Therapeutic agent for frontotemporal lobar degeneration and therapeutic composition

Abstract

The present invention addresses the problem of providing: a therapeutic agent for frontotemporal lobar degeneration (FTLD) for which no therapeutic drug has been developed so far, or a therapeutic composition for FTLD; and a method for treating FTLD.　The inventors of the present invention have found that the pathoses of FTLD in frontal lobe-type cerebral cortical neurons are ameliorated by inducing the differentiation of the frontal lobe-type cerebral cortical neurons from iPS cells derived from an FTLD patient and administering, to the frontal lobe-type cerebral cortical neurons reflecting the pathoses of FTLD, a therapeutic agent for frontotemporal lobar degeneration (FTLD) containing a compound represented by formula (1-1), a compound represented by formula (2-1), a compound represented by formula (3-1), a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

Treatment agent and composition for frontotemporal lobar degeneration

[0001] An objective of the present invention is to develop a therapeutic agent or composition for treating frontotemporal lobar degeneration (FTLD).

[0002] Frontotemporal lobar degeneration (FTLD) is a type of dementia that causes degeneration of the frontal and temporal lobes, resulting in symptoms such as behavioral and language disorders. It is designated as an intractable disease in Japan (Designated Intractable Disease 127), and it is estimated that there are approximately 12,000 patients with FTLD (Non-Patent Document 1), 50,000-60,000 patients in the United States, and more than 100,000 patients across Europe.

[0003] FTLD is broadly classified into three subtypes based on its clinical symptoms, with the characteristics shown in the table below: - behavioral variant frontotemporal dementia (bvFTD) - semantic dementia (SD) - progressive non-fluent aphasia (PNFA).

[0004]

[0005] FTLD is a pathologically and genetically diverse disease, and depending on the associated protein, it can be classified into FTLD-tau (45%), where TAU accumulation is observed, FTLD-TDP43 (45%), where TDP-43 accumulation is observed, and FTLD-FUS (9%), where FUS accumulation is observed. Genetically, the GRN gene, MAPT gene, C9ORF72 gene, and TARDBP gene are known to be typical mutated genes.

[0006] Frontotemporal dementia (FTD) is a comprehensive group of non-Alzheimer's degenerative dementia diseases primarily characterized by motor cortical lesions, and some are known to be caused by TAU degeneration, TDP-43, or FUS. TDP-43 and FUS-related dementias are divided into those with and without motor disorders (amyotrophic lateral sclerosis) (FTLD-MND) and those without (FTLD-nonMND), respectively. Meanwhile, TAU degeneration is classified into Pick's disease, primarily characterized by 3R Tau degeneration, and diseases primarily characterized by 4R TAU degeneration (corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain dementia).

[0007] In the case of bvFTD, a diagnosis can be made based on the pathology if three or more of the following evaluation items A to F are met. A. Disinhibited behavior: Any one or more of the following three symptoms are met. 1) Socially inappropriate behavior 2) Lack of courtesy and manners 3) Impulsive, reckless, or careless behavior B. Indifference or apathy C. Lack of empathy and empathy: Any one or more of the following two symptoms are met. 1) Lack of responsiveness to the needs or feelings of others 2) Diminished or lost social interest, interaction with others, or human warmth D. Fixation / Stereotypy: Any one or more of the following three symptoms are met. 1) Repetition of simple movements 2) Compulsive or ritualistic behavior 3) Stereotyped language E. Oral tendencies and changes in eating habits: Any one or more of the following three symptoms are met. 1) Changes in food preferences 2) Increased overeating, drinking, and smoking 3) Oral seeking or pica F. Neuropsychological testing reveals impaired executive function despite relatively preserved memory and visuospatial cognitive abilities.

[0008] In the case of SD, A. impaired knowledge of objects (especially those with low frequency / low familiarity), B. surface alexia / agraphia, C. preserved repetition and fluent speech, D. preserved speech (grammar and spontaneous speech), at least three of the four are present.

[0009] Currently, there is no established treatment for FTLD that aims to cure it (improve cognitive function), and symptomatic treatments are used to treat some of the symptoms. For example, it has been reported that the administration of selective serotonin reuptake inhibitors (SSRIs), an antidepressant, is effective when behavioral disturbances are prominent. It has also been reported that antipsychotics and antiepileptic drugs may be effective, although there have been some case reports. However, none of these treatments are aimed at improving cognitive function, and the development of medications that can improve cognitive function is desired.

[0010] Wada-Isoe K., et al., Epidemiological Survey of Frontotemporal Lobar Degeneration in Tottori Prefecture, Japan., Dement. Geriatr. Cogn. Dis. eNeuro, 5 (2), 2018

[0011] An objective of the present invention is to provide a therapeutic agent or composition for frontotemporal lobar degeneration (FTLD), for which no therapeutic drug has been developed so far, and a method for treating FTLD.

