GPR17 inhibitor and uses thereof

Abstract

The present invention provides a GPR17 inhibitor which comprises a compound represented by formula (I) (wherein ring A is an optionally substituted monocyclic aromatic ring, or an optionally substituted condensed ring containing the aromatic ring as a partial structure; L is a linker which gives separation corresponding to at least four bonds between the atoms to which L is bonded; and R1 and R2 are each independently an alkyl group, an aryl group, or an arylalkyl group, or are bonded to each other to form a hydrocarbon ring together with the carbon atom to which these substituents are bonded).

Description

GPR17 inhibitors and uses thereof

[0001] The present invention relates to GPR17 inhibitors and uses thereof.

[0002] G protein-coupled receptor 17 (GPR17) is a G protein-coupled receptor (GPCR) that is primarily expressed in the central nervous system (CNS), typically in organs susceptible to ischemic injury. In the CNS, GPR17 is expressed in cells of the oligodendrocyte lineage, and its levels increase during the differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes. However, its levels decrease significantly during the final maturation of myelinating oligodendrocytes. This suggests that GPR17 is a useful marker for identifying intermediate stages of OPC differentiation.

[0003] Phylogenetically, GPR17 is positioned intermediate between the purinergic P2Y receptors and the cysteinyl leukotriene (CysLT) receptors (Non-Patent Document 1). It has been reported that GPR17 recognizes two distinct ligands: uracil nucleotides such as UDP and UDP-glucose, and cysteinyl leukotrienes such as LTD4 and LTE4 (Non-Patent Documents 1 and 2). However, other studies have contradicted this (Non-Patent Document 3). Therefore, the endogenous ligand is unknown, and GPR17 is classified as an orphan receptor. A synthetic GPR17 agonist, MDL29951, has been developed and used to analyze GPR17 function (Non-Patent Document 4).

[0004] GPR17 is involved in the transition from oligodendrocyte precursor cells to mature oligodendrocytes that express a myelinating phenotype (Non-Patent Documents 2, 5, 6, and 7). Consequently, GPR17 can direct neural progenitor cells to neuronal lineages (Non-Patent Document 8). Modulation of GPR17 activity by selective compounds has advanced our understanding of diseases and disorders involving this receptor. In particular, compounds that modulate GPR17 activity may be used for neuroprotection and repair in cerebral ischemia, cardiac ischemia, renal ischemia, traumatic brain injury, and demyelinating diseases such as multiple sclerosis, schizophrenia, depression, Alzheimer's disease, Alzheimer's dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), and other neuroinflammatory diseases (Non-Patent Document 9).

[0005] The GPR17 agonist MDL29951 inhibited the maturation of primary oligodendrocytes in vitro and also in mouse cerebellar slices, suggesting that GPR17 signaling negatively regulates myelin sheath replenishment by inhibiting oligodendrocyte maturation (Non-Patent Document 10). Therefore, GPR17 antagonists may be a therapeutic strategy to alleviate the inhibition of oligodendrocyte maturation and promote myelin repair in demyelinating diseases such as multiple sclerosis.

[0006] Furthermore, uracil nucleotides and cysteinyl leukotrienes, which are believed to act on GPR17, have been reported to mediate immune responses and ischemic / inflammatory states, including stroke and currently intractable neurodegenerative diseases (Non-Patent Document 11). Therefore, GPR17 may be a potential target for novel chemicals useful in diseases such as stroke and brain or spinal cord trauma (Non-Patent Documents 2, 5, 12). Furthermore, it has been reported that GPR17 is an effector of FOXO1 appetite-stimulating signaling in agouti-related peptide (AgRP) neurons and is involved in food intake (Non-Patent Documents 13, 14), suggesting that GPR17 inhibition may be useful for the treatment of obesity. Furthermore, it has been suggested that inhibition of GPR17 activity increases glucose tolerance and / or insulin sensitivity, potentially useful for patients with impaired glucose tolerance or low insulin sensitivity (Patent Document 1).

[0007] Because the crystal structure of GPR17 is unknown, each domain of GRP17 has been modeled using the crystal structure of CXCR4 as a template, and ligands for GPR17 have been explored in silico. Abbracchio et al. identified novel GPR17 ligand compounds using an in silico experimental procedure based on comparative chimera modeling (Patent Document 2). Abbracchio et al. also proposed another group of novel compounds that selectively act on GPR17 and are useful for treating or ameliorating chronic and / or acute diseases involving GPR17 (Patent Document 3).

[0008] Muller et al. have disclosed a group of sulfonamide compounds as negative modulators of GPR17 (Patent Document 4).

[0009] Non-Patent Document 15 reports that a structural model of GPR17 was used to perform in silico high-throughput screening, identifying a chemically diverse family of ligands, and ultimately obtaining a small molecule selective GPR17 ligand that significantly delayed the onset of experimental autoimmune encephalomyelitis (EAE) associated with multiple myeloma when administered prophylactically.

