Compounds for the treatment and prevention of central nervous system disorders

Abstract

A pharmaceutical composition is provided for use in the treatment and / or prevention of brain disorders, comprising a 4-piperidine carboxylate derivative and at least one pharmaceutically acceptable excipient. [Solution] A pharmaceutical composition for use in the treatment and / or prevention of central nervous system disorders is provided, comprising a compound of formula (I) or any salt, derivative, isotope or mixture thereof, and at least one pharmaceutically acceptable excipient. JPEG2026143681000009.jpg47132

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions of 4-piperidine carboxylate derivatives. In particular, the present invention relates to pharmaceutical compositions comprising a 4-piperidine carboxylate derivative and at least one pharmaceutically acceptable excipient for use in the treatment and / or prevention of brain disorders. [Background technology]

[0002] Human brain function is fundamentally supported by synaptic activity, which is the result of the action of neurotransmitter systems along with the action of other biological targets. The complex organization of neurons and their neurotransmitter systems, particularly their presence in specific anatomical regions, makes it possible to enable and control all basic functional activity in the human body.

[0003] Brain disorders are the result of defects or significant loss of synaptic activity due to currently unknown or known factors, including but not limited to developmental disorders, gene mutations in biological targets, tumors, toxic substances, neurodegenerative processes affecting brain structure, inflammatory processes, and brain injury due to aging or traumatic events. The primary consequence of brain disorders is dysregulation leading to excessive excitation or loss of activity of neurotransmission through specific compensatory mechanisms.

[0004] Brain injuries and related syndromes are primarily characterized by such imbalances in synaptic activity. Epilepsy is characterized by dysregulation of the excitatory and inhibitory activity of neurotransmitter systems, leading to uncontrolled focal, idiopathic, and physically debilitating excitatory hyperkinesia. The origin of epilepsy can be genetic or non-genetic, including brain injury and tumors. Parkinson's disease is characterized by a significant loss of dopaminergic activity, which leads to imbalances in the function of several brain regions and neurotransmitter-controlled motor function, thus causing severely debilitating motor impairment. Other neurological disorders are associated with neurotransmitter interference, such as schizophrenia, psychiatric disorders, attention deficit, obsessive-compulsive reactivity disorder in which marked dopaminergic hyperkinesia plays a significant role, or Alzheimer's disease and cognitive impairment, which are suggested to be the result of poor hyperkinesia due to defects resulting from degenerative processes. Inflammatory processes, triggered by various factors such as toxic substances or viral infections, can have a severe impact on brain function and have been associated with or are important factors in neurodegenerative diseases. Chronic inflammation can lead to tissue damage and ultimately its destruction, often as a result of an inadequate immune response. Inflammation in the nervous system ("neuroinflammation") can be particularly harmful, especially if it is persistent. While inflammation itself does not cause disease, it plays a significant role in the pathogenesis of the central nervous system.

[0005] The consequences are devastating to patients' lives, and while several active agents have been identified and developed for the treatment of these brain disorders, such as L-DOPA or dopamine agonist therapy (in the case of Parkinson's disease) and GABA-modifying factors (in the case of epilepsy), these drugs are either only partially effective or completely ineffective for at least a significant portion of the patient population, or are associated with serious side effects, which remains a major unresolved issue for patients.

[0006] Furthermore, many brain disorders and syndromes, whether associated with or unrelated to major brain diseases such as multiple system atrophy, restless legs syndrome, dystonia, childhood epilepsy syndromes, and neuromuscular disorders, remain refractory to treatment.

[0007] There remains a large unmet medical need for the treatment of human brain diseases. The present invention provides a novel treatment for the above-mentioned disorders characterized by dysregulation of pathological synaptic activity or neurodegenerative processes. Summary of the Invention

[0008] The present invention relates to a compound of formula (I): Chemical formula or a salt, derivative, isotope or mixture thereof, wherein R1, R2 and R 11 are each independently C1-C3 alkyl; R3, R4, R5, R6, R7, R8, R9 and R 10 are each independently selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl; A is a 5- or 6-membered aromatic ring containing 0, 1 or 2 nitrogen atoms, said 5- or 6-membered aromatic ring is unsubstituted or substituted with 1, 2, 3 or 4 groups each independently selected from halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 thioalkyl), and at least one pharmaceutically acceptable excipient, The present invention relates to a pharmaceutical composition for use in the treatment and / or prevention of a central nervous system disorder.

[0009] In one embodiment, A is selected from phenyl, pyridine, pyrrole, imidazole, pyrazole, diazine and triazine; preferably A is phenyl.

[0010] In one embodiment, the compound of formula (I) is a compound of formula (II): Chemical formula (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R 11 are as defined above in formula (I); R 12 , R 13 , R 15 and R 16 are each independently selected from hydrogen, halogen, hydroxyl, -NH₃, -NO₃, -SH, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy and C₁-C₃ thioalkyl; R 14 is C₁-C₃ alkyl).

[0011] In one embodiment, R¹ is a methyl group. In one embodiment, R² is a methyl group. In one embodiment, R 11 is an ethyl group. In one embodiment, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R 10 are each independently selected from hydrogen and C₁-C₃ alkyl, preferably hydrogen. In one embodiment, R 12 , R 13 , R 15 and R 16 are each independently selected from hydrogen and C₁-C₃ alkyl, preferably hydrogen, and R 14 is C₁-C₃ alkyl, preferably methyl.

[0012] In one embodiment, the central nervous system disorder is a movement disorder, a mood disorder, a neuropathy, a neurodegenerative disorder or an inflammatory disorder (neuroinflammation) caused by a pathogenic factor or pathogen.

[0013] In one embodiment, the movement disorder is selected from Parkinson's disease, Huntington's disease, myopathy, multiple system atrophy, hereditary and non-hereditary dystonia including functional dystonia, restless legs syndrome, cerebellar diseases and drug-induced movement disorders. In one embodiment, the movement disorder is Parkinson's disease.

[0014] In one embodiment, the mood disorder is selected from mental disorders, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety disorders, panic disorder, Tourette syndrome, obsessive-compulsive disorder, and attention deficit disorder, which are among the attention deficit disorders. In one embodiment, the mood disorder is an anxiety disorder.

[0015] In one embodiment, the neurological disorder is selected from epilepsy, Alzheimer's disease (AD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD) or hyperactivity disorder, agnosia, amyotrophic lateral sclerosis (ALS), ataxia including Friedreich's ataxia, Canavan disease, dementia, neuralgia, migraine, headache, and tension headache. In one embodiment, the neurological disorder is epilepsy.

[0016] In one embodiment, the neurodegenerative disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and spinal muscular atrophy. In one embodiment, the neurodegenerative disorder is Alzheimer's disease.

