Triphenyl azole compounds

Abstract

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is useful as a drug. In addition, the present invention provides a pharmaceutical composition for treating or preventing synucleinopathies.

Description

Technical Field

[0001] The present invention relates to a triphenylazole compound that binds to a fatty acid binding protein, a pharmaceutical composition containing the compound, and a therapeutic method or a preventive method using the compound. Background Art

[0002] Alpha-synuclein is a protein composed of 140 amino acid residues encoded by alpha-synuclein gene (SNCA), and is abundantly expressed in the presynaptic terminal in the brain. The neurodegenerative disease group characterized by the abnormal accumulation of alpha-synuclein is called synuclein disease, and the accumulation in Lewy bodies and neurites in Lewy body dementia (DLB), the accumulation in the glial cytoplasm enclosure of multiple system atrophy, etc. have been known. It has been reported that polyunsaturated fatty acids participate in the oligomerization (non-patent literature 1) of alpha-synuclein. In Japan, which welcomes a real aging society, the number of patients with diseases equivalent to synuclein disease has increased significantly in recent years.

[0003] Fatty Acid Binding Protein (FABP) is a cytoplasmic protein with a molecular weight of 14-15 kDa and is expressed in tissue-specific manner. FABP uses medium-chain to long-chain fatty acids as ligands and is believed to be involved in the homeostasis of lipid metabolism and signal transduction. FABP is known to have multiple subtypes with similar molecular structures. FABP3 is expressed in the brain, heart, skeletal muscle, mammary gland, and placenta (Non-Patent Document 2). Its function is not yet fully understood, but it is believed to be related to lipid homeostasis, such as lipid uptake and transport to the β-oxidation system in mitochondria. In addition, it is believed to control the balance of neural excitation and inhibition in the brain. In addition, FABP3 has been reported to promote α-synuclein aggregation (Non-Patent Documents 4 and 5).

[0004] α-synuclein aggregates (encapsulated bodies) are expressed in dopaminergic neurons in the substantia nigra in Parkinson's disease (PD) and diffusely expressed in the cerebral cortex in dementia with Lewy bodies (DLB). It has been reported that after injecting fibrous synuclein into the striatum of rats, the aggregates not only accumulate in the substantia nigra but also spread to the cerebral cortex and form synuclein encapsulated bodies in nerve cells (Non-Patent Document 3).

[0005] FABP3 is highly expressed in dopaminergic neurons and promotes α-synuclein oligomerization and dopaminergic neuron death after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopamine neurotoxin, in vivo and in vitro. However, even when MPTP is administered to FABP3-deficient mice, no neurotoxic effect is expressed (Non-Patent Document 5). It has been reported that the LIGAND 1 compound (also known as MF1), a FABP3 ligand with FABP3 inhibitory activity, protects dopaminergic neurons from cell death caused by α-synuclein oligomerization (Patent Document 1 and Non-Patent Document 6). Prior art literature

[0006] Patent Literature Patent Document 1: WO2017 / 171053

[0007] Non-patent literature Non-patent document 1: Sharon, R et al., Neuron, Vol. 37, 583-595, February 20, 2003 Non-patent document 2: Yamamoto, Y. et al., J. Neurosci., 2018, 38(49): 10411-10423 Non-patent document 3: Paumier, KL et al., Neurobiology of Disease, 2015; 82: 185-199 Non-patent document 4: Ono Satomi et al., Summary of Lectures at the 52nd Meeting of the Tohoku Branch of the Japanese Pharmaceutical Society, 2013, vol. 52, p. 47 Non-patent document 5: Shioda, N. et al., J. Biol. Chem., 289 (2014), pp. 18957-18965 Non-patent document 6: Matsuo, K. et al., Neuropharmacology 150, (2019), 164-174 Summary of the invention Problems to be solved by the invention

[0008] For neurodegenerative diseases classified as synucleinopathies, it cannot be said that treatment methods and prevention methods that can provide sufficient effects have been established, and new treatment agents and prevention agents are being sought.

[0009] In one aspect, the present invention aims to provide a pharmaceutical composition for treating or preventing synucleinopathy. In addition, the present invention aims to provide a method for treating or preventing synucleinopathy using a specific triphenylazole compound. Means of solving problems

[0010] The present inventors have conducted intensive studies to achieve the above-mentioned objectives and have found that by introducing a halogenated C 1-6 The alkyl triphenylazole compound has the following beneficial effects: inhibiting the aggregation of α-synuclein, improving motor dysfunction and cognitive dysfunction, and having a neuroprotective effect, thereby completing the present invention. Furthermore, it was found that the triphenylazole compound of the present invention has unexpectedly higher affinity for FABP3 than the known FABP3 ligand LIGAND 1 compound (Patent Document 1). The disclosure of this specification includes the inventions described in the following [1-1] to [1-31] ​​and [2-1] to [2-31].

[0011] [1-1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0012] [Chemistry 1]

[0013] [Where R 1 is a hydrogen atom or a halogenated C 1-6 alkyl; R 2 Halogenated C 1-6 alkyl; R 3 Selected from hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy groups and halogen atoms; R 4 Selected from halogen atoms and C 1-6 alkyl; R 5 A hydrogen atom or C 1-6 alkyl; m is an integer selected from 0 to 3; n is an integer selected from 0 to 3; Het is a 5-membered nitrogen-containing aromatic heterocyclic ring in which one nitrogen atom and two carbon atoms are substituted by phenyl groups.]

[0014] [1-2] The compound as described in [1-1] or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (Ia),

[0015] [Chemistry 2]

[0016] [Where R 1 , R 2 , R 3 , R 4 , R 5, n and m are as defined in [1] above; X 1 and X 2 are independently nitrogen atoms or CR 6a ; R 6a is a hydrogen atom, a halogen atom or a C 1-6 alkyl.]

[0017] [1-3] The compound or pharmaceutically acceptable salt thereof as described in [1-1] or [1-2], wherein X 1 is a nitrogen atom, X 2 is CH, or X 1 and X 2 A nitrogen atom.

[0018] [1-4] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-3], wherein R 2 It is trifluoromethyl.

[0019] [1-5] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-4], wherein m is 0 or 1, and n is 0 or 1. [1-6] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-4], wherein m is 0 and n is 0 or 1.

[0020] [1-7] The compound or a pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-6], wherein the compound is represented by formula (Ib): [Chemistry 3]

[0021] [Where R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and m are as defined in any one of [1-1] to [1-6]].

[0022] [1-8] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-7], wherein R 1 A hydrogen atom.

[0023] [1-9] The compound or pharmaceutically acceptable salt thereof according to [1], wherein the compound is selected from: 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butanoic acid; 4-(4-fluoro-2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; and 4-(2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid.

[0024] [1-10] A pharmaceutical composition comprising the compound described in any one of [1-1] to [1-9] or a pharmaceutically acceptable salt thereof.

[0025] [1-11] The pharmaceutical composition described in [1-10], which is used for treating or preventing synucleinopathy.

[0026] [1-12] The pharmaceutical composition of [1-11], wherein the synuclein disease is Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy.

[0027] [1-13] The pharmaceutical composition as described in [1-10], which is used for treating or preventing diseases caused by dopamine nerve dysfunction.

[0028] [1-14] The pharmaceutical composition as described in

[10] is used for treating and preventing cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

[0029] [1-15] The pharmaceutical composition as described in [1-10] is used for treating or preventing mental illnesses such as autism or schizophrenia.

[0030] [1-16] The pharmaceutical composition according to any one of [1-10] to [1-15], which is for oral administration. [1-17] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-9], for use in treating or preventing synucleinopathy.

[0031] [1-18] The compound or pharmaceutically acceptable salt thereof according to [1-17], wherein the synuclein disease is Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy. [1-19] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-9], for use in treating or preventing a disease caused by dopamine nerve dysfunction.

[0032] [1-20] The compound or pharmaceutically acceptable salt thereof as described in any one of [1-1] to [1-9], which is used for treating or preventing cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

[0033] [1-21] The compound or pharmaceutically acceptable salt thereof according to any one of [1-1] to [1-9], which is used for treating or preventing mental illnesses such as autism or schizophrenia. [1-22] Use of the compound or pharmaceutically acceptable salt thereof as described in any one of [1-1] to [1-9] for preparing a pharmaceutical composition for treating or preventing synucleinopathy.

