Prophylactic agent and / or therapeutic agent for prion disease

Abstract

The purpose of the present invention is to provide a novel prophylactic agent and / or a novel therapeutic agent for a prion disease and a pharmaceutical composition containing said prophylactic agent and / or said therapeutic agent. The present invention provides a prophylactic agent and / or a therapeutic agent for a prion disease comprising, as an active ingredient, a compound represented by general formula (I) (where R represents hydrogen, a chain or cyclic hydrocarbon group that may have a substituent, or a heterocyclic group that may have a substituent, and Ar1 and Ar2 are identical to each other or different from each other and each represent a homocyclic group or a heterocyclic group that may have a substituent).

Description

Preventive and / or therapeutic agent for prion disease

[0001] The present invention relates to a preventive and / or therapeutic agent for prion diseases.

[0002] Prion diseases, including Creutzfeldt-Jakob disease (CJD), are fatal diseases caused by the transformation of normal prion proteins into transmissible, abnormal prion proteins that accumulate in the central nervous system and induce neuronal cell death. Prion diseases are also zoonotic, and other known diseases include bovine spongiform encephalopathy (BSE) in cattle.

[0003] Symptoms of prion disease in the early stages include fatigue, unsteadiness, visual abnormalities, depression, and forgetfulness. As the disease progresses, significant cognitive impairment occurs, involuntary movements (myoclonus) appear, and the patient gradually becomes unable to walk and becomes bedridden. In the final stages, the disease progresses from akinetic mutism to decorticate rigidity and flexion contracture, leading to death within 1 to 2 years of onset. Prion disease has no pre-symptomatic symptoms, and once it develops, it progresses rapidly, leaving the patient bedridden within a few months, placing a heavy mental and physical burden on family members and caregivers.

[0004] Prion diseases are broadly classified into three types based on their etiology: (1) sporadic prion diseases of unknown etiology (sporadic CJD); (2) hereditary prion diseases caused by prion protein gene mutations (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)); and (3) infectious prion diseases caused by prion infection other than those described in (1) and (2) (kuru, iatrogenic CJD, and variant CJD). Prion proteins are expressed in the brains of normal individuals and are degraded and digested by protease enzymes. However, in the brains of prion disease patients, prion proteins adopt an abnormally aggregated structure that is resistant to protease degradation (see Non-Patent Document 1). Furthermore, genetic analysis of prion disease patients has identified several gene mutations associated with prion disease (see Non-Patent Document 2).

[0005] However, there are many aspects of the pathogenesis of prion disease that are not fully understood. The prion protein gene involved in the pathology has various mutations and polymorphisms. In addition, once the disease develops, symptoms progress rapidly. Furthermore, the disease is a rare disease with an incidence of approximately one in one million people, making research and development of therapeutic drugs difficult.

[0006] Currently, patients diagnosed with prion disease are only given symptomatic treatment and general nursing care, and no effective treatment exists (see Non-Patent Document 3).

[0007] Meanwhile, the present inventors have discovered that certain curcumin derivatives have the effects of inhibiting tau aggregation, secretase inhibition, and amyloid β protein aggregation, and have reported that they are useful as a means of treating Alzheimer's disease (see Patent Documents 1 and 2).

[0008] WO2012 / 141228 WO2014 / 057772

[0009] Prusiner SB. Prions. Proc Natl Acad Sci USA. 1998;95: 13363-13383.Kai H, Teruya K, Takeuchi A, Nakamura Y, Mizusawa H, Yamada M, Kitamoto T. Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease. Heliyon, 9, e13974, 2023. Teruya K and Doh-ura K. CLINICAL NEUROSCIENCE 41(9); 2023: 1240-1243.

[0010] The present invention relates to a novel agent for preventing and / or treating prion diseases, and a pharmaceutical composition containing the agent for preventing and / or treating prion diseases.

[0011] As a result of intensive research to solve the above problems, the inventors of the present invention discovered that certain curcumin derivatives exhibit excellent effects in the prevention and / or treatment of prion diseases including CJD, and thus completed the present invention.

[0012] That is, the present invention relates to the following [1] to [8]. [1] General formula (I):

[0013]

[0014] (wherein R represents hydrogen, an optionally substituted linear or cyclic hydrocarbon group, or an optionally substituted heterocyclic group; Ar １ and Ar ２ [2] A preventive and / or therapeutic agent for prion disease, comprising a compound represented by the formula (I) or a salt thereof, wherein Ar is the same or different and represents a homocyclic group or a heterocyclic group which may have a substituent. １ [3] The prophylactic and / or therapeutic agent according to the above [1], wherein the substituent is a phenyl group which may have a substituent. １－３ C substituted with an alkyloxy group or an optionally substituted cycloalkyl group １－３ C substituted with an alkyloxy group or an optionally substituted heteroaryl group １－３ C substituted with an alkyloxy group or an aryl group which may have a substituent １－３ C substituted with an alkyloxy group or an optionally substituted dialkylamino group １－３ Alkyloxy group, C substituted with an alkyloxy group which may have a substituent １－３ C substituted with an alkyloxy group or an alkyl group which may have a substituent １－３ Alkyloxy group, unsubstituted C １－３The prophylactic and / or therapeutic agent according to [2] above, wherein the prion disease is one or more selected from the group consisting of an alkyloxy group and a disubstituted amino group. [4] The prophylactic and / or therapeutic agent according to any of [1] to [3] above, wherein the prion disease is selected from the group consisting of sporadic prion disease, hereditary prion disease (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and infectious prion disease (kuru, iatrogenic CJD, variant CJD). [5] The prophylactic and / or therapeutic agent according to any of [1] to [4] above, which is orally administered. [6] A pharmaceutical composition containing the prophylactic and / or therapeutic agent according to any of [1] to [5] above.

[0015] The preventive and / or therapeutic agent for prion disease of the present invention can suppress the production of abnormal prion protein associated with prion disease.

[0016] Furthermore, the preventive and / or therapeutic agent for prion disease of the present invention can inhibit the formation of prion protein amyloid associated with prion disease.

[0017] Furthermore, the preventive and / or therapeutic agent for prion diseases of the present invention can exert the excellent effect of suppressing the onset and / or progression of prion diseases.

[0018] Fig. 1 shows the inhibitory effect on the production of abnormal prion protein, Fig. 2 shows the inhibitory effect on prion protein amyloid formation, and Fig. 3 shows the survival period extension effect in prion disease model mice.

[0019] The preventive and / or therapeutic agent for prion disease of the present invention comprises a compound represented by the general formula (I):

[0020]

[0021] (wherein R represents hydrogen, an optionally substituted linear or cyclic hydrocarbon group, or an optionally substituted heterocyclic group; Ar １ and Ar ２and (x and y are the same or different and represent a homocyclic group or a heterocyclic group which may have a substituent), or a salt thereof, as an active ingredient. Hereinafter, the preventive and / or therapeutic agent for prion disease of the present invention may also be simply referred to as the preventive and / or therapeutic agent of the present invention.

