Novel thiohydantoin derivatives and uses thereof

Abstract

The present invention relates to thiohydantoin derivatives and compositions comprising the same for preventing or treating reduced coenzyme II (NADPH) oxidase (NOX)-related diseases, which can be used in the treatment of reduced coenzyme II oxidase-related diseases by virtue of excellent effects on NOX inhibition.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel thiohydantoin derivatives and uses thereof. BACKGROUND

[0002] Parkinson's disease is characterized by neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), which causes a gradual depletion of dopamine in the striatum. Parkinson's disease is characterized by a disruption of the basal ganglia circuit and an inability to perform the normal function of motor neurons, resulting in rigidity, tremor, akinesia. It is the second most common neurodegenerative disease in people over the age of 50, affecting 1-5% of this population.

[0003] Although the ultimate cause of Parkinson's disease is not yet clear, it is known that various symptoms occur due to the absence of dopamine, which is a brain neurotransmitter, produced in the nerve cells of the normal substantia nigra part of the midbrain.

[0004] Dopamine produced in the nerve cells distributed in the substantia nigra of the brain is connected to the basal ganglia including the corpus striatum. The basal ganglia are complexly connected to the motor cortex of the brain and other parts, and are very important parts that enable the movement of the human body to be performed gently, harmoniously and correctly. As a result of damage to such dopamine nerves, the absence of dopamine released from the basal ganglia dopamine nerve terminals is the main cause of movement disorders in Parkinson's disease.

[0005] There is no clear answer to the cause of Parkinson's disease, i.e., why the nerve cells of the substantia nigra are damaged, and thus research is actively being conducted to identify the cause. Although there are opinions that it is caused by infection from viral encephalitis, related to immunity, a genetic reason that manifests signs congenitally, an opinion that free radicals destroy nerve cells, a problem in the production and metabolism of dopamine, etc., it is still insufficient to explain all of Parkinson's disease.

[0006] On the other hand, it is known that 6-hydroxydopamine (6-OHDA) and L-glutamic acid are one of the inducing substances of the above-mentioned Parkinson's disease.

[0007] The above 6-hydroxydopamine (6-OHDA) is a neurotoxin, which is similar in chemical structure to dopamine, is known to be absorbed through dopamine transporters (DAT), to damage dopamine nerve cells by generating free radicals, thereby causing nerve cell apoptosis.

[0008] The above L-glutamate plays an important physiological role at normal concentrations, but acts as an excitotoxic amino acid when secreted in excess, causing nerve cell damage or apoptosis induced by excitotoxicity of excitatory neurotransmitters. As a result, it not only causes memory loss, cognitive impairment, but also causes various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, etc.

[0009] The above nerve cell damage caused by excitatory neurotransmitters or neurotoxins, etc. is manifested by excessive apoptosis of nerve cells in the central nervous system, and thus, inhibiting apoptosis of nerve cells will help protect nerve cells from memory loss, cognitive impairment, and further from neurodegenerative diseases.

[0010] In particular, recently, in order to protect patients from nerve cell apoptosis and degenerative neurological diseases, various drugs such as antagonists for neurotransmitter receptors, gamma-aminobutyric acid (GABA) efficacy agents, intracellular calcium antagonists, free radical scavengers, glutamate release inhibitors, etc. have been developed, but most of them have risk factors and side effects.

[0011] Also, the retina is a transparent membrane located at the innermost side of the wall of the eyeball, which is in contact with the vitreous body in the eyeball. The retina plays a role as a primary visual information organ that converts optical information of things into electrical signals and transmits images to the visual center of the brain through the optic nerve. The retina is a delicate organization formed of more than 100 million photoreceptor cells, more than 1 million ganglion cells as visual nerve cells, and many nerve cells connecting them that play the role of electrical wires. The central part of the retina, the macular lutea, which distinguishes colors and things and shows vision, is composed of a photoreceptor layer consisting of cone cells and a ganglion cell layer. In the macular lutea, the electrical signal of the image is converted into a chemical signal and conducted to the brain through the optic nerve as the axon of the ganglion cell. The retina outside the macular lutea recognizes the peripheral part and mainly functions in the dark.

[0012] When abnormalities of the retina occur due to aging or external factors, vision and visual field problems occur, and in severe cases, blindness occurs. Retinal diseases are retinal detachment in which the neural retina is separated from the retinal pigment epithelium (RPE) cell layer to induce vision impairment, peripheral retinal degeneration in which abnormalities are induced in the peripheral retina, and macular degeneration in which abnormalities occur in the macula. If the retina is separated from the pigment epithelium layer, it cannot receive optical information about the image. Also, the nerve cells lose function because they cannot receive nutrient supply from the choroid. If this state continues, blindness occurs due to permanent retinal atrophy.

[0013] The retinal pigment epithelium, which is located between the neural retina and the choroid, is a monolayer of cuboidal, polarized cells, and plays an important role in maintaining the function of the retina. Normal retinal pigment epithelium has an asymmetric structure in morphology and function. Deformation of retinal pigment epithelial cells can be prolonged to fibrotic eye diseases such as proliferative vitreoretinopathy (PVR), diabetic retinopathy (DR), and age-related macular degeneration (AMD). Under pathological conditions, retinal pigment epithelial cells not only lose their inherent morphology due to deformation, but also lose the function of extracellular release and phagocytosis.

[0014] On the other hand, if vision impairment begins to occur due to fibrosis of the retinal pigment epithelial cells, it is not possible to restore the past vision, and thus, it is important to treat it at an early stage. If fibrosis of the retinal pigment epithelial cells is detected and treated at an early stage, vision loss can be minimized, but there is no proven treatment method so far.

[0015] Inventions related to various diseases including the above-mentioned diseases are related to reduced coenzyme II (NADPH) oxidase (NADPH-oxidase).

[0016] NOX has six trans-membrane domains and is a family of enzymes that transfer electrons across biological membranes. These enzymes widely and specifically regulate redox-sensitive signaling pathways and are associated with various pathogenic mechanisms. Generally, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. Thus, the main biological function of NOX is to produce reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are small molecules derived from oxygen, including oxygen radicals (superoxide anion [*O2], hydroxyl radical [HO*], peroxyl radical [ROO*], alkoxy radical [RO*], and hydroperoxyl radical [HOO*]), and also include other non-radical compounds that are easily converted into oxidants and / or free radicals such as hydrogen peroxide (H2O2).

[0017] Various diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, and the like, commonly exhibit oxidative stress, inflammation, microglial cell activation, progressive neural cell apoptosis, and the like in the onset and progression of the disease. It has been reported that the expression of Noxl, Nox2, and Nox4 is increased in the brains of patients with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and the like, and in disease-inducing experimental animals (Parkinson's disease animal models using herbicides or LPS, MPP + and the like, Alzheimer's disease animal models overexpressing APP, and amyotrophic lateral sclerosis animal models with SODl mutations) have a neuroprotective effect when Nox is knocked out or genetically inactivated.

[0018] Further, the dysfunction of retinal pigment epithelial cells caused by oxidative stress is decisively associated with the pathogenic mechanism of macular degeneration, and the activity of Nox is strongly associated with the vascularization by upregulating the dysfunction of vascular endothelial cells and vascular endothelial growth factor (VEGF).

[0019] In view of the above problems, the present inventors have confirmed that a novel thiohydantoin derivative has an excellent effect as a Nox inhibitor. In particular, it has been confirmed that the above Nox inhibitory effect has an effect of preventing or treating degenerative brain diseases such as Parkinson's disease, and retinal diseases such as macular degeneration, thereby completing the present invention. SUMMARY

[0020] TECHNICAL PROBLEM

[0021] The problem to be solved by the present invention is to provide a novel hydantoin compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0022] Also, the present application provides a use of the novel hydantoin compound, isomers thereof, or pharmaceutically acceptable salts thereof.

[0023] Technical Solution

[0024] Compound of Chemical Formula 1

[0025] To solve the above technical problem, the present application provides a compound, isomers thereof, or pharmaceutically acceptable salts thereof represented by the following Chemical Formula 1.

[0026] Chemical Formula 1

[0027]

[0028] In the above Chemical Formula 1, R a is hydrogen, hydroxyl, or C1 to C4 alkoxy, R b is C1 to C6 linear or branched alkyl, C3 to C 10 cycloalkyl, or -(C1 to C3 alkyl)C6-C 12 aryl, R c is hydrogen or C1 to C4 alkyl, n is any integer of 1 to 4, and m is any integer of 1 to 3.

[0029] More specifically, the above compound represented by Chemical Formula 1 can be a compound, isomers thereof, or pharmaceutically acceptable salts thereof represented by the following Chemical Formula 2.

[0030] Chemical Formula 2

[0031]

[0032] In the above Chemical Formula 2, R a is hydrogen, hydroxyl, or C1 to C4 alkoxy, R b is C1 to C6 linear or branched alkyl, C3 to C 10 cycloalkyl, or -(C1 to C3 alkyl)C6-C 12 aryl, R c is hydrogen or C1 to C4 alkyl, and n is any integer of 1 to 4.