[0010] Patent documents 5-8 propose pyrimidin-2-ylsulfonamide derivatives that modulate GPR17 activity. Patent documents 9-11 propose isoquinolinone-, pyrrolopyridinone-, and thienopyridinone-sulfonamide derivatives that modulate GPR17 activity. Patent documents 12-15 propose arylsulfonamide derivatives that modulate GPR17 activity.

[0011] However, no GPR17 antagonist has yet been successfully clinically developed as a therapeutic agent for demyelinating diseases such as multiple sclerosis.

[0012] US 9309514 B2WO 2012 / 059869 A1US 9879030 B2WO 2018 / 122232 A1WO 2022 / 180136 A1WO 2024 / 17863 A1WO 2024 / 23128 A1WO 2024 / 23129 A1WO 2024 / 17856 A1WO 2024 / 17857 A1WO 2024 / 17858 A1WO 2024 / 10446 A1WO 2020 / 254289 A1WO 2019 / 243303 A1EP 3584244 A1

[0013] EMBO J., 2006; vol.25: pages 4615-4627PLoS One, 2008; vol.3 No.10: e3579J Pharmacol Exp Ther, 2013; vol.347: pages 38-46Sci. Signal., 22 October 2013; Vol.6, Issue 298; page pe34Neurosciences (Riyadh), 2009; vol.14: pages 343-348J Biol Chem, 2011; vol.286: pages 10593-10604Chem Med Chem, 2016; vol.11: pages 2567-2574Purinergic Signal, 2016; vol.12: pages 661-672Expert Opin Ther Pat., 2019 Feb; vol.29 No.2: pages 85-95Sci. Signal., 22 October 2013; Vol.6, Issue 298; page ra93Trends Neurosci., 2009; vol.32: pages 19-29Brain, 2009; vol.132: pages 2206-2218Cell, 2012; vol.149: pages 1314-1326Diabetes, 2015; vol.64: pages 3670-3679PLoS One, 2020; vol.15 No.4: e0231483

[0014] An object of the present invention is to provide a novel GPR17 inhibitor.

[0015] GPR17 is an orphan GPCR, and its natural biologically active ligands are unknown. Therefore, the complex crystal structure of GPR17 has not yet been elucidated. Previously, GRP17 domains were modeled using the crystal structure of CXCR4, which is considered to be structurally similar to GRP17, as a template. GPR17 antagonists were then searched for in silico, or high-throughput screening (HTS) was performed without using in silico techniques, resulting in the identification of numerous sulfonamide derivatives with GRP17 antagonist activity. The present inventors developed a unique drug discovery platform, the "iSiP Drug Discovery Platform," which utilizes only fuzzy 3D structural information of proteins to efficiently generate hit compounds even when structural information is scarce or unclear. Using this platform, we selected GRP17 antagonists in silico from a large compound library without relying on similar crystal structures such as CXCR4. We then evaluated the antagonist activity of each selected compound against human GPCR17 using an in vitro reporter assay system. As a result, the compounds selected in silico actually exhibited antagonist activity against GRP17, confirming the effectiveness of the iSiP drug discovery platform for orphan GPCRs. The newly obtained GPR17 antagonist had a hydantoin skeleton different from existing GPR17 antagonists. Based on these findings, the inventors conducted further studies and completed the present invention.

[0016] That is, the present invention relates to the following: [1] Formula (I):

[0017]

[0018] (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2and (II) are independently alkyl, aryl, or arylalkyl, or are bonded to each other to form a hydrocarbon ring together with the carbon atoms to which they are bonded.

[0019]

[0020] (In the formula, R 3 is alkylene, and R 4 is a bond, and R 5 is a hydrogen atom, or R 4 and R 5 are bonded to each other to form a nitrogen-containing ring together with the nitrogen atom and carbon atom to which they are bonded, 1 and * 2 represents the end of a bond, and * 1 and * 2 one of which is bonded to the nitrogen atom N* in formula (I) and the other is bonded to ring A), or formula (III):

[0021]

[0022] (In the formula, R 6 and R 7 are independently a bond or alkylene, ring B is an optionally substituted monocyclic aromatic ring, 3 and * 4 represents the end of a bond, and * 3 is bonded to the nitrogen atom N* in formula (I), 4A GPR17 inhibitor of [1], which is a divalent organic group represented by the formula: [3] The compound represented by formula (I) is 1-{2-[4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)piperidin-1-yl]-2-oxoethyl}-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione, 5-methyl-3-[2-[2-(6-methyl-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-2-oxoethyl]-5-naphthalen-2-ylimidazolidine-2,4-dione, 3-[3-[[(8-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]methyl]phenyl]-1,3-diazaspiro[4.4]nonane-2,4-dione, 5-methyl-5-naphthalen-2-yl-3-[2-oxo-2-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]ethyl]imidazolidine-2,4-dione, 2-(4-benzyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-N-(naphthalen-2-yl)acetamide, N-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, and The GPR17 inhibitor according to [1], which is any one selected from the group consisting of 1-{[4-amino-6-(phenylamino)-1,3,5-triazin-2-yl]methyl}-3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione. [4] A pharmaceutical composition for preventing or treating a GPR17-related disease, comprising the GPR17 inhibitor according to any one of [1] to [3]. [5] The pharmaceutical composition according to [4], wherein the GPR17-related disease is a demyelinating disease, schizophrenia, bipolar disorder, major depression, spinal cord injury, cerebral infarction, or traumatic brain injury. [6] The pharmaceutical composition according to [5], wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, or acute disseminated encephalomyelitis.