[0022] The preventive and / or therapeutic agent of the present invention is based on the novel finding that treatment of prion disease model cells with a compound represented by formula (I) inhibits the production of abnormal prion protein, and administration of the compound to prion disease model mice prolongs their survival. The present inventors have previously found that the compound exhibits aggregation-inhibiting activity against amyloid β protein, tau protein, and superoxide dismutase (SOD1). However, abnormal aggregation of proteins such as amyloid β, tau, and SOD1 is not generally observed in prion disease. Meanwhile, neuronal cell death is known to occur due to the abnormal aggregation of abnormal prion protein, a protein completely different from amyloid β, tau, and SOD1. However, extensive research by the present inventors has surprisingly shown that the compound represented by formula (I) has a potent inhibitory effect on the production of abnormal prion protein and prion protein amyloid formation. Furthermore, in order to enhance the absorption of the compound of the present invention into the blood and the transfer from the blood to the central nervous tissue when orally administered, the molecular weight of the compound having the above basic skeleton was reduced and the structure was examined to be less susceptible to conjugate formation and metabolic degradation in the body, and it was found that this effect was achieved. In fact, the compound of the present invention has been shown to extend the survival time when orally administered to prion disease model mice, and it is expected to become a very effective therapeutic agent for prion diseases, for which only symptomatic treatments are currently available.

[0023] In the general formula (I), R represents hydrogen, an optionally substituted linear or cyclic hydrocarbon group, or an optionally substituted heterocyclic group, and preferably represents hydrogen. The linear or cyclic hydrocarbon group is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include alkyl groups such as methyl, ethyl, propyl, and isopropyl groups (preferably C１－６ ), an alkenyl group such as a vinyl group (preferably C ２－６ ), an aryl group such as a phenyl group or a naphthyl group (preferably C ６－１２ ) and the like. The heterocyclic group is not particularly limited as long as it does not interfere with the effects of the present invention, and may be monocyclic or bicyclic, and examples thereof include 5- to 10-membered heterocyclic groups containing 1 to 4 (preferably 1 to 3) heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. Specific examples of monocyclic heterocyclic groups include 5- to 6-membered rings such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, furyl, thienyl, and oxazolyl groups, and examples of bicyclic heterocyclic groups include 9- to 10-membered rings such as indole, isoindole, benzimidazole, quinoline, isoquinoline, quinoxaline, chromene, and isochromene. The substituent is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include alkyl groups (preferably C) such as methyl and ethyl groups that are commonly used in pharmaceutical compounds. １－６ ), an aralkyl group such as a benzyl group (preferably C ７－１０ ), an acyl group such as an acetyl group or a benzoyl group (preferably C ２－７ ), an alkylcarbonyl group such as a tert-butoxycarbonyl group (preferably C ２－７ ), an alkylsulfonyl group such as a methylsulfonyl group or a p-toluenesulfonyl group (preferably C １－７ ), a hydroxy group, a nitro group, etc. can be mentioned.

[0024] In the general formula (I), Ar １ and Ar ２ represents a homocyclic group or a heterocyclic group which may have the same or different substituents. The "homocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and may be monocyclic or bicyclic. Specifically, aryl groups such as phenyl and naphthyl groups (preferably C ６－１２) can be exemplified. The "heterocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and may be monocyclic or bicyclic. Examples include 5- to 10-membered heterocyclic groups containing 1 to 4 (preferably 1 to 3) heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. Specific examples of monocyclic heterocyclic groups include 5- to 6-membered rings such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, furyl, thienyl, and oxazolyl groups, and examples of bicyclic heterocyclic groups include 9- to 10-membered rings such as indole, isoindole, benzimidazole, quinoline, isoquinoline, quinoxaline, chromene, and isochromene. The substituent is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include halogen atoms, hydroxyl groups, nitro groups, amino groups, cyano groups, and C groups which may have one or more substituents. １－６ an alkyl group, a C group optionally having one or more substituents; １－６ Alkyloxy group, mono- or di-C optionally having one or more substituents １－６ an alkylamino group, C optionally having one or more substituents; １－６ an alkylthio group, C optionally having one or more substituents; １－６ an alkylsulfonyl group, C optionally having one or more substituents; １－６ an acyl group, optionally having one or more substituents; １－６ an acylamino group, optionally having one or more substituents; ２－６ an alkenyl group, optionally having one or more substituents; ２－６ alkenyloxy group, mono- or di-C optionally having one or more substituents ２－６ an alkenylamino group, optionally having one or more substituents; ２－６ Examples include an alkenylthio group and a carbamoyl group which may have one or more substituents.

[0025] Ar １ represents a phenyl group which may have a substituent. Here, the substituent of the phenyl group is not particularly limited as long as it does not impair the effects of the present invention. However, (1) C which may have a substituent １－３Examples include an alkyloxy group, (2) an aryloxy group which may have a substituent, (3) a disubstituted amino group (two substituents may be joined together to form a ring), (4) an aryl group which may have a substituent or a heteroaryl group which may have a substituent, (5) a bromine atom, (6) an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent, (7) a nitro group, (8) an acyl group, (9) an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group, a sulfonyloxy group, and the like.

[0026] (1) C which may have a substituent １－３ Specifically, (1a) a C alkyloxy group substituted with a heterocycloalkyl group which may have a substituent １－３ (1b) an alkyloxy group substituted with an optionally substituted cycloalkyl group; １－３ (1c) an alkyloxy group, (1d) a C substituted with an optionally substituted heteroaryl group, １－３ (1d) an alkyloxy group, (1e) an alkyloxy group substituted with an optionally substituted aryl group, １－３ (1e) a C substituted with an optionally substituted dialkylamino group; １－３ (1f) an alkyloxy group substituted with an alkyloxy group which may have a substituent; １－３ Alkyloxy group, (1g) C substituted with an alkyl group which may have a substituent １－３ Examples of the alkyl group include an alkyloxy group. １－３ The "alkyloxy group" includes unsubstituted C １－３ Alkyloxy groups (e.g., methoxy, ethoxy, and propoxy groups) are also included. １－３ The alkyloxy group includes unsubstituted C １－３ C having an alkyloxy group and the substituents listed in (1a) to (1g) １－３ Alkyloxy groups are included.

[0027] (1a) C substituted with an optionally substituted heterocycloalkyl group １－３Specific examples of alkyloxy groups include a tetrahydrofuran-3-ylmethoxy group, a tetrahydrofuran-2-ylmethoxy group, a 2-(piperidin-1-yl)ethoxy group, a 2-(4-methylpiperazino)ethoxy group, a 2-(4-benzylpiperazino)ethoxy group, a 2-morpholinoethoxy group, a 2-pyrrolidinoethoxy group, a β-D-glucopyranosyloxy group, a 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy group, a 2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy group, and a 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethoxy group.