[0017] In one embodiment, the inflammatory disorder caused by a pathogenic factor or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neuropathy, SARS-CoV-2-induced neuropathy, nerve destruction, oligodendrocyte infection or injury, astrocyte infection or injury, neuronal infection or injury, and apoptotic neurons.

[0018] In one embodiment, the use of the present invention further comprises administering another therapeutic agent for treating and / or preventing central nervous system disorders. In one embodiment, the pharmaceutical composition further comprises another therapeutic agent for use in treating and / or preventing central nervous system disorders.

[0019] In one embodiment, the pharmaceutical composition is in a form suitable for oral administration. In another embodiment, the pharmaceutical composition is in the form of a film.

[0020] definition In this invention, the following terms have the following meanings:

[0021] - The word "approximately" preceding a number means plus or minus 10% of the given value.

[0022] - "Alkoxy" refers to the group of the formula -O-alkyl.

[0023] - "Alkyl" refers to any saturated linear or branched hydrocarbon chain having 1 to 12 carbon atoms; preferably 1 to 6 carbon atoms; more preferably 1 to 3 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl and its isomers (e.g., n-pentyl or i-pentyl) or hexyl and its isomers (e.g., n-hexyl or i-hexyl). Preferably, the alkyl is ethyl or methyl; more preferably methyl.

[0024] - "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, having a single ring (i.e., phenyl) or multiple aromatic rings that are condensed together (e.g., naphthyl) or covalently bonded, wherein at least one ring is aromatic. The aromatic ring may optionally contain 1 to 2 further rings (any of cycloalkyl, heterocyclyl, or heteroaryl) that are condensed thereto. Examples of aryls include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6- or 7-indenyl, 1-2-, 3-, 4- or 5-acenaphthenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl.

[0025] - The term "aromatic ring" collectively refers to aryl and heteroaryl groups.

[0026] - "Haloalkyl" refers to an alkyl group as defined above herein, in which at least one hydrogen atom is replaced by a halogen atom selected from fluorine, chlorine, bromine, and iodine. Preferably, each halogen atom in the haloalkyl is fluorine, i.e., the haloalkyl is a "fluoroalkyl".

[0027] - "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 that are condensed together or covalently bonded, wherein at least one ring is aromatic, and one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, and the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Such rings can be condensed into aryl, cycloalkyl, heteroaryl, or heterocyclyl rings. Examples of heteroaryls include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridadinyl, oxazinyl, dioxynyl, thiadinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, or thieno[3,2-b]furanyl.

[0028] The term "pharmaceutically acceptable," used in conjunction with the components of a composition, means that the components of the pharmaceutical composition are compatible with each other and are not harmful to the subject to whom the pharmaceutical composition is administered.

[0029] - "Pharmacologically acceptable excipients" refer to excipients or vehicles that, when administered to a subject, preferably a human, do not cause adverse allergic reactions or other unwanted reactions. This includes all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. For human administration, the preparation should meet the standards of sterility, pyrogenicity, overall safety, and purity as required by regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0030] - "Pharmaceutical composition" refers to a composition comprising at least one pharmaceutically active substance in relation to at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are therapeutic and relating to health. In particular, pharmaceutical compositions may be adapted for the treatment of diseases selected from eating disorders, such as obesity.

[0031] - "Solvate" refers to a molecular complex comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol, in stoichiometric or quasi-stoichiometric amounts. The term "hydrate" refers to the case where the solvent is water.

[0032] - "Subject" refers to a warm-blooded animal, preferably a mammal, more preferably a human. Preferably, the subject is a patient, i.e., a subject who is waiting to receive medical treatment, is receiving medical treatment, or will be the subject of / will be the subject of medical treatment. For example, the subject may be treated for an eating disorder, such as obesity.

[0033] - "Thioalkyl" refers to the group of the formula -S-alkyl.

[0034] - "Therapeutic agent," "activator," and "pharmaceutical activator" are synonymous terms referring to compounds for therapeutic use and related to health. In particular, therapeutic agents may be used for the treatment of eating disorders, such as obesity.

[0035] - "Treatment," "treatment," or "alleviation" refers to both therapeutic treatments and preventive or preventive measures; the purpose is to prevent or delay (mitigate) the targeted disease or condition in a person in need. Persons in need of treatment include those who already have the disease or condition, as well as those who are prone to the disorder or whose disorder should be prevented. A subject is successfully "treated" with respect to a disease or pathogenic factor if, after administration of a therapeutic dose of a compound or composition according to the present invention, the subject shows one or more observable and / or measurable reductions of: a reduction in the number of pathogenic cells; a reduction in the percentage of total cells that are pathogenic; a reduction to some extent of one or more of the symptoms associated with a particular disease or condition; a reduction in morbidity and mortality; and / or an improvement in quality of life problems. The above parameters for evaluating the success of treatment and improvement of disease are readily measurable by common procedures well known to physicians. For example, the disease may be selected from eating disorders, e.g., obesity.

[0036] - 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, cattle, sheep, and their transgenic species. In one embodiment, the individual may be a “patient,” i.e., a warm-blooded animal, more preferably a human, who is waiting to receive or receiving medical treatment, or who has been / is / will be the subject of medical treatment, or is being monitored for the onset of a disease. In one embodiment, the individual is an adult (e.g., a human subject over 18 years of age). In another embodiment, the individual is a child (e.g., a human subject under 18 years of age). In one embodiment, the individual is male. In another embodiment, the individual is female. [Brief explanation of the drawing]