[0012] The inventors of the present invention found that by inducing the differentiation of frontal cortical neurons from iPS cells derived from FTLD patients and administering a therapeutic agent for FTLD, described below, to frontal cortical neurons that reflect the pathology of FTLD, the pathology of FTLD in frontal cortical neurons is improved.

[0013] Based on this finding, the present invention has demonstrated that FTLD can be treated by a therapeutic agent for frontotemporal lobar degeneration (FTLD), which comprises a compound represented by the below-described formula (1-1), a compound represented by the formula (2-1), or a compound represented by the formula (3-1), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0014] More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects: [1]: A compound represented by the following formula (1-1):

[0015]

[0016] [In formula (1-1), R1's each independently represent an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1 to 3.], A compound represented by the following formula (2-1):

[0017]

[0018] [In formula (2-1), R 21 is selected from the group consisting of hydrogen, a fatty acid acyl group having 2 to 18 carbon atoms, and an aromatic carboxylic acid acyl group having 7 to 9 carbon atoms], a compound represented by the following formula (3):

[0019]

[0020] [In formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, and CF3; R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group and an optionally substituted nitrogen-containing aromatic heterocycle; R 33 is selected from the group consisting of hydrogen, alkyl groups having 1 to 6 carbon atoms, and cycloalkyl groups having 3 to 6 carbon atoms; R 34is selected from the group consisting of a carboxy group, a cyano group, and a 1H-tetrazolyl group], a pharmaceutically acceptable salt thereof, or a solvate thereof; [2]: The therapeutic agent for FTLD according to claim 1, wherein FTLD is one or more symptoms selected from behavioral frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). [3]: The therapeutic agent for FTLD according to claim 1 or 2, wherein n is 2 in formula (1-1). [4]: ​​The therapeutic agent for FTLD according to claim 1 or 2, wherein R1 is an n-propyl group in formula (1-1). [5]: The therapeutic agent for FTLD according to claim 3, wherein R1 is an n-propyl group in formula (1-1). [6]: The compound represented by formula (1-1) is a compound represented by the following formula (1-2):

[0021]

[0022] [7]: The FTLD therapeutic agent according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the compound represented by formula (1-1) is a compound represented by the following formula (1-2):

[0023]

[0024] [8]: The FTLD therapeutic agent according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the compound represented by formula (2-1) is a compound represented by the following formula (2-2):

[0025]

[0026] [9]: The therapeutic agent for FTLD according to [1] or [2], wherein the pharmaceutically acceptable salt of the compound represented by formula (3-1) is a compound represented by the following formula (3-2):

[0027]

[0028]

[10] : A compound represented by the following formula (1-1): (4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid).

[0029]

[0030] [In formula (1-1), R1's each independently represent an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1 to 3.], A compound represented by the following formula (2-1):

[0031]

[0032] [In formula (2-1), R 21 is selected from the group consisting of hydrogen, fatty acid acyl groups having 2 to 18 carbon atoms, and aromatic carboxylic acid acyl groups having 7 to 9 carbon atoms], a compound represented by the following formula (3-1):

[0033]

[0034] [In formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, and CF3; R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group and an optionally substituted nitrogen-containing aromatic heterocycle; R 33 is selected from the group consisting of hydrogen, alkyl groups having 1 to 6 carbon atoms, and cycloalkyl groups having 3 to 6 carbon atoms; R 34 is selected from the group consisting of a carboxy group, a cyano group, and a 1H-tetrazolyl group], a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in treating frontotemporal lobar degeneration (FTLD).

[0035] The therapeutic agents for FTLD of the present invention are compounds obtained by screening using phenotypes characteristic of human pathology as an endpoint based on an analysis using frontal cortical neurons differentiated from iPS cells derived from FTLD patients as a pathology model, and therefore can provide therapeutic agents with high therapeutic efficacy against FTLD.Furthermore, the present invention can provide therapeutic agents for FTLD that are effective against all three subtypes of FTLD pathology.