[0028] "C substituted with a heterocycloalkyl group which may have a substituent" １－３ Examples of the "phenyl group having an alkyloxy group" include a 2-methoxy-4-(tetrahydrofuran-3-ylmethoxy)phenyl group, a 2-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl group, a 2-methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl group, a 2-methoxy-4-[2-(4-methylpiperazino)ethoxy]phenyl group, a 2-methoxy-4-(2-morpholinoethoxy)phenyl group, a 4-(β-D-glucopyranosyl)oxy-2-methoxyphenyl group, a 4-(tetrahydrofuran-3-ylmethoxy)phenyl group, and a 4-(tetrahydrofuran-2-ylmethoxy)phenyl group. Examples include a 3-methoxy-4-(tetrahydrofuran-3-ylmethoxy)phenyl group, a 3-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl group, a 2-[2-(4-benzylpiperazino)ethoxy]-4-methoxyphenyl group, a 4-diethylamino-2-(2-morpholinoethoxy)phenyl group, a 4-dimethylamino-2-(2-morpholinoethoxy)phenyl group, a 4-diethylamino-2-(2-morpholinoethoxy)phenyl group, a 4-diethylamino-2-(2-pyrrolidinoethoxy)phenyl group, and a 4-diethylamino-2-[2-(piperidin-1-yl)ethoxy]phenyl group.

[0029] (1b) C substituted with an optionally substituted cycloalkyl group １－３ Specific examples of alkyloxy groups include cyclohexylmethoxy groups.

[0030] "C substituted with an optionally substituted cycloalkyl group １－３ Examples of the "phenyl group having an alkyloxy group" include a 4-cyclohexylmethoxy-2-methoxyphenyl group, a 2-cyclohexylmethoxy-4-hydroxyphenyl group, a 2-cyclohexylmethoxy-3-fluorophenyl group, a 2-cyclohexylmethoxy-5-fluorophenyl group, a 5-chloro-2-cyclohexylmethoxyphenyl group, and a 2,4-di(cyclohexylmethoxy)phenyl group.

[0031] (1c) C substituted with an optionally substituted heteroaryl group １－３ Specific examples of the alkyloxy group include a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a pyridin-4-ylmethoxy group, and a 1-pyrrolylmethoxy group.

[0032] "C substituted with an optionally substituted heteroaryl group １－３Examples of the "phenyl group having an alkyloxy group" include a 4-(pyridin-2-ylmethoxy)phenyl group, a 2-methoxy-4-(pyridin-2-ylmethoxy)phenyl group, a 2-[2-(piperidin-1-yl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl group, a 2-(2-morpholinoethoxy)-4-(pyridin-2-ylmethoxy)phenyl group, a 2-(2-pyrrolidinoethoxy)-4-(pyridin-2-ylmethoxy)phenyl group, a 2-[2-(4-methylpiperazino)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl group, a 3-methoxy-4-(pyridin-2-ylmethoxy)phenyl group, a 2-hydroxy-4-(pyridin-2-ylmethoxy)phenyl group, a 3-(pyridinyl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl group, a 4 ... Examples include a 2-methoxy-3-(pyridin-2-ylmethoxy)phenyl group, a 4-methoxy-3-(pyridin-2-ylmethoxy)phenyl group, a 3-methoxy-5-(pyridin-2-ylmethoxy)phenyl group, a 2-methoxy-5-(pyridin-2-ylmethoxy)phenyl group, a 2-(pyridin-2-ylmethoxy)phenyl group, a 4-methoxy-2-(pyridin-2-ylmethoxy)phenyl group, a 5-methoxy-2-(pyridin-2-ylmethoxy)phenyl group, a 2-nitro-5-(pyridin-3-ylmethoxy)phenyl group, a 4-diethylamino-2-(pyridin-3-ylmethoxy)phenyl group, and a 2-methoxy-2-(1-pyrrolylmethoxy)phenyl group.

[0033] (1d) C substituted with an optionally substituted aryl group １－３ Specific examples of the alkyloxy group include a phenethyloxy group, a benzyloxy group, a 1-naphthylmethoxy group, a diphenylmethoxy group, a 4-methoxybenzyloxy group, a 2-chloro-6-fluorobenzyloxy group, a 2,4-dichlorobenzyloxy group, and a 4-tert-butylbenzyloxy group.

[0034] "C substituted with an optionally substituted aryl group １－３Examples of the "phenyl group having an alkyloxy group" include a 2-methoxy-4-phenethyloxyphenyl group, a 4-benzyloxy-2-methoxyphenyl group, a 4-(1-naphthylmethoxy)-2-methoxyphenyl group, a 4-diphenylmethoxy-2-methoxyphenyl group, a 2-benzyloxy-4-hydroxyphenyl group, a 2-benzyloxy-4-chlorophenyl group, a 2-benzyloxy-3-fluorophenyl group, a 2-benzyloxy-3,5-dichlorophenyl group, a 5-benzyloxy-2-nitrophenyl group, a 5-(4-methoxybenzyloxy)-2-nitrophenyl group, a 5-(2-chloro-6-fluorobenzyloxy)-2-nitrophenyl group, a 5-(2,4-dichlorobenzyloxy)-2-nitrophenyl group, a 5-(4-tert-butyl Examples of the tert-butylbenzyloxy group include a 4-benzyloxy-2-nitrophenyl group, a 4-benzyloxy-2-bromophenyl group, a 4-benzyloxy-2-phenylphenyl group, a 2-benzyloxy-5-bromophenyl group, a 2-benzyloxy-5-phenylphenyl group, a 2-benzyloxy-5-(indol-6-yl)phenyl group, a 2-benzyloxy-4-dimethylaminophenyl group, a 2-benzyloxy-4-diethylaminophenyl group, a 4-diethylamino-2-(4-methoxybenzyloxy)phenyl group, a 4-diethylamino-2-(2-chloro-6-fluorobenzyloxy)phenyl group, a 4-diethylamino-2-(2,4-dichlorobenzyloxy)phenyl group, and a 4-diethylamino-2-(4-tert-butylbenzyloxy)phenyl group.

[0035] (1e) C substituted with an optionally substituted dialkylamino group １－３ Specific examples of the alkyloxy group include a 2-dimethylaminoethoxy group, a 3-dimethylaminopropoxy group, a 2-dimethylamino-1-methylethoxy group, and a 2-dimethylamino-1-methylethoxy group.

[0036] "C substituted with an optionally substituted dialkylamino group １－３Examples of the "phenyl group having an alkyloxy group" include a 4-(3-dimethylaminopropoxy)phenyl group, a 2-chloro-4-(3-dimethylaminoethoxy)phenyl group, a 2-bromo-5-(3-dimethylaminoethoxy)phenyl group, a 2-(2-dimethylaminoethoxy)-4-methoxyphenyl group, and a 4-diethylamino-2-(2-dimethylamino-1-methylethoxy)phenyl group.

[0037] (1f) C substituted with an alkyloxy group which may have a substituent １－３ Specific examples of the alkyloxy group include a methoxyethoxy group and a benzyloxyethoxy group.

[0038] "C substituted with an alkyloxy group which may have a substituent" １－３ Examples of the "phenyl group having an alkyloxy group" include a 2-methoxy-4-methoxyethoxyphenyl group and a 2-benzyloxyethoxy-4-methoxyphenyl group.

[0039] (1g) C substituted with an alkyl group which may have a substituent １－３ Specific examples of the alkyloxy group include an isopropoxy group, a 2-methylpropoxy group, and a 3-methyl-2-butenyloxy group.