[0034] [1-23] The use of the compound or a pharmaceutically acceptable salt thereof as described in [1-22], wherein the synuclein disease is Parkinson's disease, Lewy body dementia or multiple system atrophy. [1-24] Use of the compound described in any one of [1-1] to [1-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing a disease caused by dopamine nerve dysfunction.

[0035] [1-25] Use of a compound as described in any one of [1-1] to [1-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment or prevention of cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma. [1-26] Use of a compound as described in any one of [1-1] to [1-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment or prevention of mental illnesses such as autism or schizophrenia.

[0036] [1-27] A method for preventing or treating synucleinopathy, comprising administering to a subject an effective amount of the compound described in any one of [1-1] to [1-9] or a pharmaceutically acceptable salt thereof. [1-28] The method for prevention or treatment as described in [1-27], wherein the synuclein disease is Parkinson's disease, Lewy body dementia, or multiple system atrophy.

[0037] [1-29] A method for preventing or treating a disease caused by dopamine nerve dysfunction, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of [1-1] to [1-9].

[0038] [1-30] A method for preventing or treating cerebrovascular disorders and head trauma such as cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of [1-1] to [1-9].

[0039] [1-31] ​​A method for preventing or treating a mental illness such as autism or schizophrenia, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of [1-1] to [1-9].

[0040] [2-1] A compound represented by formula (IX) or a pharmaceutically acceptable salt thereof:

[0041] [Chemistry 4]

[0042] [Where R 1 is a hydrogen atom or a halogenated C 1-6 alkyl; R 2 Halogenated C 1-6 alkyl; R 3 Selected from hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy groups and halogen atoms; R 4 Selected from halogen atoms and C 1-6 alkyl; R 5 A hydrogen atom or C 1-6 alkyl; R 6 is a halogen atom or C 1-6 alkyl; m is an integer selected from 0 to 3; n is an integer selected from 0 to 3; p is an integer selected from 0 to 2; Het is a 5-membered nitrogen-containing aromatic heterocyclic ring in which one nitrogen atom and two carbon atoms are substituted by phenyl groups.]

[0043] [2-2] The compound according to [2-1] or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (Ia):

[0044] [Chemistry 5]

[0045] [Where R 1 , R 2 , R 3 , R 4 , R 5 , n and m are as defined in [2-1] above; X 1 and X 2 are independently nitrogen atoms or CR 6a ; R 6a is a hydrogen atom, a halogen atom or a C 1-6 alkyl.]

[0046] [2-3] The compound or pharmaceutically acceptable salt thereof according to [2-1] or [2-2], wherein X 1 is a nitrogen atom, X 2 is CH, or X 1 and X 2 A nitrogen atom.

[0047] [2-4] The compound or pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-3], wherein R 2 It is trifluoromethyl.

[0048] [2-5] The compound or pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-4], wherein m is 0 or 1, and n is 0 or 1. [2-6] The compound or pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-4], wherein m is 0 and n is 0 or 1.

[0049] [2-7] The compound or a pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-6], wherein the compound is represented by formula (Ib): [Chemistry 6]

[0050] [Where R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and m are as defined in any one of [2-1] to [2-6].]

[0051] [2-8] The compound or pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-7], wherein R 1 A hydrogen atom.

[0052] [2-9] The compound or pharmaceutically acceptable salt thereof according to [2-1], wherein the compound is selected from: 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butanoic acid; 4-(4-fluoro-2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; and 4-(2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid.

[0053] [2-10] A pharmaceutical composition comprising the compound described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof.

[0054] [2-11] The pharmaceutical composition as described in [2-10], which is used for treating or preventing synucleinopathy.

[0055] [2-12] The pharmaceutical composition of [2-11], wherein the synuclein disease is Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy.

[0056] [2-13] The pharmaceutical composition as described in [2-10], which is used for treating or preventing diseases caused by dopamine nerve dysfunction. [2-14] The pharmaceutical composition described in [2-10] is used for treating and preventing cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

[0057] [2-15] The pharmaceutical composition as described in [2-10] is used for treating or preventing mental illnesses such as autism or schizophrenia. [2-16] The pharmaceutical composition according to any one of [2-10] to [2-15], which is for oral administration.

[0058] [2-17] The compound according to any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof, for use in treating or preventing synucleinopathy. [2-18] The compound or pharmaceutically acceptable salt thereof according to [2-17], wherein the synuclein disease is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy.

[0059] [2-19] The compound according to any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease caused by dopamine nerve dysfunction. [2-20] The compound or pharmaceutically acceptable salt thereof as described in any one of [2-1] to [2-9], which is used for treating or preventing cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

[0060] [2-21] The compound or pharmaceutically acceptable salt thereof according to any one of [2-1] to [2-9], which is used for treating or preventing mental illnesses such as autism or schizophrenia. [2-22] Use of the compound described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing synucleinopathy.

[0061] [2-23] The use of the compound or a pharmaceutically acceptable salt thereof as described in [2-22], wherein the synuclein disease is Parkinson's disease, Lewy body dementia or multiple system atrophy. [2-24] Use of the compound described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing a disease caused by dopamine nerve dysfunction.

[0062] [2-25] Use of a compound as described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating or preventing cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

[0063] [2-26] Use of a compound as described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment or prevention of mental illnesses such as autism or schizophrenia.

[0064] [2-27] A method for preventing or treating synucleinopathy, comprising administering to a subject an effective amount of the compound described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof. [2-28] The method for prevention or treatment as described in [2-27], wherein the synuclein disease is Parkinson's disease, Lewy body dementia, or multiple system atrophy.

[0065] [2-29] A method for preventing or treating a disease caused by dopamine nerve dysfunction, comprising administering to a subject an effective amount of the compound or a pharmaceutically acceptable salt thereof described in any one of [2-1] to [2-9].

[0066] [2-30] A method for preventing or treating cerebrovascular disorders and head trauma such as cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage, comprising administering to a subject an effective amount of a compound described in any one of [2-1] to [2-9] or a pharmaceutically acceptable salt thereof.

[0067] [2-31] A method for preventing or treating a mental illness such as autism or schizophrenia, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of [2-1] to [2-9]. Effects of the Invention