[0036] Figure 1 shows the procedure for differentiating and inducing frontal cortical neurons using disease-specific iPS cells derived from FTLD patient cells, which can be used to screen compounds for the treatment of FTLD. Figure 2 shows the generation of frontal cortical neurons that degenerate in FTLD using disease-specific iPS cells derived from FTLD patient cells. Figure 3 shows the results of a drug discovery screening using disease-specific iPS cells derived from FTLD patient cells. Figure 4 shows the procedure for a functional analysis assay of ropinirole (ROPI) using frontal cortical neurons generated using disease-specific iPS cells derived from FTLD patient cells. Figure 5 shows the results of measuring LDH leakage rate as a parameter of neuroprotection following ropinirole administration, including the neuronal cell death phenotype (lactate dehydrogenase assay, LDH assay) (Figure 5, left) and the neuroprotective effect of ropinirole (ROPI) administration (Figure 5, right). Figure 6 shows the neuronal cell death phenotype (TUJ1 immunostaining) (Figure 6(a)) and the numerical value of the number of surviving neurons (Figure 6(b)) in frontal cortical neurons differentiated from iPS cells derived from healthy individuals and FTLD patients. Figure 7 shows the effect of various concentrations of ropinirole (ROPI) on the neuronal cell death phenotype (TUJ1 immunostaining). Figure 8 shows the effect of various concentrations of ropinirole (ROPI) on the neuronal cell death phenotype (number of TUJ1 immunostained cells) (Figure 8(a)) and the neuronal functional recovery phenotype (neurite length) (Figure 8(b)). Figure 9 shows the effect of various concentrations of ropinirole (ROPI) on lysosome hypertrophy. Figure 10 shows the results of measuring the improvement rate (%) of LDH leakage in frontal cortical neurons differentiated from iPS cells derived from FTLD patients, when various concentrations of ropinirole were added. FIG. 11 shows the results of measuring the fluorescence intensity of SiR-lysosomes in frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from FTLD patients, when various concentrations of ropinirole were added to the culture medium.Figure 12 shows the results of measuring the LDH leakage rate when various concentrations of various D2 receptor agonists were added to the culture medium of frontal lobe-type cerebral cortical neurons induced to differentiate from FTLD patient-derived iPS cells. Figure 13 shows the results of measuring the improvement rate (%) of LDH leakage when various concentrations of Torin1 were added to the culture medium of frontal lobe-type cerebral cortical neurons induced to differentiate from FTLD patient-derived iPS cells.

[0037] [Screening of FTLD therapeutic agents and pharmaceutical compositions for treating FTLD] In the present invention, iPS cells are prepared from cells collected from an FTLD patient, and frontal cortical neurons are induced to differentiate from the iPS cells. Frontal cortical neurons that reflect the pathology of FTLD are used to screen each compound contained in the compound library using the evaluation criteria of improving lysosome function and exhibiting neuroprotective effects (improving neuronal survival rate), thereby enabling the production of compounds that ameliorate the pathology of FTLD in frontal cortical neurons and have a therapeutic effect against FTLD.

[0038] One method for inducing differentiation into frontal cortical neurons is to induce differentiation of iPS cells into the cerebral nervous system using dual Smad inhibition (e.g., LDN-193189 and SB431542) and Wnt inhibition (e.g., XAX939), followed by the addition of Fgf8b (Non-Patent Document 2). The inventors' studies demonstrated that dual Smad inhibition treatment alone was insufficient to induce differentiation into the cerebral nervous system, and that treatment with a Wnt antagonist in addition to dual Smad inhibition was also insufficient to induce differentiation into the cerebral nervous system, demonstrating that dual Smad inhibition and Wnt inhibition treatments are essential for inducing differentiation into the cerebral nervous system.

[0039] Any compound library may be used for screening. For example, a library of compounds whose safety has been confirmed through clinical trials for various diseases can be used.

[0040] In the present invention, as a result of screening a compound library using this method, ropinirole, telmisartan, and sulfisoxazole were selected as compounds that improve lysosome function and exhibit neuroprotective effects (improving neuronal survival rate). Based on this finding, the inventors of the present invention have completed the present invention.

[0041] [Therapeutic agent for FTLD, pharmaceutical composition for treating FTLD] The present invention provides a compound represented by the following formula (1-1):

[0042]

[0043] [In formula (1-1), R1's each independently represent an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1 to 3.], A compound represented by the following formula (2-1):

[0044]

[0045] [In formula (2-1), R 21 is selected from the group consisting of hydrogen, fatty acid acyl groups having 2 to 18 carbon atoms, and aromatic carboxylic acid acyl groups having 7 to 9 carbon atoms], a compound represented by the following formula (3-1):

[0046]

[0047] [In formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, and CF3; R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group and an optionally substituted nitrogen-containing aromatic heterocycle; R 33 is selected from the group consisting of hydrogen, alkyl groups having 1 to 6 carbon atoms, and cycloalkyl groups having 3 to 6 carbon atoms; R 34is selected from the group consisting of a carboxy group, a cyano group, and a 1H-tetrazolyl group], a pharmaceutically acceptable salt thereof, or a solvate thereof, for medical use thereof. The present invention provides a therapeutic agent for FTLD comprising the above compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition for treating FTLD comprising the above compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0048] The FTLD disease that can be treated with the FTLD therapeutic agent or pharmaceutical composition of the present invention may be any of behavioral frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). Furthermore, based on the pathological characteristics of FTLD patients, any of FTLD patients, including FTLD-tau patients in which TAU accumulation is observed, FTLD-TDP43 patients in which TDP-43 accumulation is observed, and FTLD-FUS patients in which FUS accumulation is observed, can be treated. Furthermore, based on the genetic characteristics of FTLD patients, any of FTLD patients, including patients with mutations in the GRN gene, MAPT gene, C9ORF72 gene, and TARDBP gene, can be treated.