[0040] "C substituted with an alkyl group which may have a substituent" １－３ Examples of the "phenyl group having an alkyloxy group" include a 4-hydroxy-2-isopropoxyphenyl group, a 4-isopropoxy-2-methoxyphenyl group, a 2-methoxy-4-(2-methylpropoxy)phenyl group, a 3-fluoro-2-(2-methylpropoxy)phenyl group, a 2,5-di(2-methylpropoxy)phenyl group, a 2,4-di(2-methylpropoxy)phenyl group, a 4-diethylamino-2-isopropoxyphenyl group, and a 4-diethylamino-2-(3-methyl-2-butenyloxy)phenyl group.

[0041] (2) An aryloxy group which may have a substituent. Specific examples thereof include a phenoxy group.

[0042] Examples of the "phenyl group having an optionally substituted aryloxy group" include a 2-phenoxyphenyl group, a 3-phenoxyphenyl group, and a 4-phenoxyphenyl group.

[0043] (3) Disubstituted amino group (two substituents may be taken together to form a ring) Specific examples of a group in which two substituents do not combine to form a ring include a dimethylamino group and a diethylamino group, and examples of a group in which two substituents combine to form a ring include an imidazol-1-yl group, a pyrazol-1-yl group, a triazol-2-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group, a 4-benzylpiperidin-1-yl group, a morpholin-4-yl group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a 4-benzylpiperazin-1-yl group, a 4-benzylpiperazin-1-yl group, a 4-methyl ... Examples of the hydroxyl group include 1,4-dimethyl-1,4-diazepan-1-yl group, 4-phenylpiperazin-1-yl group, 4-(tert-butoxycarbonyl)piperazin-1-yl group, 4-(methylsulfonyl)piperazin-1-yl group, 4-(2-hydroxyethyl)piperazin-1-yl group, 1,4-diazepan-1-yl group, 4-methyl-1,4-diazepan-1-yl group, 4-benzyl-1,4-diazepan-1-yl group, and 4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl group.

[0044] Examples of the "phenyl group having a disubstituted amino group (two substituents may be taken together to form a ring)" include a 4-dimethylaminophenyl group, a 4-dimethylamino-2-methoxyphenyl group, a 4-diethylamino-2-hydroxyphenyl group, a 4-diethylamino-2-methoxyphenyl group, a 2-dimethylaminophenyl group, a 4-bromo-2-dimethylaminophenyl group, a 5-bromo-2-dimethylaminophenyl group, a 2-dimethylamino-5-trifluoromethylphenyl group, a 2-dimethylamino-4-phenylphenyl group, a 2-dimethylamino-5-trifluoromethylphenyl group, a 2-dimethylamino-4-phenylphenyl group, a 2-dimethylamino-5-hydroxy ... -phenylphenyl group, 4-dimethylamino-3-methoxyphenyl group, 4-dimethylamino-2-nitrophenyl group, 4-dimethylamino-2-chlorophenyl group, 4-dimethylamino-2-methoxymethoxyphenyl group, 4-dimethylamino-2-trifluoromethylphenyl group, 5-dimethylamino-2-nitrophenyl group, 2-benzoyloxy-4-diethylaminophenyl group, 4-diethylamino-2-ethoxycarbonyloxyphenyl group, 4-diethylamino-2-ethylaminocarbonyloxyphenyl group, 4-diethylamino- 2-(2-hydroxyethoxy)phenyl group, 4-(imidazol-1-yl)phenyl group, 4-(pyrazol-1-yl)phenyl group, 4-(triazol-2-yl)phenyl group, 4-(pyrrolidin-1-yl)phenyl group, 4-(piperidin-1-yl)phenyl group, 4-(morpholin-4-yl)phenyl group, 4-(piperazin-1-yl)phenyl group, 4-(4-methylpiperazin-1-yl)phenyl group, 4-(4-benzylpiperazin-1-yl)phenyl group, 2-(pyrrolidin-1-yl)phenyl group, 2-(piperidin-1-yl)phenyl group a 2-(4-methyl)piperazin-1-yl)phenyl group, a 2-(morpholin-4-yl)phenyl group, a 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl group, a 2-[4-(methylsulfonyl)piperazin-1-yl]phenyl group, a 2-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl group, a 2-bromo-4-(piperidin-1-yl)phenyl group, a 2-bromo-4-(4-benzylpiperidin-1-yl)phenyl group, a 2-bromo-4-(morpholin-4-yl)phenyl group, a 2-bromo-4-(4-methylpiperazin-1-yl)phenyl group,2-bromo-4-(4-benzylpiperazin-1-yl)phenyl group, 2-bromo-4-(4-phenylpiperazin-1-yl)phenyl group, 2-bromo-4-(pyrrolidin-1-yl)phenyl group, 2-bromo-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl group, 2-bromo-4-(piperazin-1-yl)phenyl group, 2-bromo-4-[4-(methylsulfonyl)piperazin-1-yl]phenyl group, 2-bromo-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl group, 4-(1,4 -diazepan-1-yl)phenyl group, 4-(4-methyl-1,4-diazepan-1-yl)phenyl group, 4-(4-benzyl-1,4-diazepan-1-yl)phenyl group, 4-[4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl]phenyl group, 2-bromo-4-(1,4-diazepan-1-yl)phenyl group, 2-bromo-4-(4-methyl-1,4-diazepan-1-yl)phenyl group, 2-bromo-4-(4-benzyl-1,4-diazepan-1-yl)phenyl group, 2-bromo-4-[4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl]phenyl group 2-(4-benzylpiperidin-1-yl)-5-hydroxyphenyl group, 5-hydroxy-2-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl group, 5-hydroxy-2-(piperazin-1-yl)phenyl group, 2-[4-(tert-butoxycarbonyl)piperazine-1-yl]phenyl group, 5-hydroxy-2-(pyrrolidin-1-yl)phenyl group, 5-hydroxy-2-(morpholin-4-yl)phenyl group, 2-(4-benzylpiperidin-1-yl)-5-hydroxyphenyl group, 5-hydroxy-2-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl group, 5-hydroxy-2-(piperazin-1-yl)phenyl group, 2-[4-(tert-butoxycarbonyl)piperazine-1-yl]phenyl group -yl]-5-hydroxyphenyl group, 5-hydroxy-2-(4-phenylpiperazin-1-yl)phenyl group, 5-hydroxy-2-(4-methylpiperazin-1-yl)phenyl group, 2-(1,4-diazepan-1-yl)-5-hydroxyphenyl group, 5-hydroxyphenyl-2-(4-methyl-1,4-diazepan-1-yl) group, 2-(4-benzyl-1,4-diazepan-1-yl)-5-hydroxyphenyl group, 2-[4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl]-5-hydroxyphenyl group,Examples include a 5-bromo-2-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl group.

