WO2019194024A1 - Spinocerebellar ataxia type 31 inhibitor - Google Patents

Abstract

The purpose of the present invention is to provide a spinocerebellar ataxia type 31 inhibitor in which an active ingredient is a small-molecule compound that directly acts on, and thereby mitigates the toxicity of, the repeat RNA that is a cause of spinocerebellar ataxia type 31. The spinocerebellar ataxia type 31 inhibitor according to the present invention is characterized by comprising a compound represented by formula (I) as an active ingredient. [In the formula, X and Y independently represent, for example, a =N- group, Z represents an m-valent linker group that bonds m structures in the brackets to each other, m represents an integer of 2-4, α represents a substituent, and l represents an integer of 0-4.]

Description

Spinocerebellar degeneration type 31 inhibitor

The present invention relates to a spinocerebellar degeneration type 31 inhibitor that directly inhibits the action of (UGGAA) _{n that} causes spinocerebellar degeneration type 31 and fundamentally improves the symptoms.

Spinocerebellar degeneration (SCA) is a general term for diseases accompanied by ataxia symptoms in which abnormalities occur in nerve tissues such as the cerebellum, brain stem, and spinal cord, and the body can move but cannot move as intended.

Among SCAs, spinocerebellar degeneration type 31 (SCA31) is an intractable hereditary neurodegenerative disease and is an intron shared by BEAN (Brain Expressed with NEDD4) and TK2 (Thymidine Kinase 2) in chromosome 16. , (TGGAA) _n , (TAGAA) _n , (TAAAAA) _n and (TAAAATAGAA) _n, etc. Of these pentanucleotide repeats, (TGGAA) _n is pathogenic and specific for spinocerebellar degeneration type 31.

Specifically, toxic (UGGAA) _n transcribed from (TGGAA) _n binds to an RNA-binding protein in the nucleus to form an RNA aggregate, which causes neuronal loss. In addition, when (UGGAA) _n is delivered from the nucleus to the cytoplasm, a loop structure formed by a plurality of such pentanucleotides is the starting point, and the AUG sequence contained in (UGGAA) _n is the start codon Therefore, translation is promoted. As a result, insoluble abnormal protein aggregates having a repeating structure of Trp-Asn-Gly-Met-Glu accumulate in the cytoplasm.

As a method for suppressing the toxicity of repeat RNA as described above, there is known a method of inhibiting the function of repeat RNA by forming a duplex with the target repeat RNA by antisense nucleic acid (ASO) targeting repeat RNA. (Non-Patent Document 1). Also known is a method of suppressing toxicity by eliminating abnormal folding of repeat RNA using RNA binding protein (RBP) (Non-patent Document 2). However, such a method using a biopolymer has a problem of high drug price and nephrotoxicity, and a problem that drug delivery is difficult, like conventional biopharmaceuticals using nucleic acids and antibodies.

On the other hand, low molecular weight drugs have also been developed as therapeutic agents for spinocerebellar degeneration (Patent Documents 1 to 8). However, spinal cerebellar degeneration type 31, which is an inherited neurodegenerative disease, cannot be a fundamental treatment even if the symptoms are alleviated unless the expression and function of repeat RNA are suppressed.

JP-A 63-290876 International Publication No. 96/003989 Pamphlet International Publication No. 99/063989 Pamphlet Japanese Patent Laid-Open No. 2003-063988 Special table 2008-512344 gazette JP 2013-10777 A JP2015-160819A Japanese Unexamined Patent Publication No. 2017-14198 JP 2003-259899 A

As described above, various therapeutic agents for spinocerebellar degeneration have been studied, but among the spinocerebellar degeneration, low molecular weight compounds that act on repeat RNA that causes spinocerebellar degeneration 31 have not been reported yet. In fact, there is no fundamental treatment for spinocerebellar degeneration type 31.
Accordingly, an object of the present invention is to provide a spinocerebellar degeneration type 31 inhibitor comprising, as an active ingredient, a low molecular weight compound that directly acts on a repeat RNA that causes spinocerebellar degeneration type 31 to reduce its toxicity. To do.

