Compounds, preventive or therapeutic agents for neurological diseases

Abstract

To prevent or treat neurological disease.SOLUTION: The invention provides a compound represented by the formula (I) in the figure. (In the formula, R1 represents a substituent; Y1 represents a single bond or a divalent linking group; Z1 represents an optionally substituted nitrogen-containing aromatic group; and n represents an integer from 1 to 5.)SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] There are few drugs that can suppress or treat the progression of neurological diseases.

[0002] Patent Document 1 describes IA9 (Lansoprazole Sulfide) and NSC228155 as compounds effective against neurological diseases, but the efficacy of these compounds against neurological diseases has been low. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Special Publication No. 2019-535804 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The present invention aims to prevent or treat neurological diseases. [Means for solving the problem]

[0005] This invention provides the following compounds, which are used for the prevention or treatment of neurological diseases. Item 1. A compound represented by the following formula (I). [ka] (In the formula, R 1 indicates a substituent. Y 1 indicates a single bond or a divalent linking group. 1 (where n is an integer between 1 and 5, it may be a substituted nitrogen-containing aromatic group.) Item 2. The compound described in Item 1, represented by the following formula (I-1) or (I-2). [ka] (In the formula, R 1 indicates a substituent. Y 1represents a single bond or a divalent linking group. R 2 represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group. R 3 , R 4 is the same or different and represents a substituent, or R 3 and R 4 together with the carbon atom to which they are attached represent an optionally substituted aryl group or an optionally substituted heteroaryl group. X 1 ~X 7 are the same or different and represent C-R 5 or N, and R 5 are the same or different and represent a substituent. n represents an integer from 1 to 5.) Item 3. The compound according to Item 1 or 2, which has an SARM1 inhibitory effect. Item 4. A prophylactic or therapeutic agent for a nervous system disease, which contains a compound represented by the following formula (I) as an active ingredient.

Chemical formula

Advantages of the Invention

[0006] The compounds of the present invention have a protective effect on nerve cells and can suppress nerve cell death, making them effective in preventing or treating neurological diseases.

[0007] The compounds of the present invention are also effective as novel preventive or therapeutic agents for CIPN (chemotherapy-induced peripheral neuropathy), for which no effective treatment has currently been established.

[0008] The compounds of the present invention can protect nerve cells based on their mitochondrial protective effects.

[0009] Since the compounds of the present invention can suppress axonal degeneration based on their SARM1 inhibitory activity, they are also effective in neurological diseases in which axonal degeneration is involved in disease progression. [Brief explanation of the drawing]

[0010] [Figure 1] This demonstrates the efficacy of the present compound against an in vitro model of CIPN. [Figure 2] The present invention demonstrates a protective effect on mitochondria. [Figure 3] The present invention demonstrates the efficacy of the compound against Parkinson's disease (PD). [Figure 4] This demonstrates the efficacy of the compound of the present invention against an in vivo model of CIPN. [Figure 5] Purification and phosphorylation of SARM1-FLAG using the compound of the present invention [Figure 6] Inhibition efficiency of NAD+ degradation activity by the compound of the present invention [Figure 7] Compound evaluation using SARM1-overexpressing cells [Modes for carrying out the invention]

[0011] The compounds of the present invention are represented by general formula (I).

[0012] [ka] (In the formula, R 1 indicates a substituent. Y 1 indicates a single bond or a divalent linking group. 1 (where n is an integer between 1 and 5, it may be a substituted nitrogen-containing aromatic group.)

[0013] A more preferred compound of the present invention is represented by the following formula (I-1) or (I-2).

[0014] [ka] (In the formula, R 1 indicates a substituent. Y 1 R indicates a single bond or a divalent linking group. 2 R represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group. 3 , R 4 These are identical or different, indicating substituents, or R 3 and R 4 The carbon atoms to which they are bonded may together form an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring. 1 ~X 7 They are the same or different, CR 5 Or indicate N, R 5 (These indicate substituents that are identical or different. n is an integer between 1 and 5.)

[0015] n represents an integer from 1 to 5, preferably 1, 2, or 3, more preferably 1 or 2.