[0023] [1a] A compound represented by formula (I) above for use in the prevention or treatment of a GPR17-related disease. [2a] A method for treating a GPR17-related disease in a subject, comprising administering to said subject an effective amount of a compound represented by formula (I) above. [3a] A method for reducing the risk of developing a GPR17-related disease in a subject at risk of developing a GPR17-related disease, comprising administering to said subject an effective amount of a compound represented by formula (I) above. [4a] Use of the compound represented by formula (I) above in the manufacture of a medicament for the prevention or treatment of a GPR17-related disease.

[0024] The present invention provides a novel GPR17 inhibitor (i.e., a GPR17 antagonist). The GPR17 inhibitor of the present invention has excellent GPR17 inhibitory activity and may be useful as a preventive or therapeutic agent for GPR17-related diseases, including demyelinating diseases such as multiple sclerosis. The GPR17 inhibitor of the present invention has a hydantoin skeleton and has a fundamental skeleton that is significantly different from that of existing GPR17 inhibitors, and therefore, a GPR17 inhibitor with chemical properties different from conventional ones may be provided.

[0025] 1. GPR17 Inhibitors The present invention provides compounds of formula (I):

[0026]

[0027] (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2are independently alkyl, aryl, or arylalkyl, or are combined with each other to form a hydrocarbon ring together with the carbon atoms to which they are attached. The present invention provides a GPR17 inhibitor (i.e., a GPR17 antagonist) (hereinafter referred to as the GPR17 inhibitor of the present invention), preferably a human GPR17 inhibitor, comprising a compound represented by formula (I). By administering an effective amount of a compound represented by formula (I) to a subject (e.g., a mammal such as a human), the function of GPR17 in the subject can be inhibited. By contacting GPR17 with the compound represented by formula (I) in vivo or in vitro, the function of GPR17 can be inhibited. Specifically, the compound represented by formula (I) inhibits the signaling cascade (biological response) downstream of GPR17 induced by stimulation with a GPR17 agonist (e.g., MDL29951).

[0028] The GPR17 inhibitors of the present invention have excellent GPR17 inhibitory activity, and when an agonist (e.g., MDL29951) is applied to human GPR17-expressing cells at an EC80 concentration, they inhibit the signal cascade downstream of GPR17 with an IC50 of, for example, less than 200 μM. The GPR17 inhibitory activity of the GPR17 inhibitors of the present invention can be competitive inhibition of the binding of a GPR17 agonist to GPR17.

[0029] Examples of the "monocyclic aromatic ring" of ring A include, but are not limited to, benzene; nitrogen-containing 6-membered aromatic rings such as pyridine, pyrimidine, pyrazine, pyridazine, and triazine (1,2,4-triazine or 1,3,5-triazine); and nitrogen-containing 5-membered aromatic rings such as pyrrole, pyrazole, imidazole, and triazole. The monocyclic aromatic ring is preferably benzene or pyridine.

[0030] The "fused ring containing a monocyclic aromatic ring as a partial structure" of ring A contains, in addition to the monocyclic aromatic ring, one or two 5- or 6-membered hydrocarbon rings or 5- or 6-membered nitrogen-containing rings as partial structures. Examples of 5- or 6-membered hydrocarbon rings include cyclopentadiene, cyclopentene, benzene, cyclohexene, and cyclohexadiene. Examples of 5- or 6-membered nitrogen-containing rings include, but are not limited to, pyrroline, pyrazoline, imidazoline, pyrrole, pyrazole, imidazole, triazole, piperideine, pyridine, pyrimidine, pyrazine, pyridazine, triazine, tetrazine, tetrazinane, and pentazinane. The 5- or 6-membered hydrocarbon ring is preferably benzene or cyclohexene. The 5- or 6-membered nitrogen-containing ring is preferably pyrroline, pyrrole, or imidazole.