The inventors of the present invention have made extensive studies to solve the above problems. As a result, a compound developed by the present inventors for recognizing a mismatched base and detecting a mismatched base pair binds to (UGGAA) _n causing causal spinal cerebellar degeneration type 31 and performs its function. The present invention was completed by finding that it can inhibit and reduce spinocerebellar degeneration type 31.
Hereinafter, the present invention will be described.

[1] A spinal cerebellar degeneration type 31 inhibitor comprising a compound represented by the following formula (I) as an active ingredient.

[Where:
X and Y independently represent a ═N— group or a ═CH— group, and at least one of X and Y is a ═N— group;
Z represents an m-valent linker group that connects m parenthesized structures to each other;
m represents an integer of 2 or more and 4 or less;
α is, C _1-6 alkyl, C _1-6 alkoxy group, hydroxyl group, halogeno group, an amino group, a mono (C _1-6 alkyl) amino group, di (C _1-6 alkyl) amino group, a nitro group and One or more substituents selected from the group consisting essentially of cyano groups;
l represents an integer of 0 or more and 4 or less;
The structures in two or more parentheses may be the same or different. ]

[2] The group in which the linker group is essentially composed of a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, a thiourea group, and a urethane group. The spinocerebellar degeneration type 31 inhibitor according to [1] above, wherein two or more selected groups are combined.

[3] The spinocerebellar degeneration type 31 inhibitor according to the above [1] or [2], wherein X and Y are = N-groups.

[4] The spinocerebellar degeneration type 31 inhibitor according to any one of the above [1] to [3], wherein α is a C _1-6 alkyl group and l is 1.

[5] The spinocerebellar degeneration type 31 inhibitor according to any one of [1] to [4] above, wherein the substituent α is bonded to the carbon adjacent to X.

[6] A method for suppressing spinocerebellar degeneration type 31, comprising
A method comprising administering to a patient a drug containing the compound represented by the above formula (I) as an active ingredient.

[7] The group in which the linker group is essentially composed of a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, a thiourea group, and a urethane group. The method according to [6] above, wherein two or more selected groups are bonded groups.

[8] The method according to [6] or [7] above, wherein X and Y are = N-groups.

[9] The method according to any one of [6] to [8] above, wherein α is a C _1-6 alkyl group and l is 1.

[10] The method according to any one of [6] to [9] above, wherein the substituent α is bonded to carbon adjacent to X.

[11] Use of a compound represented by the above formula (I) for suppressing spinocerebellar degeneration type 31.

[12] The group in which the linker group is essentially composed of a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, a thiourea group, and a urethane group. The use according to [11] above, wherein two or more groups selected from the above are linked groups.

[13] Use as described in [11] or [12] above, wherein X and Y are = N-groups.

[14] The use according to any one of [11] to [13] above, wherein α is a C _1-6 alkyl group and l is 1.

[15] The use according to any one of [11] to [14] above, wherein the substituent α is bonded to carbon adjacent to X.

The spinocerebellar degeneration type 31 inhibitor according to the present invention contains a low-molecular compound as an active ingredient. Therefore, there are fewer degradation problems due to nucleases, proteases, and the like than drugs containing biopolymers such as nucleic acids and proteins as active ingredients. In addition, the experimental findings by the present inventors indicate that the low-molecular weight compound as an active ingredient binds to RNA repeat (UGGAA) _n which is the cause of spinocerebellar degeneration 31 and significantly reduces its action. It has been revealed. That is, since the low molecular weight compound that is the active ingredient of the drug of the present invention can directly remove the cause of spinocerebellar degeneration type 31, the drug of the present invention is actually used as a preventive or therapeutic means for spinocerebellar degeneration type 31. There is a possibility that it can be utilized.