[0033] More specifically, the above compound represented by Chemical Formula 1 can be a compound, isomers thereof, or pharmaceutically acceptable salts thereof represented by the following Chemical Formula 3.

[0034] Chemical Formula 3

[0035]

[0036] In the above Chemical Formula 3, R a , R b , R cand n is the same as defined in the above Chemical Formula 2.

[0037] More specifically, the above compound represented by Chemical Formula 1 can be a compound represented by the following Chemical Formula 4, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0038] Chemical Formula 4

[0039]

[0040] In the above Chemical Formula 4, R a , R b , R c and n are the same as defined in the above Chemical Formula 2.

[0041] The meanings of the terms and symbols used in the present application are as follows.

[0042] In the present application, "alkyl" means a straight chain or branched monovalent hydrocarbon group having a structural formula of -C n H (2n+1) . Non-limiting examples thereof include methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, t-pentyl, hexyl, etc. For example, "C1-C6 alkyl" can mean methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, t-pentyl, hexyl, etc. straight chain or branched alkyl groups.

[0043] In the present application, "alkoxy" means a functional group containing an alkyl group having an oxygen atom bonded thereto. C1 to C4 alkoxy can mean methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, etc. alkoxy groups.

[0044] In the present application, "C3 to C 10 cycloalkyl" means a cyclic, monovalent hydrocarbon group having a structural formula of -C n H (2n-1) having 3 to 8 carbon atoms. Non-limiting examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0045] In the present application, "C6-C 12 aryl" means an aromatic hydrocarbon having 6 or 12 carbon atoms. For example, it can mean a monocyclic (e.g., phenyl); a bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl), etc. ring type.

[0046] The above n is any integer of 1, 2, 3 or 4.

[0047] The above m is any integer of 1, 2 or 3.

[0048] In the present application, R ahydrogen, hydroxyl, or C1 to C4 alkoxy. Preferably, R a may be hydrogen, hydroxyl, methoxy, or ethoxy.

[0049] In the present application, in R b in the case of C1 to C6 linear or branched alkyl, R b may be, for example, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, t-pentyl, hexyl, and the like, but is not limited thereto. According to an embodiment of the present application, it can be isobutyl.

[0050] In the present application, in R b in the case of C3 to C 10 cycloalkyl, preferably, it can be C5 to C8 cycloalkyl. More specifically, it can be cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. According to an embodiment of the present application, it can be cyclohexyl.

[0051] In the present application, in R b in the case of -(C1 to C3 alkyl)C6 to C 12 aryl, preferably, the above R b may be benzyl, phenethyl, phenpropyl, and the like.

[0052] In the present application, R c may be hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, or t-butyl.

[0053] In other examples, the compound represented by the above Chemical Formula 1 can be a compound in which, in Chemical Formula 1, R a is hydrogen, R b is C3 to C 10 cycloalkyl, R c is C1 to C4 alkyl, n is 1 to 4, and m is 1.

[0054] In other examples, the compound represented by the above Chemical Formula 1 can be a compound in which, in Chemical Formula 1, R a is hydrogen, R b is C1 to C6 linear or branched alkyl, R c is C1 to C4 alkyl, n is 1 to 4, and m is 1.

[0055] In other examples, the compound represented by the above Chemical Formula 1 can be a compound in which, in Chemical Formula 1, R a is hydroxyl, R b is C3 to C 10 cycloalkyl, R cis a C1 to C4 alkyl group, n is 1-4, and m is 1.

[0056] In other examples, the compound represented by the above Chemical Formula 1 may be the following compound: In Chemical Formula 1, R a is a C1 to C4 alkoxy group, R b C3 to C 10 Cycloalkyl, R c is a C1 to C4 alkyl group, n is 1-4, and m is 1.

[0057] In other examples, the compound represented by the above Chemical Formula 1 may be the following compound: In Chemical Formula 1, R a is hydrogen, R b -(C1 to C3 alkyl)C6-C 12 The aryl group, R c is a C1 to C4 alkyl group, n is 1-4, and m is 1.

[0058] In other examples, the compound represented by the above Chemical Formula 1 may be the following compound: In Chemical Formula 1, R a is hydroxyl group, R b -(C1 to C3 alkyl)C6-C 12 The aryl group, R c is a C1 to C4 alkyl group, n is 1-4, and m is 1.

[0059] In other examples, the compound represented by the above Chemical Formula 1 may be the following compound: In Chemical Formula 1, R a is a C1 to C4 alkoxy group, R b -(C1 to C3 alkyl)C6-C 12 The aryl group, R c is a C1 to C4 alkyl group, n is 1-4, and m is 1.

[0060] According to an embodiment of the present application, the compound of Chemical Formula 1 can be one selected from the group consisting of: (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; (E)-5-(4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; (Z)-5-(4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-cyclohexyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)phenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-phenethyl-5-(4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-benzyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)phenylmethylene)-1-methyl-2-thioxoimidazolin-4-one; and (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)-2-methoxyphenylmethylene)-1-methyl-2-thioxoimidazolin-4-one.

[0061] The compound of Chemical Formula 1 according to the present application can contain one or more double bonds, and accordingly, geometric isomers such as cis / trans, (E) / (Z) forms can exist.

[0062] These isomers can be separated by existing techniques, for example, the compound of Chemical Formula 1 can be separated by fractional distillation such as tube chromatography or high performance liquid chromatography.

[0063] According to an embodiment of the present application, the compound of Chemical Formula 1 can be one selected from the group consisting of:

[0064]

[0065] The compound of Example 2 above can also have the following structure according to the (E) / (Z) form.

[0066]

[0067] In the present application, the pharmaceutically acceptable salt refers to a salt generally used in the pharmaceutical industry, for example, inorganic ion salts prepared using calcium, potassium, sodium, and magnesium, inorganic acid salts prepared using hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, and sulfuric acid, organic acid salts prepared using acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, sulfonic acid salts prepared using methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, amino acid salts prepared using glycine, arginine, lysine, and ammonium salts prepared using trimethylamine, triethylamine, ammonia, pyridine, and methylpyridine, but the type of the salt is not limited to the above-listed salts.

[0068] Use of the compound of Chemical Formula 1

[0069] The present application provides use of a compound represented by the following Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0070] Chemical Formula 1

[0071]

[0072] In the above Chemical Formula 1, R a is hydrogen, hydroxyl, or C1 to C4 alkoxy, R b is C1 to C6 linear or branched alkyl, C3 to C 10 cycloalkyl, or -(C1 to C3 alkyl)C6-C 12 aryl, R c is hydrogen or C1 to C4 alkyl, n is any integer of 1 to 4, and m is any integer of 1 to 3.

[0073] The present application provides a pharmaceutical composition comprising the above compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0074] The present application provides a pharmaceutical composition comprising: the above compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0075] The present application provides a Nox inhibitor comprising the above compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0076] The compound of the present application exhibits excellent effects in the inhibition of Nox (reduced coenzyme II oxidase) and can be used in various therapeutic uses.

[0077] The present application provides a pharmaceutical composition for preventing or treating a reduced coenzyme II oxidase-related disease, comprising the above-mentioned compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0078] Members of the reduced coenzyme II oxidase family are enzymes that generate active oxygen as a main product. In order to produce superoxide anion, they generally reduce oxygen molecules by a reduced coenzyme II-dependent method. Such a mechanism of regulating active oxygen generation by the activity control of Nox is ultimately closely related to the signaling system of the cell as a whole, and thus, is highly associated with the treatment of the onset of various diseases in addition to the signaling system of the cell as a whole.

[0079] For example, various diseases of the central nervous system related to degenerative brain diseases including Parkinson's disease, Alzheimer's disease, etc. commonly occur oxidative stress and neuroinflammation in the onset and progression of the disease. In particular, Nox is identified as a master factor that regulates oxidative stress and neuroinflammation. Therefore, inactivation or pharmacological inhibition of Nox can expect a strong neuroprotective effect (e.g., dopamine neuron protection, pathological improvement of microglia, etc.) and a behavioral improvement effect of neurological diseases.

[0080] For example, dysfunction of retinal pigment epithelial cells due to oxidative stress can occur, such a dysfunction has a decisive correlation with the pathogenesis of retinal diseases, and the activity of Nox has a strong correlation with the vascularization by up-regulating the dysfunction of vascular endothelial cells and vascular endothelial growth factor, and thus, its inhibition can show an excellent effect in the treatment of diseases.

[0081] For example, Nox antagonists have an anti-tumor effect, or can also ensure sensitivity to immunotherapy and / or improve the reactivity to immunotherapy. Also, an effect of inhibiting angiogenesis can be shown. Also, the expression of inflammatory factors, etc. can be inhibited.

[0082] Accordingly, the reduced coenzyme II oxidase-related disease can be, for example, psoriasis, rheumatoid arthritis, osteoarthritis, restenosis, atherosclerosis, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, diabetes, hypertension, cardiac hypertrophy, heart failure, restenosis, cancer, autoimmune diseases, inflammatory diseases, degenerative brain diseases, retinal diseases, etc.

