comprises caprylic acid and / or PEG. Advantageously, when the composition comprises PEG as cosolvent, the PEG is of low molecular weight, preferably the PEG is PEG 400. In an alternative embodiment, when the composition comprises PEG, the PEG is of medium molecular weight, preferably is PEG 3350.

[0080] In a particular embodiment, the pharmaceutical composition of the application comprises one or more than one pharmaceutically acceptable lipid vehicle. In a preferred embodiment, the lipid vehicle is lauroyl polyhydroxy-32 glycerides. This excipient corresponds to GELUCIRE® 44 / 14 manufactured by Gattefosse (Saint-Priest - France). 44 / 14. The following reference forms of this excipient are also known: lauroyl polyoxyl-32 glycerides NF / USP (NF: National Formulary; USP: United States Pharmacopeia); lauroyl macrogol-32 glycerides EP (European Pharmacopoeia); Hydrogenated Coconut PEG-32 ester (INCI); CAS number 57107-95-6. 44 / 14 corresponds to a well-defined multi-ingredient substance consisting of mono-, di- and triglycerides and PEG-32 lauric acid (C12) mono- and di-esters. The melting point of 44 / 14 is 42.5°C to 47.5°C (average of 44°C) and the hydrophilic / lipophilic balance (HLB) value is 14.

[0081] In another embodiment, the lipid vehicle is Vitamin E TPGS. The following reference forms of this excipient are also known: D-a-tocopheryl polyethylene glycol-1000 succinate; Tocophersolan; Tocofersolan; VEGS; a-[4-[[(2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl]oxy]-1,4-dioxobutyl]-omega-hydroxy-poly(oxy-1,2-ethanediyl); and Vitamin E PEG succinate formed from Vitamin E linked together by a succinic acid linker with polyethylene glycol 1000. The melting point of Vitamin E TPGS is 37°C to 41°C and the hydrophilic / lipophilic balance (HLB) value is 13.

[0082] In one embodiment, the pharmaceutical composition of the present application comprises one or more than one antioxidant; preferably the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine and vitamin E; more preferably the antioxidant is BHT.

[0083] In some embodiments, a surfactant is added, such as polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbate (20, 80, etc.), poloxamer (188, 407, etc.), pluronic polyols, polyoxyethylene sorbitan monoesters (20, 80, etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate), polyoxyethylene hydrogenated castor oil RH40 (polyoxyl 40 hydrogenated castor oil), polyoxyethylene hydrogenated castor oil EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12- monostearate, solutol HS15 (polyoxyethylene 12-hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8 glycerides), labrafil M1944 (oleoyl polyoxyl-6 glycerides), polylactide polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer -20, -80, etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate), polyoxyethylene hydrogenated castor oil RH40 (polyoxyl 40 hydrogenated castor oil), polyoxyethylene hydrogenated castor oil EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12- monostearate, solutol HS15 (polyoxyethylene 12-hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8 glycerides), labrafil M1944 (oleoyl polyoxyl-6 glycerides), polylactide polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer

[0084] In some embodiments, a humectant is added, such as sodium lauryl sulfate, vitamin E TPGS, sodium docusate, polysorbate 80, poloxamer 407. The preferred humectant is poloxamer 407.

[0085] In some embodiments, an emulsifier is added, such as carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, triethanolamine, propylene glycol monododecanoate, propylene glycol dodecanoate, propylene glycol monocaprylate. The preferred emulsifiers are, for example, poloxamer, propylene glycol monododecanoate, propylene glycol dodecanoate and propylene glycol monocaprylate.

[0086] In some embodiments, a buffering agent is used to help maintain the pH within a suitable range close to physiological conditions. Suitable buffering agents include organic and inorganic acids and salts thereof, such as citrate buffers (e.g., monosodium citrate-disodium citrate mixtures, citric acid-trisodium citrate mixtures, citric acid-monosodium citrate mixtures, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixtures, succinic acid-sodium hydroxide mixtures, succinic acid-disodium succinate mixtures, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixtures, tartaric acid-potassium tartrate mixtures, tartaric acid-sodium hydroxide mixtures, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixtures, fumaric acid-disodium fumarate mixtures, monosodium fumarate-disodium fumarate mixtures, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixtures, gluconic acid-sodium hydroxide mixtures, gluconic acid-potassium gluconate mixtures, etc.), oxalate buffers (e.g., oxalic acid-sodium oxalate mixtures, oxalic acid-sodium hydroxide mixtures, oxalic acid-potassium oxalate mixtures, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixtures, lactic acid-sodium hydroxide mixtures, lactic acid-potassium lactate mixtures, etc.), and acetate buffers (e.g., acetic acid-sodium acetate mixtures, acetic acid-sodium hydroxide mixtures, etc.). Additionally, phosphate buffers, histidine buffers, and trisamines such as Tris can be used.