[0037] [Figure 1] Figure 1 is a graph showing the migration distance of zebrafish larvae treated with a vehicle (CTRL, white circle) and pentetrazole at a concentration of 10 mM (black circle). [Figure 2] Figure 2 is a graph showing the migration distance of zebrafish larvae treated with 10 mM pentetrazole (black circles) or simultaneously treated with 10 mM pentetrazole and 100 μM Cmpd1 (white inverted triangles) or 100 μM Cmpd1 (white circles). [Figure 3] Figure 3 is a graph showing the migration distance of zebrafish larvae treated with a vehicle (CTRL, white circle) and apomorphine at a concentration of 75 μM (black circle). [Figure 4] Figure 4 is a graph showing the migration distance of zebrafish larvae treated with a 75 μM apomorphine (black circles) or simultaneously treated with a 75 μM apomorphine and a 100 μM Cmpd1 (white inverted triangles). [Figure 5] Figure 5 is a graph showing the migration distance of zebrafish larvae treated with either the vehicle (CTRL, white circle) or Cmpd1 at a concentration of 100 μM (black inverted triangle). [Figure 6] Figure 6 is a graph showing the accumulated migration distance at 2, 22, and 60 minutes by zebrafish larvae treated with the vehicle (CTRL, dashed line) and 10 mM pentetrazole (solid line). The area under the response to pentetrazole compared to the control is represented by connected lines and a patterned background. One-way anova using Tukey's method for multiple comparisons, CTRL vs. PTZ***P<0.001, **P<0.003. [Figure 7]Figure 7 is a graph showing the accumulated migration distance at 2, 4, 10, and 20 minutes by zebrafish larvae treated with 10 mM pentetrazol (solid line), simultaneously treated with 10 mM pentetrazol and 100 μM Cmpd1 (dashed line), or treated with 100 μM Cmpd1 (thin dashed line). The area of ​​the response to pentetrazol compared to treatment with Cmpd1 alone or Cmpd1 in combination with pentetrazol is represented by connected lines and a patterned background. One-way anova using Tukey's method for multiple comparisons: Cmpd1+PTZ vs. PTZ **P<0.002; Cmpd1 vs. PTZ***P<0.0001. [Figure 8] Figure 8 is a graph showing the accumulated migration distance at 2, 4, 10, and 20 minutes by zebrafish larvae treated with the vehicle (CTRL, solid line) and apomorphine at a concentration of 55 μM (thin line). The area under the response to apomorphine compared to the control is represented by the connected lines. One-way anova using Tukey's method for multiple comparisons, CTRL vs. APO ***P<0.0003;**P<0.022. [Figure 9] Figure 9 is a graph showing the accumulated migration distance at 2, 22, and 60 minutes by zebrafish larvae treated with a 55 μM apomorphine (solid line) or simultaneously treated with a 55 μM apomorphine and a 65 μM Cmpd1 (dashed line). The area of ​​the response to apomorphine compared to treatment with a combination of apomorphine and Cmpd1 is represented by connected lines and a patterned background. One-way anova using Tukey's method for multiple comparisons: Cmpd1+APO vs APO**P<0.0046; Cmpd1 vs APO*P<0.06. [Figure 10] Figure 10 is a graph showing the accumulated migration distance at 2, 22, and 60 minutes by zebrafish larvae treated with a vehicle (CTRL, dashed line) or with 100 μM Cmpd1 (solid line). The area under the response to vehicle treatment compared to Cmpd1 treatment is represented by the connected lines. [Modes for carrying out the invention]

[0038] The present invention relates to a compound of formula (I): [ka] or its salts, derivatives, isotopes or mixtures (in the formula, -R1, R2 and R 11 Each of them is independently a C1-C3 alkyl group. -R3, R4, R5, R6, R7, R8, R9 and R 10 These are independently selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl. -A is a 5-membered or 6-membered aromatic ring containing 0, 1, or 2 nitrogen atoms, and this 5-membered or 6-membered aromatic ring is either unsubstituted (i.e., unsubstituted) or each group is substituted with 1, 2, 3, or 4 groups independently selected from halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl. At least one pharmaceutically acceptable excipient, This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0039] This is a carboxylate group (COOR 11 Since it contains a piperidine moiety substituted at the 4th position by ), the compounds of formula (I) described herein are recognized as "4-piperidine carboxylate derivatives" in the sense of the present invention.

[0040] In one embodiment, A is a 5- or 6-membered aromatic ring selected from phenyl, pyridine, pyrrole, imidazole, pyrazole, diazine (i.e., pyrazine, pyrimidine, or pyridazine), and triazine, wherein the 5- or 6-membered aromatic ring is either unsubstituted or substituted as defined above with respect to formula (I). In one embodiment, A is phenyl, which is either unsubstituted or substituted as defined above with respect to formula (I). In one embodiment, A is a 4-alkylphenyl, i.e., a phenyl that is at least substituted at the 4-position with an alkyl group (e.g., a C1-C3 alkyl group).

[0041] In one embodiment, the compound of formula (I) is the compound of formula (II): [ka] (In the formula, -R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 This is as defined above in equation (I), -R 12 , R 13 , R 15 and R 16 These are independently selected from hydrogen, halogen, hydroxyl, -NH3, -NO3, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl. -R 14 (It is a C1-C3 alkyl group.)

[0042] In one embodiment, R1 is selected from methyl, ethyl, and propyl. In one embodiment, R1 is a methyl group.

[0043] In one embodiment, R2 is selected from methyl, ethyl, and propyl. In one embodiment, R2 is a methyl group.

[0044] In one embodiment, R 11R is selected from methyl, ethyl, and propyl. In one embodiment, R 11 It is an ethyl group.

[0045] One operating mechanism, R3, R4, R5, R6, R7, R8, R9 and R 10 R4, R6, R8 and R 10 is hydrogen. In one embodiment, R3, R4, R5, R6, R7, R8, R9 and R 10 It is hydrogen.

[0046] In one embodiment, R 12 , R 13 , R 15 and R 16 R is independently selected from 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 R is independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 12 , R 13 , R 15 and R 16 It is hydrogen.

[0047] In one embodiment, R 14 is a C1-C3 alkyl group. In one embodiment, R 14 R is selected from methyl, ethyl, and propyl. In one embodiment, R 14 It is a methyl group.

[0048] In one preferred embodiment, the compound of formula (I) is ethyl 1-(N-(methylsulfonyl)-N-(p-tolyl)alanyl)piperidine-4-carboxylate of formula (1) (hereinafter referred to as "compound 1" or "Cmpd1" herein): [ka] That is the case. Compound 1 was named using ChemDraw® Professional 15.0 (PerkinElmer).

[0049] According to one embodiment, at least one pharmaceutically acceptable excipient will be apparent to those skilled in the art; see the latest edition of Remington's Pharmaceutical Sciences.

[0050] In particular, the pharmaceutical composition of the present invention may optionally contain, for example, inert substances commonly used in pharmaceutical formulations, such as cosolvents, lipid carriers, antioxidants, surfactants, wetting agents, emulsifiers, buffers, pH adjusters, preservatives (or antiseptics), isotonic agents, stabilizers, granulators or binders, precipitation inhibitors, lubricants, disintegrants, diluents or bulking agents, adsorbents, dispersants, suspending agents, fillers, release agents, sweeteners, and flavoring agents.

[0051] In preferred embodiments, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable cosolvents. Preferably, the cosolvent is selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, dimethyl isosorbide, and mixtures thereof. In specific embodiments, the pharmaceutical composition of the present invention comprises caprylic acid and / or PEG. Advantageously, if the composition comprises PEG as a cosolvent, the PEG is of low molecular weight, preferably PEG400. In alternative embodiments, if the composition comprises PEG, the PEG is of medium molecular weight, preferably PEG3350.