[0049] In the compound of formula (1-1) above, which is the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, n in formula (1-1) may be 1, 2, or 3. When the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention is ropinirole, which will be described later, n in formula (1-1) is 2. Therefore, the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention may be a compound in which n in formula (1-1) above is 2.

[0050] In addition, in the compound of the above formula (1-1) which is an active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, 1may be a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, more specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, etc. When the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention is ropinirole, which will be described later, in formula (1-1), R 1 is an n-propyl group. Therefore, the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention is a compound represented by the formula (1-1) above, 1 Regarding R 1 is an n-propyl group.

[0051] The compound represented by formula (1-1) above, which is the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, may be 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one. That is, the compound represented by formula (1-1) above may be ropinirole. The chemical formula of ropinirole is shown in formula (1-2) below.

[0052]

[0053] Ropinirole was originally developed as a therapeutic agent for Parkinson's disease because of its dopamine D2 receptor agonist activity in dopamine neurons. In the present invention, it is currently unclear whether ropinirole acts on FTLD based on the same intracellular mechanism of action or a different intracellular mechanism of action. However, clinical trials as a pharmaceutical have already been completed, and its safety when administered to living organisms has been fully confirmed. Thus, because ropinirole is an existing drug, it is possible to rapidly develop a therapeutic agent for FTLD or a pharmaceutical composition for FTLD treatment.

[0054] The compound represented by formula (2-1) above, which is the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, may be 4-amino-N-(3,4-dimethyl-5-isoxazoyl)benzenesulfonamide. That is, the compound represented by formula (2-1) above may be sulfisoxazole. The chemical formula of sulfisoxazole is shown in formula (2-2) below.

[0055]

[0056] Sulfisoxazole was originally developed as a sulfonamide antibacterial drug. In recent years, its therapeutic application for diseases such as Alzheimer's disease and Parkinson's disease, based on its ability to modify cellular stress responses, has been investigated. It is currently unclear whether sulfisoxazole acts on FTLD via the same intracellular mechanism of action as FTLD or via a different intracellular mechanism. However, clinical trials of sulfisoxazole as a pharmaceutical have already been completed, and its safety when administered to living organisms has been fully confirmed. Thus, because sulfisoxazole is an existing drug, it can be rapidly developed into a therapeutic agent for FTLD or a pharmaceutical composition for FTLD treatment.

[0057] The compound represented by the above formula (3-1), which is an active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, is

[0058] The compound represented by formula (3-1) above, which is the active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, may be 4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid. That is, the compound represented by formula (3-1) above may be telmisartan. The chemical formula of telmisartan is shown in formula (3-2) below.

[0059]

[0060] Telmisartan was originally developed as a therapeutic drug for hypertension because it has biliary excretion-type sustained AT1 receptor blocker activity. In the present invention, it is currently unclear whether telmisartan acts on FTLD based on the same intracellular mechanism of action or a different intracellular mechanism of action. However, clinical trials as a pharmaceutical have already been completed, and its safety when administered to living organisms has been fully confirmed. Thus, because telmisartan is an existing drug, it is possible to rapidly develop an FTLD therapeutic agent or a pharmaceutical composition for treating FTLD.

[0061] The active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention may be a salt of any of the compounds represented by the above formula (1-1), the compound represented by the above formula (2-1), or the compound represented by the above formula (3-1); it may be a solvate of any of the compounds represented by the above formula (1-1), the compound represented by the above formula (2-1), or the compound represented by the above formula (3-1); or it may be a solvate of a salt of any of the compounds represented by the above formula (1-1), the compound represented by the above formula (2-1), or the compound represented by the above formula (3-1).

[0062] When a salt of any of the compounds represented by the above formula (1-1), the above formula (2-1), or the above formula (3-1) is used as an active ingredient in the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, hydrobromide, nitrate, phosphate, etc.; organic acid salts such as acetate, mesylate, succinate, maleate, fumarate, citrate, tartrate, etc.; alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; metal salts such as aluminum salt, zinc salt, etc.; ammonium salts such as ammonium salt, tetramethylammonium salt, etc.; organic amine addition salts such as morpholine, piperidine, etc.; and amino acid addition salts such as glycine, phenylalanine, lysine, aspartic acid, glutamic acid, etc.

[0063] Furthermore, when a solvate of any of the compounds represented by the above formula (1-1), the compound represented by the above formula (2-1), or the compound represented by the above formula (3-1), or a salt thereof is used in the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention, the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and examples thereof include hydrates, organic solvates, etc.

[0064] The active ingredient of the therapeutic agent for FTLD or the pharmaceutical composition for treating FTLD of the present invention may be 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride, that is, ropinirole hydrochloride.

[0065] The active ingredient of the therapeutic agent for FTLD or pharmaceutical composition for treating FTLD of the present invention may be 4-amino-N-(3,4-dimethyl-5-isoxazoyl)benzenesulfonamide, i.e., sulfisoxazole.