[0016] R 3 and R 4Examples of aromatic rings that can be formed by the carbon atoms to which they are bonded include phenyl and naphthyl, while examples of heteroaromatic rings include pyrrole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, quinoline, isoquinoline, pyridine, pyrimidine, pyridazine, quinoxaline, indole, benzimidazole, benzoisothiazole, benzoxazole, benzoisoxazole, and benzotriazole.

[0017] Y 1 As a divalent linking group represented by , C 1-6 Linear or branched alkylene groups, cycloalkylene groups, optionally substituted arylene groups, optionally substituted aralkylene groups, -O-, -NR 6 -(R 6 C is a hydrogen atom. 1-6 Examples include linear or branched alkyl groups, optionally substituted phenyl groups, or optionally substituted aralkyl groups, -CH(OH)-, -S-, -CO-, -CONH-, -NHCO-, -CO-O-, -O-CO-, -NH-CO-O, -O-CO-NH-, -NH-CO-NH-, and one or more of these can be combined to form a divalent linking group.

[0018] Z 1 Examples of nitrogen-containing aromatic groups represented by include pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, pyridadinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, and benzotriazolyl.

[0019] In this specification, substituents or rings that may be substituted, such as nitrogen-containing aromatic groups, aryl groups, aralkyl groups, heteroaryl groups, arylene groups, aralkylene groups, phenyl groups, aromatic rings, and heteroaromatic rings, are used. 5The substituents represented include halogen atoms, trifluoromethyl groups, hydroxyl groups, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group, trifluoromethoxy group, trifluoroethoxy group, C 1-6 Alkylsulfonylamino group, C 1-2 Alkyl sulfonyl group, cyano group, nitro group, amino group, mono or disubstituted amino group, C 1-6 Alkoxycarbonylamino group, carbamoyl group, mono- or disubstituted carbamoyl group, sulfamoyl group, mono- or disubstituted sulfamoyl group, C 1-6 Alkylcarbonyloxy, arylcarbonyloxy, aryl-substituted C 1-4 Alkylcarbonyloxy, C 1-6 Alkylaminocarbonyloxy, arylaminocarbonyloxy, or aryl-substituted C 1-4 Alkylaminocarbonyloxy, aryl-substituted C 1-4 Alkyloxy, aryl group, heteroaryl group, C 1-6 Examples include alkoxycarbonyl groups, arylmethyloxycarbonyl groups, carboxyl groups, 5-tetrazolyl groups, sulfo groups (-SO2OH), or fluorosulfonyl groups. The number of substituents that groups such as nitrogen-containing aromatic groups, aryl groups, aralkyl groups, heteroaryl groups, arylene groups, aralkylene groups, and phenyl groups may have is 1 to 5, preferably 1 to 3, and more preferably 1 or 2.

[0020] Examples of cycloalkylene groups include cyclopentylene and cyclohexylene.

[0021] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0022] C 1-6The linear or branched alkyl group may be linear or branched, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.

[0023] "C 3-7 Specific examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0024] "C 2-6 An "alkenyl group" refers to a group that is linear, branched, or cyclic and has at least one double bond. Examples include vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohexenyl, and 3-methyl-3-butenyl.

[0025] "C 2-6 The term "alkynyl group" refers to a group that is linear, branched, or cyclic and has at least one triple bond. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, and 1-methyl-2-propynyl.

[0026] In mono- or disubstituted amino groups, mono- or disubstituted carbamoyl groups, or mono- or disubstituted sulfamoyl groups, "mono-substituted" means that one of the hydrogen atoms bonded to the nitrogen atom of the amino group, carbamoyl group, or sulfamoyl group is C 1-6 This means that the group is substituted with an alkyl group. "Di-substituted" means that two hydrogen atoms bonded to the nitrogen atom of the amino group, carbamoyl group, or sulfamoyl group are the same or different C atoms. 1-6This means that the molecule is substituted with an alkyl group or with a nitrogen-containing cyclic group having 3 to 8 members, preferably 5 or 6 members. Specific examples of nitrogen-containing cyclic groups include morpholino, 1-pyrrolidinyl, piperidino, and 4-methyl-1-piperazinyl.

[0027] C 1-6 Examples of amino groups monosubstituted with alkyl groups include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, and hexylamino.