1, the present invention compound or or without (UGGAA) ₉ RNA sample is the melting temperature curve graph showing the relationship between the differential absorbance and temperature (UAGAA) ₉ RNA samples, and (UAAAA) ₉ RNA samples . FIG. 2 is a mass spectrum of an RNA sample containing the UGGAA / UGGAA motif that does not contain the compound of the present invention or is contained at a concentration of 5 to 40 μM. FIG. 3 is a fluorescence micrograph of cells cultured in a medium containing or not containing the compound of the present invention and fluorescently labeled with an RNA aggregate containing (UGGAA) ₇₆ . FIG. 4 is a graph showing the number and area of RNA aggregates containing (UGGAA) ₇₆ in cells cultured in a medium containing or not containing the compound of the present invention. FIG. 5 is a photomicrograph of the eyes of Drosophila bred on a feed containing or not containing the compound of the present invention. FIG. 6 is a graph showing the area of the eyes of Drosophila bred with feed containing or not containing the compound of the present invention.

The spinocerebellar degeneration type 31 inhibitor according to the present invention contains a compound represented by the formula (I) (hereinafter sometimes abbreviated as “compound (I)”) as an active ingredient.

In compound (I), both X and Y are preferably ═N—. In this case, in the hairpin structure formed by RNA repeats (UGGAA) _n, Compound (I) is considered a relatively strong bond via guanine hydrogen bonds as in guanosine follows.

In formula (I), Z represents an m-valent linker group that connects m parenthesized structures to each other. “Structure in parentheses” indicates the following structure. The structures in two or more parentheses may be the same or different from each other, but are preferably the same.

The “linker group” is a group that binds m number of the structures in the parentheses, and increases the positional freedom of the structure in the parentheses to increase the binding performance of the compound (I) to (UGGAA) _n . It has the effect | action which raises and manufactures compound (I) easily.

The “linker group” is not particularly limited as long as it has the above-mentioned action. For example, a C _1-6 alkylene group, an amino group (—NH— or> N—), an ether group (—O—) , A thioether group (—S—), a carbonyl group (—C (═O) —), a thionyl group (—C (═S) —), an ester group (—C (═O) —O— or —O—C (═O) —), amide group (—C (═O) —NH— or —NH—C (═O) —), urea group (—NH—C (═O) —NH—), thiourea group ( Selected from the group consisting essentially of —NH—C (═S) —NH—) and a urethane group (—NH—C (═O) —O— or —O—C (═O) —NH—). A group in which two or more groups are bonded can be exemplified. Among the amino groups, —NH— is a C _1-6 alkyl group which may be substituted with one or two or more substituents β, or C which may be substituted with one or two or more substituents β. _It may be substituted with a _1-6 acyl group. Examples of the substituent β include a C _1-6 alkoxy group, a hydroxyl group, a halogeno group, an amino group (—NH ₂ ), a mono (C _1-6 alkyl) amino group, a di (C _1-6 alkyl) amino group, and a nitro group. And one or more substituents selected from the group consisting essentially of cyano groups.

In the linker group Z, the part that binds to the amino group (—NH—) in the structure in parentheses is preferably a carbonyl group from the viewpoint of ease of synthesis of the compound (I). Furthermore, a urethane group or a urea group may be formed by the amino group in the structure in the parentheses and the above portion.

Examples of the linker group Z when m is 2 include the following linker groups. In the following linker group, preferably A ¹ and A ² are the same group, it is preferred that R ¹ and R ² may be the same group.

[Wherein, A ¹ and A ² independently represent —O—, —NH— or a single bond, R ¹ and R ² independently represent a C _1-6 alkylene group, and R ³ represents —H A C _1-6 alkyl group which may be substituted with one or two or more substituents β, or a C _1-6 acyl group which may be substituted with one or two or more substituents β. ]

Examples of the linker group Z when m is 4 include the following linker groups.

[Wherein, A ³ to A ⁶ independently represent —O—, —NH— or a single bond, R ⁴ to R ⁷ independently represent a C _1-6 alkylene group, and R ⁸ represents C _{1 -10 represents an} alkylene group. ]

M represents the number of structures in parentheses in the compound (I), preferably 2 or 4, and more preferably 2.

L represents the number of substituents on the quinoline ring or naphthyridine ring in the structure in parentheses, and represents an integer of 0 or more and 4 or less. The number is preferably 3 or less, more preferably 2 or less, and even more preferably 1.