[0068] One aspect of the present invention provides a compound that has binding activity with fatty acid binding protein, particularly FABP3. Another aspect of the present invention provides a compound that has inhibitory activity against fatty acid binding protein, particularly FABP3. Still another aspect of the present invention provides a compound that has a therapeutic effect or a preventive effect on synucleinopathy. Still another aspect of the present invention provides a pharmaceutical composition for treating or preventing synucleinopathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] [ Figure 1 ] is a diagram showing the base sequences of GST-FABP3, GST-FABP4, GST-FABP5, and GST-FABP7 sequenced in Experimental Example 1. [ Figure 2 ] is a graph showing the cognitive function evaluation results of the passive avoidance test of Experimental Example 2. [ Figure 3 ] is a graph showing the cognitive function evaluation results of the new object recognition test of Experimental Example 3. [ Figure 4 ] is a graph showing the motor function evaluation results of the rotarod test of Test Example 4. [ Figure 5 ] is a graph showing the motor function evaluation results of the balance beam test of Test Example 4. [ Figure 6 ] is a graph showing the number of neurons expressing tyrosine hydroxylase (TH) in the brain slice containing the substantia nigra region prepared in Experimental Example 5. [ Figure 7 ] is a photograph of tyrosine hydroxylase-positive cells in a brain section containing the substantia nigra region prepared in Experimental Example 5 after staining. [ Figure 8] is a graph showing the number of neurons expressing tyrosine hydroxylase (TH) in the brain slice containing the ventral tegmental area (VTA) prepared in Experimental Example 5. [ Fig. 9 ] is a photograph of tyrosine hydroxylase-positive cells stained in a brain slice containing the ventral tegmental area (VTA) prepared in Experimental Example 5. [ Fig.10 ] is a photograph of a brain section containing substantia nigra (SNpc) prepared in Experimental Example 5 after staining for phosphorylated α-synuclein. [ Fig.11 ] is a graph showing that in the brain slice of the substantia nigra (SNpc) prepared in Experimental Example 5, Example Compound 2 protected dopaminergic neurons from the toxicity of α-synuclein. [ Fig.12 ] is a photograph of a brain section containing the ventral tegmental area (VTA) prepared in Experimental Example 5 after staining for phosphorylated α-synuclein. [ Fig.13 ] is a diagram showing that Example Compound 2 protects dopaminergic neurons from the toxicity of α-synuclein in the brain slice of the ventral tegmental area (VTA) prepared in Experimental Example 5. [ Fig.14 ] is a photograph of a brain section containing substantia nigra (SNpc) prepared in Experimental Example 5 after double staining of phosphorylated α-synuclein and FABP3. [ Fig.15 ] is a graph showing that the interaction between phosphorylated α-synuclein and FABP3 in dopaminergic neurons in the substantia nigra (SNpc) brain slice prepared in Test Example 5 is inhibited by Example Compound 2. [ Fig.16 ] is a photograph of a brain slice containing the ventral tegmental area (VTA) prepared in Experimental Example 5 after double staining of phosphorylated α-synuclein and FABP3. [ Fig.17 ] is a graph showing that the interaction between phosphorylated α-synuclein and FABP3 in dopaminergic neurons in the brain slice of the ventral tegmental area (VTA) prepared in Test Example 5 is inhibited by Example Compound 2. [ Fig.18 ] is a photograph of brain sections stained 24 hours after administration of various doses of Example Compound 1 30 minutes after reperfusion in the focal cerebral ischemia model prepared in Experimental Example 6. [ Fig.19 ] is a graph showing the infarct volume of brain sections 24 hours after administration of various doses of Example Compound 1 30 minutes after reperfusion in the focal cerebral ischemia model prepared in Test Example 6 and a graph showing the neurological score. [ Fig. 20 ] are photographs of brain sections stained in the focal cerebral ischemia model prepared in Test Example 6 when Example Compound 1 was administered 0.5, 1, and 2 hours after reperfusion. [ Fig.21 ] is a graph showing the infarct volume after staining of brain sections when Example Compound 1 was administered 0.5, 1, and 2 hours after reperfusion in the focal cerebral ischemia model prepared in Test Example 6, and a graph showing the neurological score. [ Fig. 22 ] is a photograph of brain sections stained 7 days after administration of various doses of Example Compound 1 30 minutes after reperfusion in the focal cerebral ischemia model prepared in Experimental Example 6. [ Fig.23 ] is a graph showing the infarct volume of brain sections 7 days after administration of various doses of Example Compound 1 30 minutes after reperfusion in the focal cerebral ischemia model prepared in Test Example 6 and a graph showing the neurological score. [ Fig.24 ] is to indicate Figures 18 to 23 Graph of mouse survival rate in . [ Fig.25 ] is a diagram showing the mechanism by which Example Compound 2 exerts its effects on dopaminergic neurons of PD (Parkinson's disease) model mice prepared by MPTP treatment ( Fig.25 Citation: Journal of Pharmacological Sciences, 152 (2023) 30-38 Figure 6 ). DETAILED DESCRIPTION

[0070] Hereinafter, the present invention will be described in more detail.

[0071] According to one aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing synuclein disease or illness, which contains a compound represented by formula (I) or formula (IX) or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment, there is provided a pharmaceutical composition for treating or preventing synuclein disease or illness containing a compound represented by formula (Ia) or formula (Ib) as an active ingredient. In this specification, the compound represented by formula (I) or formula (IX) includes a compound represented by formula (Ia) or formula (Ib).

[0072] In this manual, “C 1-6The term "alkyl" refers to a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl, and includes, for example, C 1-4 Alkyl and C 1-3 Alkyl, etc.

[0073] In this manual, “C 1-6 "Alkoxy" refers to an alkoxy group having a defined carbon number of 1 to 6 alkyl groups as the alkyl part [-O-(C 1-6 alkyl)], for example, including: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentoxy, cyclohexyloxy, cyclopropylmethoxy, etc., for example, also including C 1-4 Alkoxy and C 1-3 Alkoxy, etc.

[0074] Examples of the halogen atom include a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I). In this specification, "halogenated C 1-6 The term "alkyl group" refers to an alkyl group substituted with one or more halogen atoms, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and iodomethyl.

[0075] In formula (I), (Ia), (Ib) or (IX), when m is 0, R 3 In addition, when m is 2 or more, R 3 The substituents represented by may be the same or different. In addition, in formula (I), (Ia) or (IX), when n is 0, R 4 In addition, when n is 2 or more, R 4 The substituents represented by may be the same or different. In addition, in formula (IX), when p is 0, R 6 In addition, when p is 2, R 6 The substituents represented may be the same or different.

[0076] In the present specification, Het of formula (I) or formula (IX) represents a 5-membered nitrogen-containing aromatic heterocycle having at least one nitrogen atom. In which, one nitrogen atom and two carbon atoms contained as ring atoms in Het are substituted by phenyl groups, and each phenyl group may have a substituent represented by formula (I) or formula (IX). Examples of 5-membered nitrogen-containing aromatic heterocycles in the 5-membered nitrogen-containing aromatic heterocycle include: pyrrole, imidazole, pyrazole and triazole. In the present specification, compounds represented by formula (Ia) include compounds represented by the following formulas (Ia-1), (Ia-2), (Ia-3) and (Ia-4) or pharmaceutically acceptable salts thereof. [Chemistry 7]

[0077] In the present specification, the compound represented by formula (Ib) includes compounds represented by the following formulae (Ib-1), (Ib-2), (Ib-3) and (Ib-4) or pharmaceutically acceptable salts thereof. [Chemistry 8]

[0078] When the compound of formula (I) or formula (IX) or its pharmaceutically acceptable salt forms a solvate such as a hydrate, the present invention can be implemented using the solvate. In addition, the compound of the present invention or its pharmaceutically acceptable salt can be appropriately implemented in the form of a mixture, solution, polymorph, etc.

[0079] As the compound of the present invention, for example, the compounds described in the examples of this specification can be used, and more specifically, the following compounds or pharmaceutically acceptable salts thereof can be used: 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butanoic acid; 4-(4-fluoro-2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; and 4-(2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid.

[0080] The "pharmaceutically acceptable salt" of the compound of formula (I) or (IX) is not particularly limited to salts that can be used as medicines. Examples of the salts formed by the compound of the present invention with bases include: salts formed with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; and salts formed with organic bases such as methylamine, ethylamine, and ethanolamine.

[0081] In one embodiment of the present invention, the compound of formula (I) or formula (IX), its enantiomer, its diastereomer or a pharmaceutically acceptable salt thereof is administered as a prodrug and converted into an active compound in the organism.

[0082] In the present invention, "synucleinopathy" refers to a neurodegenerative disease characterized by abnormal deposition of α-synuclein, such as PD (Parkinson's disease), DLB (dementia with Lewy bodies) or multiple system atrophy. The pharmaceutical compositions and methods of the present invention can be used, for example, to inhibit the development of synucleinopathy.

[0083] In the pharmaceutical composition and method of the present invention, there is no particular limitation on the degree of progression, severity and condition of the synucleinopathy to be treated. The severity classification of Parkinson's disease (PD) adopts Yahr I to V grades. Dementia with Lewy bodies (DLB) has early, middle and late stages, and can be divided into brainstem-preferred type, limbic type and neocortical type according to the expression site of α-synuclein aggregates. In addition, in the severity classification of multiple system atrophy, the modified Rankin scale 1 to 6 is used, and it is classified into Shy Drager syndrome, olivopontocerebellar atrophy, striatonigral degeneration, etc. according to the condition of the disease. These are all disease groups in which α-synuclein aggregates are expressed in nerve cells or glial cells, and the pharmaceutical composition and method of the present invention can be used to treat or prevent diseases selected from these disease groups.

[0084] Dementia is thought to develop due to the death of neurons in the prefrontal cortex or hippocampus. In the present invention, it is claimed that FABP3 ligand inhibits the aggregation of α-synuclein. As a result, the death of neurons caused by α-synuclein aggregates in the brain is inhibited.

[0085] The pharmaceutical compositions and methods of the present invention are particularly useful for the treatment and prevention of PD and DLB.

[0086] In addition, the pharmaceutical composition and method of the present invention can improve motor dysfunction, cognitive dysfunction, mental illnesses such as autism and schizophrenia and inhibit their development.

[0087] Examples of motor dysfunction include tremor (shaking of the hands or feet), akinesia (slow movements), rigidity (muscle stiffness, resistance to flexion and extension of joints), and postural reflex disorders (difficulty in maintaining body balance) in PD (Parkinson's disease). In DLB (dementia with Lewy bodies), there are also Parkinson's symptoms. In multiple system atrophy, in addition to Parkinson's symptoms, there are also autonomic nervous system disorders (urinary disorders, erectile dysfunction, orthostatic hypotension, decreased sweating, etc.), cerebellar movement disorders (dysregulated gait and dysarthria, movement disorders of the limbs, or cerebellar eye movement disorders), etc.