[0031] Examples of the "fused ring containing a monocyclic aromatic ring as a partial structure" of ring A include bicyclic hydrocarbon rings such as naphthalene, tetrahydronaphthalene, indene, and 2,3-dihydro-1H-indene; indoline, benzimidazole, azaindole (4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole), azaindazole (4-azaindazole, 5-azaindazole, 6-azaindazole, and 7-azaindazole); Examples of the nitrogen-containing ring include, but are not limited to, bicyclic rings such as azaindazole, purine, tetrahydroquinoline, dihydroquinoline, dihydroisoquinoline, quinoline, isoquinoline, quinoxaline, naphthalazine, quinazoline, cinnoline, 1,8-naphthyridine, pyridopyrimidine, pyridopyrazine, and pteridine; and tricyclic rings such as carbazole, tetrahydrocarbazole, β-carboline, and tryptoline.

[0032] When the monocyclic aromatic ring of ring A or the fused ring containing a monocyclic aromatic ring as a partial structure is substituted, examples of the substituent include an alkyl group, a halogen atom, an oxo group, and the like, but are not limited to these.

[0033] The alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, and an isohexyl group, but are not limited to these.

[0034] Halogens include fluorine, chlorine, iodine, and astatine.

[0035] When ring A has a substituent, the number of the substituents is not particularly limited, but is preferably 1 to 4, more preferably 1 or 2 (ie, mono- or di-substitution).

[0036] L is a linker that provides a separation between the atoms to which L is bonded that corresponds to at least four bonds. That is, there are at least three atoms in the main chain of the linker L between the atoms to which L is bonded. The length of the linker L typically corresponds to a separation between the atoms to which L is bonded that corresponds to 4 to 10 bonds, preferably 4 to 7 bonds. That is, the number of atoms contained in the main chain of the linker L is typically 3 to 9, preferably 3 to 6.

[0037] The structure of L is not particularly limited as long as it provides a separation corresponding to at least four bonds between the atoms to which L is bonded. Preferably, the main chain of L contains at least one linking group selected from the group consisting of alkylene, an amide bond, and a secondary amine bond.

[0038] In one embodiment, L is a group of formula (II):

[0039]

[0040] (In the formula, R 3 is alkylene, and R 4 is a bond, and R 5 is a hydrogen atom, or R 4 and R 5 are bonded to each other to form a nitrogen-containing ring together with the nitrogen atom and carbon atom to which they are bonded, 1 and * 2 represents the end of a bond, and * 1 and * 2one of which is bonded to the nitrogen atom N* in formula (I) and the other is bonded to ring A) is a divalent organic group represented by the formula (I).

[0041] R 3 is a straight-chain or branched alkylene group having usually 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. 3 Examples of the alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0042] R 4 is a bond, and R 5 is a hydrogen atom, L is a group represented by formula (IIa):

[0043]

[0044] (In the formula, R 3 , * 1 and * 2 The definition of is the same as in formula (II).

[0045] R 4 and R 5 The nitrogen-containing heterocycle formed by bonding these together with the nitrogen atom and carbon atom to which they are bonded is preferably a 5- or 6-membered nitrogen-containing ring, more preferably a 5- or 6-membered saturated nitrogen-containing ring. Examples of the 5- or 6-membered saturated nitrogen-containing ring include, but are not limited to, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, etc.

[0046] * 1 is bonded to the nitrogen atom N* in formula (I), 2 may be bonded to ring A, or * 2 is bonded to the nitrogen atom N* in formula (I), 1 may be attached to ring A.

[0047] Specific examples of the divalent organic group represented by formula (II) include the following.

[0048]

[0049] In another embodiment, L is a group of formula (III):

[0050]

[0051] (In the formula, R 6 and R 7 are independently a bond or alkylene, ring B is an optionally substituted monocyclic aromatic ring, 3 and * 4 represents the end of a bond, and * 3 is bonded to the nitrogen atom N* in formula (I), 4 is bonded to ring A).

[0052] R 6 and R 7 Although both may be a bond or an alkylene, preferably, one is a bond and the other is an alkylene. That is, preferably, R 6 is a bond, and R 7 is alkylene, or R 6 is alkylene, and R 7 is a bond. R 6 and R 7 The alkylene in R is a straight-chain or branched alkylene having usually 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. 6 and R 7 Examples of the alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0053] Examples of the monocyclic aromatic ring of ring B include, but are not limited to, benzene; nitrogen-containing 6-membered aromatic rings such as pyridine, pyrimidine, pyrazine, pyridazine, and triazine (1,2,4-triazine or 1,3,5-triazine); and nitrogen-containing 5-membered aromatic rings such as pyrrole, pyrazole, imidazole, and triazole. The monocyclic aromatic ring is preferably benzene or triazine.

[0054] When the monocyclic aromatic ring of ring B is substituted, examples of the substituent include an amino group, a hydroxyl group, and the like, but are not limited to these.

[0055] When ring B has a substituent, the number of the substituents is not particularly limited, but is preferably 1 to 4, more preferably 1 (ie, mono-substitution).

[0056] Specific examples of the divalent organic group represented by formula (III) include the following.