[0028] C 1-6 Examples of amino groups disubstituted with alkyl groups include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-tert-butylamino, di-n-pentylamino, diisopentylamino, and dihexylamino.

[0029] C 1-6 Examples of carbamoyl groups monosubstituted with alkyl groups include methyl carbamoyl, ethyl carbamoyl, n-propyl carbamoyl, isopropyl carbamoyl, n-butyl carbamoyl, isobutyl carbamoyl, tert-butyl carbamoyl, n-pentyl carbamoyl, isopentyl carbamoyl, and hexyl carbamoyl.

[0030] C 1-6 Examples of carbamoyl groups disubstituted with alkyl groups include dimethylcarbamoyl, diethylcarbamoyl, di-n-propylcarbamoyl, diisopropylcarbamoyl, di-n-butylcarbamoyl, diisobutylcarbamoyl, di-tert-butylcarbamoyl, di-n-pentylcarbamoyl, diisopentylcarbamoyl, and dihexylcarbamoyl.

[0031] C 1-6Examples of alkyl monosubstituted sulfamoyl groups include methylsulfamoyl, ethylsulfamoyl, n-propylsulfamoyl, isopropylsulfamoyl, n-butylsulfamoyl, isobutylsulfamoyl, tert-butylsulfamoyl, n-pentylsulfamoyl, isopentylsulfamoyl, and hexylsulfamoyl.

[0032] C 1-6 Examples of alkyl-disubstituted sulfamoyl groups include dimethylsulfamoyl, diethylsulfamoyl, di-n-propylsulfamoyl, diisopropylsulfamoyl, di-n-butylsulfamoyl, diisobutylsulfamoyl, di-tert-butylsulfamoyl, di-n-pentylsulfamoyl, diisopentylsulfamoyl, and dihexylsulfamoyl.

[0033] An "aryl group" refers to a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic hydrocarbon ring. Specific examples include phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, chromanyl, 2,3-dihydro-1,4-dioxanaphthalenyl, indanyl, and phenanthryl.

[0034] The arylene group refers to a monocyclic or polycyclic divalent group consisting of a 5- or 6-membered aromatic hydrocarbon ring. Specific examples include phenylene, biphenylene, phenoxyphenylene, naphthylene, anthracenylene, phenantrenylene, and fluorenylene.

[0035] Examples of aralkylene groups include the bendiylene group and the phenethylene group.

[0036] A "heteroaryl group" refers to a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from N, O, and S. In the case of a polycyclic group, at least one ring must be an aromatic ring. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, quinolyl, isoquinolyl, benzo[b]thienyl, and benzimidazolyl.

[0037] Examples of arylmethyloxycarbonyl groups include phenylmethyloxycarbonyl, naphthylmethyloxycarbonyl, fluorenylmethyloxycarbonyl, anthrylmethyloxycarbonyl, biphenylylmethyloxycarbonyl, tetrahydronaphthylmethyloxycarbonyl, chromanylmethyloxycarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylmethyloxycarbonyl, indanylmethyloxycarbonyl, and phenanthrylmethyloxycarbonyl.

[0038] C 1-6 Specific examples of alkylcarbonyloxy include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy.

[0039] Specific examples of arylcarbonyloxy include phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy.

[0040] Aryl substitution C1-4 Specific examples of alkylcarbonyloxy include benzylcarbonyloxy, naphthylmethylcarbonyloxy, fluorenylmethylcarbonyloxy, anthrylmethylcarbonyloxy, biphenylylmethylcarbonyloxy, tetrahydronaphthylmethylcarbonyloxy, chromanylmethylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylmethylcarbonyloxy, indanylmethylcarbonyloxy and phenanthrylmethylcarbonyloxy, phenethylcarbonyloxy, naphthylethylcarbonyloxy, fluorenylethylcarbonyloxy, anthrylethylcarbonyloxy, biphenylylethylcarbonyloxy, tetrahydronaphthylethylcarbonyloxy, chromanylethylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethylcarbonyloxy, indanylethylcarbonyloxy and phenanthrylethylcarbonyloxy.