[0066] The active ingredient of the therapeutic agent for FTLD or pharmaceutical composition for treating FTLD of the present invention may be 4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid, i.e., telmisartan.

[0067] The pharmaceutical composition for treating FTLD of the present invention may be formulated as a pharmaceutical composition and can be administered orally in the form of, for example, tablets, capsules, elixirs, microcapsules, etc., or parenterally in the form of injections, suppositories, topical skin preparations, etc. More specific examples of topical skin preparations include dosage forms such as ointments and patches.

[0068] In the pharmaceutical composition for treating FTLD of the present invention, the pharmaceutically acceptable carrier may be any carrier commonly used in the formulation of pharmaceutical compositions, without any particular limitation. More specifically, examples thereof include binders such as hypromellose, dextrin, macrogol 400, gelatin, corn starch, tragacanth gum, and gum arabic; excipients such as lactose hydrate, D-mannitol, starch, crystalline cellulose, and alginic acid; solvents for injections such as water, ethanol, and glycerin; and adhesives such as rubber-based adhesives and silicone-based adhesives.

[0069] The pharmaceutical composition for treating FTLD of the present invention may contain additives, such as lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin, and maltitol; flavorings such as peppermint and rhododendron oil; stabilizers such as carmellose sodium, hydrogenated oil, light anhydrous silicic acid, povidone, glycerin fatty acid esters, benzyl alcohol, and phenol; buffers such as phosphates and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; and colorants such as yellow ferric oxide, red ferric oxide, black ferric oxide, and titanium oxide.

[0070] The pharmaceutical composition for treating FTLD of the present invention can be formulated by appropriately combining the above-mentioned active ingredient with the above-mentioned pharmaceutically acceptable carriers and additives, and mixing them in a unit dosage form required for generally accepted pharmaceutical practice. The pharmaceutical composition for treating FTLD of the present invention may use one active ingredient alone or two or more active ingredients in combination.

[0071] In general, an appropriate daily dose of a pharmaceutical composition for treating FTLD of the present invention is an amount containing the minimum effective dose of the active ingredient to produce a therapeutic effect. This minimum effective dose depends on various factors, including the activity of the active ingredient contained in the pharmaceutical composition for treating FTLD, functional group modifications that determine lipid solubility and water solubility, the route of administration, the time of administration, the excretion rate of the specific active ingredient used, the duration of treatment, other drugs, compounds, and / or substances used concomitantly, the age, sex, body weight, illness, health condition, and medical history of the patient, and other factors well known in the medical arts. Typically, the pharmaceutical composition for treating FTLD of the present invention is administered to a patient at a daily dose containing about 0.0001 to about 100 mg / kg body weight of the active ingredient. The pharmaceutical composition for treating FTLD of the present invention may be administered once a day or in divided doses about two to four times a day.

[0072] In particular, when the active ingredient is a compound represented by formula (1-2), the dosage of the pharmaceutical composition for treating FTLD of the present invention is, for example, a sustained-release ropinirole formulation, thought to be orally administered once a day at a dose of 2 mg of the active ingredient, which is increased every week so as not to exceed 16 to 24 mg of the active ingredient per day.

[0073] In particular, when the active ingredient is a compound represented by formula (2-2), the dosage of the pharmaceutical composition for treating FTLD of the present invention is considered to be, for example, sulfisoxazole, orally administered in 4 to 6 divided doses per day at a dose of 4,000 mg, and gradually increased so as not to exceed a daily dose of 8,000 mg of the active ingredient.

[0074] In particular, when the active ingredient is a compound represented by formula (3-2), the dosage of the pharmaceutical composition for treating FTLD of the present invention is considered to be, for example, a sustained-release telmisartan formulation, where 20 mg of the active ingredient is orally administered once a day, and then gradually increased so as not to exceed 80 mg of the active ingredient per day.

[0075] [Other Embodiments] In another aspect, the present invention provides a method for treating FTLD, comprising administering to a patient in need of such treatment any of the compounds represented by formula (1-1), (2-1), and (3-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. In this aspect of the present invention, the compound represented by formula (1-1), (2-1), and (3-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof used as the active ingredient may be the same as those described above. In addition, in this aspect of the present invention, the dosage of the active ingredient can be determined by considering the appropriate dosage for each compound. For example, the dosage is as described above when ropinirole is used as the active ingredient.

[0076] The present invention provides a compound represented by the above formula (1-1), a compound represented by the above formula (2-1), or a compound represented by the above formula (3-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating FTLD. In this aspect of the present invention, the compound represented by the above formula (1-1), a compound represented by the above formula (2-1), or a compound represented by the above formula (3-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof, can be the same as those described above.

[0077] The present invention will be specifically illustrated by the following examples, which are not intended to limit the present invention in any way.