When l is 2 or more, the two or more substituents α may be the same or different, but are preferably the same. The position of the substituent α is preferably a carbon atom adjacent to X. As the substituent α, a C _1-6 alkyl group is preferable, a C _1-4 alkyl group is more preferable, a C _1-2 alkyl group is further more preferable, and methyl is particularly preferable.

The compound (I) according to the present invention has a relatively simple structure and can be easily synthesized by those skilled in the art. For example, the compound (I) in which the portion of the linker group Z that binds to the amino group in the structure in the parenthesis is a carbonyl group is disclosed in Japanese Patent Application Laid-Open No. 2003-259899, Kazuhiko Nakatani et al., Current Protocols in Nucleic Acid Chemistry, 8.6.1-8.6.21 (2008), Jinxing Li et al., CHEMISTRY AN ASIAN JOURNAL, Volume 11, Issue 13, Pages 1971-1981 (2016). . For example, it can be synthesized by the following method.

In the above reaction formula, Z ′ corresponds to a structure obtained by removing the terminal carbonyl group from Z. The structures in parentheses may be the same or different. When the structures in parentheses are different, a raw material compound corresponding to each structure is prepared and each structure is reacted one by one. The aminoquinoline compound or aminonaphthyridine compound as a raw material is a commercially available product or can be easily synthesized from a commercially available product by those skilled in the art.

Compound (I) in which a urethane group or a urea group is formed by the amino group in the structure in parentheses and the terminal portion of Z can be synthesized, for example, by the following method. In the following chemical reaction formula, a synthesis method of the compound (I) having a urethane group is representatively shown.

In the above reaction formula, Z ″ corresponds to the structure obtained by removing the terminal ester group (—C (═O) —O—) from Z. The structures in parentheses may be the same as or different from each other. When the structures in parentheses are different, raw material compounds corresponding to each structure may be prepared, and each structure may be reacted one by one. The starting raw material compound includes a diol compound containing Z ″ and It can be synthesized by reacting with N, N′-disuccinimidyl carbonate.

The dosage form of the spinocerebellar degeneration type 31 inhibitor according to the present invention is not particularly limited. For example, with the development of drug delivery systems, compound (I) crosses the blood-brain barrier and reaches the brain by oral administration to patients, and binds to (UGGAA) _n causing spinocerebellar degeneration type 31, There is a possibility that brain neurons can be prevented from falling off. Although it does not restrict | limit especially as an oral formulation, For example, a tablet, a powder, a capsule, a sugar-coated tablet, a granule etc. can be mentioned. For the spinocerebellar degeneration type 31 inhibitor according to the present invention, a pharmaceutically acceptable additive may be used in accordance with the dosage form. Examples of such additives include excipients, bases, preservatives, auxiliaries, stabilizers, wetting agents, pH adjusting agents, antioxidants, colorants, sweeteners and the like.

Alternatively, the spinocerebellar degeneration type 31 inhibitor according to the present invention may be administered as an infusion to a patient, or may be directly injected into the patient's brain. In that case, as the solvent, an isotonic solution of plasma such as a physiological saline adjusted with pH or an aqueous glucose solution can be used. Alternatively, when the compound (I) is dried with salts or the like, pure water, distilled water, sterilized water, or the like can be used if the solution finally becomes isotonic or nearly isotonic with plasma. The concentration may be that of a normal injection, for example, 0.001 mg / mL or more and about 10 mg / mL.

Compound (I), which is an active ingredient of a spinocerebellar degeneration type 31 inhibitor according to the present invention, binds to (UGGAA) _n causing spinocerebellar degeneration type 31, and is an RNA aggregate in the nucleus of cranial nerve cells. And the formation of abnormal protein aggregates in the cytoplasm can be inhibited. Therefore, it is considered that the progression of symptoms can be prevented and spinocerebellar degeneration type 31 can be treated. In addition, since spinocerebellar degeneration type 31 is an inherited neurological disease, there is a possibility that it can be used prophylactically for humans who may develop spinocerebellar degeneration type 31. That is, the spinocerebellar degeneration type 31 inhibitor according to the present invention can be used not only as a therapeutic agent but also as a prophylactic agent.