[0052] In certain embodiments, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable lipid carriers. In preferred embodiments, the lipid carrier is lauroyl polyoxyl-32 glyceride. This excipient corresponds to Gelucire® 44 / 14, manufactured by Gattefosse (Saint-Priest-France). This excipient is also known by the following reference names: Lauroyl Polyoxyl-32 Glyceride NF / USP (NF: U.S. National Pharmacopoeia; USP: United States Pharmacopoeia); Lauroyl Macrogol-32 Glyceride EP (European Pharmacopoeia); Hydrogenated Coconut PEG-32 Ester (INCI); CAS number 57107-95-6. Gelucire® 44 / 14 corresponds to a clearly defined multi-component substance consisting of mono-, di-, and triglycerides and PEG-32 mono- and diesters of lauric acid (C12). Gelucire® 44 / 14 has a melting point in the range of 42.5°C to 47.5°C (average 44°C) and a hydrophilic / lipophilic balance (HLB) value of 14.

[0053] In another embodiment, the lipid carrier is vitamin E TPGS. This excipient is also known by the following reference names: D-α-tocopherol polyethylene glycol-1000 succinate; tocophersolane; tocophersolane; VEGS; α-[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-dioxybutyl]-ω-hydroxy-poly(oxy-1,2-ethanediyl); vitamin E PEG succinate, and is formed from vitamin E conjugated to polyethylene glycol 1000 via a succinate linker. The melting point of vitamin E TPGS is in the range of 37-41°C, and the hydrophilic / lipid-soluble balance (HLB) value is 13.

[0054] In one embodiment, the pharmaceutical composition of the present invention comprises one or more antioxidants; preferably, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine, and vitamin E; more preferably, the antioxidant is BHT.

[0055] In some embodiments, surfactants 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 monoethers (TWEEN®-20, TWEEN®-80, etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate), Cremophore RH40 (polyoxyl 40 hydrogenated castor oil), Cremophore EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12-Monosteart, Solutol HS15 (polyoxyethylated 12-hydroxystearic acid), Labrasol (caprylocaproyl polyoxyl-8 glyceride), Labrafil M1944 (oleoyl polyoxyl-6 glyceride), polylactide polyethylene glycol copolymer, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) are added.

[0056] In some embodiments, humectants such as sodium lauryl sulfate, vitamin E TPGS, sodium docusate, polysorbate 80, and poloxamer 407 are added. Poloxamer 407 is a preferred humectant.

[0057] In some embodiments, emulsifiers such as carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid ester, sorbitan ester, triethanolamine, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprilate are added. Preferred emulsifiers include, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprilate.

[0058] In some embodiments, buffers are used to help maintain pH within a range that approximates physiological conditions. Suitable buffers include both organic and inorganic acids and their salts, such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citrate-trisodium citrate mixture, citrate-monosodium citrate mixture, etc.), succinate buffers (e.g., succinate-monosodium succinate mixture, succinate-sodium hydroxide mixture, succinate-disodium succinate mixture, etc.), tartaric acid buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumarate-monosodium fumarate mixture, fumarate-disodium fumarate mixture, monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconate-sodium gluconate mixture, gluconate-sodium hydroxide mixture, gluconate-potassium glyconate (potassium These include gluconate (gluconate) mixtures, oxalate buffers (e.g., oxalate-sodium oxalate mixture, oxalate-sodium hydroxide mixture, oxalate-potassium oxalate mixture, etc.), lactate buffers (e.g., lactate-sodium lactate mixture, lactate-sodium hydroxide mixture, lactate-potassium lactate mixture, etc.), and acetate buffers (e.g., acetate-sodium acetate mixture, acetate-sodium hydroxide mixture, etc.). Furthermore, phosphate buffers, histidine buffers, and trimethylamine salts, such as Tris, can be used.

[0059] In some embodiments, pH adjusters 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 are added.

[0060] In some embodiments, preservatives are added to delay microbial growth. Suitable preservatives for use with the present disclosure include phenol, benzyl alcohol, meta-cresol, methylparaben, propylparaben, octadecyldimethylbenzylammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkylparabens, such as methylparaben or propylparaben, as well as catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0061] In some embodiments, isotonic agents, sometimes known as “stabilizers,” are added, which include polyhydric sugar alcohols, such as trihydric or higher-valent sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a broad category of excipients whose function can range from fillers to additives that solubilize therapeutic agents, or which help prevent denaturation or adsorption to the container wall, or which help inhibit the precipitation, particle growth, or aggregation of active ingredients. Typical stabilizers include polyhydric sugar alcohols (listed above); amino acids, e.g., arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, e.g., lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, etc. (including cyclitols such as inositol); polyethylene glycol; amino acid polymers; sulfur-containing reducing agents, e.g., urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or less); proteins, e.g. Human serum albumin, bovine serum albumin, gelatin or immunoglobulin; hydrophilic polymers, e.g., polyvinylpyrrolidone; poloxamer 407; cellulose derivatives, e.g., hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); monosaccharides, e.g., xylose, mannose, fructose, glucose; disaccharides, e.g., lactose, maltose, sucrose, and trisaccharides, e.g., raffinose; polysaccharides, e.g., dextran; polyethylene glycol methyl ether-block-poly(DL-lactide) copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1.Preferred stabilizers include, for example, glycerol; 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(DL-lactide) copolymer; and poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and polyvinylpyrrolidone polyvinyl acetate copolymer.

[0062] In some embodiments, granulators / binders, such as starch, gum (including natural, semi-synthetic, and synthetic), microcrystalline cellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, and polymers, such as povidone and polyvinylpyrrolidone polyvinyl acetate copolymer, are added. Preferred granulators include, for example, methylcellulose, hydroxypropylcellulose, povidone, and polyvinylpyrrolidone polyvinyl acetate copolymer.

[0063] In some embodiments, precipitation inhibitors are added, such as hydroxypropyl methylcellulose and water-soluble derivatives and polymers of cellulose including methylcellulose, such as polyvinylpyrrolidone, polyvinylpyrrolidone polyvinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or poloxamer 407. A preferred precipitation inhibitor is hydroxypropyl methylcellulose.

[0064] In some embodiments, lubricants such as magnesium stearate, glyceryl esters, behenoyl polyoxyl-8 glyceride Nf (Compritol HD5 ATO), and sodium stearyl fumarate are added.

[0065] In some embodiments, disintegrants, such as synthetic compounds like sodium starch glycolate, crospovidone, croscarmellose sodium, and coridone CL, as well as naturally occurring ones like locust bean gum, are added.

[0066] In some embodiments, lubricants such as talc, magnesium stearate, colloidal silicon dioxide, and starch are added.