[0045] (4) Aryl Groups Which May Have Substituted Groups or Heteroaryl Groups Which May Have Substituted Groups Specific examples of "aryl groups Which may have substituted groups" include phenyl groups, 2-methylphenyl groups, 2-ethoxyphenyl groups, 1-naphthyl groups, and 2-naphthyl groups, and examples of "heteroaryl groups Which may have substituted groups" include 2-pyridyl groups, 3-pyridyl groups, 4-pyridyl groups, imidazol-1-yl groups, 1H-1,2,4-triazol-1-yl groups, 4-ethoxycarbonyl-1H-1,2,3-triazol-1-yl groups, and 5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl groups. Examples include a 1-benzyl-1H-1,2,3-triazol-4-yl group, a 1-benzyl-1H-1,2,3-triazol-5-yl group, a 1-ethoxycarbonylmethyl-1H-1,2,3-triazol-4-yl group, a 1-ethoxycarbonylmethyl-1H-1,2,3-triazol-5-yl group, a 1H-benzimidazol-1-yl group, a 1H-tetrazol-5-yl group, a 1-benzyl-1H-tetrazol-5-yl group, and a 1-ethoxycarbonylmethyl-1H-tetrazol-5-yl group.

[0046] Examples of the "phenyl group having an optionally substituted aryl group or an optionally substituted heteroaryl group" include a 2-phenylphenyl group, a 3-phenylphenyl group, a 4-phenylphenyl group, a 5-hydroxy-2-phenylphenyl group, a 5-fluoro-2-phenylphenyl group, a 5-chloro-2-phenylphenyl group, a 5-hydroxy-2-(2-methylphenyl)phenyl group, a 2-(2-ethoxyphenyl)-5-hydroxyphenyl group, a 2-(1-naphthyl)phenyl group, a 2-(2-naphthyl)phenyl group, a 5-hydroxy-2-(1-naphthyl)phenyl group, a 2-(2-pyridyl)phenyl group, a 2-(3-pyridyl)phenyl group, a 2-(4-pyridyl)phenyl group, a 4-(2-pyridyl)phenyl group, a 4-(imidazol-1-yl)phenyl group, a 4-(1H-benzimidazol-1-yl)phenyl group, a 2-(1H- 1,2,4-triazol-1-yl)phenyl group, 2-(4-ethoxycarbonyl-1H-1,2,3-triazol-1-yl)phenyl group, 2-(5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl)phenyl group, 2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl group, 2-(1-benzyl-1H-1,2,3-triazol-5-yl)phenyl group, 2-(1 Examples include a 2-(1-ethoxycarbonylmethyl-1H-1,2,3-triazol-4-yl)phenyl group, a 2-(1-ethoxycarbonylmethyl-1H-1,2,3-triazol-5-yl)phenyl group, a 2-(1H-tetrazol-5-yl)phenyl group, a 2-(1-benzyl-1H-tetrazol-5-yl)phenyl group, and a 2-(1-ethoxycarbonylmethyl-1H-tetrazol-5-yl)phenyl group.

[0047] (5) Bromine Atom Examples of the "phenyl group having a bromine atom" include a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-bromo-3-hydroxyphenyl group, a 2-bromo-4-hydroxyphenyl group, a 2-bromo-5-hydroxyphenyl group, a 2-bromo-5-methoxyphenyl group, a 2-bromo-5-methoxymethoxyphenyl group, a 4-bromo-2-fluorophenyl group, a 5-bromo-2-fluorophenyl group, a 2-bromo-4-hydroxy-5-methoxyphenyl group, a 2-bromo-5-hydroxy-4-methoxyphenyl group, a 2,4-dibromo-5-hydroxyphenyl group, and a 2,3-dibromo-4-hydroxy-5-methoxyphenyl group.

[0048] (6) An alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent. Specifically, an isopropyl group, a hydroxymethyl group, an n-propyl group, a 2-cyclopropylethyl group, a 2-(methoxymethyl)ethyl group, a 2-(dimethylaminomethyl)ethyl group, a 2-(diethylaminomethyl)ethyl group, a phenethyl group, a 2-(pyridin-2-yl)ethyl group, a 2-(pyridin-3-yl)ethyl group, a 2-(pyridin-4-yl)ethyl group, a 2-methylethenyl group, a 2-cyclopropylethenyl group, a 2-(methoxymethyl)ethenyl group, a 2-(dimethylaminomethyl)ethenyl group Examples include a 2-(diethylaminomethyl)ethenyl group, a 2-(diethylaminomethyl)ethenyl group, a styryl group, a 2-(pyridin-2-yl)ethenyl group, a 2-(pyridin-3-yl)ethenyl group, a 2-(pyridin-4-yl)ethenyl group, a 1-propynyl group, a cyclopropylethynyl group, a methoxymethylethynyl group, a 2-(dimethylaminomethyl)ethynyl group, a 2-(diethylaminomethyl)ethynyl group, a phenylethynyl group, a pyridin-2-ylethynyl group, a pyridin-3-ylethynyl group, and a pyridin-4-ylethynyl group.

[0049] Examples of the "phenyl group having an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group" include a 4-isopropylphenyl group, a 2-(hydroxymethyl)phenyl group, a 2-methoxy-4-(n-propyl)phenyl group, a 4-(2-cyclopropylethyl)-2-methoxyphenyl group, a 2-methoxy-4-[2-(methoxymethyl)ethyl]phenyl group, a 4-[2-(dimethylaminomethyl)ethyl]-2-methoxyphenyl group, a 4-[2-(diethylaminomethyl)ethyl] -2-methoxyphenyl group, 2-methoxy-4-phenethylphenyl group, 2-methoxy-4-[2-(pyridin-2-yl)ethyl]phenyl group, 2-methoxy-4-[2-(pyridin-3-yl)ethyl]phenyl group, 2-methoxy-4-[2-(pyridin-4-yl)ethyl]phenyl group, 2-styrylphenyl group, 2-methoxy-4-(2-methylethenyl)phenyl group, 4-(2-cyclopropylethenyl)-2-methoxyphenyl group, 2-methoxy-4-[2-(methoxymethyl)ethenyl]phenyl group, 4-[2-( 2-(2-(dimethylaminomethyl)ethenyl)-2-methoxyphenyl group, 4-[2-(diethylaminomethyl)ethenyl]-2-methoxyphenyl group, 2-methoxy-4-styrylphenyl group, 2-methoxy-4-[2-(pyridin-2-yl)ethenyl]phenyl group, 2-methoxy-4-[2-(pyridin-3-yl)ethenyl]phenyl group, 2-methoxy-4-[2-(pyridin-4-yl)ethenyl]phenyl group, 2-methoxy-4-(1-propynyl)phenyl group, 4-(2-cyclopropylethynyl)-2-methoxyphenyl Examples include a 2-methoxy-4-[2-(methoxymethyl)ethynyl]phenyl group, a 4-[2-(dimethylaminomethyl)ethynyl]-2-methoxyphenyl group, a 4-[2-(diethylaminomethyl)ethynyl]-2-methoxyphenyl group, a 2-methoxy-4-(phenylethynyl)phenyl group, a 2-methoxy-4-[2-(pyridin-2-yl)ethynyl]phenyl group, a 2-methoxy-4-[2-(pyridin-3-yl)ethynyl]phenyl group, and a 2-methoxy-4-[2-(pyridin-4-yl)ethynyl]phenyl group.