[0087] In some embodiments, a pH adjusting agent is added, such as sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid.

[0088] In some embodiments, a preservative is added to inhibit the growth of microorganisms. Suitable preservatives for use in the present disclosure include phenol, benzyl alcohol, m-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl parabens such as methyl or propyl parabens, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0089] In some embodiments, isotonic agents, sometimes known as "stabilizers", are added, including, for example, polyhydric sugar alcohols, such as trihydric or more, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a broad class of excipients, the function of which ranges from bulking agents to solubilizing the therapeutic agent or additional additives that help prevent denaturation or sticking to the container wall or help inhibit precipitation, particle growth, or agglomeration of the active ingredient. Typical stabilizers can be polyhydric sugar alcohols (enumerated above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, and the like; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, inositol, galactitol, glycerol, and the like, including cyclitols such as inositol; polyethylene glycols; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioethanolate, thio-glycerol, alpha-monothioglycerol, and sodium thio sulfate; low molecular weight polypeptides (e.g., peptides having 10 residues or fewer); proteins such as human serum albumin, bovine serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; poloxamer 407; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); monosaccharides, such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose, and trisaccharides such as raffinose; polysaccharides such as dextran; polyethylene glycol methyl ether-block-poly(D-L-lactide) copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1. Preferred stabilizers are, for example, glycerin; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); polyethylene glycol methyl ether-block-poly(D-L-lactide) copolymer; and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone polyvinyl acetate copolymer.

[0090] In some embodiments, granulating agents / binders are added, such as starches, gums (including natural, semisynthetic, and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polymers such as povidone, polyvinylpyrrolidone polyvinyl acetate copolymer, and the like. Preferred granulating agents are, for example, methyl cellulose, hydroxypropyl cellulose, povidone, and polyvinylpyrrolidone polyvinyl acetate copolymer.

[0091] In some embodiments, a precipitation inhibitor, such as a water-soluble derivative of cellulose, including hydroxypropyl methylcellulose and methylcellulose, and water-soluble polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone polyvinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or poloxamer 407, is added. The preferred precipitation inhibitor is hydroxypropyl methylcellulose.

[0092] In some embodiments, a lubricant, such as magnesium stearate, glyceryl esters, glyceryl behanate, Compritol HD5 ATO, sodium stearyl fumarate, and the like, is added.

[0093] In some embodiments, a disintegrant, such as synthetic, e.g., sodium starch glycolate, crosscarmellose sodium, cross-linked carboxymethylcellulose sodium, kollidon CL, and natural sources, e.g., locust bean gum, and the like, is added.

[0094] In some embodiments, a glidant, such as talc, magnesium stearate, colloidal silicon dioxide, starch, and the like, is added.

[0095] In some embodiments, a diluent (or filler), such as dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, dicalcium phosphate dehydrate, starch, and the like, is added.

[0096] In some embodiments, a sorbent, such as silicon dioxide, purified aluminum silicate, and the like, is added.

[0097] In some embodiments, the pharmaceutical composition comprising the combination of the application is in the form of a tablet and tablet excipients, such as granulating agents, binding agents, lubricating agents, disintegrants, glidants, diluents, sorbents, and the like, are added.

[0098] In some embodiments, the pharmaceutical composition of the application is in the form of a capsule, wherein the capsule shell is composed of gelatin or non-animal derived products such as cellulose and its derivatives such as hydroxypropyl methylcellulose. The capsule shell can contain other ingredients such as polyethylene glycol as a plasticizer; pigments such as titanium dioxide or iron oxide for providing opacity and different colors; lubricants such as carnauba wax; gelling agents such as carrageenan and wetting agents such as sodium lauryl sulfate. In one embodiment, the pharmaceutical composition of the application is made in the form of a capsule, wherein the capsule shell is composed of gelatin and optionally contains additional ingredients in the capsule shell such as polyethylene glycol and sodium lauryl sulfate.