[0067] In some embodiments, diluents (or bulking agents), such as dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, anhydrous calcium sulfate, and starch are added.

[0068] In some embodiments, adsorbents, such as silicon dioxide or purified aluminum silicate, are added.

[0069] In some embodiments, the pharmaceutical composition comprising the combination of the present invention is in tablet form, and tableting excipients, such as granulators, binders, lubricants, disintegrants, flow promoters, diluents, and adsorbents, are added.

[0070] In some embodiments, the pharmaceutical composition of the present invention is in the form of a capsule, in which case the capsule shell is composed of gelatin or a non-animal product such as cellulose and its derivatives such as hydroxypropyl methylcellulose. Other components, such as polyethylene glycol acting as a plasticizer; pigments such as titanium dioxide or iron oxide providing opacity and color differences; lubricants such as carnauba wax; gelling agents such as carrageenan; and wetting agents such as sodium lauryl sulfate may be included in the capsule shell. In one embodiment, the pharmaceutical composition of the present invention is formulated as a capsule in which the capsule shell is composed of gelatin, and further components such as polyethylene glycol and sodium lauryl sulfate are optionally included in the capsule shell.

[0071] Without limitation, the pharmaceutical compositions of the present invention may be in a form suitable for oral administration, parenteral administration (e.g., intravenous, intramuscular, or subcutaneous injection or intravenous infusion), topical administration (including ocular), rectal administration, inhalation administration, skin patch administration, implant administration, or suppository administration. Such suitable administration forms, which may be solid, semi-solid, or liquid depending on the method of administration, as well as methods for use in their preparations, and carriers, diluents, and excipients, will be apparent to those skilled in the art; see the latest edition of Remington's Pharmaceutical Sciences.

[0072] This composition may be formulated to provide rapid release, sustained release, or delayed release of the active compound contained herein.

[0073] According to one embodiment, the pharmaceutical composition of the present invention is in a form adapted for oral administration. The form adapted for oral administration may be a solid, semi-solid, or liquid. Some preferred but non-limiting examples of such forms include liquids, pastes, or solid compositions and, more specifically, films, tablets, tablets formulated for extended or sustained release, capsules (including soft and hard gelatin capsules), pills, sugar-coated tablets, lozenges, sachets, cachets, powders, liquids, gels, syrups, slurries, elixirs, emulsions, solutions, and suspensions.

[0074] In one embodiment, the pharmaceutical composition of the present invention is in a form designed for film-based drug delivery. In one embodiment, the pharmaceutical composition of the present invention is in the form of a film. In one embodiment, the film is a thin film, a soluble film, an oral drug strip, a biological film, and / or a 3D-printed film. In one embodiment, the film form of the pharmaceutical composition of the present invention is designed for oral administration.

[0075] According to another embodiment, the pharmaceutical composition of the present invention is in a form adapted for injection, particularly for injection into a target by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection, or intravenous drip infusion.

[0076] According to another embodiment, the pharmaceutical composition of the present invention is in a form adapted for topical administration. Examples of forms adapted for topical administration include, but are not limited to, liquids, pastes, or solid compositions, and more specifically, aqueous solutions, drops, dispersants, sprays, ointments, claims, lotions, microcapsules, microparticles or nanoparticles, polymeric patches or controlled-release patches.

[0077] In another embodiment, the pharmaceutical composition of the present invention is in a form adapted for rectal administration. Examples of forms adapted for rectal administration include, but are not limited to, suppositories, microenemas, enemas, gels, enema foams, creams, and ointments.

[0078] According to another embodiment, the pharmaceutical composition of the present invention is in a form adapted for administration by inhalation. Examples of forms adapted for administration by inhalation include, but are not limited to, aerosol formulations.

[0079] The pharmaceutical preparations of the present invention are preferably in unit dosage forms, for example, in a box, blister, vial, bottle, sachet, ampoule or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled); optionally, they may be appropriately packaged with one or more leaflets containing product information and / or instructions for use.

[0080] All references to compounds of formula (I) or (II) include references to their salts, solvates, multicomponent complexes, and liquid crystals. All references to compounds of formula (I) or (II) include references to their polymorphs and crystal habits. All references to compounds of formula (I) or (II) include references to pharmaceutically acceptable prodrugs and their prodrugs.

[0081] Compounds of formula (I) or (II) and their subformulaes contain at least one chiral center and therefore can exist in the form of different stereoisomers. Accordingly, all references to compounds of formula (I) or (II) include references to all possible stereoisomers, including not only racemic compounds but also individual enantiomers and non-racemic mixtures thereof. If a compound is desired as a single enantiomer, such a single enantiomer may be obtained by stereospecific synthesis, each known in the art, by separation of the final product or some convenient intermediate, or by chiral chromatography. Separation of the final product, intermediate, or starting material may be carried out by any suitable method known in the art. Bonding from asymmetric carbons in compounds is generally [ka] This is indicated using [a specific symbol]. The use of either a black wedge or a dotted wedge to indicate a bond from a chiral carbon atom signifies that only the stereoisomers shown are included.

[0082] All references to compounds of formula (I) or (II) include references to isotopically labeled compounds of formula (I) or (II), including deuterated compounds of formula (I) or (II).

[0083] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. pharmaceutically acceptable salts of the compounds of formula (I) or (II) include their acid addition salts and basic salts.

[0084] Appropriate acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipine, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, and lactic acid. Examples include salts, malates, maleates, malons, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, and xinofoates.

[0085] Suitable basic salts are formed from bases that form non-toxic salts. Examples include 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.

[0086] Hemi salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0087] Preferred pharmaceutically acceptable salts include hydrochloride / chloride, hydrobromide / bromide, disulfate / sulfate, nitrate, citrate, and acetate.

[0088] If the compound of formula (I) or (II) contains both an acidic group and a basic group, the compound of the present invention may also form an internal salt, and such a compound is within the scope of the present invention. If the compound of the present invention contains a hydrogen-donating heteroatom (e.g., NH), the present invention also includes salts and / or isomers formed by the transfer of the hydrogen atom to an intramolecular basic group or atom.

[0089] A pharmaceutically acceptable salt of the compound of formula (I) or (II) may be prepared by one or more of these methods: (i) by reacting a compound of formula (I) or (II) with a desired acid; (ii) By reacting a compound of formula (I) or (II) with a desired base; (iii) by removing an acid- or base-unstable protecting group from a suitable precursor of the compound of formula (I) or (II), or by opening the ring of a suitable cyclic precursor, such as a lactone or lactam, using a desired acid; and / or (iv) By converting one salt of the compound of formula (I) or (II) to another by reaction with a suitable acid or by a suitable ion exchange column.

[0090] All of these reactions generally occur in solution. The salt can be precipitated from the solution and recovered by filtration, or by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to nearly non-ionized.