[0041] C 1-6 Specific examples of alkylaminocarbonyloxy include methylaminocarbonyloxy, ethylaminocarbonyloxy, n-propylaminocarbonyloxy, isopropylaminocarbonyloxy, n-butylaminocarbonyloxy, isobutylaminocarbonyloxy, tert-butylaminocarbonyloxy, n-pentylaminocarbonyloxy, isopentylaminocarbonyloxy, and hexylaminocarbonyloxy.

[0042] Specific examples of arylaminocarbonyloxy include phenylaminocarbonyloxy, naphthylaminocarbonyloxy, fluorenylaminocarbonyloxy, anthrylaminocarbonyloxy, biphenylylaminocarbonyloxy, tetrahydronaphthylaminocarbonyloxy, chromanylaminocarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylaminocarbonyloxy, indanylaminocarbonyloxy, and phenanthrylaminocarbonyloxy.

[0043] Aryl substitution C1-4 Specific examples of alkylaminocarbonyloxy include benzylaminocarbonyloxy, naphthylmethylaminocarbonyloxy, fluorenylmethylaminocarbonyloxy, anthrylmethylaminocarbonyloxy, biphenylylmethylaminocarbonyloxy, tetrahydronaphthylmethylaminocarbonyloxy, chromanylmethylaminocarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylmethylaminocarbonyloxy, indanylmethylaminocarbonyloxy and phenanthrylmethylaminocarbonyloxy, phenethylaminocarbonyloxy, naphthylethylaminocarbonyloxy, fluorenylethylaminocarbonyloxy, anthrylethylaminocarbonyloxy, biphenylylethylaminocarbonyloxy, tetrahydronaphthylethylaminocarbonyloxy, chromanylethylaminocarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethylaminocarbonyloxy, indanylethylaminocarbonyloxy and phenanthrylethylaminocarbonyloxy.

[0044] C 1-6 Specific examples of alkoxys include methoxyxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, and hexyloxy.

[0045] Specific examples of aryloxy include phenyloxy, naphthyloxy, fluorenyloxy, anthryloxy, biphenylyloxy, tetrahydronaphthyloxy, chromanyloxy, 2,3-dihydro-1,4-dioxanaphthalenyloxy, indanyloxy, and phenanthryloxy.

[0046] Aryl substitution C 1-4Specific examples of alkyloxy include benzyloxy, naphthylmethyloxy, fluorenylmethyloxy, anthrylmethyloxy, biphenylylmethyloxy, tetrahydronaphthylmethyloxy, chromanylmethyloxy, 2,3-dihydro-1,4-dioxanaphthalenylmethyloxy, indanylmethyloxy and phenanthrylmethyloxy, phenethyloxy, naphthylethyloxy, fluorenylethyloxy, anthrylethyloxy, biphenylylethyloxy, tetrahydronaphthylethyloxy, chromanylethyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethyloxy, indanylethyloxy and phenanthrylethyloxy.

[0047] C 1-6 Specific examples of alkoxycarbonylamino groups include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, isopentyloxycarbonylamino, and hexyloxycarbonylamino.

[0048] C 1-6 Specific examples of alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino, isopentylsulfonylamino, and hexylsulfonylamino.

[0049] C 1-6 Specific examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl.

[0050] C 1-2 Examples of alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.

[0051] The compound of formula (I) of the present invention can be produced by known methods or in accordance with known methods, for example, by the following method.

[0052] [ka] JPEG0007856952000007.jpg72131 (in the formula, Z 1 , R 1 n is as defined above. X represents a halogen atom. Y 1a Y represents a single bond, an alkylene group, a cycloalkylene group, an optionally substituted arylene group, or an optionally substituted aralkylene group. 1b This indicates CONH. 1c This indicates NHCO. 1d This indicates OCONH. Y 1e This indicates NHCOO. 1f Y indicates COO. 1g This indicates OCO. 1h This indicates NHCONH. Y 1g (This indicates NHCONH.)

[0053] By using 1 mole of compound (2) and 1 mole or an excess amount of compound (1), and reacting them at a temperature of -20°C to room temperature for 1 to 24 hours, the compound of formula (Ia) can be obtained.