The administration frequency and dosage of the spinocerebellar degeneration type 31 inhibitor according to the present invention may be appropriately adjusted according to the severity, age, sex, condition, etc. of the patient. For example, the dose per dose of oral preparation can be 100 ng / kg body weight or more and 500 μg / kg body weight or less, and the dose per injection can be 1 ng / kg body weight or more and 100 μg / kg body weight or less. It can be. The number of administrations per day is preferably 1 or more and 5 or less, more preferably 1 or more and 3 or less.

This application claims the benefit of priority based on Japanese Patent Application No. 2018-73666 filed on Apr. 6, 2018. The entire contents of the specification of Japanese Patent Application No. 2018-73666 filed on April 6, 2018 are incorporated herein by reference.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

Example 1: Evaluation of selective binding to UGGAA sequence (1) Synthesis of test compound Method described in Kazuhiko Nakatani et al., Current Protocols in Nucleic Acid Chemistry, 8.6.1-8.21 (2008) The following compounds were synthesized according to Hereinafter, the compound is abbreviated as “NCD” (Naphthyridine carbamate dimer).

(2) Measurement of heat denaturation temperature NCD was dissolved in 10 mM sodium cacodylate buffer (pH 7.0) containing 100 mM NaCl at a concentration of 20 μM. Further, (UGGAA) ₉ was added at a concentration of 2 μM, and a spectrophotometer (“UV-2700” manufactured by Shimadzu Corporation) equipped with a T _m analysis system (“TMSPC-8” manufactured by Shimadzu Corporation) was used to The absorbance at 260 nm was measured when the temperature was raised from 1 ° C. to 100 ° C. at a rate of 1 ° C./min. Further, for comparison, it was carried out in the case of not adding the NCD, even when using (UAGAA) ₉ and (UAAAA) ₉ instead of (UGGAA) _9, the measured similarly. FIG. 1 shows a graph showing the relationship between differential absorbance and temperature.
As shown in the results of FIG. 1, the melting temperatures of (UAGAA) ₉ and (UAAAAA) ₉ (FIGS. 1 (2) and (3)) hardly change with or without NCD, whereas (UGGAA) ₉ The melting temperature (FIG. 1 (1)) was shifted to a higher temperature side due to the presence of NCD. Such a result is considered to indicate that NCD selectively binds to (UGGAA) ₉ and forms a stable complex.

Example 2: Evaluation of binding to UGGAA sequence Samples were prepared by adding hairpin RNA and NCD containing UGGAA / UGGAA motif to 50% methanol water containing 100 mM ammonium acetate at concentrations of 10 μM and 0-40 μM, respectively. . The obtained sample was analyzed in a negative mode using a 4G mass spectrometer (“JMS-T100LP AccuTOF LC-plus” manufactured by JEOL). The spray temperature was fixed at −10 ° C., and the sample flow rate was 20 mL / min. The measurement results are shown in FIG.
As shown in FIG. 2, pentavalent and hexavalent RNA negative ion peaks were observed in the mass spectrum of the sample containing only the hairpin RNA (FIG. 2 (1)). Furthermore, in the mass spectrum of the sample to which NCD was added (FIGS. 2 (2) to (5)), in addition to the molecular ion peak of RNA, a peak in which two molecules of NCD were bound to RNA was observed. These results revealed that NCD binds to the UGGAA / UGGAA motif at a 2: 1 stoichiometric ratio.