[0091] The pharmaceutical composition of the present invention can be manufactured by methods well known to those skilled in the art.

[0092] Compounds of formula (I) or (II) may be purchased and / or prepared by standard synthetic procedures, both of which are well known to those skilled in the art, as well as by extraction and / or purification methods commonly used in the field of organic synthesis chemistry.

[0093] The present invention also relates to pharmaceutical compositions according to the present invention as described herein for use as pharmaceuticals. The present invention further relates to the use of compounds of formula (I) according to the present invention as described herein for the preparation or manufacture of pharmaceuticals.

[0094] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of brain disorders. In one embodiment, brain disorder is a disorder of the central nervous system (CNS). In one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of disorders of the central nervous system or disorders of its function.

[0095] In some embodiments, brain disorders include motor disorders, mood disorders, neurological disorders, and neurodegenerative disorders. In some embodiments, brain disorders may be the consequence of neurotransmission disorders. In some embodiments, brain disorders may be characterized by pathological synaptic dysregulation or neurodegenerative processes. According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of disorders characterized by pathological synaptic dysregulation or neurodegenerative processes.

[0096] In some other embodiments, brain damage may be a consequence of the action of a pathogenic factor or pathogen. According to one embodiment, the pathogenic factor or pathogen may be a bacterium, virus, fungus, or parasite. According to another embodiment, the pathogenic factor or pathogen may be an addictive substance such as alcohol or drugs. According to yet another embodiment, the pathogenic factor or pathogen may further be any molecule or substance that causes inflammation, particularly neurogenic inflammation, whether external to the body or produced / secreted by the body.

[0097] In one embodiment, the bacteria may be Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, Listeria monocytogenes, Escherichia coli, or Streptococcus agalactiae.

[0098] In one embodiment, the virus may be an enterovirus, poliovirus, Epstein-Barr virus, herpesvirus, cytomegalovirus, measles virus, human immunodeficiency virus (HIV), SARS-CoV-2 and its variants, or Zika virus.

[0099] In one embodiment, the parasite may be Toxoplasma gondii.

[0100] In one embodiment, the molecule or substance that causes inflammation is H + They can be ions, radical oxygen species (ROS), or amyloid.

[0101] In some embodiments, central nervous system disorders may include motor disorders, mood disorders, neurological disorders, or neurodegenerative disorders. In some embodiments, central nervous system disorders may be the result of neurotransmission disorders. In some other embodiments, central nervous system disorders may be the consequence of the action of pathogenic factors or pathogens.

[0102] According to one embodiment, the pharmaceutical composition is for use in the treatment and / or prevention of neurotransmitter disorders. According to the present invention, “neurotransmitter disorder” means disorders related to or resulting from changes in the neurotransmitter system / pathway, or interference / dysfunction of neurotransmitter metabolism. The term “neurotransmitter disorder” may be used interchangeably with the term “neurotransmitter disorder.”

[0103] In one embodiment, neurotransmission disorder is a disorder associated with alterations in adrenergic, dopaminergic, GABAergic, glutamatergic, noradrenergic, and / or serotonergic neurotransmission. Within the scope of the present invention, the term “altered” encompasses both increased or decreased activity of neurotransmitters compared to reference activity levels. In one embodiment, neurotransmission disorder is a disorder associated with increased activity of adrenergic, dopaminergic, GABAergic, glutamatergic, noradrenergic, and / or serotonergic neurotransmitters.

[0104] As used herein, increased or decreased activity can be evaluated by a change of at least 10% in the level of neurotransmitter activity compared to a reference level. Within the scope of the present invention, 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%, 1,000%, and more.

[0105] Neurotransmitter levels can be assessed according to some recognized method from prior art. Neurotransmitter levels can be assessed from saliva, blood, or urine samples, in practice, using commercially available kits. Alternatively, biosensors may be used.

[0106] In one embodiment, the neurotransmission disorder may be a motor disorder, a mood disorder, a neurological disorder, a neurodegenerative disorder, or an inflammatory disorder caused by a pathogenic factor or pathogen.

[0107] According to one embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of motor disorders.

[0108] In one embodiment, the movement disorder is selected from or includes Parkinson's disease, Huntington's disease, myopathy, multiple system atrophy, hereditary and non-hereditary dystonias including functional dystonia, restless legs syndrome, cerebellar disorders, and drug-induced movement disorders.

[0109] In certain embodiments, the movement disorder is Parkinson's disease. According to the present invention, the term "Parkinson's disease" includes, but is not limited to, hereditary and idiopathic (or non-hereditary) Parkinson's disease.

[0110] In some embodiments, the movement disorder is a drug-induced movement disorder. In other words, a drug-induced movement disorder is a disorder induced by treatment for a movement disorder, such as treatment for Parkinson's disease. In other words, a drug-induced movement disorder is an adverse side effect of treatment for a movement disorder. In certain embodiments, a drug-induced movement disorder is an adverse side effect of treatment for Parkinson's disease.

[0111] In certain embodiments, the pharmaceutical composition is intended for use in treating and / or preventing adverse effects caused by pharmaceuticals used to treat motor disorders. According to the present invention, the term “adverse effects caused by another drug therapy” refers to, but is not limited to, adverse effects caused by or occurring during treatment with, for example, dopamine agonists, dopamine partial agonists, L-DOPA, MAO inhibitors, etc.

[0112] In certain embodiments, ataxia is an example of a cerebellar disorder, but is not limited to this.

[0113] According to another embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of mood disorders.

[0114] In one embodiment, mood disorders are selected from or from the group including mental disorders, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety disorders, panic disorder, Tourette syndrome, obsessive-compulsive disorder, and attention deficit disorders, including attention deficit hyperactivity disorder.

[0115] In certain embodiments, mood disorders are anxiety disorders.

[0116] According to one embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of neurological disorders.

[0117] In one embodiment, the neurological disorder is selected from the group including or comprising epilepsy, Alzheimer's disease (AD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD) or hyperactivity disorder, agnosia, amyotrophic lateral sclerosis (ALS), ataxia including Friedreich's ataxia, Canavan disease, dementia, neuralgia, migraine, headache and tension headache.

[0118] In certain embodiments, the neurological disorder is epilepsy. According to the present invention, the term “epilepsy” includes, but is not limited to, diseases characterized by recurrent epileptic seizures or epileptic episodes, such as refractory epilepsy, hereditary epilepsy, epileptic disorders, childhood / infant epilepsy, and, for example, Dravet syndrome. In one embodiment, diseases characterized by recurrent epileptic seizures or epileptic episodes include, or comprise, injury-induced epilepsy, seizure-induced epilepsy, trauma-induced epilepsy, and tumor-induced epilepsy.