[0099] By way of non-limiting example, the pharmaceutical composition of the application can be in a form suitable for oral administration, parenteral administration (e.g. by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (including ophthalmic), rectal administration, administration by inhalation, administration by dermal patch, administration by implant, administration by suppository, and the like. Depending on the different modes of administration, these suitable administration forms can be solid, semi-solid or liquid, and the methods and carriers, diluents and excipients used during the preparation process will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0100] The composition is formulated to provide rapid, sustained or delayed release of the active compound(s) contained in the composition.

[0101] According to one embodiment, the pharmaceutical composition of the application is in a form suitable for oral administration. Forms suitable for oral administration can be solid, semi-solid or liquid. Some preferred, but non-limiting examples of these forms include liquid, paste or solid compositions, more particularly films, tablets, tablets made for prolonged or sustained release, capsules (including soft and hard gelatin capsules), pills, sugar-coated pills, lozenges, sachets, cachets, powders, liquids, gels, syrups, slurries, elixirs, emulsions, solutions and suspensions.

[0102] In one embodiment, the pharmaceutical composition of the application is in a form designed for film drug delivery. In one embodiment, the pharmaceutical composition of the application is in a film form. In one embodiment, the film is a thin film, a dissolving film, an oral drug test strip, a biofilm and / or a 3D printed film. In one embodiment, the film form of the pharmaceutical composition of the application is designed for oral administration.

[0103] According to another embodiment, the pharmaceutical composition of the application is in a form suitable for injection, in particular injection into a subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, dermal injection or infusion.

[0104] According to another embodiment, the pharmaceutical composition of the application is in a form suitable for topical administration. Examples of forms suitable for topical administration include, but are not limited to, liquid, paste or solid compositions, and more particularly aqueous solutions, drops, dispersions, sprays, ointments, creams, lotions, microcapsules, microparticles or nanoparticles, polymeric patches or controlled release patches, and the like.

[0105] According to another embodiment, the pharmaceutical composition of the application is in a form suitable for rectal administration. Examples of forms suitable for rectal administration include, but are not limited to, suppositories, microenemas, enemas, gels, rectal foams, creams, ointments, and the like.

[0106] According to another embodiment, the pharmaceutical composition of the present application is in a form suitable for administration by inhalation. Examples of forms suitable for administration by inhalation include, but are not limited to, aerosols.

[0107] The pharmaceutical preparation of the present application is preferably in unit dosage form and can be suitably packaged, for example, packaged as a box, blister pack, vial, bottle, sachet, ampoule or any other suitable single-dose or multi-dose packaging or container (which can be suitably labeled); optionally with one or more leaflets containing product information and / or instructions for use.

[0108] All references to a compound of formula (I) or formula (II) include references to salts, solvates, polymeric complexes and liquid crystals thereof. All references to a compound of formula (I) or formula (II) include references to polymorphs and crystal habits thereof. All references to a compound of formula (I) or formula (II) include references to pharmaceutically acceptable prodrugs thereof and prodrugs thereof.

[0109] Compounds of formula (I) or formula (II) and subformulae thereof contain at least one asymmetric center and can therefore exist as different stereoisomeric forms. Accordingly, all references to a compound of formula (I) or formula (II) include references to all possible stereoisomers and not just the racemates but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such a single enantiomer can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatography methods well-known in the art. Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method, including but not limited to, fractional crystallization, salt formation and counter- ion exchange, and the like. The bond to an asymmetric carbon atom in a compound is generally depicted using a solid line solid wedge or a dotted wedge Description. The use of a solid wedge or a dotted wedge to describe the bond to an asymmetric carbon atom means that only the depicted stereoisomer is included.

[0110] All references to a compound of formula (I) or formula (II) include references to isotopically-labeled compounds of formula (I) or formula (II), including deuterium-containing compounds of formula (I) or formula (II).

[0111] The compounds of the present application can be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of formula (I) or formula (II) include acid addition salts and base salts thereof.

[0112] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, heptanoate, hexanoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / diphosphate / hydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0113] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)-ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0114] Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

[0115] Preferred pharmaceutically acceptable salts include the hydrochloride / chloride, hydrobromide / bromide, bisulfate / sulfate, nitrate, citrate, and acetate.