[0057]

[0058] R 1 and R 2 The alkyl is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, and an isohexyl group, but are not limited to these.

[0059] R 1 and R 2 The aryl is preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, and anthracenyl.

[0060] R 1 and R 2 The "alkyl" in the arylalkyl of the above R 1 and R 2 Examples of alkyl groups include those exemplified in R 1 and R 2 The "aryl" in the aryl alkyl of the above R 1 and R 2 Examples of the aryl group include those exemplified in R 1 and R 2 Examples of the arylalkyl include, but are not limited to, benzyl, naphthylmethyl, and the like.

[0061] R 1 and R 2The hydrocarbon ring formed by bonding together with the carbon atoms to which they are bonded is preferably a monocyclic or bicyclic ring. Examples of monocyclic hydrocarbon rings include, but are not limited to, cycloalkanes and cycloalkenes having 3 to 6 carbon atoms. Examples of cycloalkanes having 3 to 6 carbon atoms include cyclopropane, cyclobutane, cyclopentane, and cyclohexane. Examples of cycloalkenes having 3 to 6 carbon atoms include cyclopropene, cyclobutene, cyclopentene, and cyclohexene. Examples of bicyclic hydrocarbon rings include tetrahydronaphthalene and indane (2,3-dihydro-1H-indene).

[0062] Specific examples of the compound represented by formula (I) include the compounds listed in Table 1 below. When the compound represented by formula (I) contains an asymmetric carbon, it may be provided as an optically active enantiomer (R- or S-form) or as a mixture of multiple enantiomers (e.g., a racemate), so long as it has GPR17 inhibitory activity. With respect to a certain optically active compound, the R-form refers to the presence of the R-form with an optical purity of, for example, 90 to 100% ee, preferably 95 to 100% ee. With respect to a certain optically active compound, the S-form refers to the presence of the S-form with an optical purity of, for example, 90 to 100% ee, preferably 95 to 100% ee.

[0063] 2. Manufacturing Method The manufacturing method of the compound represented by formula (I) will be explained, focusing on the case where L is a divalent organic group represented by formula (II) or formula (III). (1) Step 1 In the compound represented by formula (I), L is a divalent organic group represented by formula (II), and * 1 is bonded to the nitrogen atom N* in formula (I), 2 The compound in which is bonded to ring A (compound represented by the following formula (IA)) can be produced by an amidation reaction using compound 1-1 and compound 1-2.

[0064]

[0065] The amidation reaction can be carried out under commonly known conditions. For example, a mixture of compound 1-1 and compound 1-2 is stirred in THF at 20°C for 20 hours using DCC. Alternatively, a mixture of compound 1-1 and compound 1-2 is stirred in DMF at 20°C for 24 hours using TBTU, HOBt, and DIPEA.

[0066] (2) Step 2 In the compound represented by formula (I), L is a divalent organic group represented by formula (IIa), and * 2 is bonded to the nitrogen atom N* in formula (I), 1 The compound in which is bonded to ring A (compound represented by the following formula (IB)) can be produced by the same amidation reaction as in Production Method 1 using Compound 2-1 and Compound 2-2.

[0067]

[0068] (3) Step 3: In the compound represented by formula (I), L is a divalent organic group represented by formula (III), and R 6 A compound in which is a bond (a compound represented by the following formula (IC)) can be produced by Ullmann coupling reaction using compound 3-1 and compound 5.

[0069]

[0070] X in compound 3-1 represents Br or I. The Ullmann coupling reaction can be carried out under commonly known conditions. For example, a mixture of compound 3-1 and compound 5 is stirred in DMF at 85°C using copper(I) iodide and potassium carbonate for 15 hours.

[0071] (4) Step 4 In the compound represented by formula (I), L is a divalent organic group represented by formula (III), and R 7 A compound in which is a bond (a compound represented by the following formula (ID)) can be produced by reacting compound 4-1 and compound 5 in the presence of a base.

[0072]

[0073] Y in compound 4-1 represents Cl, Br, or I. The alkylation reaction can be carried out under generally known conditions. Potassium carbonate or NaH is used as the base. DMF, acetonitrile, THF, etc. are used as the solvent. The reaction temperature is preferably 20 to 90°C, and the reaction time is preferably 0.5 to 12 hours.

[0074] (5) Step 5 (Construction of Hydantoin Skeleton) Compound 5 can be produced by Bucherer-Bergs reaction using compound 5-1, potassium cyanide, and ammonium carbonate.

[0075]

[0076] The solvent is preferably water, ethanol, or a mixture of water and ethanol. The temperature is preferably 50 to 130°C. The reaction time is preferably 0.1 to 34 hours. The reaction can also be carried out in a sealed tube. The reaction can also be carried out under microwave irradiation.