[0078] Example 1 Screening of Compounds for Treating FTLD In this example, disease-specific iPS cells derived from cells of an FTLD patient were used to differentiate and induce frontal cortical neurons that can be used to screen for compounds for treating FTLD, and compounds that can ameliorate the pathology of FTLD in these frontal cortical neurons were screened.

[0079] (1-1) Differentiation and induction of frontal lobe-type cerebral cortical neurons It is known that familial FTLD is caused by mutations in the GRN gene, MAPT gene, or C9ORF72 gene. Therefore, we used iPS cells derived from healthy individuals and FTLD patients with a mutation in the GRN gene (GRN), a representative of familial FTLD, to differentiate and induce frontal lobe-type cerebral cortical neurons. S116X iPS cells derived from a bvFTD patient with a GRN gene mutation were differentiated into frontal cortical neurons using the culture method shown in Figure 1. The GRN gene mutation was S116X.

[0080] Specifically, each cell line (Ngn2-iPSC in Figure 1) was first transformed using the PiggyBac method with a plasmid carrying the Ngn2 gene linked to a promoter whose expression is induced in the presence of DOX. The cell lines were cultured for 6 days in a medium containing a final concentration of 50 nM LDN-193189 (CAS No.: 1062368-24-4), a final concentration of 2 μM SB431542 (CAS No.: 301836-41-9), and a final concentration of 1 μM XAV939 (CAS No.: 284028-89-3) to induce cortical neural stem cells. The medium was changed every 2–3 days.

[0081] Next, the obtained cerebral cortical neural stem cells were dissociated into individual cells and cultured in a medium containing Fgf8b for 3 days.

[0082] Subsequently, the cells were induced with 0.25 ng / mL doxycycline (CAS No.: 24390-14-5) to express NGN2 protein, a transcription factor expressed in the early stage of neuronal differentiation. At the same time, the cells were cultured for 5 days in a medium containing 3 μM DAPT (CAS No.: 208255-80-5) and 2 μM palbolic acid (CAS No.: 571190-30-2). The medium was changed every 2–3 days.

[0083] The differentiated frontal cortical neurons were immunostained using anti-Beta III tubulin antibody (Chemicon) and anti-Pea3 antibody (Abcam) to examine the expression of βIII-tubulin and polyomavirus enhancer activator 3 (Pea3). The results are shown in Figure 2. The resulting neurons were confirmed to express the frontal lobe marker PEA3 using anti-Pea3 (Abcam) antibody at D6 (based on the culture days in Figure 1) and the pan-neuronal marker TUJ1 using anti-Beta III tubulin antibody (Chemicon) at D13 (based on the culture days in Figure 1), confirming that the resulting cells were frontal cortical neurons.

[0084] (1-2) Results of drug discovery screening using frontal lobe-type cerebral cortical neurons. S116X Using frontal cortical neurons derived from FTLD disease-specific iPS cells derived from a patient with bvFTD (a patient with a bvFTD mutation), we screened existing drug libraries for drugs that reverse the FTLD phenotype (bringing it closer to wild-type) using lactate dehydrogenase (LDH) leakage, a marker of neuronal death, the number of TUJ1-positive cells, and the fluorescence intensity of LAMP1 immunostaining, a marker of lysosome abnormalities. LDH leakage was measured using a commercially available kit (model number G7891, Promega). TUJ1-positive cells were counted by immunostaining with anti-Beta III tubulin antibody (Chemicon), and LAMP1 immunostaining, a marker of lysosome abnormalities, was performed using anti-LAMP1 antibody [H4A3] (Abcam).

[0085] Compounds from the existing drug library were added to the culture medium on days 13 to 17 after the start of differentiation induction, and screening was performed. As a result, three drugs, ropinirole, telmisartan, and sulfisoxazole, were identified as promising FTLD treatments. Figure 3 shows the percentage improvement of the FTLD phenotype when these drugs were added to the culture medium.

[0086] The improvement rate (%) of the FTLD phenotype for each parameter was calculated using the following formula (1): Improvement rate (%) = (AB) / (AC) × 100 ... (1) [In formula (1), A represents the measured value of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from an FTLD patient in the absence of a drug, B represents the measured value of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from an FTLD patient in the presence of a drug, and C represents the measured value of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from a healthy subject in the absence of a drug.]

[0087] Figure 3 shows the results of adding the three drugs (ropinirole, telmisartan, and sulfisoxazole) obtained above at final concentrations of 100 nM, 1 μM, and 10 μM to the culture medium of frontal cortical neurons differentiated from iPS cells derived from FTLD patients. The results showed that all three drugs had neuroprotective effects and improved lysosomal function at least within the range of 100 nM to 10 μM. Of these three drugs, ropinirole was further investigated in the following examples.

[0088] Example 2: Effect of ropinirole In this example, a functional analysis assay was performed on the ropinirole obtained in Example (1-2) using frontal lobe-type cerebral cortical neurons generated using disease-specific iPS cells derived from cells of an FTLD patient.