[0116] When the compounds of the application contain both an acidic group and a basic group, the compounds of the application are also capable of forming inner salts, and such compounds are within the scope of the application. When the compounds of the application contain a hydrogen atom donating heteroatom (e.g., NH), the application also includes salts and / or isomers formed by the transfer of said hydrogen atom to a basic group or atom in the molecule.

[0117] The pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (II) can be prepared by one or more of these methods:

[0118] (i) by reacting a compound of Formula (I) or Formula (II) with the desired acid;

[0119] (ii) by reacting a compound of Formula (I) or Formula (II) with the desired base;

[0120] (iii) by removing an acidic or basic labile protecting group from a suitable precursor of a compound of formula (I) or formula (II) or by ring opening of a suitable cyclic precursor, for example, a lactone or lactam, using a desired acid; and / or

[0121] (iv) by converting one salt of a compound of formula (I) or formula (II) into another salt by reaction with a suitable acid or by suitable ion exchange column methods.

[0122] All these reactions are generally carried out in solution. The salts can precipitate in solution and be collected by filtration or can be recovered by evaporation of the solvent. The level of ionisation in the salts varies from fully ionised to almost non-ionised.

[0123] The pharmaceutical compositions of the present application can be manufactured by methods known to those skilled in the art.

[0124] The compounds of formula (I) or formula (II) can be commercially available and / or manufactured by standard synthetic procedures and extraction and / or purification methods generally used in the art of organic synthesis chemistry, which are well known to those skilled in the art.

[0125] The present application also relates to a pharmaceutical composition according to the present application as described above for use as a medicament. The present application also relates to the use of a compound of formula (I) according to the present application as described above for the preparation or manufacture of a medicament.

[0126] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a brain disease. In one embodiment, the brain disease is a central nervous system (CNS) disease. In one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a disease of the central nervous system or of central nervous system function.

[0127] In some embodiments, the brain disease comprises a movement disorder, a mood disorder, a neurological disease and a neurodegenerative disease. In some embodiments, the brain disease can be a consequence of a neurotransmission disorder. In some embodiments, the brain disease can be characterised by a pathological synaptic activity disorder or a neurodegenerative process. According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a disease characterised by a pathological synaptic activity disorder or a neurodegenerative process.

[0128] In some other embodiments, the brain disease can be a consequence of the action of a disease-causing agent or pathogen. According to one embodiment, the disease-causing agent or pathogen can be a bacterium, a virus, a fungus or a parasite. According to another embodiment, the disease-causing agent or pathogen can also be a substance of addiction such as alcohol or a drug. According to yet another embodiment, the disease-causing agent or pathogen can also be any molecule or substance causing inflammation, in particular neuroinflammation, whether produced / secreted by the body or not.

[0129] In one embodiment, the bacteria can be Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, Listeria monocytogenes, Escherichia coli, or Streptococcus agalactiae.

[0130] In one embodiment, the virus can be an enterovirus, poliovirus, Epstein-Barr virus, herpes virus, cytomegalovirus, measles virus, human immunodeficiency virus (HIV), SARS-Cov-2 and variants thereof, or Zika virus.

[0131] In one embodiment, the parasite can be Toxoplasma gondii.

[0132] In one embodiment, the molecule or substance causing inflammation can be H + ions, oxygen radical species (ROS), amyloid substances.

[0133] In some embodiments, the central nervous system disease can comprise a movement disorder, a mood disorder, a neurological disease, or a neurodegenerative disease. In some embodiments, the central nervous system disease can be a consequence of a neurotransmission disorder. In some other embodiments, the central nervous system disease can be a consequence of the action of a pathogenic factor or pathogen.

[0134] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a neurotransmission disorder. According to the present application, a “neurotransmission disorder” refers to a disease associated with or caused by an alteration of the neurotransmission system / pathway, a neurotransmitter metabolism disorder / dysfunction. The term “neurotransmission disorder” can be used interchangeably with the term “neurotransmitter disorder”.

[0135] In one embodiment, the neurotransmission disorder is a disease associated with an alteration of the noradrenergic, dopaminergic, GABAergic, glutamatergic, noradrenergic and / or serotonergic neurotransmission. Within the scope of the present application, the term “alteration” includes an increase or a decrease of activity of the neurotransmitter compared to a reference activity level. In one embodiment, the neurotransmission disorder is a disease associated with an increase of the noradrenergic, dopaminergic, GABAergic, glutamatergic, noradrenergic and / or serotonergic neurotransmission.