[0083] Autoimmune diseases include alopecia areata, amyotrophic lateral sclerosis, antiphospholipid syndrome, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA neuropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 or immune-mediated diabetes, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis, giant cell arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis, but are not limited thereto.

[0084] Examples of inflammatory diseases that can be prevented or treated by the composition of the present application include asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease, allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthritides, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation caused by chronic viral or bacterial infection, but are not limited thereto.

[0085] According to a preferred example of the present application, cancers that can be prevented or treated by the composition of the present application include brain cancer, neuroendocrine cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, large intestine cancer, colon cancer, cervical cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer, and urethral cancer, but are not limited thereto.

[0086] More specifically, the above-described compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof of the present application are effective in the prevention or treatment of degenerative brain diseases.

[0087] Accordingly, the present application provides a pharmaceutical composition for preventing or treating degenerative brain diseases, which comprises the above-described compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0088] Non-limiting examples of the degenerative brain disease in the present application can be Parkinson's disease, Huntington's disease, Alzheimer's disease, mild cognitive impairment, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy, Frontotemporal Dementia, and the like.

[0089] More specifically, the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof of the present application are effective in the prevention or treatment of retinal diseases.

[0090] Accordingly, the present application provides a pharmaceutical composition for preventing or treating retinal diseases, which comprises the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0091] Non-limiting examples of the retinal disease in the present application can be glaucoma, retinopathy of prematurity, proliferative retinopathy, corneal graft rejection, proliferative vitreoretinopathy, diabetic retinopathy, macular degeneration, choroidal neovascularization, or retinal edema, and the like. Specifically, the above-mentioned macular degeneration can be wet macular degeneration or dry macular degeneration.

[0092] Also, in terms of drug delivery, it can also exhibit excellent efficacy in passing through the blood-brain barrier (BBB).

[0093] For administration, the pharmaceutical composition of the present application can further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable carriers can use physiological saline, sterilized water, Ringer's solution, buffered physiological saline, glucose solution, maltodextrin solution, glycerol, ethanol, and one or more of the above components, and other general additives such as antioxidants, buffers, bacteriostatic agents, etc. can be added as needed. Also, diluents, dispersants, surfactants, binders, and lubricants can be added to be formulated into an injection dosage form such as an aqueous solution, suspension, emulsion, etc., a pill, a capsule, a granule, or a tablet. Thus, the pharmaceutical composition of the present application can be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc. These formulations can be prepared by a general method used in formulation in the technical field to which the present application pertains or a method disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and can be formulated into various formulations according to each disease or ingredient.

[0094] The pharmaceutical composition of the present application can be orally administered or parenterally administered (e.g., intravenous, subcutaneous, intraperitoneal, or local administration) according to the intended method, and the amount of administration varies depending on the body weight, age, sex, health status, diet, administration time, administration method, metabolic rate, type of disease, and severity of the disease of the patient. The daily administration amount of the compound of Chemical Formula 1 of the present application is about 0.01 mg / kg to 1000 mg / kg, preferably, 0.1 mg / kg to 100 mg / kg, and can be administered once a day or divided into several times.

[0095] That is, the composition can be administered by any general route capable of reaching the target tissue, but can be administered by subcutaneous injection, intradermal injection, intravenous injection, intraperitoneal injection, or intravitreal injection using an osmotic pump, etc.

[0096] In addition to the compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof described above, the pharmaceutical composition of the present application can further include one or more effective ingredients exhibiting the same or similar pharmacological effects.

[0097] The present application provides a method for treating or preventing a disease related to reduced form coenzyme II oxidase, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0098] The present application provides a method for treating or preventing a degenerative brain disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0099] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0100] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0101] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0102] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0103] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0104] The present application provides a method for treating or preventing a retinal disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound represented by Chemical Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof.

[0105] The compound of Chemical Formula 1 used to prepare a medicament can be mixed with an adjuvant, a diluent, a carrier, etc., and can be prepared into a composite preparation together with other active agents, thereby playing a role in increasing the active ingredient.

[0106] The present invention also includes the following embodiments: a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein, for use as a medicament; a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein, for use in the prevention or treatment of the above-mentioned diseases discussed herein; a method for treating the above-mentioned diseases, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein, to a subject in need thereof; a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein, for preparing a medicament for treating the above-mentioned diseases; a Nox inhibitor comprising a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein; and an antioxidant comprising a compound represented by Chemical Formula 1, an isomer, or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein.

[0107] All examples, isomers thereof, or pharmaceutically acceptable salts thereof may be claimed individually or in any combination of any number of the embodiments described in the present application.

[0108] Matters mentioned in the composition, use, and treatment method of the present invention are also applicable unless they are inconsistent with each other.

[0109] Effects of the Invention

[0110] The compound represented by Chemical Formula 1, its isomers, or pharmaceutically acceptable salts of the present invention exhibits excellent Nox inhibitory effects, particularly in the treatment of reduced coenzyme II oxidase-related diseases including degenerative brain diseases and retinal diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1 IC values ​​for confirming the Nox inhibitory effect of the compounds of the present invention are shown. 50 Value measurement results.

[0112] Figure 2 IC values ​​for confirming the Nox inhibitory effect of the compounds of the present invention are shown. 50 Value measurement results.

[0113] Figure 3The results of analysis of the Nox inhibitory effects of the compound of Example 1 (E7240-17) and the compound of Example 2 (E7240-40) in BV2 cells are shown.

[0114] Figure 4 The results of confirming the therapeutic effect of the compound of Treatment Example 1 in the MPTP-induced Parkinson's disease model are shown.

[0115] Figure 5 The results of immunohistochemical staining of the compound of Example 1 in the MPTP-induced Parkinson's disease model are shown.

[0116] Figure 6 Shown are the results of a behavioral test in which the compound of Example 1 was treated in an MPTP-induced Parkinson's disease model.

[0117] Figure 7 The graph shows a comparison of the amount of fluorescent α-synuclein in the hippocampus (HP CA1, HPCA2) of Huα-Syn transformed mice when the compound of Example 1 was administered.

[0118] Figure 8 The graph shows the pathological results of astrocytes in the prefrontal cortex (Pfcx) of Huα-Syn transformed mice after administration of the compound of Example 1.

[0119] Figure 9 The graph shows the pathological changes of microglia in the hippocampus (HP CA1) of Huα-Syn transformed mice after administration of the compound of Example 1.

[0120] Figure 10 The graph shows the degree of improvement in neuromuscular function of Huα-Syn transformed mice after administration of the compound of Example 1.

[0121] Figure 11 Comparison shows the amount of α-synuclein in PFF-injected mice after administration of the compound of Example 2.

[0122] Figure 12 The graph shows the pathological results of astrocytes in the prefrontal cortex (Pfcx) of PFF-injected mice after administration of the compound of Example 2.

[0123] Figure 13 The pathological results of microglia in PFF-injected mice after administration of the compound of Example 2 are shown.

[0124] Figure 14 The degree of improvement in neuromuscular function of PFF-infused mice after administration of the compound of Example 2 is shown.

[0125] Figure 15Results of laser-induced choroidal neovascularization (CNV) inhibition after administration of the compound of Example 1 are shown.

[0126] Figure 16 Results of improvement of post-synaptic function after administration of the compound of Example 1 are shown.

[0127] Figure 17 Results of weakening of laser coagulation-induced choroidal neovascularization lesions after administration of the compound of Example 1 are shown.

[0128] Figure 18 Results of inhibition of laser coagulation-induced apoptosis after administration of the compound of Example 1 are shown.

[0129] Figure 19 Results of inhibition of vascular endothelial growth factor (VEGF) expression after administration of the compound of Example 1 are shown.

[0130] Figure 20 Results of improvement of Mϋller cell and astrocyte activation after administration of the compound of Example 1 are shown. DETAILED DESCRIPTION

[0131] Hereinafter, an embodiment of the present application will be described in detail so that those skilled in the art to which the present application pertains can easily implement the present application. However, the present application can be implemented in various different forms, and is not limited to the embodiment described herein.

[0132] Unless otherwise specified, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Company, TCI Company.

[0133] All compounds were analyzed by HPLC using a Shimadzu LC-20A system (Shimadzu Corporation, Kyoto, Japan) equipped with a Phenomenex Gemini-NX column (Phenomenex, Torrance, CA, USA) and a UV detector. 1 H-, 13 C-NMR were measured using a Bruker AV-500, with CDCl3 (d H = 7.26 ppm and d C = 77.0 ppm) as internal standards. NMR data were processed using MNova 10.0 processing software (Mestrelab Research Company).

[0134] High resolution mass spectrometry analysis was performed using a Joel JMS-700 mass spectrometer based on ionization.

[0135] Example 1. Synthesis of (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)- 1 -methyl-2-thioxoimidazolin-4-one (E7240-17)

[0136]

[0137] (1) Synthesis of 3-cyclohexyl-l-methyl-2-thioxoimidazolin-4-one (8.51 g, 80% yield, white solid).

[0138] To a stirred solution of cysteine (4.45 g, 50.0 mmol) in absolute ethanol (50 mL) was added cyclohexyl isothiocyanate (7.77 g, 55.0 mmol). The reaction mixture was refluxed for 6 h and cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to obtain the corresponding thiohydantoin.