Example 3: Inhibition of formation of RNA aggregates by NCD HeLa cells (from RIKEN) were treated with Dulbecco's modified Eagle medium containing 10% fetal calf serum (MP Biomedicals), penicillin and streptomycin (Thermo). (Manufactured by Sigma) at 37 ° C. in a 5% CO ₂ atmosphere.
A total of 1 × 10 ⁵ of the above cultured cells were seeded in a 24-well plate equipped with a cover slip. After culturing for 24 hours, cell culture medium containing NCD was added to the cells. For comparison, only the same amount of cell culture medium was added. Then, the plasmid (500 ng) expressing (UGGAA) _76, was transfected into the cells using the transfection reagent ( "FuGENE HD" manufactured by Promega, 2 [mu] L). Twenty-four hours after transfection, the cells were washed with phosphate buffer (PBS) and fixed with 4% paraformaldehyde for 30 minutes at 4 ° C. The fixed cells were washed with PBS and permeabilized with PBS containing 2% acetone precooled at −20 ° C. for 5 minutes at 4 ° C. The cells were then washed with PBS and stored overnight at −20 ° C. in 70% ethanol. The cells were then washed with PBS and rehydrated with 30% formamide in 30% 2 × SSC at room temperature for 10 minutes before the cells were hybridized with buffer (30% formamide, 2 × SSC, 66 mg / mL yeast). Incubate for 30 minutes at 37 ° C. in tRNA, 0.02% BSA, 10% dextran sulfate, 2 mM vanadyl-ribonucleoside) and further contain 1 nM DNA / LNA probe (TTCCA) ₅ labeled with Alexa647, a red dye Hybridization was performed in hybridization buffer at 37 ° C. for 2 hours. The coverslips were washed 3 times with 2 × SSC containing 50% formamide, 2 times with 1 × SSC, 2 times with 0.1 × SSC, and at 55 ° C. for 20 minutes. An anti-fading mounting medium (“SlowFade Diamond” manufactured by Thermo) containing DAPI, a blue pigment, was added to the cells and placed on a microscope slide. Fluorescence images of the cells were taken with a fluorescence microscope (“BZ-9000” manufactured by KEYENCE), and the images were analyzed using ImageJ software (http://imagej.nih.gov/ij/). The fluorescence micrograph is shown in FIG. 3, the number of RNA aggregates is shown in FIG. 4 (1), and the total area of RNA aggregates is shown in FIG. 4 (2).
As shown in FIG. 3 and FIG. 4, in the control example, RNA aggregates were produced by RNA having a UGGAA repeat sequence, but when NCD was added to the medium, such aggregates were remarkably suppressed. It was proved.

Example 4: In vivo test It is known that RNA having a UGGAA repeat sequence results in the loss of Drosophila compound eyes. In Drosophila, the GAL4 / UAS system was used to forcibly express the (TGGAA) _n gene downstream of the UAS sequence with compound eyes. Specifically, in this experiment, GAL4 is expressed specifically in the compound eye using the GMR promoter that expresses the gene only in the compound eye, and the repeat RNA gene is combined only with the compound eye using the fact that the generated GAL4 protein binds to UAS. Expressed.
Specifically, a medium for mutagenicity testing using Drosophila (“Instant Drosophila medium Blue”) containing dry yeast is mixed with ultrapure water or an NCD aqueous solution, and feed containing no NCD or 100 μM NCD is prepared. Produced. Using this feed, a parental fly (GMR-GAL4 driver) having a GAL4 gene downstream of a GMR promoter that specifically acts on compound eyes, and a parental fly (UAS- (UGGAA) having a pathogenicity (UGGAA) _n sequence gene downstream of UAS ) _Exp ) or a parental fly (UAS- (UAGAAA) (UAAAAAUAGAA) _exp ) having a non-pathogenic repeat sequence gene downstream of UAS and mating to produce a pup fly having both genes at 25 ° C. using the same feed I let you. After birth of the fly, the morphology of the eyes of the fly 1 to 2 days old was observed using a stereo microscope (“SZX10” manufactured by Olympus). Further, the obtained microscopic image was analyzed by image analysis software (“ImageJ” (http://imagej.nih.gov/ij/)), and the area of the eye was calculated. Further, regarding the result of the eye area, a significant difference test was performed by Welch's t test. A photomicrograph is shown in FIG. 5, and the total area of the compound eye is shown in FIG.
As shown in FIG. 5 and FIG. 6, in the control group in which non-pathogenic (UAGAA) (UAAAAAUAGA) _n RNA was expressed, no abnormality was observed in the eyes regardless of whether or not NCD was ingested. On the other hand, when the pathogenic (UGGAA) _n RNA was strongly expressed, clear ocular omission was observed and the eye area decreased. However, the ingestion of NCD clearly suppressed compound eye drop and the eye area also increased significantly.
From these results, it was proved that NCD can remarkably suppress the adverse effects caused by (UGGAA) _n RNA.