[0088] As cognitive dysfunction, in DLB, there are: memory impairment, frontal and parietal lobe dysfunction (attention impairment, visuospatial impairment, dysarthria, executive dysfunction, etc.), cognitive fluctuations, hallucinations, etc. In PD, in the early stage, there are sometimes: executive function (planning, setting conversion and maintenance, problem solving, etc.), working memory, procedural memory and other memory functions, visual-spatial function and higher brain dysfunction. As the symptoms progress, there are sometimes: hallucinations, visuospatial cognitive impairment, slow thinking and other symptoms similar to DLB. In multiple system atrophy, there are sometimes: amnesia and other dementia conditions.

[0089] Additionally, the pharmaceutical compositions and methods of the present invention can be used to treat and prevent neurodegenerative diseases. Examples of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), PD, Alzheimer's dementia, DLB, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuritis, multiple sclerosis, and neuromyelitis optica.

[0090] In addition, since the pharmaceutical composition and method of the present invention have a neuron-protective effect, they can be used to prevent and treat cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage and other cerebrovascular disorders and head trauma. In addition, it can be used to prevent and treat diseases caused by dopamine.

[0091] The pharmaceutical composition of the present invention can be prepared into various dosage forms, for example, for oral administration, it can be prepared into tablets, capsules, powders, granules, pills, liquid preparations, emulsions, suspensions, solutions, alcohols, syrups, extracts, elixirs, as non-oral preparations, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches, ointments or lotions; sublingual preparations and oral patches for oral administration; and aerosols for nasal administration, but not limited thereto. These preparations can be manufactured by known methods commonly used in preparation processes.

[0092] The pharmaceutical composition of the present invention may contain various commonly used ingredients, for example, it may contain one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, colorants, sweeteners, flavoring agents, suspending agents, wetting agents, emulsifiers, dispersants, adjuvants, preservatives, buffers, binders, stabilizers, coating agents, etc. The pharmaceutical composition of the present invention may also be a sustained-release or sustained-release dosage form.

[0093] The dosage of the pharmaceutical composition of the present invention can be appropriately selected according to the route of administration, the patient's body shape, age, physical condition, degree of disease, time after onset, etc. The pharmaceutical composition of the present invention may contain a therapeutically effective amount and / or a preventively effective amount of the compound of the above-mentioned formula (I) or formula (IX). In the present invention, the compound of the above-mentioned formula (I) or formula (IX) can be administered at the following dosage: generally 1 μg to 1000 mg / day / adult, for example, 1 μg to 200 mg / day / adult, specifically 5 μg to 100 mg / day / adult, more specifically 10 μg to 50 mg / day / adult. The administration of the pharmaceutical composition may be a single administration or multiple administrations.

[0094] The pharmaceutical composition of the present invention may contain conventionally known colorants, preservatives, spices, flavoring agents, coating agents, antioxidants, vitamins, amino acids, peptides, proteins, and mineral components (iron, zinc, magnesium, iodine, etc.) as required. The pharmaceutical composition of the present invention may be prepared in a form suitable for oral administration, for example, in the form of various solid preparations such as granules (including dry syrups), capsules (soft capsules, hard capsules), tablets (including chewables, etc.), powders (granules, powders), pills, or liquid preparations such as oral liquid preparations (including liquid preparations, suspensions, syrups, etc.).

[0095] As the additive for formulation, for example, can enumerate: excipient, lubricant, adhesive, disintegrant, glidant, dispersant, wetting agent, preservative, thickener, pH adjusting agent, coloring agent, flavoring agent, surfactant, solubility promoter. In addition, in the case of the form of making liquid preparation, can coordinate thickeners such as pectin, xanthan gum, guar gum. In addition, also can use coating agent to make coated tablet, or make the jelly of pasty state. In addition, in the case of making the preparation of other forms, can prepare according to the method in the past.

[0096] The treatment method or prevention method of the present invention can be implemented based on the above description. The subject to which the compound of formula (I) or formula (IX) or a pharmaceutically acceptable salt thereof is administered includes mammals, such as humans.

[0097] (Manufacturing method) Hereinafter, the method for producing the compound of the present invention will be described with reference to examples, but the present invention is not limited thereto.

[0098] The intermediates and target compounds in the following manufacturing methods can be converted into other compounds included in the present invention by appropriately changing their functional groups. As a protecting group, the common protecting agents recorded in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons, Inc., New York (1999)) etc. can be used, and the introduction and removal of the protecting group can be carried out by the commonly used method in organic synthetic chemistry (such as the method recorded in the above-mentioned literature, etc.) or the method based on this. Specifically, as the protecting agent of amino, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. can be mentioned, and in addition, as the protecting group of hydroxyl, for example, trialkylsilyl, acetyl, benzyl, etc. can be mentioned.

[0099] The starting materials and intermediates in the following production methods can be obtained by purchasing commercial products, synthesizing according to known literature, or synthesizing from known compounds by known methods. In addition, the starting materials and intermediates can be used as salts thereof as necessary.

[0100] The inert solvent in the following production method refers to a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction. In addition, the prodrug of the compound of formula (I) or formula (IX) can be prepared by introducing a specific group in the preparation stage from the raw material to the intermediate, or by further reacting the obtained compound of formula (I), similarly to the above-mentioned protecting group. The reaction can be carried out by conventional methods known to those skilled in the art such as esterification, amidation, dehydration, etc.

[0101] (First method) As a representative production method, the case where Het is pyrazole in the compound represented by the general formula (I) will be described.

[0102] [Chemistry 9]

[0103] (Where R 1 ~R 5 , m and n are as defined above. ) (1st step) This step is a step of obtaining a compound of formula (IV) by cyclization reaction of a compound of formula (II) with a compound of formula (III). In this reaction, the compound of formula (II) and the compound of formula (III) are used in equivalent amounts or in excess, and their mixture is stirred in a reaction-inert solvent or in the absence of a solvent, from cooling to heating under reflux, for example, at room temperature to 120°C, usually for 1 hour to 3 days. Examples of solvents used here are not particularly limited, and include: diethyl ether, THF, 1,4-dihydro- ... Ethers such as alkanes, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, acetic acid, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, etc. can facilitate the smooth progress of the reaction.

[0104] (Second step) This step is a step of obtaining a compound of formula (Ia-3) by oxidizing formula (IV). In this reaction, the compound of formula (IV) and the oxidant are used in equivalent amounts or in excess, and their mixture is stirred in a reaction-inert solvent or in the absence of a solvent, from cooling to heating reflux, for example, at room temperature to 120°C, usually for 1 hour to 3 days. Examples of solvents used here are not particularly limited, and include: ether, THF, 1,4-dihydro- ... Ethers such as alkanes, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate can facilitate the smooth progress of the reaction. The oxidant used herein is not particularly limited, and examples thereof include: oxygen, manganese dioxide, potassium permanganate, sodium tungstate, hydrogen peroxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, etc. Adding metals such as copper chloride, palladium acetate, platinum, etc. can facilitate the smooth progress of the reaction.

[0105] (Second method) The case where Het is triazole in the compound represented by the general formula (I) is described. [Chemistry 10]

[0106] (Where R 1 ~R 5 , m and n are as defined above, and Hal represents a halogen atom. )

[0107] (1st step) This step is a step of obtaining a compound of formula (VII) by ring-closing reaction of a compound of formula (V) with a compound of formula (VI). In this reaction, the compound of formula (V) and the compound of formula (VI) are used in equivalent amounts or in excess, and their mixture is stirred in a reaction-inert solvent or in the absence of a solvent, from cooling to heating under reflux, for example, at room temperature to 120°C, usually for 1 hour to 3 days. Examples of solvents used here are not particularly limited, and include: diethyl ether, THF, 1,4-dihydro- ... Ethers such as alkanes, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, acetic acid, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, etc. can facilitate the smooth progress of the reaction.