[0119] According to one embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of neurodegenerative disorders.

[0120] In one embodiment, the neurodegenerative disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and spinal muscular atrophy.

[0121] In certain embodiments, the neurodegenerative disease is Alzheimer's disease.

[0122] According to one embodiment, the pharmaceutical composition is intended for use in the treatment and / or prevention of inflammatory disorders caused by pathogenic factors or pathogens.

[0123] In one embodiment, the inflammatory disorder caused by a pathogenic factor or pathogen is chronic inflammation.

[0124] In one embodiment, the inflammatory disorder caused by a pathogenic factor or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neuropathy, SARS-CoV-2-induced neuropathy, nerve destruction, oligodendrocyte infection or damage, astrocyte infection or damage, neuronal infection or damage, and apoptotic neurons.

[0125] In one embodiment, the inflammatory disorder caused by a pathogenic factor or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neuropathy, SARS-CoV-2-induced neuropathy, and oligodendrocyte infection or damage.

[0126] According to another embodiment, the pharmaceutical composition is administered simultaneously with the other therapeutic agent described herein. In one embodiment, the other therapeutic agent is administered in the same pharmaceutical composition. In another embodiment, the other therapeutic agent is administered in a different pharmaceutical composition.

[0127] According to one embodiment, the pharmaceutical composition further comprises another therapeutic agent. In one embodiment, the therapeutic agent is for treating and / or preventing brain disorders, preferably CNS disorders. In one embodiment, the therapeutic agent is for treating and / or preventing motor disorders, mood disorders, neurological disorders, or neurodegenerative disorders. 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.

[0128] Accordingly, the present invention also relates to a method for treating and / or preventing a disorder, comprising administering a therapeutically effective amount of the pharmaceutical composition according to the present invention as described herein to a subject in need thereof. Accordingly, the present invention also relates to the use of the pharmaceutical composition according to the present invention as described herein in the manufacture of pharmaceuticals.

[0129] Another object of the present invention is a method of treating a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition according to the present invention as described herein.

[0130] In one embodiment, the method of the present invention 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 may be administered before, during, or after administration of the pharmaceutical composition according to the present invention. In some embodiments, the administration of the other therapeutic agent may be sequential or simultaneous with the administration of the pharmaceutical composition according to the present invention.

[0131] In one embodiment, the subject suffers from a neurological or neurodegenerative disorder. In one embodiment, the subject is at risk of developing a neurological or neurodegenerative disorder. In one embodiment, the subject suffers from a disorder induced by a pathogenic factor or pathogen, preferably an inflammatory disorder induced by a pathogenic factor or pathogen.

[0132] The present invention also relates to a method for improving the cognition and / or memory of a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to the present invention as described herein. Yet another object of the present invention is a method for restoring neurotransmission of a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to the present invention as described herein.

[0133] In certain embodiments, the therapeutically effective dose administered may depend on the substance selected for administration, whether the administration is a single dose or multiple doses, and various parameters including individual parameters such as age, health status, size, weight, and severity of disability.

[0134] In certain embodiments, the effective amount of the activator, i.e., the compound of formula (I), may be about 0.001 mg to about 3,000 mg per dose unit, preferably about 0.05 mg to about 100 mg per dose unit.

[0135] Within the scope of this invention, approximately 0.001 mg to approximately 3,000 mg per dose unit refers to approximately 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 g, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 20mg, 3 0mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550m g, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1,000mg, 1,100mg, 1,150mg, 1,200mg, 1,250mg, 1 ,300mg, 1,350mg, 1,400mg, 1,450mg, 1,500mg, 1,550mg, 1,600mg, 1,650mg, 1,700mg, 1,750mg, 1,800mg, 1,850 Includes mg, 1,900 mg, 1,950 mg, 2,000 mg, 2,100 mg, 2,150 mg, 2,200 mg, 2,250 mg, 2,300 mg, 2,350 mg, 2,400 mg, 2,450 mg, 2,500 mg, 2,550 mg, 2,600 mg, 2,650 mg, 2,700 mg, 2,750 mg, 2,800 mg, 2,850 mg, 2,900 mg, 2,950 mg, and 3,000 mg.

[0136] In certain embodiments, the activator, i.e., the compound of formula (I), may be at a dose level sufficient to deliver a target body weight of approximately 0.001 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 50 mg / kg, preferably approximately 0.1 mg / kg to approximately 40 mg / kg, preferably approximately 0.5 mg / kg to approximately 30 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, more preferably approximately 1 mg / kg to approximately 25 mg / kg per day.

[0137] In certain embodiments, each dose unit may be administered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks.

[0138] In a particular embodiment, the therapeutic treatment comprises the administration of multiple dose units, including two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more doses.

[0139] The present invention further relates to a kit of parts comprising the pharmaceutical composition of the present invention and means for optionally administering the pharmaceutical composition to a subject requiring it. In one embodiment, the kit of parts of the present invention further comprises another pharmaceutical composition comprising another therapeutic agent and means for optionally administering the other pharmaceutical composition. [Examples]

[0140] The present invention is further illustrated by the following embodiments.

[0141] Example 1: Cmpd1 in an epileptic activity model method The compounds were tested in typical zebrafish responses to environmental stimuli, epileptic activity, and dopaminergic hypermotility. The zebrafish used in this study were housed in appropriately sized tanks under normal conditions with a circadian rhythm (12:12 photoperiod, light / dark). Instant Ocean® was used as the water medium for maintenance and experimental conditions. The water was maintained at a temperature between 27°C and 29°C, with a pH of 7.2–7.5 and a conductivity of 480–520 μS. Zebrafish embryos were placed in sterile petri dishes and then transferred to plates after hatching.

[0142] For experimental studies, larvae up to 5 dpf were placed in a flat-bottomed 96-well plate. During the treatment time, the medium was replaced with 150 μL of fresh medium. Pentetrazole (PTZ) and / or Cmpd1 (treatment) or vehicle (control) were added to the wells (up to 210–240 μL), followed by video recording.

[0143] Spontaneous larval movement was recorded using a Noldus daniovisio system equipped with infrared light detection. Ethovision XT15 software controlled the plate temperature (28°C) and chamber lighting conditions. The experiment was recorded in cycles of a bright period (20 minutes) followed by a dark period (45 minutes). After recording, the data was analyzed using the Ethovision XT15 software package. Larval movement distance was calculated as the accumulated distance value for each 2-minute recording cycle (Figures 1-6 and 10) or at 2 minutes (start), 4 minutes, 10 minutes, and 20 minutes (switch to dark), or 60 minutes (end of recording) (Figures 7 and 8).