[0139] 1 H NMR (500 MHz, CDC13): δ H 4.52 (tt, J = 12.6, 3.7 Hz, 1H), 3.95 (s, 2H), 3.33 (s, 3H), 2.22 (qd, J = 13.5, 3.3 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.37 (qt, J = 13.2, 3.5 Hz, 2H), 1.24 (qt, J = 13.0, 3.4 Hz, 1H) ppm. J= J= J= J= J=

[0140] (2) Synthesis of (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-l-methyl-2- thioxoimidazolin-4-one (3.14 g, 84% yield, orange solid).

[0141] A Teflon sealed glass vessel (20 mL capacity) was charged with 3-cyclohexyl-l-methyl-2- thioxoimidazolin-4-one (2.12 g, 10.0 mmol), N-methyl-N-(2-hydroxyethyl)-4-aminobenzaldehyde (1.97 g, 11.0 mmol), piperidine (1.70 g, 20.0 mmol) and ethanol (10 mL) and introduced into the microwave cavity at 135 °C and 3.50 Bar - 5.00 Bar for 12 min at a power of 60 Watts. The temperature of the reaction mixture was allowed to reach room temperature. The solid formed was filtered, washed with ethanol (10 mL) and dried to obtain the product. ​​​​​

[0142] 1 H NMR (500 MHz, DMSO-d6): δ H 8.15 (d, J= 9.1 Hz, 2H), 6.80 (s, 1H), 6.77 - 6.72 (m, 2H), 4.75 (bs, 1H), 4.67 - 4.57 (m, 1H), 3.57 (m, 5H), 3.50 (t, J= 6.0 Hz, 2H), 3.04 (s, 3H), 2.27 (q, J= 12.4 Hz, 2H), 1.82 (d, J= 12.9 Hz, 2H), 1.71 - 1.56 (m, 3H), 1.36-1.23 (m, 2H), 1.23-1.12 (m, 1H) ppm; 13 CNMR (125 MHz, DMSO-d6): δ C 173.9, 161.6,151.0, 134.0, 124.9, 124.3, 120.0, 111.4, 58.7, 55.2, 54.3, 31.6, 28.7, 26.1,25.4 ppm; HRMS (EI) m / z [M]+ C 20 H 27 N3O2S, calc 373.1824, found 373.1824.

[0143] Example 2. Synthesis of 5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3- isobutyl-1-methyl-2-thioxoimidazolin-4-one (E7240-40)

[0144]

[0145] (1) Synthesis of 3-isobutyl-l-methyl-2-thioxoimidazolin-4-one (4.07 g, 87% yield, brown solid).

[0146] To a stirred solution of sarcosine (2.23 g, 25.0 mmol) in absolute ethanol (25 mL) was added isobutyl isothiocyanate (3.17 g, 27.5 mmol). The reaction mixture was refluxed for 6 h and cooled to room temperature. The precipitated solid was filtered, washed with ethanol (10 mL) and dried to obtain the corresponding thiohydantoin;

[0147] 1 H NMR (500 MHz, CDCl3): δ 4.04 (d, J=0.6 Hz, 2H), 3.64 (d, J= 7.5 Hz, 2H), 3.35 (s, 3H), 2.35 - 2.16 (m, 1H), 0.93 (d, J= 6.7 Hz, 6H) ppm.

[0148] (2) Synthesis of 5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one (2.81 g, 81% yield, orange solid).

[0149] 3-Isobutyl-1-methyl-2-thioxoimidazolin-4-one (1.86 g, 10.0 mmol), N-methyl-N-(2-hydroxyethyl)-4-aminobenzaldehyde (1.97 g, 11.0 mmol), piperidine (1.70 g, 20.0 mmol), and ethanol (10 mL) were placed in a Teflon-sealed glass container (20 mL capacity) and introduced into a microwave cavity at 135°C and 3.50-5.00 bar at a power of 60 watts for 12 minutes. The reaction mixture was allowed to reach room temperature. The resulting solid was filtered, washed with ethanol (10 mL), and dried to provide the product as a 1:1.25 E / Z mixture.

[0150] 1 H NMR (500 MHz, CDCl3): δ H 8.12(d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.9 Hz, 5H), 6.93 (s, 1H), 6.83 - 6.74 (m, 4H), 6.47 (s, 1H), 3.89 (s, 4H), 3.78 (dd, J= 9.9, 7.5 Hz, 4H), 3.65 (s, 3H), 3.61 (dt, J= 11.1, 5.7 Hz, 4H), 3.49 (s, 3H), 3.10 (d, J= 11.9 Hz, 5H), 2.34 (dt, J= 14.3, 7.1 Hz, 2H), 0.97 (dd, J= 6.7, 4.3 Hz, 11H) ppm.

[0151] Example 3. Synthesis of (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one (LMT-1890)

[0152]

[0153] (1) Synthesis of 4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzaldehyde (318 mg, 47% yield, white solid).

[0154] To a solution of 2-(methylamino)ethanol (0.4 mL, 4.9 mmol) and Na2C03(515 mg, 4.9 mmol) in dimethyl sulfoxide (DMSO) (20 mL) was added 4-fluoro-2- substituted benzaldehyde (500 mg, 3.2 mmol) and 18-crown-6 (86 mg, 0.3 mmol). The reaction mixture was stirred at 100 °C for 24 h. The mixture was extracted with ethyl acetate (10 mL) (x 3). After drying the combined organic layers over anhydrous MgS04, it was filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to obtain the product.

[0155] 1 H NMR (500 MHz, DMSO-d6): δ H 10.00 (s, 1H), 7.50 (d, J= 8.85 Hz, 1H), 6.39 (dd, J= 9.00, 1.68 Hz, 1H), 6.21 (d, J= 2.14 Hz, 1H), 4.79 (t, J= 5.34 Hz, 1H), 3.87 (s, 3H), 3.58 (q, J= 5.39 Hz, 2H), 3.55-3.48 (m, 2H), 3.07 (s, 3H) ppm.

[0156] (2) Synthesis of (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2- methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one (153 mg, 64% yield, orange solid).

[0157] To a stirred solution of 3-cyclohexyl-l-methyl-2-thioxoimidazolin-4-one (127 mg, 0.6 mmol), 4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzaldehyde (150 mg, 0.7), piperidine (0.08 mL, 0.9 mmol) in 1,4-dioxane (5 mL) was added AICI3(8 mg, 0.1 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x 3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The filtered residue was purified using silica gel chromatography to obtain the product.

[0158] 1 H NMR (500 MHz, CDC13): δ H 8.56 (d, J= 8.80 Hz, 1H), 6.96 (s, 1H), 6.46-6.36 (m, 1H), 6.20 (d, J= 2.45 Hz, 1H), 4.77-4.66 (m, 1H), 3.92-3.83 (m, 5H), 3.67-3.52 (m, 5H), 3.13-3.02 (m, 3H), 2.43-2.26 (m, 2H), 1.83 (d, J= 12.72 Hz, 2H), 1.55-1.77 (m, 6H), 1.36 (q, J= 13.21 Hz, 2H), 1.25 (t, J= 12.96 Hz, 1H) ppm; 13 CNMR (125 MHz, CDC13): δ C 174.9, 161.9, 159.9, 152.9, 132.5, 125.6, 116.7, 109.8, 104.2, 94.0, 60.4, 55.5, 54.6, 39.1, 35.3, 31.3, 28.6, 26.0, 25.2 ppm; HRMS (EI) m / z [M]+C 21 H 29 N3O3S, calc. 402.1, found 402.3.

[0159] Example 4. Synthesis of (E)-3-cyclohexyl-5-(2-hydroxy-4-((2- hydroxyethyl)(methyl)amino)benzylidene)-l-methyl-2-thioxoimidazolin-4-one (15 mg, 52% yield, orange solid) (LMT-1891)

[0160]

[0161] Next, the compound from Example 3 was used. A solution of (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one was stirred in anhydrous dichloromethane and dried under a nitrogen atmosphere, then cooled in an ice / acetone bath. BBr₃ (0.05 mL, 0.6 mmol) was added dropwise. After removing the cooling bath, the reaction mixture was stirred at room temperature for 3 hours. After cooling the mixture in an ice bath, methanol was added dropwise to remove (quench) the excess BBr₃. The resulting solution was stirred at room temperature for 2 hours. After removing the solvent, the residue was treated with H₂O (10 mL) and ethyl acetate (10 mL). The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography to obtain the product of Example 3.