[0054] By using 1 mole of compound (3) and 1 mole or an excess amount of compound (1), and reacting them at a temperature of -20°C to room temperature for 1 to 24 hours, the compound of formula (Ib) can be obtained.

[0055] Compound (Ic) can be obtained by reacting 1 mole to an excess amount of hydrazine with 1 mole of compound (Ib) at a temperature of 0°C to approximately the boiling point of the solvent for 1 to 24 hours. Examples of solvents include lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride, and aromatic hydrocarbons such as toluene.

[0056] Compound (Id) can be obtained by using 1 mole to an excess amount of compound (5) per mole of compound (4), and reacting the mixture for 1 to 24 hours at room temperature to approximately the boiling point of the solvent, in the presence of a coupling agent such as dicyclohexylcarbodiimide, water-soluble carbodiimide, or carbonyldiimidazole as needed. Examples of solvents include lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and dimethylformamide.

[0057] Compound (Ie) can be obtained by using 1 mole to an excess amount of compound (7) per mole of compound (6), and reacting the mixture for 1 to 24 hours at room temperature to approximately the boiling point of the solvent, in the presence of a condensing agent such as dicyclohexylcarbodiimide, water-soluble carbodiimide, or carbonyldiimidazole as needed. Examples of solvents include lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride, and aromatic hydrocarbons such as toluene.

[0058] By using 1 mole of compound (8) and 1 mole or an excess of compound (9), and reacting them at room temperature to approximately the boiling point of the solvent for 1 to 24 hours, the compound of formula (If) can be obtained. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and acetonitrile.

[0059] Compound (Ig) can be obtained by reacting 1 mole or an excess of compound (11) with 1 mole of compound (10) at room temperature to approximately the boiling point of the solvent for 1 to 24 hours. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and acetonitrile.

[0060] Compound (Ih) can be obtained by reacting compound (11) with compound (1) in an excess of 1 mole per mole of compound (4) for 1 to 24 hours at room temperature to approximately the boiling point of the solvent, in the presence of a coupling agent such as dicyclohexylcarbodiimide, water-soluble carbodiimide, or carbonyldiimidazole as needed. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, acetonitrile, and dimethylformamide.

[0061] Compound (Ii) can be obtained by reacting compound (7) with compound (7) in an excess of 1 mole per mole of compound (8) for 1 to 24 hours at room temperature to approximately the boiling point of the solvent, in the presence of a coupling agent such as dicyclohexylcarbodiimide, water-soluble carbodiimide, or carbonyldiimidazole, if necessary. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, acetonitrile, and dimethylformamide.

[0062] Compound (Ij) can be obtained by reacting compound (9) with compound (9) in an excess of 1 mole per mole of compound (6) for 1 to 24 hours at room temperature or around the boiling point of the solvent. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and acetonitrile.

[0063] Compound (Ik) can be obtained by reacting compound (5) with compound (5) in an excess of 1 mole per mole of compound (10) at room temperature to approximately the boiling point of the solvent for 1 to 24 hours. Examples of solvents include halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and acetonitrile.

[0064] Neurological disorders include diabetic neuropathy, Parkinson's disease, amyotrophic lateral sclerosis (ALS), neuropathy, multiple sclerosis, spinocerebellar degeneration, Alzheimer's disease, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, chemotherapy-induced peripheral neuropathy (CIPN), Lewy body dementia, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's syndrome, primary lateral sclerosis, Charcot-Marie-Tooth disease, collagen disease, familial amyloid polyneuropathy, progressive multifocal leukoencephalopathy, subacute combined degeneration of the spinal cord, prion disease, viral encephalitis, neuromyelitis optica, and glaucoma, with Parkinson's disease and amyotrophic lateral sclerosis (ALS) being particularly noteworthy.

[0065] Preferred compounds of the present invention have SARM1 inhibitory activity. More preferred compounds have phosphorylated SARM1 inhibitory activity. Examples of SARM1 phosphorylation sites include the Ser residue at position 548 of human SARM1.