[0144] All compounds were dissolved in the medium or a medium containing DMSO to the specified concentration.

[0145] result Larvae treated with the vehicle exhibited normal spontaneous movement (Figures 1 and 5), and their activity increased after switching to darkness, peaking after 20 minutes, and then decreasing to a normal level of spontaneous movement around the end of the recording.

[0146] Treatment of zebrafish larvae with pentetrazol, a pro-epileptic / seizure-inducing compound, induced a significant increase in spontaneous motility activity in both light and dark conditions (Figures 1 and 2, black circles, and Figure 6). This increase is associated with seizure-inducing activity. Co-treatment with 100 μM Cmpd1 and 10 mM pentetrazol induced a decrease in spontaneous motility activity in ZF larvae that was induced by pentetrazol alone (Figure 2, inverted triangle, and Figure 7). Cmpd1 stabilized spontaneous motility to a level close to normal spontaneous motility observed in vehicle-treated zebrafish (Figure 2, white circles, and Figure 7).

[0147] Therefore, these results indicate that Cmpd1 possesses antiepileptic activity.

[0148] Example 2: Cmpd1 in a model of excessive dopaminergic neuronal activity method For Example 2, the same method as disclosed in Example 1 was followed, except that pentetrazole was replaced with apomorphine (APO).

[0149] result Treatment of zebrafish larvae with the dopamine agonist apomorphine induces a significant increase in spontaneous motor activity under light conditions (Figure 3, black circles and Figure 8). This increase is associated with the hyperactivity of dopaminergic neurotransmission pathways that lead to hyperactivity.

[0150] Simultaneous treatment with 100 μM Cmpd1 and 75 μM (Figure 4, inverted triangle) or 55 μM (Figure 9) apomorphine induced a decrease in the spontaneous motility of zebrafish larvae that was not induced by apomorphine alone.

[0151] Cmpd1 stabilizes spontaneous movement to a level close to the normal spontaneous movement observed in vehicle-treated zebrafish (Figure 5, black inverted triangle, and Figures 9 and 10). Cmpd1 strongly reduces apomorphine-induced spontaneous movement activity during the initial period of the assay (up to ~20 minutes, Figure 9). Cmpd1 alone maintains low levels of spontaneous movement activity and suppresses the peak caused by the transition to darkness (Figures 5 and 10).

[0152] Therefore, Cmpd1 has been demonstrated to be a stabilizer of excessive dopaminergic neuronal activity. Its inhibitory effect on the transition from light to dark states also indicates the effect of Cmpd1 on stress-mood disorders induced by challenging environments. These results suggest that this compound may be used to treat motor and mood disorders.

Claims

1. Equation (I): 【Chemistry 1】 A compound of which, in the formula, R １ , R ２ and R １１ Each of them is independently C １ -C ３ It is alkyl, R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently selected from hydrogen, halogen, hydroxyl, -NH ３ , -NO ３ , -SH, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy and C １ -C ３ thioalkyl, respectively, A is a five-membered or six-membered aromatic ring containing 0, 1, or 2 nitrogen atoms, wherein the five-membered or six-membered aromatic ring is unsubstituted or each group is a halogen, hydroxyl, or -NH ３ , -NO ３ ,-SH,C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy and C １ -C ３ Substituted with one, two, three, or four groups independently selected from thioalkyl groups, A compound or its salt, derivative, isotope, or mixture At least one pharmaceutically acceptable excipient, A pharmaceutical composition for use in the treatment and / or prevention of central nervous system disorders, including the following.

2. The pharmaceutical composition for use according to claim 1, wherein A is selected from phenyl, pyridine, pyrrole, imidazole, pyrazole, diazine, and triazine; preferably phenyl.

3. The compound of formula (I) is of formula (II): 【Chemistry 2】 It is a compound of the formula, in which, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ This is as defined in claim 1, R １２ , R １３ , R １５ and R １６ is hydrogen, halogen, hydroxyl, -NH ３ , -NO ３ ,-SH,C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy and C １ -C ３ Each is independently selected from thioalkyl groups, R １４ is C １ -C ３ It is alkyl. A pharmaceutical composition for use according to claim 1 or claim 2.

4. R １ A pharmaceutical composition for use according to any one of claims 1 to 3, wherein is a methyl group.

5. R ２ A pharmaceutical composition for use according to any one of claims 1 to 4, wherein is a methyl group.

6. R １１ A pharmaceutical composition for use according to any one of claims 1 to 5, wherein is an ethyl group.

7. R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ hydrogen and C １ -C ３ A pharmaceutical composition for use according to any one of claims 1 to 6, wherein each element is independently selected from alkyl groups, preferably hydrogen.

8. R １２ , R １３ , R １５ and R １６ However, hydrogen and C １ -C ３ Each is independently selected from alkyl groups, preferably hydrogen. R １４ However, C １ -C ３ It is alkyl, preferably methyl. A pharmaceutical composition for use according to any one of claims 1 to 7.

9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the central nervous system disorder is a motor disorder, mood disorder, neurological disorder, neurodegenerative disorder, or inflammatory disorder induced by a pathogenic factor or pathogen.

10. The pharmaceutical composition for use according to claim 9, wherein the motor disorder is selected from Parkinson's disease, Huntington's disease, myopathy, multiple system atrophy, hereditary and non-hereditary dystonias including functional dystonia, restless legs syndrome, cerebellar disease, and drug-induced motor disorder.

11. The pharmaceutical composition for use according to claim 10, wherein the motor disorder is Parkinson's disease.

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

13. The pharmaceutical composition for use according to claim 12, wherein the mood disorder is an anxiety disorder.

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

15. The pharmaceutical composition for use according to claim 14, wherein the neurological disorder is epilepsy.

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

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

18. The pharmaceutical composition for use according to claim 9, wherein the inflammatory disorder induced by a pathogenic factor or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neuropathy, SARS-CoV-2-induced neuropathy, nerve destruction, oligodendrocyte infection or damage, astrocyte infection or damage, neuronal infection or damage, and apoptotic neurons.

19. The pharmaceutical composition for use according to claim 18, wherein the inflammatory disorder induced by the pathogenic factor or pathogen is selected from encephalitis, myelitis, meningitis, gray matter atrophy, encephalopathy, HIV-induced neuropathy, SARS-CoV-2-induced neuropathy, and oligodendrocyte infection or damage.

20. A pharmaceutical composition for use according to any one of claims 1 to 19, wherein the use further comprises administering another therapeutic agent for use in the treatment and / or prevention of central nervous system disorders.

21. The pharmaceutical composition for use according to claim 20, further comprising another therapeutic agent for use in the treatment and / or prevention of central nervous system disorders.

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

23. A pharmaceutical composition for 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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