[0050] (7) Nitro Group Examples of the “phenyl group having a nitro group” include a 2-nitrophenyl group, a 4-hydroxy-3-nitrophenyl group, a 3-methoxy-4-nitrophenyl group, a 5-methoxy-2-nitrophenyl group, a 5-methoxymethoxy-2-nitrophenyl group, a 5-fluoro-2-nitrophenyl group, a 5-hydroxy-2-nitrophenyl group, a 5-chloro-2-nitrophenyl group, a 2-chloro-5-nitrophenyl group, and a 4,5-dimethoxy-2-nitrophenyl group.

[0051] (8) Acyl Group Examples of the "phenyl group having an acyl group" include a 2-hydroxycarbonylphenyl group, a 3-hydroxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, a 3-methoxycarbonylphenyl group, a 4-methoxycarbonylphenyl group, a 2-dimethylaminocarbonylphenyl group, and a 3-(di-n-propylaminocarbonyl)phenyl group.

[0052] (9) Alkylcarbonylamino Group, etc. Phenyl groups having an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group, or a sulfonyloxy group are also included in the above-mentioned "phenyl groups which may have a substituent".

[0053] The number of the above substituents (1) to (9) is not particularly limited, and the same or different substituents may be introduced singly or in plural. The positions of the above substituents (1) to (9) on the phenyl group are also not particularly limited, and they may be introduced at any of the ortho, meta, and para positions, but are preferably introduced at the ortho or para positions. Ar １ The phenyl group represented by the formula (I) may have a substituent such as a hydroxy group or a halogen atom other than a bromine atom in addition to the substituents (1) to (9) above.

[0054] Ar in the general formula (I) ２ represents preferably a homocyclic group or heterocyclic group which may have a substituent, more preferably a monocyclic or bicyclic homocyclic group or heterocyclic group which may have a substituent, and even more preferably a bicyclic heterocyclic group which may have a substituent.

[0055] The "bicyclic heterocyclic group" is not particularly limited as long as it does not interfere with the effects of the present invention, but preferred examples include an indol-2-yl group, an indol-3-yl group, an indol-4-yl group, an indol-5-yl group, an indol-6-yl group, an indol-7-yl group, a benzotriazol-5-yl group, a benzimidazol-5-yl group, a quinoxalin-6-yl group, a benzofuran-2-yl group, a benzothiophen-2-yl group, a 1H-indazol-5-yl group, a 7-azaindole-3-yl group, a quinolin-2-yl group, a quinolin-5-yl group, a quinolin-8-yl group, a 1,4-benzodioxan-6-yl group, a 1,3-benzodioxol-5-yl group, a chromone-3-yl group, a coumarin-6-yl group, a 7-methoxycoumarin-4-yl group, and a 4-methoxycoumarin-6-yl group. Examples of the substituent of the bicyclic heterocyclic group include a methyl group, an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonyl group, a hydroxy group, and a nitro group.

[0056] The "optionally substituted bicyclic heterocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and preferred examples thereof include unsubstituted bicyclic heterocyclic groups, as well as alkyl groups (e.g., C １－６ etc.), aralkyl groups (e.g., C ７－１０ etc.), acyl groups (e.g., C ２－１０ and bicyclic heterocyclic groups substituted with a hydroxyl group, a nitro group, or the like.

[0057] The compound represented by the general formula (I) preferably has the following structure in view of its inhibitory effect on the production of abnormal prion protein and on the formation of prion protein amyloid.

[0058] In the general formula (I), Ar １ is preferably a phenyl group having the above-mentioned substituent (1) or (3), more preferably a phenyl group having the above-mentioned substituent (1a) or (1c), or a phenyl group having a disubstituted amino group in which two substituents combine to form a ring. Specific examples include a 2-methoxy-4-(pyridin-2-ylmethoxy)phenyl group, a 2-methoxy-4-(2-morpholinoethoxy)phenyl group, a 4-(pyridin-2-ylmethoxy)phenyl group, a 2-fluoro-4-(pyridin-2-ylmethoxy)phenyl group, and a 4-methylpiperazin-1-yl group.

[0059] In the general formula (I), Ar ２is preferably a monocyclic or bicyclic heterocyclic group. Specific examples thereof include an optionally substituted pyrrolyl group, an optionally substituted pyrrolinyl group, an optionally substituted imidazolyl group, an optionally substituted pyrazolyl group, an optionally substituted indol-2-yl group, an optionally substituted indol-3-yl group, an optionally substituted indol-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted indol-6-yl group, an optionally substituted indol-7-yl group, an optionally substituted benzotriazol-5-yl group, an optionally substituted benzimidazol-5-yl group, an optionally substituted quinoxaline-6-yl group, and the like.

[0039] The benzoyl group is preferably an indolyl group, an optionally substituted benzofuran-2-yl group, an optionally substituted benzothiophen-2-yl group, or an optionally substituted pyrrole group, more preferably an indol-2-yl group, an indol-3-yl group, an indol-6-yl group, a 1-methyl-indol-6-yl group, a benzotriazol-5-yl group, a benzimidazol-5-yl group, a quinoxalin-6-yl group, a benzofuran-2-yl group, a benzothiophen-2-yl group, or a 1-methyl-pyrrol-2-yl group, and even more preferably a 1-methyl-pyrrolyl-2-yl group, an indol-6-yl group, or a 1-methyl-indol-6-yl group.

[0060] Specific examples of the compound represented by formula (I) include compounds selected from the following:

[0061]

[0062] The present invention also encompasses salts of the compounds represented by the general formula (I). Such salts are preferably pharmacologically acceptable salts, and examples thereof include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate, and bicarbonate; organic carboxylates such as acetate, oxalate, maleate, tartrate, and fumarate; organic sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and camphorsulfonate; amino acid salts such as aspartate and glutamate; salts with amines such as trimethylamine salt, triethylamine salt, procaine salt, pyridine salt, and phenethylbenzylamine salt; alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt, with hydrochloride and oxalate being preferred.

[0063] The compound represented by the general formula (I) can be produced by referring to the methods described in, for example, Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172, WO 2008 / 066151, WO 2009 / 145219, or a combination thereof. Specifically, the compound can be produced by the following steps 1 and 2. In the following formula, Ar １ and Ar ２ has the same meaning as above.

[0064]

[0065] Step 1 is a step of reacting an aldehyde represented by general formula (A) with a compound represented by general formula (B) in the presence of a solvent and a catalyst to obtain a diketone represented by general formula (C). The diketone represented by general formula (C) or a salt thereof is also included in the present invention. In the above formula, the aldehyde represented by general formula (A) is Ar １ and the compound represented by general formula (B) is Ar ２ However, Ar ２ and an aldehyde represented by general formula (A) having Ar １With a compound represented by general formula (B) having the formula:

[0066] The aldehyde represented by general formula (A) and the compound represented by general formula (B) used in step 1 can be commercially available products or compounds synthesized by known methods (e.g., the methods described in WO 2008 / 066151 and WO 2009 / 145219). The amounts of the starting compounds used in step 1 and the reaction conditions can be appropriately set in accordance with known techniques. The solvent, catalyst, and, if necessary, auxiliary agents are not particularly limited and can be appropriately selected from known compounds.