[0089] (2-1) Procedure for cell treatment with ropinirole The efficacy of ropinirole was evaluated in the same manner as in Example 1-2, except that the timing of adding ropinirole to the culture was changed to days 8 to 13 from the start of differentiation induction, as shown in Figure 4.

[0090] Specifically, ropinirole was added to the culture medium of frontal cortical neurons differentiated from iPS cells derived from an FTLD patient with a mutation in the GRN gene (GRN-FTLD) on days 8 and 10, and assays were performed on day 13. Ropinirole was added to the culture medium at final concentrations of 10 nM, 30 nM, 100 nM, and 300 nM.

[0091] (2-2) Neuroprotective Effect of Ropinirole As a parameter of neuroprotective effect, the LDH leakage rate due to ropinirole administration was measured. The LDH leakage rate was measured using a commercially available kit (model "G7891", Promega) in the same manner as in Example 1 (1-2). The results are shown in Figure 5.

[0092] Figure 5 (left) shows iPS cells derived from a healthy individual and GRN S116X This graph shows the results of measuring the LDH leakage rate of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from FTLD patients. In the center left of Figure 5, the vertical axis shows the LDH leakage rate (relative value) of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from FTLD patients, calculated based on the average LDH leakage rate of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from healthy individuals. "**", "##", and "&&" represent GRNs, respectively. S116X This shows that there is a significant difference at a risk level of less than 1% between FTLD patient-derived cerebral cortical neurons and healthy subject-derived cerebral cortical neurons (RC802, ND025, ND554).

[0093] In contrast, the right side of Figure 5 shows the GRN S116XThis graph shows the results of measuring LDH leakage rates when various concentrations of ropinirole (30 nM, 100 nM, 300 nM, and 1 μM) were added to the culture medium of frontal cortical neurons differentiated from iPS cells derived from FTLD patients. In the right panel of Figure 5, the vertical axis shows the LDH leakage rate (relative value) calculated based on the LDH leakage rate without ropinirole (0 nM), and the horizontal axis shows the results when ropinirole was added to the culture medium at 30 nM, 100 nM, 300 nM, or 1 μM. In the right panel of Figure 5, "**" indicates a significant difference at a significance level of less than 1%.

[0094] As a result, even on days 8 to 13 after the start of differentiation induction, the addition of ropinirole was found to have a neuroprotective effect (reduced LDH leakage). 50 = 38.1 nM (calculated using ImageJ and Excel), indicating that neuroprotective effects can be exerted at very low doses.

[0095] (2-3) Effect of Ropinirole on Neuronal Cell Death First, we investigated the neuronal cell death phenotype using TUJI expression as a parameter in frontal cortical neurons differentiated from iPS cells derived from healthy individuals and frontal cortical neurons differentiated from iPS cells derived from FTLD patients (TUJ1 immunostaining). TUJ1 immunostaining was performed using Anti-Beta III Tubulin Antibody (Chemicon) as in Example 1 (1-1). The results are shown in Figure 6.

[0096] Specifically, Figure 6 shows the results of TUJ1 immunostaining of frontal cortical neurons induced to differentiate from iPS cells derived from healthy individuals and FTLD patient-derived iPS cells (Figure 6(a)), and a graph (Figure 6(b)) showing the numerical values ​​of the number of surviving neurons based on the results. In Figure 6(b), the vertical axis shows the number of TUJ1-positive cells (relative value) in frontal cortical neurons induced to differentiate from FTLD patient-derived iPS cells, calculated based on the average number of TUJ1-positive cells in frontal cortical neurons induced to differentiate from iPS cells derived from healthy individuals. "**", "##", and "&" indicate GRN, respectively. S116XThe figures show that there are significant differences between FTLD patient-derived cortical neurons and healthy subject-derived cortical neurons (RC802, ND025, ND554) at a risk level of less than 1%, less than 1%, and less than 5%, respectively.

[0097] As a result, the characteristics of the frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells were as follows: GRN S116X Neuronal death (a decrease in the number of TUJ1-positive cells) was observed in frontal cortical neurons differentiated from iPS cells derived from FTLD patients.

[0098] Next, we investigated the role of GRN in FTLD patients with mutations in the GRN gene (GRN S116X Ropinirole was added to the culture medium of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from FTLD (Faculty with Early Developmental Disorders (FTLD)) on days 8 to 13 after the start of differentiation induction, and the number of TUJ1-positive cells, a parameter of neuronal death, and neurite length, a parameter of neuronal function, were measured. Ropinirole was added to the culture medium at final concentrations of 30 nM, 100 nM, 300 nM, and 1 μM. The results are shown in Figures 7 and 8.

[0099] Figure 7 shows the GRN S116X This is a staining image showing the results of TUJ1 immunostaining when ropinirole was added to the culture medium of frontal lobe-type cerebral cortical neurons induced to differentiate from iPS cells derived from FTLD patients. "ROPI" indicates the results of adding ropinirole to the culture medium at each concentration. The results showed that ropinirole has a neuroprotective effect.