[0162] 1 H NMR (500 MHz, CDCl3): δ H 8.64(d, J= 9.29 Hz, 1H), 7.14 (s, 1H), 6.31 (dd, J= 9.29, 2.45 Hz, 1H), 6.17 (d, J= 2.45 Hz, 1H), 4.74 (bs, 1H), 3.78-3.66 (m, 2H), 3.58 (s, 2H), 3.55-3.46 (m, 2H), 3.43 (s, 1H), 3.09-2.99 (m, 3H), 2.44-2.24 (m, 2H), 1.87(d, J= 13.21, 2H)、1.69(t, J= 11.74 Hz, 3H), 1.37 (q, J= 12.88 Hz, 2H), 1.31-1.17 (m, 2H) ppm; 13 CNMR (125 MHz, CDCl3): δ C 171.4, 164.4, 158.7, 136.7, 132.2, 120.6, 113.3,109.7, 106.5, 102.9, 60.3, 54.3, 39.1, 31.6, 28.6, 25.9, 25.1 ppm; HRMS (EI) m / z [M]+ C 20 H 27 N3O3S, calculated value 388.1, measured value 388.3.

[0163] Example 5. Synthesis of (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)benzylidene)- 1 -methyl-2-thioxoimidazolin-4-one (LMT-1889)

[0164]

[0165] (1) Synthesis of 4-((3-hydroxypropyl)(methyl)amino)benzaldehyde (870 mg, 75% yield, orange liquid).

[0166] To a solution of 3-(methylamino)propanol (0.9 mL, 9.0 mmol) and Na2C03 (954 mg, 9.0 mmol) in dimethyl sulfoxide (20 mL) was added 4-fluorobenzaldehyde (500 mg, 6.0 mmol) and 18-crown-6 (158 mg, 0.6 mmol). The reaction mixture was stirred at a temperature of 100 °C for 24 h. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to obtain the product.

[0167] 1 H NMR (500 MHz, DMSO-d6): δ H 9.65 (s, 1H), 7.76-7.60 (m, 2H), 6.80 (m, J= 8.85 Hz, 2H), 4.59 (t, J= 5.04 Hz, 1H), 3.50 (t, J= 7.32 Hz, 2H), 3.48-3.42 (m, 2H), 3.01 (s, 3H), 1.74-1.64 (m, 2H) ppm.

[0168] (2) Synthesis of 3-benzyl-l-methyl-2-thioxoimidazolin-4-one (1.062 g, 86% yield, orange liquid).

[0169] To a stirred solution of sarcosine (499 mg, 5.60 mmol) in anhydrous ethanol (20 mL) was added benzyl isothiocyanate (836 mg, 5.60 mmol). The reaction mixture was refluxed for 3 h and then cooled to room temperature. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to obtain the product.

[0170] 1 H NMR (500 MHz, DMSO-d6): δ H7.41-7.19 (m, 5H), 4.89 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm.

[0171] (3) Synthesis of (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)benzylidene)- 1 -methyl-2-thioxoimidazolin-4-one (83 mg, 46% yield, red solid).

[0172] To a stirred solution of 3-benzyl-l-methyl-2-thioxoimidazolin-4-one (100 mg, 0.46 mmol), 4-((3-hydroxypropyl)(methyl)amino)benzaldehyde (107 mg, 0.55 mmol), piperidine (0.06 mL, 0.69 mmol) in 1,4-dioxane (5 mL) was added AICI3(4 mg, 0.05 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The filtered residue was purified using silica gel chromatography to obtain the product.

[0173] 1 H NMR (500 MHz, CDC13): δ H 8.08 (m, J= 8.80 Hz, 2H), 7.53 (d, J= 7.34 Hz, 2H), 7.34-7.18 (m, 3H), 6.70 (m, J= 8.80 Hz, 2H), 6.44 (s, 1H), 5.28-5.06 (m, 2H), 3.71 (br. s., 2H), 3.61 (s, 3H), 3.54 (t, J= 7.09 Hz, 2H), 3.10-2.98 (m, 3H), 1.85 (quin, J= 6.24 Hz, 2H) ppm.

[0174] 13 CNMR (125 MHz, CDC13): δ C 174.4, 161.6, 150.7, 136.3, 133.5, 128.8, 128.4, 127.7, 125.1, 123.5, 119.9, 111.3, 60.2, 48.9, 45.1, 38.4, 30.8, 29.8 ppm; HRMS (EI) m / z [M]+ C 22 H 25N3O2S, calc 396.1, found 396.3.

[0175] Example 6. Synthesis of (E)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1- methyl-3-phenethyl-2-thioxoimidazolin-4-one (LMT-1845)

[0176]

[0177] (1) Synthesis of 4-((2-hydroxyethyl)(methyl)amino)benzaldehyde (910 mg, 63% yield, yellow liquid).

[0178] To a solution of 2-(methylamino)ethanol (1.0 mL, 12.1 mmol) and Na2CO3(1282 mg, 12.1 mmol) in dimethyl sulfoxide (20 mL) was added 4-fluorobenzaldehyde (1000 mg, 8.1 mmol) and 18-crown-6 (211 mg, 0.8 mmol). The reaction mixture was stirred at 100 °C for 24 h. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to give the product.

[0179] 1 H NMR (500 MHz, CDC13): δ H 9.64 (d, J= 1.83 Hz, 1H), 7.81-7.59 (m, 2H), 6.80-6.63 (m, 2H), 3.85 (br. s., 2H), 3.61 (t, J= 5.80 Hz, 2H), 3.11 (s, 3H) ppm.

[0180] (2) Synthesis of 1-methyl-3-phenethyl-2-thioxoimidazolin-4-one (940 mg, 71% yield, orange solid).

[0181] To a stirred solution of sarcosine (500 mg, 5.65 mmol) in anhydrous ethanol (20 mL) was added phenethyl isothiocyanate (922 mg, 5.65 mmol). The reaction mixture was refluxed for 4 h and cooled to room temperature. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to give the product.

[0182] 1 H NMR (500 MHz, DMSO-d6): δH 7.36-7.26 (m, 2H), 7.26-7.16 (m, 3H), 4.24 (s, 2H), 3.92-3.75 (m, 2H), 3.22 (s, 3H), 2.95-2.77 (m, 2H) ppm.

[0183] (3) Synthesis of (E)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1- methyl-3-phenethyl-2-thioxoimidazolin-4-one (103 mg, 61% yield, orange solid).

[0184] To a stirred solution of 1-methyl-3-phenethyl-2-thioxoimidazolin-4-one (100 mg, 0.43 mmol), 4-((2-hydroxyethyl)(methyl)amino)benzaldehyde (91 mg, 0.51 mmol), piperidine (0.06 mL, 0.65 mmol) in 1,4-dioxane (5 mL) was added AICI3(4 mg, 0.04 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The filtered residue was purified using silica gel chromatography to obtain the product.

[0185] 1 H NMR (500 MHz, CDC13): δ H 8.07 (d, J= 9.29 Hz, 2H), 7.36-7.28 (m, 4H), 7.25-7.19 (m, 1H), 6.75 (d, J= 8.80 Hz, 2H), 6.43 (s, 1H), 4.19-4.08 (m, 2H), 3.86 (d, J= 4.89 Hz, 2H), 3.65-3.53 (m, 5H), 3.13-3.04 (m, 3H), 3.04-2.95 (m, 2H) ppm; 13 CNMR (25 MHz, CDC13): δ C 174.4, 161.5, 151.0, 138.3, 133.3, 129.0, 128.5, 126.5, 125.1, 123.1, 120.5, 111.6, 60.3, 54.4, 43.2, 39.0, 34.0, 30.6 ppm; HRMS (EI) m / z [M]+C 22 H 25N3O2S, calculated 364.1, found 364.3.

[0186] Example 7. Synthesis of (E)-3-benzyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1 -methyl-2-thioxoimidazolin-4-one (LMT-2006)

[0187]

[0188] (1) Synthesis of 4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzaldehyde (318 mg, 47% yield, white solid).

[0189] To a solution of 2-(methylamino)ethanol (0.4 mL, 4.9 mmol) and Na2CO3(515 mg, 4.9 mmol) in dimethylsulfoxide (20 mL) was added 4-fluoro-2-substituted benzaldehyde (500 mg, 3.2 mmol) and 18-crown-6 (86 mg, 0.3 mmol). The reaction mixture was stirred at 100 °C for 24 h. The mixture was extracted with ethyl acetate (10 mL) (x 3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to give the product.

[0190] 1 H NMR (500 MHz, DMSO-d6): δ H 10.00 (s, 1H), 7.50 (d, J= 8.85 Hz, 1H), 6.39 (dd, J= 9.00, 1.68 Hz, 1H), 6.21 (d, J= 2.14 Hz, 1H), 4.79 (t, J= 5.34 Hz, 1H), 3.87 (s, 3H), 3.58 (q, J= 5.39 Hz, 2H), 3.55-3.48 (m, 2H), 3.07 (s, 3H) ppm.

[0191] (2) Synthesis of 3-benzyl-1-methyl-2-thioxoimidazolin-4-one (1.062 g, 86% yield, orange liquid).

[0192] To a solution of sarcosine (499 mg, 5.60 mmol) stirred in anhydrous ethanol (20 mL) was added benzyl isothiocyanate (836 mg, 5.60 mmol). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was filtered and purified by silica gel chromatography to obtain the product. 1 H NMR (500 MHz, DMSO-d6): δ H 7.41-7.19 (m, 5H), 4.89 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm.

[0193] (3) Synthesis of (E)-3-benzyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one (114 mg, 61% yield, orange solid).