[0077] (6) Process 6

[0078]

[0079] Compound 6-2 can be produced using Compound 6-1 and Compound 5 by the same reaction as in Step 4. In Compound 6-1, Y represents Cl, Br, or I, and R 8 represents an alkyl group (e.g., methyl, ethyl, t-butyl) or an arylalkyl (e.g., benzyl). R in Compound 6-2 8 When R is methyl or ethyl, compound 1-2 can be produced by stirring compound 6-2 in ethanol under commonly known alkaline hydrolysis conditions, for example, in the presence of an aqueous potassium hydroxide solution. 8 When R is t-butyl, compound 1-2 can be prepared by stirring compound 6-2 in dichloromethane in the presence of trifluoroacetic acid under commonly known acid hydrolysis conditions. 8 When is benzyl, compound 1-2 can be produced by stirring compound 6-2 under commonly known catalytic reduction conditions, for example, in the presence of palladium on carbon in ethanol under a hydrogen atmosphere.

[0080] (7) Process 7

[0081]

[0082] Compound 2-2 can be produced by heating compound 5 in hydrazine monohydrate. The temperature is preferably 100 to 150°C, and when heated above the boiling point of hydrazine monohydrate, the reaction is carried out in a sealed tube.

[0083] The method for producing a compound represented by formula (I) has been described mainly in the case where L is a divalent organic group represented by formula (II) or formula (III), but even if L is a linker other than a divalent organic group represented by formula (II) or formula (III), a person skilled in the art can produce a compound represented by formula (I) by appropriately setting conditions with reference to the above production method. If the compound represented by formula (I) is commercially available, it may be purchased.

[0084] 3. Pharmaceutical Uses GPR17-mediated signaling is known to negatively regulate myelin sheath replenishment by inhibiting oligodendrocyte maturation, and is therefore involved in the onset, progression, and exacerbation of demyelinating diseases such as multiple sclerosis. Therefore, the GPR17 inhibitors of the present invention (i.e., compounds represented by formula (I)) are useful for preventing or treating GPR17-related diseases. By administering an effective amount of the GPR17 inhibitors of the present invention (i.e., compounds represented by formula (I)) to a subject (e.g., a mammal such as a human) suffering from a GPR17-related disease, the GPR17-related disease in the subject can be treated. Furthermore, by administering an effective amount of the GPR17 inhibitors of the present invention (i.e., compounds represented by formula (I)) to a subject (e.g., a mammal such as a human) at risk of developing a GPR17-related disease, the risk of developing a GPR17-related disease in the subject can be reduced.

[0085] "GPR17-related disease" refers to a disease whose onset, progression, or exacerbation is caused by signal transduction via GPR17. Examples of GPR17-related diseases include, but are not limited to, demyelinating diseases, schizophrenia, bipolar disorder, major depression, spinal cord injury, cerebral infarction, and traumatic brain injury. Demyelinating diseases refer to neurological diseases caused by damage to the myelin sheath of myelinated nerves. Examples of demyelinating diseases include, but are not limited to, multiple sclerosis, neuromyelitis optica, and acute disseminated encephalomyelitis.

[0086] As used herein, the term "effective amount" refers to an amount that produces a desired effect (e.g., a therapeutic effect) in a subject, and means, for example, that the symptoms or condition of a disease are alleviated, mitigated, or eliminated, or the progression of the disease is delayed or inhibited in a subject to whom this amount is administered, compared to a subject to whom this amount is not administered. The effective amount can be determined appropriately by a physician depending on the age, weight, sex, severity of symptoms, etc. of the subject.

[0087] As used herein, the term "prevention" refers to preventing a disease or disorder (e.g., a GPR-related disease) from developing into a state before it occurs, reducing the risk of developing into such a state, or alleviating or mitigating such a state.

[0088] The organisms to which the preventive or therapeutic agents of the present invention are administered may be any organisms suffering from a GPR17-related disease or at risk of developing a GPR17-related disease, and examples thereof include, in addition to humans, mammals such as rats, hamsters, guinea pigs, mice, cattle, sheep, pigs, goats, monkeys, chimpanzees, and rabbits; and birds such as chickens and ostriches.

[0089] The prophylactic or therapeutic agent of the present invention may be prepared as a pharmaceutical composition containing, as needed, a pharmaceutically acceptable carrier in addition to the GPR17 inhibitor of the present invention (i.e., the compound represented by Formula (I)) to prepare it into the desired dosage form and formulation. Examples of pharmaceutically acceptable carriers include suspending agents such as methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, carboxymethylcellulose sodium, polyoxyethylene sorbitan monolaurate, etc.; solubilizing agents such as polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, and magrogol; stabilizers such as human serum albumin, dextran, methylcellulose, gelatin, sodium sulfite, and sodium metabisulfite; and stabilizers such as human serum albumin, lecithin, dextran, ethylene oxide-propylene oxide copolymer, hydroxypropylcellulose, methylcellulose, and polyoxyethylene sorbitan monolaurate. Examples of suitable additives include, but are not limited to, anti-adsorption agents such as hydroxyethylene hydrogenated castor oil and polyethylene glycol; excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate and calcium carbonate; binders such as cellulose, methylcellulose, hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose and starch; disintegrants such as starch, carboxymethylcellulose, hydroxypropyl starch, sodium bicarbonate, calcium phosphate and calcium citrate, lubricants such as magnesium stearate; diluents such as water and physiological saline; lipids; buffers; emulsifiers; coloring agents; flavoring agents; sweeteners, etc.