[0108] (Second step) This step is a step of obtaining a compound of formula (Ia-4) by an etherification reaction of a compound of formula (VII) with a compound of formula (VIII). In this reaction, an equivalent amount of a compound of formula (VII) and a compound of formula (VIII) are used or any of them are used in excess, and their mixture is stirred in a reaction-inert solvent or in the absence of a solvent, from cooling to heating reflux, for example, at room temperature to 120°C, usually for 1 hour to 3 days. Examples of solvents used here are not particularly limited, and include: diethyl ether, THF, 1,4-dihydro- ... Ethers such as alkanes, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, etc. can facilitate the smooth progress of the reaction. Example

[0109] Hereinafter, the present invention will be described in more detail by showing examples, but the present invention is not limited to these examples. The abbreviations described in this specification are as follows. Et: ethyl, iPr: isopropyl, DMF: dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, NMP: N-methyl-2-pyrrolidone.

[0110] Example 1: 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid [Step 1] Preparation of (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

[0111] [Chemistry 11]

[0112] Potassium hydroxide (37 g) was added to ethanol (700 mL) to dissolve it. 2-acetyl-4-fluorophenol (20 g) was added to the solution at room temperature, followed by 2-(trifluoromethyl)benzaldehyde (25 g). The resulting mixture was stirred at room temperature for 3 hours, cooled with ice, and 1M aqueous hydrochloric acid solution (440 mL) was added dropwise. The precipitated solid was recovered by filtration and washed with water. The obtained solid was dried under reduced pressure at 40 ° C to obtain the orange compound of the title (33 g, yield 81%).

[0113] 1 H NMR (400 MHz, CDCl 3 )δ (ppm): 12.37 (1H, s), 8.29 (1H, d, J = 15.6Hz), 7.86 (1H, d, J = 8.0Hz), 7.76 (1H, d, J = 7.6Hz), 7.65 (1H, t, J=7.6Hz), 7.54-7.57 (2H, m), 7.48 (1H, d, J=15.6Hz), 7.24-7.29 (1H, m), 7.02 (1H, dd, J=4.8, 9.6Hz).

[0114] Mass spectrometry analysis ESI (-): 309 [mH] (calculated value: 310).

[0115] [Step 2] Preparation of ethyl (E)-4-(4-fluoro-(2-(3-(2-trifluoromethyl)phenyl)prop-2-enoyl)phenoxy)butanoate

[0116] [Chemistry 12]

[0117] Potassium carbonate (13 g) was added to a DMF (120 mL) solution of (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (23 g), and the mixture was stirred at room temperature. Ethyl 4-bromobutyrate (12 mL) was added to the resulting mixture, and the mixture was stirred at room temperature for 3 hours. Water (230 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and washed with water. The organic layer was dehydrated and concentrated under reduced pressure to obtain the title compound (33 g). It was used in the next step without purification.

[0118] 1 H NMR (400 MHz, CDCl 3)δ (ppm): 7.97 (1H, d, J = 15.7Hz), 7.8 (1H, d, J = 7.6Hz), 7.71 (1H, d, J = 7.6Hz), 7.59 (1H, t, J = 7.6Hz), 7.49 (1H, t, J = 7.6Hz), 7.34-7.38 (2H, m), 7.16 (1H, m), 6.93 (1H, dd, J = 9.2 and 4.4 Hz), 4.03-4.08 (4H, m), 2.40 (2H, t, J = 7.3), 2.04-2.11 (2H, m), 1.18 (3H, t, J = 7.1 Hz).

[0119] Mass spectrum analysis ESI (+): 425 [m+H], 447 [m+Na], 463 [m+K], 871 [2m+Na] (calculated value: 424).

[0120] [Step 3] Preparation of ethyl 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)butanoate

[0121] [Chemistry 13]

[0122] Phenylhydrazine (11 mL) was added to a solution of ethyl (E)-4-(4-fluoro-(2-(3-(2-trifluoromethyl)phenyl)prop-2-enoyl)phenoxy)butanoate (33 g) in ethanol (310 mL), and the mixture was stirred under heating reflux for 2 hours. The reaction mixture was ice-cooled and the precipitated solid was recovered by filtration. The obtained solid was washed with cooled ethanol to obtain the yellow-white compound of the title (18 g, yield 47%).

[0123] 1 H NMR (400 MHz, CDCL 3 )δ(ppm):7.71-7.75(2H,m),7.33-7.44(3H,m),7.15-7.19(2H,m),6.70-6.92(3H,m),6.76-6.79(2H,m),5.67(1H,q,J=6. 3Hz), 3.92-4.14 (5H, m), 3.23 (1H, dd, J = 18.1, 5.7Hz), 2.41 (2H, t, J = 7.3Hz), 2.05 (2H, q, J = 6.7Hz), 1.23 (3H, t, J = 7.1Hz).

[0124] Mass spectrum analysis ESI (+): 515, 537, 553 (calculated value: 514).

[0125] [Step 4] Preparation of ethyl 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate

[0126] [Chemistry 14]

[0127] To a solution of ethyl 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)butanoate (12 g) in ethyl acetate (240 mL) was added manganese dioxide (5 g), and the mixture was stirred under heating reflux for 17 hours. The insoluble matter in the reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (12 g) as a colorless to yellow oil. This was used in the next step without purification.

[0128] 1 H NMR (400 MHz, CDCl 3 )δ (ppm): 7.91 (1H, dd, J = 10.1, 3.2Hz), 7.77 (1H, d, J = 7.3Hz), 7.39-7.48 (2H, m), 7.18-7.31 (6H, m), 7.14 (1H, s), 6.9 3-6.98(1H,m),6.87-6.90(1H,m),4.05-4.12(4H,m),2.52(2H,t,J=7.3Hz),2.14-2.17(2H,m),1.19(3H,t,J=7.1Hz).

[0129] Mass spectrum analysis ESI (+): 513, 535, 551 (calculated value: 512).

[0130] [Step 5] Preparation of 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butyric acid

[0131] [Chemistry 15]

[0132] Ethanol (60 mL) and 1M aqueous sodium hydroxide solution (60 mL) were added to ethyl 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate (12 g), and the mixture was stirred at room temperature overnight. 1M aqueous hydrochloric acid solution (5 mL) was added dropwise, and the precipitated solid was recovered by filtration. The solid was washed with cooled ethanol and dried. The title white compound (10 g, yield 91%) was obtained.

[0133] 1 H NMR (400 MHz, CDCl 3)δ(ppm):7.86(1H,dd,J=9.6,3.2Hz),7.75-7.77(1H,m),7.40-7.48((2H,m),7.17-7.30(6H,m),7.09(1H, s), 6.95-7.00 (1H, m), 6.87-6.91 (1H, m), 4.08 (2H, t, J = 6.0Hz), 2.57 (2H, t, J = 7.2Hz), 2.11-2.18 (2H, m).

[0134] ESI (+): 485 [m+H], 969 [2m+H], 991 [2m+Na] (calculated value: 484).

[0135] Example 2: 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid

[0136] [Step 1] Preparation of (E)-1-(2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

[0137] [Chemistry 16]

[0138] Potassium hydroxide (4.12 g) was added to ethanol (70 mL) to dissolve it. 2-Hydroxyacetophenone (2 g) was added to the solution at room temperature, followed by 2-(trifluoromethyl)benzaldehyde (2.81 g). The resulting mixture was stirred at room temperature for 17 hours, cooled with ice, and a 2M aqueous hydrochloric acid solution was added dropwise. The precipitated solid was recovered by filtration, washed with water, and dried under reduced pressure at 40°C to obtain orange (E)-1-(2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (3.2 g, yield 75%).

[0139] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):12.65(1H,s),8.23-8.28(1H,m),7.83-7.90(2H,m),7.74(1H,d,J=7.8Hz), 7.03(1H,d,J=8.7Hz,6.92-6.96(1H,m).

[0140] Mass spectrometry analysis ESI (-): 291, ESI (+): 293 (calculated value: 292).

[0141] [Step 2] Preparation of ethyl (E)-4-(2-(3-(2-trifluoromethyl)phenyl)prop-2-enoyl)phenoxy)butanoate

[0142] [Chemistry 17]

[0143] Potassium carbonate (0.3 g) was added to a DMF (2.5 mL) solution of (E)-1-(2-hydroxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (0.5 g), and the mixture was stirred at room temperature. Ethyl 4-bromobutyrate (0.4 mL) was added to the resulting mixture, and the mixture was stirred at room temperature for 17 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and washed with water. The organic layer was dehydrated and concentrated under reduced pressure to obtain a white solid (0.7 g) of the title compound. This was used in the next step without purification.