[0136] As used herein, hyperactivity or hypoactivity can be assessed by at least a 10% change in the level of neurotransmitter activity compared to a reference level. In the context of the present application, the term "at least 10%" includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, and more than 1000%.

[0137] The level of neurotransmitter can be assessed according to methods recognized in the art. The level of neurotransmitter can be assessed from saliva, blood or urine samples using commercial kits. Alternatively, biosensors can be used.

[0138] In one embodiment, the neurotransmission disorder can be a movement disorder, a mood disorder, a neurological disease, a neurodegenerative disease or an inflammatory disease caused by a pathogenic agent or a pathogen.

[0139] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a movement disorder.

[0140] In one embodiment, the movement disorder is selected from the group consisting of Parkinson's disease, Huntington's disease, muscular irregularities, multiple system atrophy, genetic and non-genetic dystonia including functional dystonia, restless leg syndrome, cerebellar dysfunctions and drug-induced movement disorders.

[0141] In a particular embodiment, the movement disorder is Parkinson's disease. According to the present application, the term "Parkinson's disease" includes, but is not limited to, genetic and idiopathic (or non-genetic) Parkinson's disease.

[0142] In some embodiments, the movement disorder is a drug-induced movement disorder. In other words, a drug-induced movement disorder is a disease caused by a treatment for a movement disorder, for example a disease caused by a treatment for Parkinson's disease. In yet other words, a drug-induced movement disorder is a side effect of a treatment for a movement disorder. In a particular embodiment, the drug-induced movement disorder is a side effect of a treatment for Parkinson's disease.

[0143] In a particular embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of side effects induced by a drug for the treatment of movement disorders. According to the application, the term "side effects induced by another drug" refers, but is not limited to, side effects that occur or appear upon treatment with, for example, dopamine agonists, dopamine partial agonists, levodopa, monoamine oxidase inhibitors, and the like.

[0144] In a particular embodiment, the cerebellum dysfunction includes, but is not limited to, ataxia.

[0145] According to another embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a mood disorder.

[0146] In an embodiment, the mood disorder is selected from the group consisting of psychotic disorders, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety, panic disorder, Tourette syndrome, obsessive-compulsive disorder, and attention deficit disorders including attention deficit hyperactivity disorder.

[0147] In a particular embodiment, the mood disorder is anxiety.

[0148] According to an embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a neurological disease.

[0149] In an embodiment, the neurological disease is selected from the group consisting of epilepsy, Alzheimer's disease (AD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD), or hyperactivity, agnosia, amyotrophic lateral sclerosis (ALS), ataxia including Friedreich's ataxia, spongiform leukoencephalopathy, dementia, neuropathic pain, migraine, headache, and tension headache.

[0150] In a particular embodiment, the neurological disease is epilepsy. According to the application, the term "epilepsy" includes, but is not limited to, intractable epilepsy, genetic epilepsy, epileptic diseases, pediatric / infantile epilepsy such as Dravet syndrome, diseases characterized by recurrent seizures or seizure attacks. In an embodiment, the diseases characterized by recurrent seizures or seizure attacks include or consist of injury-induced epilepsy, stroke-induced epilepsy, brain trauma-induced epilepsy, and tumor-induced epilepsy.

[0151] According to an embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of a neurodegenerative disease.

[0152] In an embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy.

[0153] In a particular embodiment, the neurodegenerative disease is Alzheimer's disease.

[0154] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of an inflammatory disease caused by a pathogenic agent or pathogen.

[0155] In one embodiment, the inflammatory disease caused by a pathogenic agent or pathogen is a chronic inflammation.

[0156] In one embodiment, the inflammatory disease caused by a pathogenic agent or pathogen is selected from the group consisting of encephalitis, myelitis, meningitis, leukomalacia, encephalopathy, HIV-induced neurological disease, SARS-CoV-2-induced neurological disease, neuronal destruction, infection or damage of oligodendrocytes, infection or damage of astrocytes, infection or damage of neurons and neuronal apoptosis.