[0066] The preventive or therapeutic agent for neurological diseases containing the compound of formula (I) of the present invention as an active ingredient can be appropriately administered in terms of method of administration, dosage form, and dosage according to its intended use. For example, the drug containing the compound of the present invention as an active ingredient may be administered orally or parenterally. Examples of dosage forms include oral preparations such as tablets, powders, capsules, granules, extracts, and syrups, or parenteral preparations such as injections, infusions, or suppositories. These preparations can be manufactured as pharmaceutical compositions containing the compound of the present invention and pharmaceutically acceptable excipients. The effective dose of the compound of the present invention as a preventive or therapeutic agent for neurological diseases is usually about 0.1-3000 mg per day for oral administration and about 0.01-500 mg per day for parenteral administration to adults, administered once or multiple times a day. The dosage varies depending on various conditions, so a smaller amount than the above dosage range may be sufficient in some cases. [Examples]

[0067] The present invention will be described in more detail below based on examples.

[0068] The structures of CD388, CE9, and CE221 used in the examples are shown below.

[0069] [ka] CD388, CE9, and CE221 are publicly known compounds provided by the Pharma Valley Center of the Fujinokuni Medical Town Promotion Foundation and are sold by Enamine.

[0070] Example 1 • Efficacy of SARM1 inhibitors in a chemotherapy-induced peripheral neuropathy (CIPN) in vitro model using human nerve cells

[0071] To investigate the effects of SARM1 inhibitors on CIPN, a disease in which axonal degeneration is involved in disease progression, nerve cells differentiated from human iPS cells were analyzed after being treated with the anticancer drugs vincristine (VCR) and cisplatin. Human nerve cells were treated with 50 μM CD388, IA9, and NSC228155, followed by 50 nM VCR or 10 μM cisplatin. Cell viability was measured after 24 hours using the CellTiter-Glo assay. As shown in Figure 1A, CD388 suppressed cell death induced by VCR and cisplatin, but IA9's cell death inhibitory effect was lower than that of CD388. NSC228155 was highly toxic, killing most cells upon treatment with NSC228155 alone. For further investigation, cells were collected after 24 hours under the same conditions as above and subjected to Western blot analysis. VCR treatment resulted in an increase in the cell death marker (Cl. Caspase 3) and degradation of axonal components (NF-M, NF-L) (Figure 1B). IA9 slightly improved these phenomena, but CD388 more strongly suppressed cell death and axonal component degradation (Figure 1B). NSC228155 was highly cytotoxic and could not be evaluated. Based on these results, CD388 is considered to have superior SARM1 inhibitory and cytoprotective effects compared to the compounds described in Patent Document 1.

[0072] To elucidate the mechanism of action of the neuroprotective effect of CD388, an analysis related to mitochondrial function was performed. CD388 was added at 50 μM to neurons differentiated from human iPS cells, and VCR was further added at 50 nM. After 24 hours, the amounts of NAD + ATP, and reactive oxygen species (ROS) were measured by NAD / NADH-Glo assay (Promega), CellTiter-Glo assay (Promega), and CM-H2DCFDA staining (Thermo Fisher Scientific), respectively. The amounts of NAD + and ATP were calculated for their concentrations using standard solutions. The addition of VCR resulted in a decrease in the amounts of NAD + and ATP and an increase in the amount of ROS (Figure 2 A-C). CD388 inhibits the NAD + degrading activity of SARM1 activated by VCR, suppresses the decrease in the amount of NAD + and as a result protects mitochondrial function and suppresses the decrease in the amount of ATP and the generation of ROS (Figure 2 A-C).

[0073] · Effect of SARM1 inhibitor on a Parkinson's disease (PD) in vitro model using human neurons

[0074] To verify the effect of the SARM1 inhibitor on PD in which axonal degeneration is thought to be involved in the disease progression, an analysis was performed by adding rotenone, which is known to induce PD-like symptoms, to neurons differentiated from human iPS cells. CD388 and IA9 were added at 50 μM to human neurons, and rotenone was further added at 10 μM. After 24 hours, an analysis by Western blot was performed. The addition of rotenone induced cell death (increase in Cl.Caspase and degradation of axonal components (decrease in NF-M), but CD388 suppressed these phenomena and showed a cell-protective effect. On the other hand, IA9 showed almost no cell-protective effect (Figure 3).