[0144] 1 H NMR (400 MHz, CDCl 3 )δ (ppm): 7.96 (1H, dd, J = 1.8, 15.6Hz), 7.80 (1H, d, J = 7.8Hz), 7.70 (1H, d, J = 7.8Hz), 7.64 (1H, dd, J=1.8, 7.8Hz), 5.58 (1H, t, J=7.5Hz), 7.44-7.49 (2H,, m ),7.37(1H,d,J=15.6Hz),7.04(1H,t,J=7.5Hz),6.97(1H,d,J=8.2Hz),4.02- 4.11 (4H, m), 2.41 (2H, t, J = 7.3Hz), 2.05-2.12 (2H, m), 1.18 (3H, t, J = 7.1Hz).

[0145] Mass spectrum analysis ESI (+): 407 [m+H], 429 [m+Na], 445 [m+K], 835 [2m+Na] (calculated value: 406).

[0146] [Step 3] Preparation of ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)butanoate

[0147] [Chemistry 18]

[0148] Phenylhydrazine (3.2 mL) was added to a solution of ethyl (E)-4-(2-(3-(2-trifluoromethyl)phenyl)prop-2-enoyl)phenoxy)butanoate (13 g) in ethanol (70 mL), and the mixture was stirred under heating reflux for 17 hours. The reaction mixture was ice-cooled and the precipitated solid was recovered by filtration. The solid was washed with cooled ethanol to obtain the yellow-white compound of the title (3 g, yield 19%).

[0149] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):7.98(1H,dd,J=1.8,7.8Hz), 7.71(1H,d,J=7.8Hz), 7.23-7.44(4H,m),7.14-7.19(2H,m), 6.97-7.00(3H,m),6.86(1H,d,J=8.2Hz), 6.7 6(1H,t,J=7.3Hz), 5.65(1H,m), 3.97-4.14(5H,m), 3.24(1H,dd,J=5.7,1 7.6Hz), 2.41(2H,t,J=7.3Hz), 2.04-2.07(2H,m), 1.23(3H,t,J=7.1Hz).

[0150] Mass spectrometry analysis ESI (+): 497, 519, 535 (calculated value: 496).

[0151] [Step 4] Preparation of ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate

[0152] [Chemistry 19]

[0153] To a solution of ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)butanoate (2.9 g) in ethyl acetate (30 mL) was added manganese dioxide (5 g), and the resulting mixture was stirred under heating reflux for 17 hours. Insoluble matter was filtered from the reaction mixture, and the filtrate was concentrated to obtain the title compound (2.9 g) as a solid. This was used in the next step without purification.

[0154] 1 H NMR (400MHz, CDCl;) δ (ppm): 8.14 (1H, dd, J = 1.6, 7.5Hz), 7.74 (1H, d, J = 7.3Hz), 7.34-7.43 (2H, m), 7.13-7.32 (7H, m), 7, 10 (1H, s) ,7.01(1H,t,J=7.4Hz),6.94(1H,d,J=8.4Hz),4.04-4.09(4H,m),2.51(2H,t,J=7.3Hz),2.11-2.18(2H,m),1.17(3H,t,J=7.2Hz).

[0155] Mass spectrum analysis ESI (+) 495, 533, 517 (calculated value: 494).

[0156] [Step 5] Preparation of 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butyric acid

[0157] [Chemistry 20]

[0158] Ethanol (60 mL) and 1M aqueous sodium hydroxide solution (60 mL) were added to ethyl 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoate (2.9 g), and the resulting mixture was stirred at room temperature overnight. 5 mL of 1M aqueous hydrochloric acid solution was added dropwise to the reaction mixture, and the precipitated solid was filtered and recovered, washed with cooled ethanol and dried. The title compound (2.5 g, yield 90%) was obtained as a white solid.

[0159] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.08 (1H, dd, J = 1.6, 7.5Hz), 7.75-7.77 (1H, m), 7.40-7.45 (2H, m), 7.19-7.33 (8 H,m),7.03-7.07(2H,m),6.96-6.99(1H,m),4.13(2H,t,J=5.9Hz), 2.58(2H,t,J=7.1Hz),2.15-2.20(2H,m).

[0160] Mass spectrum analysis ESI (+): 467, 489, 505, 955, 971 (calculated value: 466).

[0161] Example 3: 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butanoic acid [Step 1] Preparation of N-phenyl-2-(trifluoromethyl)benzamide

[0162] [Chemistry 21]

[0163] To a solution of aniline (2.7 g) in DMSO (25 mL) was added 55% sodium hydride (oily, 1.5 g), and the mixture was stirred at room temperature for 5 minutes. To the resulting mixture was added 2-trifluoromethylcyanobenzene (10 g), and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform / methanol=100:1) to obtain the title compound (3.5 g, yield 45%).

[0164] 1 H NMR (400 MHz, CDCl 3 )δ (ppm): 7.13 (d, J = 7.7Hz, 1H), 7.70-7.47 (m, 3H), 7.42-7.26 (m, 2H), 7.12-6.92 (m, 3H). Mass spectral analysis ESI (+): 265 (calculated 264).

[0165] [Step 2] Preparation of 2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenol

[0166] [Chemistry 22]

[0167] A mixture of 2-cyanophenol (4.3 g), N-phenyl-2-(trifluoromethyl)benzamidine (2.4 g), 1,10-phenanthroline (41 mg), copper acetate (41 mg) and sodium carbonate (3.9 g) in toluene (100 mL) was stirred under heating reflux for 17 hours. After cooling, water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were combined, washed with water, and the solvent was distilled off under reduced pressure to obtain a yellow oil. Purification by column chromatography (chloroform / methanol=100:1) gave 2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenol (120 mg).

[0168] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):9.68(1H,s),7.81-7.33(11H,m),7.03-7.07(2H,m),6.96-6.99(1H,m). Mass spectral analysis ESI (+): 382, ​​404 (calculated value 381).

[0169] [Step 3] Preparation of 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butyric acid

[0170] [Chemistry 23]

[0171] A mixture of 2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenol (100 mg), potassium carbonate (120 mg) and ethyl 4-bromobutyrate (200 μL) in DMF (5 mL) was stirred at 90° C. for 2 hours. The reaction mixture was extracted twice with ethyl acetate, and the organic layers were combined and washed with water, and the solvent was removed by distillation after dehydration.

[0172] Ethanol (5 mL) and 2M sodium hydroxide aqueous solution (5 mL) were added to the obtained product and stirred at room temperature for 24 hours. The reaction mixture was neutralized with 2M hydrochloric acid aqueous solution, extracted twice with ethyl acetate, the organic layers were combined and washed with water, dehydrated, and then the solvent was distilled off. The concentrate was dissolved in ethanol and decolorized with activated carbon. Water was added dropwise, and the precipitated solid was recovered by filtration, washed, and dried to obtain the title compound (40 mg).

[0173] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):7.81-7.33(12H,m),7.05-7.08(2H,m),4.23(2H,m),2.60(2H,m),2.25-2.30(2H,m). Mass spectral analysis ESI (+): 468, 490, 506 (calculated value 467).

[0174] Example 4: 4-(4-fluoro-2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid

[0175] [Chemistry 24]

[0176] The title compound was prepared as a yellow-white solid by the same method as in Example 1, except that 4-isopropylphenylhydrazine was used instead of phenylhydrazine in step 3 of Example 1.

[0177] 1 H NMR (400 MHz, CDCl 3)δ(ppm):7.84(1H,dd,J=9.6,3.2Hz),7.75-7.77(1H,m),7.40-7.48(2H,m),7.17-7.25(3H,m),7.09-7.12(2H,m),6.94-6.99(1 H, m), 6.87-6.90 (1H, m), 4.08 (2H, t, J = 5.9Hz), 2.81-2.88 (1H, m), 2.57 (2H, J = 7.3Hz), 2.11-2.18 (2H, m), 1.20 (6H, d, J = 7.3Hz). Mass spectrometry analysis ESI (+): 527, 549, 565 (calculated value: 526).

[0178] Example 5: 4-(2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid

[0179] [Chemistry 25]

[0180] The title compound was prepared as a white solid by the same method as in Example 1, except that 4-isopropylphenylhydrazine was used instead of phenylhydrazine in step 3 of Example 2.

[0181] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):7.84(1H,dd,J=9.6,3.5Hz),7.75-7.77(1H,m),7.40-7.38(3H,m),7.17-7.25(3H,m),7.09-7.12(2H,m),6.94-6.95(1 H,m),6.86-6.91(1H,m),4.11(2H,t,J=5.7Hz),2.81-2.89(1H,m),2.59(2H,J=7.3Hz), 2.10-2.17(2H,m),1.20(6H,d,J=7.3Hz). Mass spectrometry analysis ESI (+): 509, 531, 547 (calculated value: 508).