[0067] Step 2 is a step of reacting a diketone represented by the general formula (C) with hydrazine or a derivative thereof in the presence of a solvent to obtain a compound represented by the general formula (I). Step 2 is a step of reacting a diketone represented by the general formula (C) with hydrazine or a derivative thereof (H ２ The method may include a step of adding a substituent to the compound obtained by reacting the compound represented by the formula (I) with a compound represented by the formula (I)-NHR or a salt thereof.

[0068] The hydrazine used is not particularly limited, and examples thereof include hydrazine monohydrate, an aqueous hydrazine solution, anhydrous hydrazine, hydrazine acetate, hydrazine monohydrochloride, and derivatives thereof. The amounts of the raw material compounds used in step 2 and the reaction conditions can be appropriately determined according to known techniques. The solvent, and optionally the catalyst and auxiliary agent, are also not particularly limited, and can be appropriately selected from known ones.

[0069] The prophylactic and / or therapeutic agent of the present invention is not particularly limited in terms of other ingredients, so long as it contains a compound represented by general formula (I) or a salt thereof. The compound represented by general formula (I) or a salt thereof can be used alone or in combination of two or more kinds, and the content of the compound represented by general formula (I) or a salt thereof in the prophylactic and / or therapeutic agent of the present invention is usually about 0.00001 to 100% by weight.

[0070] The compound represented by general formula (I) of the present invention has an inhibitory effect on the production of abnormal prion protein, an inhibitory effect on prion protein amyloid formation, etc., and therefore can be suitably used as a preventive, ameliorating, and / or therapeutic agent for prion diseases and symptoms associated therewith. Specifically, the compound can be suitably used as a preventive, ameliorating, and / or therapeutic agent for sporadic prion disease (sporadic CJD), hereditary prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), infectious prion diseases (kuru, iatrogenic CJD, variant CJD) and symptoms associated therewith.

[0071] The form of the prophylactic and / or therapeutic agent of the present invention is not limited, as long as the compound represented by general formula (I) or a salt thereof can be ingested into the body. For example, the agent can be formulated into oral or parenteral preparations such as tablets, powders, granules, capsules, liquids, emulsions, elixirs, suspensions, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, and lotions. Because of their high absorption into the blood and transferability from the blood to the central nervous tissue, the agent may also be formulated as an oral preparation.

[0072] Currently, there is no cure for prion disease. Because prion disease typically leads to death within several months to one to two years after onset, treatment is limited to symptomatic treatment, such as alleviating symptoms and discomfort. The compounds of the present invention inhibit the production of abnormal prion protein, which is the direct cause of prion disease, and further inhibit prion protein amyloid formation, demonstrating superior efficacy not found in existing treatments. Additionally, the compounds have a long blood retention time (Okuda et al., 2015, PLoS ONE 10(2): e0117511). Furthermore, as exemplified in the test examples below, they are highly safe, have low toxicity, and exhibit low mutagenicity. Therefore, they can be developed into oral formulations, suggesting their suitability as preventive and / or therapeutic agents for prion disease.

[0073] The dosage of the prophylactic and / or therapeutic agent of the present invention is not fixed and is determined appropriately depending on the form, purpose of administration, and the type, age, body weight, and symptoms of the recipient. For example, the effective human dosage of the compound represented by general formula (I) or a salt thereof of the present invention is preferably about 0.01 to 100 mg / kg per day, more preferably about 1 to 50 mg / kg per day. Administration may be performed in a single dose or in several divided doses within the desired dosage range within a day. The administration period is also optional. For example, the compound may be orally administered once a day.

[0074] The subjects of administration of the preventive and / or therapeutic agent of the present invention are preferably humans requiring treatment for sporadic prion diseases (sporadic CJD), hereditary prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and / or infectious prion diseases (kuru, iatrogenic CJD, variant CJD). However, in view of the zoonotic nature of prion diseases, the subjects of administration may also be livestock animals such as cows, horses, and goats, pet animals such as dogs, cats, and rabbits, or laboratory animals such as mice, rats, guinea pigs, and monkeys. Furthermore, from the viewpoint of oral intake, subjects of administration include a wide range of subjects, from patients exhibiting early symptoms who are primarily treated at home to patients in the middle and end stages who require hospitalization and full-body care.

[0075] The present invention also provides a pharmaceutical composition containing the preventive and / or therapeutic agent of the present invention. The form of the composition is not particularly limited as long as it allows the compound represented by general formula (I) or a salt thereof to be taken up into the body, and examples of the form include an external preparation composition and an internal preparation composition.

[0076] Specifically, the composition can be formulated into tablets, powders, fine granules, granules, coated tablets, capsules, liquids, emulsions, elixirs, suspensions, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, and the like.

[0077] The pharmaceutical compositions of the present invention having the above-described forms, so long as they contain a compound represented by general formula (I) or a salt thereof, can be prepared according to conventional methods by appropriately blending carriers, bases, and / or additives commonly used in the pharmaceutical field, etc., within the scope of achieving the objectives of the present invention. Specifically, for example, excipients, binders, lubricants, colorants, flavoring agents, odorants, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. may be used as needed. The pharmaceutical compositions of the present invention are formulated according to conventional methods by blending appropriate amounts of ingredients commonly used as raw materials for pharmaceutical formulations within the scope that does not impair the effects of the present invention. The content of the compound represented by general formula (I) or a salt thereof in the pharmaceutical composition of the present invention will vary depending on the dosage form, administration method, carrier, etc., but is typically 0.01 to 100 wt %, preferably 0.1 to 95 wt %, of the pharmaceutical composition of the present invention.

[0078] The compound represented by general formula (I) of the present invention or a salt thereof can be applied to prion diseases in general. In one embodiment, the compound can be used in a method for treating sporadic prion diseases (sporadic CJD), genetic prion diseases (e.g., familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and / or infectious prion diseases (kuru, iatrogenic CJD, variant CJD). Specific examples of the method include the following (a) to (g): (a) A method for treating sporadic CJD, comprising the step of administering the compound represented by general formula (I) or a salt thereof to a patient with sporadic CJD. (b) A method for treating familial CJD primary lateral sclerosis (GSS), comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with familial CJD. (c) A method for treating GSS, comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with GSS. (d) A method for treating FFI, comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with FFI. (e) A method for treating kuru, comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with kuru. (f) A method for treating iatrogenic CDJ, comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with iatrogenic CJD. (g) A method for treating variant CDJ, comprising the step of administering a compound represented by the general formula (I) or a salt thereof to a patient with variant CJD.

[0079] Furthermore, as one aspect of the present invention, there is provided use of a compound represented by general formula (I) or a salt thereof for the prevention and / or treatment of sporadic prion diseases (sporadic CJD), hereditary prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and / or infectious prion diseases (kuru, iatrogenic CJD, variant CJD). Furthermore, as one embodiment of the present invention, there is provided use of a compound represented by general formula (I) or a salt thereof for producing an agent for preventing and / or treating sporadic prion diseases (sporadic CJD), hereditary prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and / or infectious prion diseases (kuru, iatrogenic CJD, variant CJD).

[0080] The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited thereto. The compound (Compound A) used in the following tests has the structure shown below and was prepared according to the method described in Example 2 of WO2012 / 141228.