[0075] · Effect of SARM1 inhibitor on a CIPN-in vivo model using mice

[0076] To investigate the effects of SARM1 inhibitors on CIPN in vivo, we performed an analysis using VCR-treated mice. C57BL / 6J mice (9 weeks old, male, n=3) were intraperitoneally administered 10 mg / kg of CD388, followed two hours later by intraperitoneal administration of 1 mg / kg of VCR. This administration was continued for five consecutive days, and 15 days after the start of administration, we analyzed hyperalgesia and collected plantar tissue. Body weight changes from the start of administration were also recorded. CD388 monotherapy had no significant effect on the mice, and body weight changes were the same as in the control group (Figure 4A, CD388 group). VCR administration reduced the mice's body weight to approximately 85% of pre-administration weight (VCR group), but gradually recovered after peaking on day 8 of administration. CD388 administration did not affect the weight loss caused by VCR administration (Figure 4A, CD388+VCR group). Hyperalgesia to mechanical stimuli was analyzed using the von Frey test with up-down stimulation. Starting with a 0.6 g filament, stimulation was performed with a smaller filament if an avoidance response was observed, and with a larger filament if no response was observed. The two responses before and after a change in response to stimulation were considered the initial responses, and the 50% threshold was calculated using a formula based on the results obtained from a total of six up-down stimulations. Hyperalgesia to mechanical stimulation was observed with VCR administration, but suppression of VCR-induced hyperalgesia was observed with CD388 administration (Figure 4B).

[0077] Hyperalgesia to thermal stimulation was analyzed using the Hargreaves test with a thermal analgesia measurement device (Ugo Basile). Mice were placed in cages one hour prior to measurement to allow them to acclimate to the environment, and then measurements were started. Infrared thermal stimulation was applied to the hind limbs of mice under conditions of 40% output and a maximum duration of 20 seconds, and the time it took for the hind limbs to retract was measured. Six measurements were taken for each mouse, and the average time was calculated after removing the maximum and minimum times. Hyperalgesia to thermal stimulation was observed with VCR administration, but suppression of VCR-induced hyperalgesia was observed with CD388 administration (Figure 4C).

[0078] To analyze changes in peripheral nerve status associated with VCR and CD388 administration, immunohistochemical staining of intraepidermal nerve fibers in the plantar tract was performed using the nerve fiber marker PGP9.5 antibody. Fifteen days after the start of compound administration, plantar tissue was collected using a derma punch (3 mm), immersed in Zamboni solution (Wako), and fixed at 4°C for 24 hours. Next, it was transferred to a 30% sucrose solution and treated twice at 4°C for 24 hours, followed by cryoprotection. After rapid freezing with dry ice, the plantar tissue was mounted in OCT compound (Sakura FineTech). Frozen sections were prepared to a thickness of 50 μm using a microtome, washed with PBS, and blocked with PBS-T containing 10% goat serum (Vectashield). Anti-PGP9.5 antibody (Proteintech) was added as the primary antibody at a 1000-fold dilution and reacted at 4°C for 16 hours. After PBS-T washing, anti-rabbit IgG-Alexa 594 (Thermo Fisher Scientific) was added as a secondary antibody at a 1000-fold dilution and reacted at room temperature for 2 hours. After PBS-T washing, the tissue was arranged on a glass slide and dried. It was mounted using a mounting solution containing DAPI (Vectashield) and observed with a confocal laser microscope LSM780 (Zeiss). VCR administration reduced the number of nerve fibers in the plantar epidermis, but CD388 administration suppressed the VCR-induced reduction in nerve fiber count (Figure 4D, white arrow).