Claims (15)

1. A spinal cerebellar degeneration type 31 inhibitor comprising a compound represented by the following formula (I) as an active ingredient.
   

   

   [Where:
   X and Y independently represent a ═N— group or a ═CH— group, and at least one of X and Y is a ═N— group;
   Z represents an m-valent linker group that connects m parenthesized structures to each other;
   m represents an integer of 2 or more and 4 or less;
   α is a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxyl group, a halogeno group, an amino group, a mono (C _1-6 alkyl) amino group, a di (C _1-6 alkyl) amino group, a nitro group, and One or more substituents selected from the group consisting essentially of cyano groups;
   l represents an integer of 0 or more and 4 or less;
   The structures in two or more parentheses may be the same or different. ]
2. The linker group is selected from the group consisting essentially of C _1-6 alkylene group, amino group, ether group, thioether group, carbonyl group, thionyl group, ester group, amide group, urea group, thiourea group and urethane group. The spinocerebellar degeneration type 31 inhibitor according to claim 1, wherein two or more groups are combined.
3. 3. The spinocerebellar degeneration type 31 inhibitor according to claim 1 or 2, wherein X and Y are = N-groups.
4. The spinocerebellar degeneration type 31 inhibitor according to any one of claims 1 to 3, wherein α is a C _1-6 alkyl group and 1 is 1.
5. 5. The spinocerebellar degeneration type 31 inhibitor according to claim 1, wherein the substituent α is bonded to carbon adjacent to X.
6. A method for inhibiting spinocerebellar degeneration type 31, comprising:
   A method comprising administering to a patient a drug containing a compound represented by the following formula (I) as an active ingredient.
   

   

   [Where:
   X and Y independently represent a ═N— group or a ═CH— group, and at least one of X and Y is a ═N— group;
   Z represents an m-valent linker group that connects m parenthesized structures to each other;
   m represents an integer of 2 or more and 4 or less;
   α is a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxyl group, a halogeno group, an amino group, a mono (C _1-6 alkyl) amino group, a di (C _1-6 alkyl) amino group, a nitro group, and One or more substituents selected from the group consisting essentially of cyano groups;
   l represents an integer of 0 or more and 4 or less;
   The structures in two or more parentheses may be the same or different. ]
7. The linker group is selected from the group consisting essentially of C _1-6 alkylene group, amino group, ether group, thioether group, carbonyl group, thionyl group, ester group, amide group, urea group, thiourea group and urethane group. The method according to claim 6, wherein two or more groups are bonded groups.
8. The method according to claim 6 or 7, wherein X and Y are = N- groups.
9. The method according to any one of claims 6 to 8, wherein α is a C _1-6 alkyl group and l is 1.
10. The method according to any one of claims 6 to 9, wherein the substituent α is bonded to carbon adjacent to X.
11. Use of a compound represented by the following formula (I) for suppressing spinocerebellar degeneration type 31.
    

    

    [Where:
    X and Y independently represent a ═N— group or a ═CH— group, and at least one of X and Y is a ═N— group;
    Z represents an m-valent linker group that connects m parenthesized structures to each other;
    m represents an integer of 2 or more and 4 or less;
    α is, C _1-6 alkyl, C _1-6 alkoxy group, hydroxyl group, halogeno group, an amino group, a mono (C _1-6 alkyl) amino group, di (C _1-6 alkyl) amino group, a nitro group and One or more substituents selected from the group consisting essentially of cyano groups;
    l represents an integer of 0 or more and 4 or less;
    The structures in two or more parentheses may be the same or different. ]
12. The linker group is selected from the group consisting essentially of C _1-6 alkylene group, amino group, ether group, thioether group, carbonyl group, thionyl group, ester group, amide group, urea group, thiourea group and urethane group. The use according to claim 11, wherein two or more groups are bonded groups.
13. The use according to claim 11 or 12, wherein X and Y are = N- groups.
14. Use according to any of claims 11 to 13, wherein α is a C _1-6 alkyl group and l is 1.
15. The use according to any one of claims 11 to 14, wherein the substituent α is bonded to carbon adjacent to X.

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