[0157] In one embodiment, the inflammatory disease caused by a pathogenic agent or pathogen is selected from the group consisting of encephalitis, myelitis, meningitis, leukomalacia, encephalopathy, HIV-induced neurological disease, SARS-CoV-2-induced neurological disease and infection or damage of oligodendrocytes.

[0158] According to another embodiment, the pharmaceutical composition is administered in combination with another therapeutic agent as described above. In one embodiment, the other therapeutic agent is administered in the same pharmaceutical composition. In another embodiment, the other therapeutic agent is administered in another pharmaceutical composition.

[0159] According to another embodiment, the pharmaceutical composition further comprises another therapeutic agent. In one embodiment, the therapeutic agent is a therapeutic agent for the treatment and / or prevention of a brain disease, preferably a CNS disease. In one embodiment, the therapeutic agent is a therapeutic agent for the treatment and / or prevention of a movement disorder, a mood disorder, a neurological disease or a neurodegenerative disease. In one embodiment, the therapeutic agent is a dopamine agonist, a dopamine precursor inhibitor (or L-DOPA inhibitor) or a monoamine oxidase inhibitor (or MAO inhibitor), etc.

[0160] The present application therefore also relates to a method of treating and / or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to the present application as described above. The present application also relates to the use of a pharmaceutical composition according to the present application as described above for the manufacture of a medicament.

[0161] Another object of the present application is a method of treating a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition according to the present application as described above.

[0162] In one embodiment, the method of the present application further comprises the administration of another therapeutic agent, such as a dopamine agonist, a dopamine precursor inhibitor (or L-DOPA inhibitor) or a monoamine oxidase inhibitor (or MAO inhibitor). In some embodiments, the other therapeutic agent can be administered before, during or after the administration of the pharmaceutical composition according to the present application. In some embodiments, the administration of the other therapeutic agent can be sequential or simultaneous to the administration of the pharmaceutical composition according to the present application.

[0163] According to one embodiment, the subject suffers from a neurodegenerative disease or a nervous system degenerative disease. In one embodiment, the subject is at risk of developing a neurodegenerative disease or a nervous system degenerative disease. According to one embodiment, the subject suffers from a disease caused by a pathogenic agent or pathogen, preferably an inflammatory disease caused by a pathogenic agent or pathogen.

[0164] The present application also relates to a method for improving cognition and / or memory in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the present application as described above. Another object of the present application is a method for restoring neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the present application as described above.

[0165] In certain embodiments, the therapeutically effective amount administered depends on various parameters including the substance chosen for administration, whether it is a single dose administration or a multiple dose administration and individual parameters including age, physical condition, size, weight and severity of disease.

[0166] In certain embodiments, the effective amount of active drug, i.e. compound of formula (I), can comprise from about 0.001 mg to about 3000 mg per dosage unit, preferably from about 0.05 mg to about 100 mg per dosage unit.

[0167] In the context of the present application, about 0.001 mg to about 3000 mg includes, about 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6, mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, and 3000 mg per dosage unit.

[0168] In certain embodiments, the active drug, i.e. the compound of formula (I), can be present at a dosage level sufficient to release an amount per day according to the subject's body weight of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably about 1 mg / kg to about 25 mg / kg.

[0169] In certain embodiments, the dosage unit can be administered three times a day, twice a day, once a day, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks.

[0170] In certain embodiments, the method of treatment comprises administration of multiple dosage units, including two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more than fourteen administrations.

[0171] The present application also relates to kits comprising a pharmaceutical composition of the present application, and optional tools for administering said pharmaceutical composition to a subject in need thereof. In one embodiment, the kit of parts of the present application further comprises another pharmaceutical composition comprising another therapeutic agent, and optional tools for administering said another pharmaceutical composition.

[0172] Examples

[0173] The present application is further illustrated by the following examples.

[0174] Example 1 : Cmpd1 in a model of epileptiform activity

[0175] Methods

[0176] The compounds were tested in zebrafish model organisms in response to environmental stimuli, epileptiform activity and dopaminergic hyperactivity. Zebrafish used in this study were housed in tanks of suitable size and circadian rhythm (12:12 light cycle, light / dark) under regular conditions. The water culture medium used for maintenance and experimental conditions was Instant Ocean®. The temperature of the water was maintained at 27°C or 29°C, the pH was maintained at 7.2 to 7.5 and the conductivity was maintained at 480 to 520 μ8. Zebrafish embryos were placed on sterile Petri dishes and then transferred to flat plates after hatching. The temperature of the water was maintained at 27°C or 29°C, the pH was maintained at 7.2 to 7.5 and the conductivity was maintained at 480 to 520 μ8. Zebrafish embryos were placed on sterile Petri dishes and then transferred to flat plates after hatching.