[0182] Test Example 1: Affinity evaluation test of FABP ligand using ANS GST-FABP3, GST-FABP4, GST-FABP5 and GST-FABP7 were expressed in Escherichia coli [BL21(DE3) strain] and then affinity purified using a glutathione column.

[0183] The cloning of GST-FABP3, GST-FABP4, GST-FABP5 and GST-FABP7 vectors was performed by the following method. After reverse transcription of mRNA isolated from mouse heart into cDNA, FABP3 gene (Ref Seq ID: NM_010174.1) and FABP4 gene (Ref Seq ID: NM_024406.2) were amplified by PCR. These cDNAs were inserted between the BamHI / EcoRI cut sites of pGEX-2T vector (GE HealthCare Japan, Tokyo) using DNA ligation kit (Takara Bio, Kusatsu) and In-fusion kit (Takara Bio USA, CA, USA), respectively, to prepare vectors.

[0184] Figure 1 The sequenced base sequences of GST-FABP3, GST-FABP4, GST-FABP5 and GST-FABP7 are described in (the first and last GGATTC and GAATTC are restriction endonuclease cleavage sites).

[0185] Purification of GST fusion protein was performed using a GST purification kit (Takara Bio USA). After recovering E. coli by centrifugation, the attached Extraction buffer and alumina powder were added and crushed with a mortar. The supernatant of the centrifugation was added to the attached glutathione column and allowed to stand on ice for 30 minutes. Then, the supernatant in the column was discarded, washed with Extraction buffer, and eluted with elution buffer containing glutathione. The protein concentration of the eluted product was calculated based on the absorbance at 280 nm and used for ANS testing.

[0186] 1-anilinonaphthalene-8-sulfonic acid (ANS, final concentration 4 mM, 10 mM KH 2 PO 4 , 40mM KCl, pH7.4 solution) and FABP protein (final concentration 0.4mM), and various ligands at 0nM, 100nM, 1000nM, 2000nM, 4000nM (final) concentrations were incubated for 2 minutes, and the fluorescence of ANS was measured (Ex / Em=355nm / 460nm). The fluorescence intensity at each ligand concentration was converted to a relative value (%) relative to the ANS fluorescence intensity in the absence of the ligand, and then the dissociation constant Kd (nM) was calculated by non-regression analysis using the following formula.

[0187] F=F 0 -{[1+(P t +L t)Ka-[(P t -L t ) 2 Ka 2 +2(P t +L t )Ka+1] 1 / 2 ] / [2P t Ka]}(F 0 -F max ) F: relative fluorescence intensity under certain conditions (%); F 0 : Fluorescence intensity in the absence of ligand (=100); P t : FABP protein concentration (=400 nM); L t : ligand concentration (=100, 1000, 2000, 4000 nM); Ka: the reciprocal of the dissociation constant Kd (nM -1 ); F max *: Relative fluorescence intensity when FABP is fully occupied by ligand.

[0188] As ligands, the compounds of Examples 1 to 5 (referred to as Example Compound 1 to Example Compound 5, respectively) and the known compound LIGAND 1 (described in WO2017 / 171053) were used.

[0189] The dissociation constant Kd calculated from the measurement results is shown in Table 1. In particular, it was confirmed that Example Compounds 1 to 5 had a smaller dissociation constant Kd than LIGAND 1 for FABP3.

[0190] [Table 1-1] Table 1. Kd values ​​of FABP in various ligands (nM) [Table 1-2]

[0191] The Kd values ​​in the above table are expressed as the average value ± SE of three measurements. When the Kd value is 1,000,000 or more, it indicates "no binding". In addition, Example compounds 1 to 5 in the table are sometimes also referred to as compounds 1 to 5, respectively.

[0192] Test Example 2: Cognitive function evaluation test using PD model animals The dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg / kg, intraperitoneal injection (ip), purchased from Sigma-Aldrich (St Louis, MO)) was administered once a day for 5 consecutive days (Day 1 to 5) to 8-10 week old male C57BL6 N mice, and the mice showed PD-like symptoms 20 days after the start of the experiment (Day 20). As this model animal, the solvent or FABP3 ligand (the compound of Example 1 (Example Compound 1), 0.05, 0.1 and 0.3 mg / kg, oral administration (po), n = 7 in each group) was administered twice a day for 2 consecutive weeks starting from 20 days after the start of the experiment (Day 20). Cognitive function was evaluated by passive avoidance test 34 days after the start of the experiment (Day 34). The passive avoidance task was as follows: In the trial training, the mouse was placed in the light chamber, and an electrical stimulus (0.3 mA, 2 seconds) was given when the mouse entered the dark chamber. After 24 hours, the mouse was placed in the light chamber again, and the time until the mouse entered the dark chamber was measured (corresponding to Figure 2 The vertical axis is "Latency" (s). The results are as follows Figure 2 As shown. In the group of mice to which the ligand was administered, it was confirmed that the waiting time was prolonged in a concentration-dependent manner. In addition, the latency of the solvent control group (veh) was confirmed to be significantly different from that of the saline, so it can be said that the method of this test example is appropriate.

[0193] In the above model mouse preparation, the normal mouse group administered with saline instead of MPTP is indicated as "saline" in the figure, and the group administered with 0.5% carboxymethylcellulose instead of FABP3 ligand is indicated as "vehicle control (veh)" in the figure.

[0194] Test Example 3: Cognitive function evaluation test using PD model animals The compound of Example 2 (Example Compound 2; 0.03, 0.1 and 0.3 mg / kg) was administered as a ligand of FABP3. In addition, the model mice treated in the same manner as in Experimental Example 2 were evaluated for cognitive function by a novel object recognition task 34 days after the start of the experiment (Day 34). In the novel object recognition task, objects of the same shape were placed in the trial training for the mice to remember. In the trial test, a new object was used to replace one object, and the contact ratio of the mice to the two objects (corresponding to Figure 3 The vertical axis is "Discrimination index" (%). The results are as follows Figure 3In the novel object recognition test, there was a significant difference in the ratio of mice's contact with novel objects and known objects in the ligand-administered group, confirming a tendency toward improved cognitive function.

[0195] Test Example 4: Motor function evaluation test using PD model animals The model mice were treated in the same manner as in Experimental Example 2 except that Example Compound 2 (0.03, 0.1 and 0.3 mg / kg) or LIGAND 1 (compound represented by the following formula; 0.3 mg / kg) was administered as a ligand of FABP3. The rotarod task and beam walking task were performed 34 days after the start of the experiment (Day 34) to evaluate motor function. In the rotarod test, mice were allowed to stand on a roller, and the time until the mouse fell off when the roller was rotated at a speed of 20 rpm (latency, corresponding Figure 4 In the balance beam test, mice were placed on a narrow board and walked, and the number of times they stumbled before reaching the target box was measured (corresponding to Figure 5 The vertical axis in the chart is “Number of foot slips”).

[0196] [Chemistry 26]

[0197] The results are as follows Figure 4 and Figure 5 In the rotarod test, in the group administered with Example Compound 2, even in the group with the smallest dosage, improvement in motor function was observed. No improvement was observed in the group administered with LIGAND 1. In the balance beam test, improvement in motor function was confirmed in all groups administered with Example Compound 2. Improvement was also observed in the LIGAND 1 administered group.

[0198] Test Example 5: Dopamine neuroprotection evaluation test using PD model animals The model mice were treated in the same manner as in Test Example 2 except that Example Compound 2 (0.1, 0.3 and 1.0 mg / kg) or LIGAND 1 (0.3 mg / kg) was administered as a ligand of FABP3. The mice were perfused and fixed 34 days after the start of the test (Day 34), and brain slices containing the substantia nigra region (SNpc) and the ventral tegmental area (VTA) with a thickness of 50 μm were prepared. The TH antibody (mouse monoclonal antibody 22941 manufactured by Immunostar, 1:1000), the α-synuclein antibody (rabbit polyclonal antibody SC-70110R manufactured by Santa Cruz, 1:200) and the FBAP3 antibody (under confirmation) were reacted and detected with a fluorescently labeled secondary antibody (Alexa 594 anti-mouse IgG (manufactured by Jackson ImmunoResearch, 1:500). The results of the substantia nigra region are shown in Figure 6 , Figure 7 , Fig.10 , Fig.11 , Fig.14 and Fig.15 The results for the ventral tegmental area are shown in Figure 8 , Fig. 9 , Fig.12 , Fig.13 , Fig.16 and Fig.17 middle( Figure 6 and Figure 8 The vertical axis "TH + Number of TH cells + "cells)" corresponds to the number of dopaminergic neurons. Fig.11 and 13 The vertical axis "double positive cells / TH + Number of double-positive cells / TH + The positive cells”)” (%) corresponds to the proportion of cells containing phosphorylated α-synuclein among dopaminergic neurons. Fig.15 and Fig.17 The vertical axis “Triple-positive cells / TH-positive cells” corresponds to the proportion of cells containing both FABP3 and phosphorylated α-synuclein among dopaminergic neurons).