[0194] To a solution of 3-benzyl-1-methyl-2-thioxoimidazolin-4-one (100 mg, 0.45 mmol), 4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzaldehyde (113 mg, 0.54 mmol), and piperidine (0.07 mL, 0.68 mmol) stirred in 1,4-dioxane (5 mL) was added AlCl₃ (5 mg, 0.05 mmol). The stirred reaction mixture was heated to 68°C-80°C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was filtered and purified by silica gel chromatography to obtain the product.

[0195] 1 H NMR; δ H 8.64(d, J= 9.0 Hz, 1H), 7.52 (d, J= 7.1 Hz, 2H), 7.30-7.22 (m, J= 14.6, 7.2 Hz, 4H), 7.00 (s, 1H), 6.39 (dd, J= 9.0, 2.3 Hz, 1H), 6.19 (d, J= 2.2 Hz, 1H), 5.15 (s, 2H), 3.91 - 3.82 (m, 5H), 3.62 (s, 3H), 3.58 (t, J= 5.6 Hz, 2H), 3.08 (d, J= 11.1 Hz, 3H) ppm.

[0196] (4) Synthesis of (E)-3-benzyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)benzylidene)- 1 -methyl-2-thioxoimidazolin-4-one (17 mg, 56% yield, orange solid).

[0197] A solution of (E)-3-benzyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzylidene)-1- methyl-2-thioxoimidazolin-4-one in anhydrous dichloromethane was stirred under a nitrogen atmosphere and cooled using an ice / acetone bath. BBr3(0.05 mL, 0.6 mmol) was added dropwise. After removing the cooling bath, the reaction mixture was stirred at room temperature for 3 hours. After cooling the mixture in an ice bath, methanol was added dropwise to quench the excess BBr3. The resulting solution was stirred at room temperature for 2 hours. After removing the solvent, the residue was treated with H2O (10 mL) and ethyl acetate (10 mL). After washing the combined organic layers with H2O, they were dried over Na2SO4and concentrated. The residue was purified using silica gel chromatography to give the product.

[0198] 1 H NMR (500 MHz, DMSO-d6): δ H , 8.69 (d, J= 9.1 Hz, 1H), 7.35-7.30 (m, 4H), 7.26 (t, J= 6.6 Hz, 1H), 7.11 (s, 1H), 6.28 (d, J= 9.1 Hz, 1H), 6.19 (s, 1H), 5.05 (s, 2H), 4.78 (s, 1H), 3.61-3.51 (m, 5H), 3.43 (t, J= 5.8 Hz, 2H), 2.97 (d, J= 13.1 Hz, 3H) ppm; 13 CNMR (125 MHz, DMSO-d6): δ C 172.7, 161.4, 153.4, 137.1, 132.3, 128.8, 128.0, 127.7, 123.0, 119.1, 108.3, 104.2, 97.3, 58.6, 54.3, 44.8, 31.1 ppm; HRMS (EI) m / z [M]+ C 21 H 23 N3O3S, calc. 398.2, found 398.2.

[0199] Example 8. Synthesis of (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)-2- methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one (LMT-2007)

[0200]

[0201] (1) Synthesis of 4-((3-hydroxypropyl)(methyl)amino)-2-methoxybenzaldehyde (177 mg, 49% yield, white solid).

[0202] To a solution of 3-(methylamino)propanol (0.2 mL, 2.4 mmol) and Na2C03 (256 mg, 2.4 mmol) in dimethylsulfoxide (10 mL) was added 4-fluoro-2-substituted benzaldehyde (250 mg, 1.6 mmol) and 18-crown-6 (45 mg, 0.2 mmol). The reaction mixture was stirred at 100 °C for 24 h. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo before using in the next reaction.

[0203] (2) Synthesis of 3-benzyl-1-methyl-2-thioxoimidazolin-4-one (1.062 g, 86% yield, orange liquid).

[0204] To a stirred solution of sarcosine (499 mg, 5.60 mmol) in anhydrous ethanol (20 mL) was added benzyl isothiocyanate (836 mg, 5.60 mmol). The reaction mixture was refluxed for 3 h before cooling to room temperature. The mixture was extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was filtered and purified using silica gel chromatography to give the product.

[0205] 1 H NMR (500 MHz, DMSO-d6): δ H 7.41-7.19 (m, 5H), 4.89 (s, 2H), 4.33 (s, 2H), 3.23 (s, 3H) ppm.

[0206] (3) Synthesis of (E)-3-benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)-2-methoxybenzylidene)-1- methyl-2-thioxoimidazolin-4-one (99 mg, 53% yield, orange solid).

[0207] To a stirred solution of 3-benzyl-l-methyl-2-thioxoimidazolin-4-one (100 mg, 0.45 mmol), 4-((3-hydroxypropyl)(methyl)amino)-2-methoxybenzaldehyde (121 mg, 0.54 mmol), piperidine (0.07 mL, 0.68 mmol) in 1,4-dioxane (5 mL) was added AICI3(5 mg, 0.05 mmol). The stirred reaction mixture was heated to 68-80 °C until the reaction was complete. The mixture was then extracted with ethyl acetate (10 mL) (x3). The combined organic layers were dried over anhydrous MgS04, filtered and concentrated in vacuo. The filtered residue was purified using silica gel chromatography to obtain the product.

[0208] 1 H NMR (500 MHz, CDC13): δ H 8.67 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.1 Hz, 2H), 7.23 (d, J = 7.0 Hz, 1H), 7.02 (s, 1H), 6.36 (d, J = 8.8 Hz, 1H), 6.15 (s, 1H), 5.14 (s, 2H), 3.85 (s, 3H), 3.68 (t, J = 5.4 Hz, 2H), 3.61 (s, 3H), 3.53 (t, J = 6.6 Hz, 2H), 3.02 (s, 3H) ppm; J= J= J= J= J= J= J= 13 CNMR (125 MHz, CDC13): δ C 173.9, 161.6, 160.2, 152.9, 136.4, 132.5, 128.7, 128.4, 127.6, 124.5, 117.9, 109.3, 104.2, 93.5, 77.3, 77.1, 76.8, 59.9, 55.5, 49.0, 45.1, 38.4, 30.9, 30.0 ppm; HRMS (EI) m / z [M]+C 22 H 25 N3O3S, calc 426.2, found 426.2.

[0209] Experimental Example 1. Luminol chemiluminescence assay test

[0210] Experimental Method

[0211] ​​​​​​​Human Nox lysosymes were obtained from transformed fruit flies expressing human Nox lysosymes in a daughterless (Da)-GAL4 promoter. The genotypes of each fruit fly for the long dispersed nuclear element are shown below.

[0212] 1) Human Nox1: UAS-hNox1 / UAS-dDuox-RNAi; Da-GAL4 / +

[0213] 2) Human Nox2: UAS-hNox2 / UAS-dDuox-RNAi; Da-GAL4 / +

[0214] 3) Human Nox4: UAS-hNox4 / UAS-dDuox-RNAi; Da-GAL4 / +

[0215] The fruit fly membranes for each Nox lysosyme were obtained by homogenizing the transformed fruit flies using a phosphate buffered solution (PBS) containing protease inhibitors (aprotinin, leupeptin). The membranes were incubated with the compounds (100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0 μM) for 10 minutes in a shaker. Then, a mixture of 500 μM reduced nicotinamide adenine dinucleotide phosphate (NADPH) (b-nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt hydrate; Sigma-Aldrich) and 400 μM lucigenin (N,N'-dimethyl-9,9'-biacridine nitrate; Sigma-Aldrich) in IX HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) was added to the membranes. The lucigenin chemiluminescence was measured for 10 minutes at 1 minute intervals using a multi-mode microplate reader (SpectraMax iD3, Molecular Devices). The IC 50 values were calculated using Graph-Pad Prism 5 (GraphPad Software).

[0216] (1) IC 50 value measurements

[0217] The lucigenin chemiluminescence assay was performed using fruit fly membranes expressing hNoxl, hNox2 and hNox4. The assay was repeated 3 times to confirm the average IC 50 values.

[0218] The results for the compounds of Example 1, Example 2, Example 4 of the present application are shown in Table 1 and Figure 1

[0219] Table 1

[0220] ​

[0221] Furthermore, the following Table 2 and Figure 2 The results are shown for the compounds of Examples 3, 5, 6, 7, and 8 of the present invention. The effects of Examples 3, 5, 6, 7, and 8 on Nox2 and Nox4 were confirmed.

[0222] Table 2

[0223]

[0224] (2) Analysis of the Nox Inhibitory Effects of the Compounds of Example 1 and Example 2 in BV2 Cells

[0225] BV2 cells were washed with Hank's balanced salt solution (HBSS) and incubated in HBSS at 37°C for 30 minutes. Compounds (the compound of Example 1 or the compound of Example 2) were then treated at various concentrations (0 nM, 1 nM, 10 nM, 100 nM, 1000 nM, and 10,000 nM). Thirty minutes later, 200 ng / ml lipopolysaccharide (LPS) and 200 μM lucigenin were added to the cells. Lucigenin chemiluminescence was measured using a luminometer (GLOMA, Promega) for 15 minutes at 10-second intervals.