[0177] For experimental studies, larvae at five days post-fertilization were placed on flat bottom 96-well plates. During the treatment phase, the culture medium was replaced by 150 μΐ^ of fresh culture medium. Pentylenetetrazol (PTZ) and / or Cmpd1 (treatment), or vehicle (control) were added to the wells, followed by video recording.

[0178] The movement of the larvae was recorded using a Noldus daniovisio system equipped with infrared detection. Ethovision XT15 software controlled the temperature of the plate (28°C) and the light conditions of the chamber. Experimental recordings were done in cycles of light phase (20 min) and dark phase (45 min). Data were analyzed after recording using the Ethovision XT15 software package. The distance traveled by the larvae was recorded every 2 min (distance traveled) and the number of crossings of the center of the well was counted (crossings). Figures 1 to 6 and Figure 10) or the accumulated distance of larval movement at 2 min (initial), 4 min, 10 min and 20 min (transition to darkness) or 60 min (end of recording) Figure 7 and Figure 8 ) were calculated.

[0179] All compounds were dissolved in culture medium or culture medium containing the indicated concentration of DMSO.

[0180] Results

[0181] Larvae treated with vehicle showed normal movement Figure 1 and Figure 5 , an increase in larval activity after transition to darkness, reaching a maximum after 20 min and then decreasing until reaching normal levels at the end of recording.

[0182] Treatment of zebrafish larvae with pentylenetetrazole, a pro-epileptic / seizure-inducing compound, resulted in a clear increase in locomotor activity Figure 1 and Figure 2 , black circles, and Figure 6 under both light and dark conditions. This increase is related to activity caused by epileptic seizures. The combined treatment with Cmpdl at a concentration of 100 μΜ and pentylenetetrazole at a concentration of 10 mM resulted in a decrease in locomotor activity of zebrafish larvae Figure 2 , inverted triangles, and Figure 7 induced by pentylenetetrazole alone Figure 2 , open circles, and Figure 7 . Cmpdl stabilized the movement at a level close to the normal movement observed in vehicle-treated zebrafish

[0183] These results thus show that Cmpdl has anti-epileptic activity.

[0184] Example 2: Cmpdl in a model of hyperdopaminergic activity

[0185] Methods

[0186] The same method as disclosed in Example 1 was implemented in Example 2, except that pentylenetetrazole was replaced by apomorphine (APO).

[0187] Results

[0188] Treatment of zebrafish larvae with apomorphine, a dopamine agonist, resulted in a clear increase in locomotor activity Figure 3 , black circles, and Figure 8 under light conditions. This increase is related to hyperactivity of the dopaminergic neurotransmission pathway leading to hypermotility.

[0189] Cmpdl at a concentration of 100 μM and apomorphine at a concentration of 75 μM ( Figure 4 , inverted triangles) or 55 μM ( Figure 9 ) in combination induced a reduction in locomotor activity in zebrafish larvae that was caused by apomorphine alone.

[0190] Cmpdl stabilized locomotion at a level close to the normal locomotion observed in vehicle-treated zebrafish ( Figure 5 , black inverted triangles, and Figure 9 and Figure 10 ). During the first phase of the test (up to about 20 min, Figure 9 ), Cmpdl significantly reduced the locomotor activity caused by apomorphine. Cmpdl alone maintained locomotor activity at a lower level while also compressing the peak caused by the change to dark conditions ( Figure 5 and Figure 10 ).