[0199] according to Figures 6 to 9 The results shown confirmed that Example Compound 2 inhibited the decrease in dopaminergic neurons in MPTP-administered mice. On the other hand, no improvement was observed in the LIGAND 1-administered group. Figures 10 to 13The results shown confirmed that the phosphorylation level of α-synuclein, which was increased in dopaminergic neurons of MPTP-administered mice, was reduced by administration of Example Compound 2. Figures 14 to 17 The results shown confirmed that the localization of FABP3 and phosphorylated α-synuclein in dopaminergic neurons produced by administering MPTP to mice was reduced by administering Example Compound 2. Considering that the aggregation of α-synuclein increases by phosphorylation of α-synuclein (Samuel, F. et al., J. Biol. Chem. 291 (2016) 4374-4385), and that α-synuclein aggregates when FABP3 and α-synuclein coexist (Fukui, N. et al., J. Biol. Chem. 296 (2021) 100663), these results show that Example Compound 2 has an effect of improving the aggregation of α-synuclein, which is useful for improving Parkinson's disease ( Fig.25 ). It should be noted that according to reports showing the spread of aggregates of α-synuclein (Lee, VMY et al., J. Exp. Med. Vol. 209, No. 5, 975-986), Example Compound 2 may have the effect of inhibiting the spread of aggregates of α-synuclein by improving the aggregation of α-synuclein. In addition, according to reports that phosphorylated α-synuclein is more easily propagated than wild-type α-synuclein (Li, YM. et al., Sci Rep. 2016; 6, 37130), Example Compound 2 may have the effect of inhibiting the spread of α-synuclein by reducing the phosphorylation level of α-synuclein. In summary, it can be said that Example Compound 2 protects dopaminergic neurons from phosphorylated α-synuclein induced by MPTP. In addition, it can be said that Example Compound 2 inhibits the interaction between phosphorylated α-synuclein and FABP3 in dopaminergic neurons.

[0200] Test Example 6: Cerebral nerve protection evaluation test using local cerebral ischemia model Male ICR mice (5 weeks old, 25-30g) were purchased from SLC, Japan (Shizuoka Prefecture, Japan). The animals were raised under constant temperature and humidity conditions, raised under a 12-hour light-dark cycle (lighting: 09:00-21:00), and fed continuously. All mice were anesthetized with a combination of 0.3mg / kg medetomidine, 4.0mg / kg midazolam, and 5.0mg / kg butorphanol. A 6-0 suture (Doccol, USA) coated with silicon was inserted from the right external carotid artery to the internal carotid artery until the beginning of the middle cerebral artery. After being placed for 2 hours, the suture was removed for reperfusion to make a model mouse of local cerebral ischemia model (tMCAO). For mice in the sham operation group, except for the insertion of sutures, the same treatment was received. After reperfusion, the mice were killed at the specified time. During the I / R (ischemia and reperfusion) operation, the deep body temperature of the mouse was maintained at 37°C using a thermostatic blanket, and the regional cerebral blood flow (rCBF) was monitored by a laser Doppler flowmeter (FLOC1, OMEGAWAVE, Tokyo, Japan) to confirm whether the right hemisphere of the brain was in an ischemic state. As mentioned above, the operation was considered successful when the CBF was reduced by about 70-90%. After 24 hours or 7 days of reperfusion, the neurological score was calculated using the neurological disorder grading system, and then the mouse was decapitated, the brain was quickly removed, and cooled at -30°C for 10 minutes. The brain was cut into 5 slices of 2 mm thickness, incubated at 37°C for 20 minutes in 1% 2,3,5-triphenyltetrazolium chloride (TTC, Wako, Japan), and immersed in 4% paraformaldehyde (PFA; Sigma, USA) overnight, with non-infarct sites showing gray and infarct sites showing white. Infarct volume was measured using ImageJ software and expressed as a ratio relative to the entire right hemisphere of the brain (corresponding to Fig.19 B. Fig.21 E. Fig.23 H. To explain, Fig.19 C. Fig.21 F. Fig.23 The vertical axis "Neurological score" of I represents neurological deficit. Fig.24 The vertical axis “Survival rate” (%) corresponds to the survival rate of mice).

[0201] The compound of Example 1 was suspended in 0.5% carboxymethylcellulose (CMC), and a corresponding amount of 0.5% CMC was orally administered to a solvent control group.

[0202] Mice were subjected to 2 hours of tMCAO, and then given Example Compound 1 at different concentrations (0.5, 0.1, 0.3, 1.0 mg / kg) 30 minutes after reperfusion. Fig.18 A and Fig.19 As shown in B and C. Fig.18 A and Fig.19 B and C are representative images of TTC staining (A), quantitative analysis of infarct volume (B), and neurological impairment (C) 24 hours after reperfusion (n=7-9). Example compound 1 (0.3 mg / kg) was administered at 0.5, 1, and 2 hours after reperfusion. Fig. 20 D and Fig.21 E and F. Fig. 20 D and Fig.21 E and F are representative images of TTC staining (D), quantitative analysis of infarct volume (E), and neurological impairment (F) 24 hours after reperfusion (n=7-8). After 30 minutes of reperfusion, the compound of Example 1 was administered at different doses (0.5, 0.1, and 0.3 mg / kg). Fig. 22 G and Fig.23 H and I. Fig. 22 G and Fig.23 H and I are representative images of TTC staining (G), quantitative analysis of infarct volume (H), and nerve injury (I) on day 7 after reperfusion. The number of mice surviving each day in each group was recorded, and the survival rate was calculated ( Fig.24 J) (n=9-12). In particular, in mice administered with 0.3 mg / kg of Example Compound 1, the volume of cerebral infarction was smaller than that of the vehicle control group (Vehicle) mice, and the survival rate of the mice was higher than that of the vehicle control group (Vehicle) mice.

Claims

1. A compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, In the formula, R 1 is a hydrogen atom or a halogenated C 1-6 alkyl; R 2 Halogenated C 1-6 alkyl; R 3 Selected from hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy groups and halogen atoms; R 4 Selected from halogen atoms and C 1-6 alkyl; R 5 A hydrogen atom or C 1-6 alkyl; R 6 is a halogen atom or C 1-6 alkyl; m is an integer selected from 0 to 3; n is an integer selected from 0 to 3; p is an integer selected from 0 to 2; Het is a 5-membered nitrogen-containing aromatic heterocyclic ring in which one nitrogen atom and two carbon atoms are substituted by phenyl groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is represented by formula (Ia): In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m as defined in claim 1; X 1 and X 2 are independently nitrogen atoms or CR 6a ; R 6a is a hydrogen atom, a halogen atom or a C 1-6 alkyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 is a nitrogen atom, X 2 is CH, or X 1 and X 2 A nitrogen atom.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R 2 It is trifluoromethyl.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: m is 0 or 1, and n is 0 or 1.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: m is 0, and n is 1 or 0.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: The compound is represented by formula (Ib): In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and m is as defined in any one of claims 1 to 6.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: R 1 A hydrogen atom.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is selected from: 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; 4-(2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)butanoic acid; 4-(4-fluoro-2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid; and 4-(2-(1-(4-isopropylphenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10, which is used for treating or preventing synucleinopathy.

12. The pharmaceutical composition according to claim 11, wherein The synucleinopathy is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy.

13. The pharmaceutical composition according to claim 10, which is used for treating or preventing diseases caused by dopamine nerve dysfunction.

14. The pharmaceutical composition according to claim 10, which is used for treating and preventing cerebral vascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and head trauma.

15. The pharmaceutical composition according to claim 10, which is used for treating or preventing mental illnesses such as autism or schizophrenia.

16. The pharmaceutical composition according to any one of claims 10 to 15, which is for oral administration.

Images