[0226] Specifically, BV2 cells were pretreated with compound (A) of Example 1 or compound (B) of Example 2 for 30 minutes, and then assayed after generating reactive oxygen species and treating with LPS (200 ng / ml). Data are presented as mean ± SD (N = 3). Figure 3 shown.

[0227] pass Figure 3 It was confirmed that the treatment with the compound of Example 1 (E7240-17) and the compound of Example 2 (E7240-40) of the present invention exhibited an excellent NOx inhibitory effect, thereby significantly suppressing the generation of active oxygen.

[0228] Experimental Example 2. Experimental study on compounds treating MPTP-induced Parkinson's disease

[0229] (1) Experimental methods

[0230] 1) Experimental analysis of the efficacy of compounds on MPTP-induced Parkinson's disease

[0231] To evaluate the effect of the compound of Example 1 on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride; Sigma-Aldrich) induced Parkinson's disease, 26 C57BL / 6 male mice (9 weeks old) were randomly divided into three groups.

[0232] (1) Saline + solvent

[0233] (2) MPTP + solvent

[0234] (3) MPTP + compound of Example 1 (10 mg / kg)

[0235] MPTP (15 mg / kg) was intraperitoneally injected to the mice four times at intervals of 2 hours, and in contrast, the control group of mice was treated with the same volume of saline. The compound of Example 1 was dissolved in a solvent composed of 4% dimethyl sulfoxide (Sigma-Aldrich) and 96% corn oil (Sigma-Aldrich). From the day before the MPTP injection, 10 mg / kg of the compound of Example 1 was intraperitoneally injected to the mice every day for 8 days.

[0236] 2) Immunohistochemical staining experiment

[0237] Dopamine neurons were detected using an anti-tyrosine hydroxylase antibody (1:2000-4000, ABCAM) and microglia were measured using an anti-Iba1 antibody (1:1000, Wako). Biotinylated goat anti-rabbit antibody (VECTOR, BA-1000) was used as a secondary antibody, and an ABC solution (VECTOR, BA-1000) was used. Then, the immunoreactive region was transformed into brown using 3-3' diaminobenzidine (DAB, Dako).

[0238] Seven days after the injection of MPTP (one day after the final injection of the compound of Example 1), the mice were euthanized to recover the brain. The brain was formed into a coronal section (thickness 30 μm) using a cryostat (CM1850, Leica), and was stored in an anti-freezing solution (containing 30% sucrose, 1% polyvinylpyrrolidone, and 30% ethylene glycol in 1X phosphate buffer solution) at a temperature of -20°C.

[0239] The substantia nigra was collected in every 150 μM of 6 coronal sections from bregma -2.80 mm to -3.80 mm and 3 coronal sections from bregma +0.98 mm to +0.50 mm, and was stained and analyzed using ImagePro pluse 7.0 software.

[0240] 3) Behavioral test (rotarod test)

[0241] The rotarod test was performed on the mice in a manner of 3 times (1 day before MPTP injection, 3 days and 6 days after MPTP injection) and 3 tests / day. The speed of the rotarod was gradually increased from 4 RPM to 40 RPM, and the time of staying on the rotarod was analyzed.

[0242] (2) Experimental results on the compound of Example 1

[0243] 1) Experimental results on the compound of Example 1 treated in MPTP-induced Parkinson's disease

[0244] The compound of Example 1 protected dopamine neurons in MPTP-induced Parkinson's disease. In Figure 4 , A shows representative tyrosine hydroxylase (Th) immunostaining images of the substantia nigra and the striatum, B shows the Th + cell counts of 6 sections in the substantia nigra, and C shows the Th + fiber density of 3 sections in the striatum measured. The asterisk shows a significant difference (* p<0.05, *** p<0.0005 determined by Student's t-test).

[0245] From the above experimental results, it can be confirmed that the treatment of the compound of the present application shows an excellent effect in the protection of dopamine neurons.

[0246] 2) Immunohistochemical staining results

[0247] The compound of Example 1 improved the pathology of microglia in MPTP-induced Parkinson's disease. In Figure 5 , A shows representative Iba1 immunostaining images of the substantia nigra and the striatum, and the Iba1 + counts in the substantia nigra (B) and the striatum (C) are shown. The asterisk shows a significant difference (* p<0.05, ** p<0.005, *** p<0.0005 determined by Student's t-test).

[0248] The treatment of the compound of the present application shows an excellent effect in the improvement of the pathology of microglia.

[0249] 3) Behavioral test results

[0250] The compound of Example 1 improved motor function in MPTP-induced Parkinson's disease. The time of staying on the rotarod was evaluated by the rotarod test 1 day before MPTP injection, 3 days and 6 days after MPTP injection, and is shown in Figure 6 . The data are expressed as mean ± SD. The asterisk shows a significant difference (* p<0.05, ** p<0.005 determined by Student's t-test).

[0251] The treatment of the compound of the present application greatly increased the time of staying on the rotarod in the rotarod fatigue test, showing an excellent improvement effect.

[0252] Experimental Example 3. Experiment of treating compound to Huα-Syn transformed mouse

[0253] (1) Experimental method

[0254] In order to evaluate the effect of the compound of Example 1 on Huα-Syn transformed mouse, 6-month-old transformed mice or wild type mice were divided into 4 groups.

[0255] (1) Wild type (WT) + solvent

[0256] (2) Transformation (TG) + solvent

[0257] (3) Wild type + compound of Example 1 (10 mg / kg)

[0258] (4) Transformation + compound of Example 1 (10 mg / kg)

[0259] The compound of Example 1 was dissolved in a solvent composed of 4% dimethyl sulfoxide (Sigma-Aldrich) and 96% corn oil (Sigma-Aldrich). The compound of Example 1 was intraperitoneally injected to the mice at 10 mg / kg per day for three months.

[0260] (2) Experimental results of administering the compound of Example 1 to Huα-Syn transformed mouse

[0261] The above-mentioned experimental results are shown in Figure 7 The compound of Example 1 reduced the amount of fluorescent α-synuclein in Huα-Syn transformed mouse. Specifically, the immunoreactivity of fluorescent α-synuclein was significantly increased in the prefrontal cortex (Pfcx) and hippocampi (HP) of transformed mice. However, the amount of fluorescent α-synuclein in the hippocampi (HP CA1, HP CA2) of Huα-Syn transformed mouse treated with the compound of Example 1 for 3 months was reduced compared to that of Huα-Syn transformed mouse treated with solvent.

[0262] Also, as shown in Figure 8As shown, the compound of Example 1 improved astrocyte pathology in the prefrontal cortex (Pfcx) of Huα-Syn transformed mice. Huα-Syn transformed mice express a significantly increased amount of GFAP immunopositive astrocytes. Compared to Huα-Syn transformed mice treated with vehicle, transformed mice treated with the compound of Example 1 showed a reduced number of astrocytes in the prefrontal cortex.

[0263] Also, as shown, the compound of Example 1 improved microglia pathology in the hippocampus (HPC A1) of Huα-Syn transformed mice. In transformed mice with increased Ibal immunopositive microglia in the prefrontal cortex and hippocampus, transformed mice treated with the compound of Example 1 showed a reduced number of microglia in the HPC A1 compared to transformed mice treated with vehicle. Figure 9 Furthermore, as shown, the compound of Example 1 improved neuromuscular function in Huα-Syn transformed mice. The maximum force of the forelimbs was recorded using a grip strength meter. The grip strength of transformed mice treated with vehicle was reduced compared to wild type mice of the same age. The grip strength of Huα-Syn transformed mice treated with the compound of Example 1 for 3 months was improved.

[0264] Figure 10 Experiment 4. Treatment of PFF-induced Parkinson’s disease with the compound of Example 2

[0265] To induce PFF (preformed fibrils)-induced Parkinson’s disease, 5 μg of PFF were stereotaxically injected into the right dorsal striatum (AP + 0.2 mm, mL + 0.2 mm, DV 2.6 mm) of 8-12 weeks old C57BL / 6. Five months after the single injection of PFF, animals were injected intraperitoneally with 10 mg / kg of the compound of Example 2 daily for 3 months.

[0266] In particular, as shown, the compound of Example 2 reduced the amount of α-synuclein in the hippocampus (HPC A1, HPC A3) of PFF-injected mice. In PFF-injected mice treated with vehicle, the accumulation of α-synuclein in the hippocampus was increased. In contrast, by 3 months of dosing with the compound of Example 2, the amount of α-synuclein in the hippocampus (HPC A1, HPC A3) was significantly reduced.

[0267] In particular, as shown, the compound of Example 2 reduced the amount of α-synuclein in the hippocampus (HPC A1, HPC A3) of PFF-injected mice. In PFF-injected mice treated with vehicle, the accumulation of α-synuclein in the hippocampus was increased. In contrast, by 3 months of dosing with the compound of Example 2, the amount of α-synuclein in the hippocampus (HPC A1, HPC A3) was significantly reduced. Figure 11 Also, as shown, the compound of Example 1 improved microglia pathology in the hippocampus (HPC A1) of Huα-Syn transformed mice. In transformed mice with increased Ibal immunopositive microglia in the prefrontal cortex and hippocampus, transformed mice treated with the compound of Example 1 showed a reduced number of microglia in the HPC A1 compared to transformed mice treated with vehicle.