[0090] The content of the compound represented by formula (I) in the pharmaceutical composition is not particularly limited, but is, for example, about 0.00001 to 100% by weight, or 0.0001 to 99.9% by weight, of the total pharmaceutical composition.

[0091] The dosage form of the preventive or therapeutic agent of the present invention is not particularly limited and can be appropriately determined depending on the desired administration form, etc. Examples of dosage forms of the preventive or therapeutic agent of the present invention include, but are not limited to, tablets, pills, capsules, drinkable liquids, powders, suspensions, emulsions, granules, extracts, fine granules, syrups, troches, injections (liquids, suspensions, etc.), inhalants, creams, sprays, nasal drops, aerosol liquids, suppositories, enemas, patches, ointments, jellies, pastes, infusions, eye drops, poultices, liniments, lotions, and plasters. In the case of injections, the agent may be in the form of a powder (e.g., a lyophilized powder) to be dissolved in physiological saline or the like before use.

[0092] The prophylactic or therapeutic agent of the present invention can be administered either orally or parenterally. Parenteral administration includes, but is not limited to, intravenous administration, topical administration, subcutaneous administration, intradermal administration, intramuscular administration, transdermal administration, etc.

[0093] The dose of the prophylactic or therapeutic agent of the present invention can be adjusted as appropriate depending on the severity of the disease, the type of disease, the activity and type of the active ingredient, the mode of administration (e.g., oral, parenteral), the drug tolerance, body weight, age, etc. of the subject to be administered.

[0094] All references cited herein, including publications, patent documents, and the like, are incorporated herein by reference to the same extent as if each was individually and specifically incorporated by reference and the contents thereof were specifically set forth in their entirety.

[0095] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited thereto.

[0096] [Examples 1-7] The compounds tested (Examples 1-7) are listed in Table 1. These compounds could be synthesized using the manufacturing method described above, but were also available commercially from Enamine. Except for the compound in Example 6, all compounds contained one or two asymmetric carbon atoms. Each compound was provided as a mixture of two or four optically active forms (racemate). [Example 8] 1. Methods (1) Cell Preparation: The antagonist activity of each compound against human GPCR17 was evaluated using Tanso Biosciences' reporter assay system (WO2020 / 026979). In this system, upon stimulation of the GPCR under evaluation, a membrane-bound transcription factor and protease are expressed. The protease then recognizes the anchor sequence of the membrane-bound transcription factor and detaches it from the cell membrane. The released transcription factor translocates to the nucleus, where it expresses the reporter gene. According to standard procedures, reporter cells were cultured in DMEM supplemented with 10% FCS and penicillin / streptomycin. Cells were released using trypsin-EDTA and suspended in DMEM containing 10% dialyzed FCS. The suspended cells were seeded at 24,000 cells per well in a 96-well white microplate. The cells were cultured overnight at 37°C in the presence of 5% CO2 to allow them to adhere to the microplate bottom. Plasmids expressing human GPCR17, Gα protein, and a luciferase reporter were mixed, and the reporter cells were transfected with a total of 100 ng of plasmid per well using transfection reagent (FuGENE 6, Promega). The transfectants were cultured overnight at 37°C in the presence of 5% CO2.

[0097] (2) Antagonist Test Using the iSiP Drug Discovery Platform, a unique drug discovery platform developed by iSiP, which utilizes only fuzzy three-dimensional structural information of proteins to efficiently generate hit compounds even when structural information is scarce or ambiguous, the following seven compounds were selected in silico from a large-scale compound library (manufactured by Enamine) as GPR17 antagonist candidates, and their GPR17 antagonist activity was evaluated in a wet system.

[0098]

[0099] Test compound solutions were prepared at 300x the final test concentration. Just before the assay, the test compound solutions were diluted with DMEM containing 10% dialyzed FCS to 7x the final test concentrations (40 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 630 nM). The newly prepared 7x test compound solutions were added to each well to achieve the desired final test concentrations. The final test compound solvent concentration was 0.3%. Immediately after test compound addition, a standard agonist solution (MDL29951 (300 μM)) was added to each well to a final concentration of EC80. Cells were cultured for 6 hours at 37°C in the presence of 5% CO2. After 6 hours of test compound stimulation, the medium was aspirated. Luciferase assay reagent (Steady-Glo, Promega) was added to the wells. Luciferase luminescence was measured using a plate reader (Victor Nivo, Perkin Elmer). Data analysis was performed using the Python scientific calculation library Scipy, where concentration-dependent measurements were fitted to the Hill equation using the nonlinear least-squares method. Four parameters were calculated: IC50, Hill coefficient, curve bottom, and curve top.