[0191] Therefore, it can be concluded that Cmpdl is a stabilizer of dopaminergic activity. The inhibitory effect on the changes caused by light to dark also indicates that Cmpdl has an effect on stress-mood disorders caused by environmental changes. These results indicate that the compound can be useful in the treatment of motor diseases and mood disorders.​​​​

Claims

1. Use of a pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of diseases of the central nervous system, wherein the pharmaceutical composition comprises a compound of formula (I) or a salt, derivative, isotope, or mixture thereof, and at least one pharmaceutically acceptable excipient. in: -R1, R2 and R 11 They are independently C1-C3 alkyl groups. -R3, R4, R5, R6, R7, R8, R9 and R 10 They are independently selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl, and -A is a 5- or 6-membered aromatic ring containing 0, 1, or 2 nitrogen atoms, wherein the 5- or 6-membered aromatic ring is not substituted or is substituted by 1, 2, 3, or 4 groups, each group being independently selected from halogens, hydroxyl groups, -NH3, -NO3, -SH, C1-C3 alkyl groups, C1-C3 haloalkyl groups, C1-C3 alkoxy groups, and C1-C3 thioalkyl groups.

2. The use according to claim 1, wherein A is selected from phenyl, pyridyl, pyrroleyl, imidazolyl, pyrazolyl, diazinyl, and triazinyl; preferably phenyl.

3. The use according to claim 1 or claim 2, wherein the compound of formula (I) has formula (II): in: -R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 It is as defined in claim 1. -R 12 R 13 R 15 and R 16 They are independently selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl, and -R 14 It is a C1-C3 alkyl group.

4. The use according to any one of claims 1 to 3, wherein R1 is a methyl group.

5. The use according to any one of claims 1 to 4, wherein R2 is a methyl group.

6. The use according to any one of claims 1 to 5, wherein R 11 It is an ethyl group.

7. The use according to any one of claims 1 to 6, wherein R3, R4, R5, R6, R7, R8, R9 and R 10 The components are independently selected from hydrogen and C1-C3 alkyl groups, and are preferably hydrogen.

8. The use according to any one of claims 1 to 7, wherein: -R 12 R 13 R 15 and R 16 The components are independently selected from hydrogen and C1-C3 alkyl groups, and preferably hydrogen. -R 14 It is a C1-C3 alkyl group, preferably a methyl group.

9. The use according to any one of claims 1 to 8, wherein the central nervous system disease is a movement disorder, mood disorder, neurological disease, neurodegenerative disease, or inflammatory disease caused by a pathogen or causative agent.

10. The use according to claim 9, wherein the movement disorder is selected from Parkinson's disease, Huntington's disease, muscle arrhythmia, multiple system atrophy, hereditary and non-hereditary dystonia including functional dystonia, restless limb syndrome, cerebellar dysfunction and drug-induced movement disorders.

11. The use according to claim 10, wherein the movement disorder is Parkinson's disease.

12. The use according to claim 9, wherein the mood disorder is selected from mental illnesses, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety, panic disorder, Tourette syndrome, obsessive-compulsive disorder, and attention deficit disorder including attention deficit hyperactivity disorder.

13. The use according to claim 12, wherein the mood disorder is anxiety.

14. The use according to claim 9, wherein the neurological disease is selected from epilepsy, Alzheimer's disease (AD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD) or ADHD, agnosia, amyotrophic lateral sclerosis (ALS), ataxia including Friedrich's ataxia, spongiform leukoencephalopathy, dementia, neuralgia, migraine, headache, and tension headache.

15. The use according to claim 14, wherein the neurological disease is epilepsy.

16. The use according to claim 9, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

17. The use according to claim 16, wherein the neurodegenerative disease is Alzheimer's disease.

18. The use according to claim 9, wherein the inflammatory disease caused by the pathogenic factor or pathogen is selected from encephalitis, osteomyelitis, meningitis, gray matter atrophy, encephalopathy, neurological diseases caused by HIV, neurological diseases caused by SARS-CoV-2, neuronal destruction, infection or damage of oligodendrocytes, infection or damage of astrocytes, infection or damage of neurons, and neuronal apoptosis.

19. The use according to claim 18, wherein the inflammatory disease caused by the pathogenic factor or pathogen is selected from encephalitis, osteomyelitis, meningitis, gray matter atrophy, encephalopathy, neurological diseases caused by HIV, neurological diseases caused by SARS-CoV-2, and infection or damage to oligodendrocytes.

20. The use according to any one of claims 1 to 19, wherein the medicament is administered in combination with another therapeutic agent.

21. The use according to claim 20, wherein the pharmaceutical composition further comprises another therapeutic agent.

22. The use according to any one of claims 1 to 21, wherein the pharmaceutical composition is in a form suitable for oral administration.

23. The use according to any one of claims 1 to 22, wherein the pharmaceutical composition is in the form of a film.

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