[0268] Figure 12 ​​As shown in FIG. 6, the compound of Example 2 improved astrocyte pathology in the prefrontal cortex of PFF-injected mice. A single injection of PFF (5 pg) increased GFAP-immunopositive astrocytes in both the prefrontal cortex and the hippocampus (HPC AI). The compound of Example 2 reduced GFAP-immunopositive astrocytes in the prefrontal cortex of PFF-injected mice after 3 months of administration.

[0269] Also, as shown in FIG. 7, the compound of Example 2 improved microglial pathology in PFF-injected mice. A single inoculation of PFF in the dorsal striatum increased Ibal-immunoreactivity in both the prefrontal cortex and the hippocampus (HPC AI). The compound of Example 2 reduced Ibal-immunopositive activated microglia in the prefrontal cortex and HPC AI after 3 months of administration. Figure 13

[0270] Finally, as shown in FIG. 8, the compound of Example 2 improved neuromuscular function in PFF-injected mice. The maximum force of the forelimb was recorded using a grip test apparatus. A single inoculation of PFF impaired the grip strength of the forelimb. The compound of Example 2 improved the grip strength of PFF-injected mice after 3 months of administration. Figure 14

[0271] The above results confirm that the compound of the present application has excellent Nox inhibitory effect and excellent antioxidant effect. Also, it is confirmed that the compound of the present application exhibits excellent effects, particularly in the prevention and treatment of degenerative brain diseases.

[0272] Experimental Example 5. Administration of the compound of Example 1 to diabetic retinopathy (DR) and aged-related macular degeneration (AMD)

[0273] (1) Experimental method

[0274] Choroidal neovascularization (CNV) was induced in 7-week-old female C57BL / 6 mice by laser photocoagulation (200 mW for 80 ms, 4 points). The mice were divided into 5 groups.

[0275] (1) Blank group

[0276] (2) Solvent group (laser and injection of solvent)

[0277] (3) Aflibercept 1 pg group (laser and intravitreal injection of 1 pg of aflibercept)

[0278] ​​(4) Aflibercept 20 pg group (laser and intravitreal injection of 20 pg of aflibercept)

[0279] (5) Compound of Example 1 group (laser and 5 pl of the compound of Example 1 (1 mg / ml), eye drop)

[0280] Intravitreal injection of 1 pl of aflibercept (1 mg / ml or 20 mg / ml) was performed on the first day after laser injury. 5 pl of the compound of Example 1 (1 mg / ml) was added to the eyeball 4 times a day for 12 days from the day after laser injury. On the 12th day after laser injury, the area of choroidal neovascularization was measured using fundus fluorescein angiography and histopathological assay. Visual function was evaluated using electrophysiology. Apoptotic cells were detected by TUNEL staining. Vascular endothelial growth factor and GFAP were detected by immunofluorescence staining.

[0281] (2) Experimental results of administration of the compound of Example 1

[0282] As shown in Figure 15 , the compound of Example 1 (E7240-17) inhibited choroidal neovascularization induced by laser. The compound of Example 1 (1 mg / mL, 5 pl, 4 times / day, for 12 days) administered as an eye drop reduced the leakage of choroidal neovascularization to a comparable degree of efficacy to intravitreal injection of 20 pg of aflibercept.

[0283] Also, as shown in Figure 16 , the compound of Example 1 improved postsynaptic function. On the 13th day after injury, the amplitude of the b-wave in the solvent group was lower than that in the blank group, but the eye drop of the compound of Example 1 improved the amplitude of the b-wave similarly to intravitreal injection of 20 pg of aflibercept.

[0284] On the other hand, as shown in Figure 17 , the compound of Example 1 attenuated choroidal neovascular lesions induced by laser coagulation. In order to investigate the histology of choroidal neovascular lesions, hematoxylin-eosin staining was performed. The lesion size of the compound of Example 1 group was significantly smaller than that of the solvent group.

[0285] As shown in Figure 18As shown, the compound of Example 1 inhibited apoptosis induced by laser coagulation. Mouse eyeball sections were stained using a TdT-UDP nick end labeler. TUNEL-positive cells were significantly increased in the solvent-treated group, but the eye drop of the compound of Example 1 similarly reduced TUNEL-positive cells to intravitreal injection of 20 μg of aflibercept. Yellow arrows show TUNEL-positive cells.

[0286] As shown, the compound of Example 1 inhibited expression of vascular endothelial growth factor. Immunofluorescence staining of eyeball sections was performed using an anti-vascular endothelial growth factor antibody. The immunolabeling of vascular endothelial growth factor was increased in the choroidal neovascularization of the solvent-treated group. However, the eye drop of the compound of Example 1 similarly reduced expression of vascular endothelial growth factor to intravitreal injection of 20 μg of aflibercept. Yellow arrows show vascular endothelial growth factor-positive cells. Figure 19

[0287] Finally, as shown, the compound of Example 1 improved activation of Muller cells and astrocytes. Activation of Muller cells and astrocytes was observed by immunostaining using an anti-GFAP antibody. Activation of Muller cells and astrocytes was observed in the solvent group 13 days after choroidal neovascularization. However, the eye drop of the compound of Example 1 similarly improved activation of Muller cells and astrocytes to intravitreal injection of 20 μg of aflibercept. Yellow arrows show GFAP-positive cells. Figure 20

[0288] From the above results, it was confirmed that the compound of the present application has an excellent Nox inhibitory effect and an excellent antioxidant effect. Also, it was confirmed that the compound of the present application particularly exhibits an excellent effect in the prevention and treatment of retinal diseases.

[0289] The present application has been described above by way of examples. It will be appreciated by persons skilled in the art that the present application can be embodied in other specific forms without changing the technical idea or essential characteristics thereof. Therefore, it will be appreciated that the above examples are merely illustrative, not restrictive. Rather than the detailed description, the scope of the present application is shown in the appended claims, and it will be appreciated that the meaning, scope and all modified or transformed forms derived by equivalent concepts are included in the scope of the present application.​​

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: It is represented by the following chemical formula 1, Chemical formula 1: In the above chemical formula 1, R a is hydrogen, hydroxy or C1 to C4 alkoxy, R b is isobutyl, cyclohexyl, benzyl or phenethyl, R c is hydrogen or a C1 to C4 alkyl group, n is any integer from 1 to 4, m is any integer from 1 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound represented by the above Chemical Formula 1 is a compound represented by the following Chemical Formula 3, Chemical formula 3: In the above chemical formula 3, R a is hydrogen, hydroxy or C1 to C4 alkoxy, R b is isobutyl, cyclohexyl, benzyl or phenethyl, R c is hydrogen or a C1 to C4 alkyl group, n is any integer from 1 to 4.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that The compound represented by the above Chemical Formula 1 is a compound represented by the following Chemical Formula 4, Chemical formula 4: In the above chemical formula 4, R a is hydrogen, hydroxy or C1 to C4 alkoxy, R b is isobutyl, cyclohexyl, benzyl or phenethyl, R c is hydrogen or a C1 to C4 alkyl group, n is any integer from 1 to 4.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The above R a is hydrogen, hydroxy, methoxy or ethoxy.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The above R c It is any one selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R a is hydrogen, hydroxy, methoxy or ethoxy, R b is any one selected from the group consisting of isobutyl, cyclohexyl, benzyl and phenethyl, R c is hydrogen, methyl or ethyl, n is 1, 2 or 3, m is 1.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound of the above Chemical Formula 1 is any one selected from the group consisting of the following compounds: (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one; (E)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; (Z)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-cyclohexyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one; (E)-3-Benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one; (E)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-3-phenethyl-2-thioxoimidazolin-4-one; (E)-3-Benzyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one; and (E)-3-Benzyl-5-(4-((3-hydroxypropyl)(methyl)amino)-2-methoxybenzylidene)-1-methyl-2-thioxoimidazolin-4-one.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that The compound of the above Chemical Formula 1 is any one selected from the group consisting of the following compounds: (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one; (E)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; (Z)-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-3-isobutyl-1-methyl-2-thioxoimidazolin-4-one; and (E)-3-Cyclohexyl-5-(2-hydroxy-4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolin-4-one.

9. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating NADPH oxidase (NOX)-related diseases. The above-mentioned NADPH oxidase (NOX)-related diseases are degenerative brain diseases or retinal diseases. wherein the degenerative brain disease is Parkinson's disease, The retinal disease is diabetic retinopathy or macular degeneration.

10. A pharmaceutical composition, characterized in that Include: The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier.

11. A pharmaceutical composition for preventing or treating NADPH oxidase (NOX)-related diseases, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in, The NADPH oxidase (NOX)-related disease is a degenerative brain disease or a retinal disease, wherein the degenerative brain disease is Parkinson's disease, The retinal disease is diabetic retinopathy or macular degeneration.

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