[0100]

[0101] 2. Results The results are shown in Table 2. In the table, Activity A means an IC50 of greater than 1 μM and less than 10 μM, Activity B means an IC50 of greater than 10 μM and less than 20 μM, and Activity C means an IC50 of greater than 20 μM. The compounds of Examples 1 to 7 selected in silico also exhibited GPR17 antagonist activity in a wet system. These results demonstrated the effectiveness of the iSiP drug discovery platform for structure-based drug design (SBDD) against orphan GPCRs.

[0102]

[0103] The present invention provides a novel GPR17 inhibitor (i.e., a GPR17 antagonist). The GPR17 inhibitor of the present invention has excellent GPR17 inhibitory activity and may be useful as a preventive or therapeutic agent for GPR17-related diseases, including demyelinating diseases such as multiple sclerosis. The GPR17 inhibitor of the present invention has a hydantoin skeleton and has a fundamental skeleton that is significantly different from that of existing GPR17 antagonists, and therefore, a GPR17 antagonist with chemical properties different from conventional ones may be provided.

[0104] This application is based on patent application No. 2024-135480 filed in Japan (filing date: August 14, 2024), the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I): (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2 are independently alkyl, aryl, or arylalkyl, or are bonded to each other to form a hydrocarbon ring together with the carbon atoms to which they are bonded.

2. L is a compound of formula (II): (In the formula, R 3 is alkylene, and R 4 is a bond, and R 5 is a hydrogen atom, or R 4 and R 5 are bonded to each other to form a nitrogen-containing ring together with the nitrogen atom and carbon atom to which they are bonded, 1 and * 2 represents the end of a bond, and * 1 and * 2 one of which is bonded to the nitrogen atom N* in formula (I) and the other is bonded to ring A), or formula (III): (In the formula, R 6 and R 7 are independently a bond or alkylene, ring B is an optionally substituted monocyclic aromatic ring, 3 and * 4 represents the end of a bond, and * 3 is bonded to the nitrogen atom N* in formula (I), 4 The GPR17 inhibitor according to claim 1, wherein the ring A is bonded to a divalent organic group represented by the formula:

3. The compound represented by formula (I) is 1-{2-[4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)piperidin-1-yl]-2-oxoethyl}-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione, 5-methyl-3-[2-[2-(6-methyl-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-2-oxoethyl]-5-naphthalen-2-ylimidazolidine-2,4-dione, 3-[3-[[(8-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]methyl]phenyl]-1,3-diazaspiro[4.4]nonane-2,4-dione, 5-methyl-5-naphthalen-2-yl-3-[2-oxo-2-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]ethyl]imidazolidine-2,4-dione, 2-(4-benzyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-N-(naphthalen-2-yl)acetamide, N-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, and 2. The GPR17 inhibitor according to claim 1, which is any one selected from the group consisting of 1-{[4-amino-6-(phenylamino)-1,3,5-triazin-2-yl]methyl}-3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione.

4. A pharmaceutical composition for preventing or treating a GPR17-related disease, comprising the GPR17 inhibitor according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 4, wherein the GPR17-related disease is a demyelinating disease, schizophrenia, bipolar disorder, major depression, spinal cord injury, cerebral infarction, or traumatic brain injury.

6. The pharmaceutical composition according to claim 5, wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, or acute disseminated encephalomyelitis.

7. A compound of formula (I) for use in the prevention or treatment of a GPR17-related disease: (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2 are independently alkyl, aryl, or arylalkyl, or are bonded to each other to form a hydrocarbon ring together with the carbon atoms to which they are attached.

8. A subject suffering from a GPR17-related disease is administered a compound of formula (I): (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2 and (iii) are independently alkyl, aryl, or arylalkyl, or are bonded to each other to form a hydrocarbon ring together with the carbon atoms to which they are attached.

9. A subject at risk of developing a GPR17-related disease is administered a compound of formula (I): (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2 and (iii) are independently alkyl, aryl, or arylalkyl, or are bonded to each other to form a hydrocarbon ring together with the carbon atoms to which they are attached.

10. A compound of formula (I): in the manufacture of a drug for the prevention or treatment of a GPR17-related disease: (wherein, ring A is an optionally substituted monocyclic aromatic ring or an optionally substituted fused ring containing the aromatic ring as a partial structure, L is a linker that provides a separation corresponding to at least four bonds between the atoms to which L is bonded, and R 1 and R 2 are independently alkyl, aryl, or arylalkyl, or are joined together to form a hydrocarbon ring together with the carbon atoms to which they are attached.

Images