[0081]

[0082] Test Example 1 To verify the inhibitory effect on the production of abnormal prions, an evaluation test was carried out using Neuro2A (N2a) cells, which are derived from mouse neuroblastoma; ScN2a cells, which are N2a cells persistently infected with RML prions; and N167 cells, which are N2a cells persistently infected with 22L prions. Each cell was cultured in Opti-MEM medium supplemented with 10% fetal bovine serum and 0.9% antibiotics (kanamycin and streptomycin). The cells were cultured in a 6-well cell culture plate (9 cm 2Cells were seeded in 1000 x g / well plates and treated with compound A (final concentrations of 10 μM to 128 pM). After three days of treatment, the cells were harvested, proteins were extracted, and normal prions were degraded by proteinase K treatment (final concentration 10 μg / mL, 37°C, 30 minutes). Detection samples containing abnormal prions were prepared by centrifugation (12,000 rpm, 10 minutes). A control sample was also prepared without proteinase K treatment. Abnormal prions were detected by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Western blotting was performed using SAF83 (mouse monoclonal, SPI-BIO, diluted 1:5,000) and anti-beta-actin antibody (mouse monoclonal, SIGMA, diluted 1:20,000) as primary antibodies, and alkaline phosphatase-conjugated goat anti-mouse immunoglobulin antibody (Promega, diluted 1:20,000) as secondary antibody. Chemiluminescent detection reagent (CDP-Star detection reagent, Amersham) was used for detection. Compound cytotoxicity was also assessed using uninfected N2a cells. Two days after seeding, cells were treated with compound A (final concentrations of 10 μM to 128 pM). One day later, cytotoxicity was assessed using the Cell Counting Kit-8 (CCK-8, Dojindo Laboratories). The results are shown in Figure 1.

[0083] As shown in Figure 1, Compound A concentration-dependently inhibited abnormal prion production in N2a cells (Figure 1A). In particular, Compound A exhibited a significant inhibitory effect in ScN2a cells persistently infected with the RML strain, with a median inhibitory concentration (IC50) of 0.51 ± 0.09 nM (Figure 1B). The toxic concentration (50% lethal concentration: LD50) of Compound A was approximately 8,000 times the IC50 (4.0 ± 2.3 μM, Figure 1C), demonstrating the extremely high safety profile of Compound A.

[0084] Test Example 2: To verify the inhibitory effect on prion protein amyloid formation, an evaluation test was conducted using recombinant mouse prion protein PrP(23-230) (recPrP) and thioflavin T (ThT), a fluorescent substance that specifically binds to protein β-sheet structures. recPrP (final concentration: 4 μM) and Compound A (final concentrations: 0, 0.080, 0.40, 2.0, and 10 μM) were dissolved in 50 mM HEPES buffer (pH 7.2) containing guanidine-HCl (2 M), NaCl (150 mM), and ThT (10 μM). 180 μL aliquots were dispensed into a 96-well assay plate and subjected to aggregation reaction at 37°C for 55 hours. The prion protein amyloid formation and its progression rate were evaluated by monitoring ThT fluorescence intensity (excitation wavelength: 444 nm, emission wavelength: 482 nm) during this period. The results are shown in Figure 2.

[0085] As shown in Figure 2, Compound A concentration-dependently reduced ThT fluorescence intensity, which is an indicator of the amount of prion protein amyloid (β-sheet structure) formed (Figure 2A), and also significantly delayed the progression of aggregation (Figure 2B). These results indicate that Compound A directly inhibits prion protein amyloid formation.

[0086] Test Example 3: To verify the therapeutic and symptom-ameliorating effects of Compound A on prion disease, the efficacy of Compound A against prion disease was evaluated using prion gene-overexpressing mice, Tga20 mice and Tg7 mice (6-10 weeks old, obtained from Scripps Research Institute and NIAID's Rocky Mountain Laboratories, respectively). To induce prion disease in the mice, Tga20 mice were intracerebroventricularly injected with RML prion-infected brain homogenate, and Tg7 mice were intracerebroventricularly injected with 263K prion-infected brain homogenate (1% (w / v), 20 μL). After injection, Compound A was dissolved in polyethylene glycol 400 at 25 mg / mL and mixed into the feed at a 2% concentration (equivalent to a Compound A dose of approximately 75 mg / kg / day). A control (vehicle) group received polyethylene glycol 400 alone mixed into the feed at a 2% concentration. During the administration period, mice were observed daily for symptoms. If severe prion disease symptoms (loss of grooming behavior and coordination, immobility, stiff tail, arched back, etc.) or a weight loss of 10% or more within one week were observed, the study was terminated and the mice were euthanized. Compound A was evaluated by comparing the vehicle group and the Compound A-administered group using the number of days of survival from prion injection to euthanasia as an index. The results are shown in Figure 3.

[0087] As shown in Figure 3, when RML prion was injected into Tga20 mice (Figure 3A) and when 263K prion was injected into Tg7 mice (Figure 3B), the survival time was significantly longer in the compound A-treated group compared to the vehicle group (RML-Tga20: P=0.000004, 263K-Tg7: P=0.0002, Logrank test), demonstrating that compound A suppresses the onset and progression of prion disease symptoms.

[0088] The preventive and / or therapeutic agent of the present invention has an inhibitory effect on the production of abnormal prions and / or an inhibitory effect on the aggregation of abnormal prions, and can be suitably used as a preventive and / or therapeutic agent for prion diseases in general, such as sporadic prion diseases (sporadic CJD), genetic prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and / or infectious prion diseases (kuru, iatrogenic CJD, variant CJD).

Claims

1. General formula (I): (wherein R represents hydrogen, an optionally substituted linear or cyclic hydrocarbon group, or an optionally substituted heterocyclic group; Ar １ and Ar ２ and the groups may be the same or different and represent a homocyclic or heterocyclic group which may have a substituent, or a salt thereof.

2. Ar in formula (I) １ The preventive and / or therapeutic agent according to claim 1 , wherein is an optionally substituted phenyl group.

3. A C group substituted with an optionally substituted heterocycloalkyl group. １－３ C substituted with an alkyloxy group or an optionally substituted cycloalkyl group １－３ C substituted with an alkyloxy group or an optionally substituted heteroaryl group １－３ C substituted with an alkyloxy group or an aryl group which may have a substituent １－３ C substituted with an alkyloxy group or an optionally substituted dialkylamino group １－３ Alkyloxy group, C substituted with an alkyloxy group which may have a substituent １－３ C substituted with an alkyloxy group or an alkyl group which may have a substituent １－３ Alkyloxy group, unsubstituted C １－３ 3. The preventive and / or therapeutic agent according to claim 2, wherein the group is one or more selected from the group consisting of an alkyloxy group and a disubstituted amino group.

4. The preventive and / or therapeutic agent according to any one of claims 1 to 3, wherein the prion disease is selected from the group consisting of sporadic prion disease (sporadic CJD), hereditary prion diseases (familial CJD, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI)), and infectious prion diseases (kuru, iatrogenic, variant CJD).

5. The preventive and / or therapeutic agent according to any one of claims 1 to 4, which is administered orally.

6. A pharmaceutical composition containing the preventive and / or therapeutic agent according to any one of claims 1 to 5.

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