[0079] • Expression and purification of phosphorylated SARM1 protein

[0080] Phosphorylated full-length SARM1 protein was expressed and purified using insect cells ExpiSf9 and the ExpiSf Expression System (Thermo Fisher Scientific). DNA encoding SARM1 (724 amino acids) with a FLAG tag sequence added to the C-terminus was incorporated into a pFastBac1 vector. The constructed vector was transformed into DH10Bac competent cells, and positive colonies were obtained. Bacmid DNA with confirmed insertion of SARM1-FLAG DNA was purified using the PureLink HiPure Plasmid Prep Kit. ExpiSf9 cells were cultured, and transfection was performed in Opti-MEM by mixing ExpiFectamine Sf transfection reagent and SARM1-FLAG bacmid DNA according to the manual. Culture supernatant containing P0 baculovirus was collected 5 days after transfection. ExpiSf9 cells were divided into 5 x 10⁶ cells. 6 Cells were cultured for 24 hours with ExpiSf enhancer added at a concentration of cells / ml, followed by the addition of P0 baculovirus and further culture for 72 hours. The cells were harvested and stored at -80°C. Cells expressing SARM1-FLAG were lysed in a solution containing 1% Triton-X 100 and 20% sucrose, and the supernatant was collected after centrifugation. 1 ml of agarose (SIGMA) with anti-FLAG antibody was added and the mixture was reacted at 4°C for 3 hours. The agarose was thoroughly washed with PBST and PBS, and PBS containing 0.5 mg / ml FLAG peptide (Wako) was added and reacted for 1 hour to elute SARM1-FLAG. Purification and phosphorylation of SARM1-FLAG were confirmed using FLAG antibody and phosphorylated SARM1 antibody (Figure 5).

[0081] • Compound screening using phosphorylated SARM1 protein

[0082] Using 1,920 compounds provided by the Pharma Valley Center of the Fujinokuni Medical Town Promotion Foundation, we investigated the NAD of SARM1. +Screening of compounds that inhibit the cleavage activity was performed. As a method, 500 ng of phosphorylated SARM1 protein was placed in each well of a 96-well plate, a compound was added at a final concentration of 10 μM, and the reaction was carried out at 37 °C for 30 minutes. Next, NAD + was added at a final concentration of 1 μM, and the reaction was carried out at 37 °C for 30 minutes. Finally, NAD / NADH-Glo (Promega) solution was added, and the amount of NAD + was measured as the luminescence amount. Taking the luminescence amount of the well to which only 1 μM NAD + was added as 100%, the inhibition efficiency of the NAD + cleavage activity of SARM1 was calculated (Figure 6A). CD388, CE9, and CE221 that inhibit the activity of phosphorylated SARM1 by 50% or more were found and used for subsequent analysis.

[0083] The inhibitory effects of the compounds (IA9 (Lansoprazole Sulfide), NSC228155) described in Patent Document 1 on phosphorylated SARM1 were evaluated. The two compounds were added at a final concentration of 10 μM, and analysis was performed in the same manner as above. Compared with CD388, the SARM1 inhibitory effects of IA9 and NSC228155 were low (Figure 6B).

[0084] Example 2 HEK293T cells, a human kidney-derived cell line, were transfected with pDNA encoding control or SARM1, and seeded in a 96-well plate at a number of 6×10 4 after 8 hours. Compounds (CD388, CE9, CE221) were added at a concentration of 50 μM, and the cells were cultured for 16 hours. The cell viability was measured using the CellTiter-Glo assay.

[0085] The addition of the compound of the present invention suppressed the cell death occurring in SARM1-overexpressing cells (Figure 7).

[0086] Based on these results, the SARM1 inhibitor compound we discovered suppresses axonal degeneration and cell death that occur in CIPN and PD, making it a useful candidate compound for the development of therapeutic drugs for neurological diseases in which axonal degeneration is involved in disease progression.

Claims

1. A preventive or therapeutic agent for neurological disorders, comprising a compound represented by CD388, CE9, or CE221 as an active ingredient. 【Chemistry 1】

2. Neurological disorders include diabetic neuropathy, Parkinson's disease, amyotrophic lateral sclerosis (ALS), neuropathy, multiple sclerosis, spinocerebellar degeneration, Alzheimer's disease, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, chemotherapy-induced peripheral neuropathy (CIPN), Lewy body dementia, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's syndrome, primary lateral sclerosis, Charcot-Marie-Tooth disease, collagen disease, familial amyloid polyneuropathy, and progressive multifocal white blood cell carcinoma. A preventive or therapeutic agent for a neurological disease according to claim 1, selected from the group consisting of encephalopathy, subacute combined degeneration of the spinal cord, prion disease, viral encephalitis, neuromyelitis optica, and glaucoma.

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