[0100] Also, GRN S116X When various concentrations of ropinirole were added to the culture medium of frontal cortical neurons induced to differentiate from iPS cells derived from FTLD patients, the characteristics of the cortical neurons were examined using the number of TUJ1-positive cells and neurite length as parameters. The results are shown in Figure 8.

[0101] Here, Figure 8(a) shows the GRN S116X8(a) and 8(b) are graphs showing the results of measuring the number of TUJ1-positive cells when various concentrations of ropinirole were added to the culture medium of frontal cortical neurons induced to differentiate from FTLD patient-derived iPS cells. In Figure 8(a), the vertical axis shows the number of TUJ1-positive cells (relative value) calculated based on the number of TUJ1-positive cells without ropinirole (0 nM). "ROPI" indicates the results when ropinirole was added to the culture medium at each concentration.

[0102] Figure 8(b) shows the GRN S116X This graph shows the results of measuring neurite length when various concentrations of ropinirole were added to the culture medium of frontal cortical neurons differentiated from iPS cells derived from FTLD patients. In Figure 8(b), the vertical axis shows the neurite length (relative value) calculated based on the neurite length without ropinirole (0 nM). "ROPI" indicates the results when ropinirole was added to the culture medium.

[0103] These results indicate that the addition of ropinirole on days 8 to 13 after the start of differentiation induction resulted in a neuroprotective effect (an increase in the number of TUJ1-positive cells) and a functional recovery of neurons (an increase in neurite length). In other words, the neuroprotective effect of ropinirole was demonstrated by methods other than the LDH assay.

[0104] (2-4) Effect of ROPI on Lysosome Hypertrophy Lysosome hypertrophy is known to be a characteristic of FTLD neurons. Therefore, we investigated whether the addition of ropinirole altered lysosome hypertrophy. The efficacy of ropinirole was evaluated by immunostaining for LAMP1, a marker of lysosome abnormalities, in the same manner as in Example 1 (1-2), except that the timing of ropinirole addition was changed to days 8 to 13 after the start of differentiation induction.

[0105] Specifically, FTLD patients with a mutation (S116X) in the GRN gene (GRN S116XVarious concentrations of ropinirole were added to the culture medium of frontal cortical neurons induced to differentiate from iPS cells derived from FTLD (Faculty with Early Developmental Disorders (FTLD)). The fluorescence intensity of LAMP1 immunostaining, a membrane protein in the lysosome inner membrane, was measured. The fluorescence intensity of LAMP1 immunostaining was measured using anti-LAMP1 antibody [H4A3] (Abcam) as in Example 1 (1-2). Ropinirole was added to the culture medium at final concentrations of 10 nM, 30 nM, 100 nM, and 300 nM. The results are shown in Figure 9.

[0106] Figure 9 is a graph showing the results of measuring the fluorescence intensity of LAMP1 immunostaining when various concentrations of ropinirole were added to the culture medium of frontal cortical neurons differentiated from iPS cells derived from FTLD patients. In Figure 9, the vertical axis shows the LAMP1 fluorescence intensity (relative value) calculated based on the LAMP1 fluorescence intensity in the absence of ropinirole (0 nM). The horizontal axis shows the concentration of ropinirole added. "ROPI" indicates the results when ropinirole was added to the culture medium. In Figure 9, "**" indicates that there is a significant difference at a significance level of less than 1%.

[0107] As a result, even on days 8 to 13 after the start of differentiation induction, the addition of ropinirole improved lysosomal function (decreased LAMP1 fluorescence intensity), and the EC 50 was 16.7 nM.

[0108] Example 3: Study using various FTLD strains In this example, the effect of ropinirole on neuronal cell death was investigated using disease-specific iPS cells from FTLD patients with various causes.

[0109] (3-1) Neuronal cell death suppression effect of ropinirole. M1L FTLD, GRN S116X FTLD, GRN R493X FTLD, MAPT R406WiPS cells derived from FTLD (one case each) and sporadic FTLD patients (two cases of SD (sFTD1, sFTD2), one case of bvFTD (sFTD3), and one case of unknown clinical symptoms (sFTD4)) were differentiated into frontal cortical neurons. Various concentrations of ropinirole were added to the culture medium of each frontal cortical neuron type induced from FTLD patient-derived iPS cells on days 8–13 after the start of differentiation induction, and LDH leakage was measured as a parameter of neuronal death using a commercially available kit (model number G7891, Promega). Ropinirole was added to the culture medium at final concentrations of 10 nM, 30 nM, 100 nM, and 300 nM. LDH leakage was measured in n=3–5 sets for each experimental condition. Based on these measurement results, the LDH leakage improvement rate (relative value) was calculated from the LDH leakage value before ropinirole application (0 nM) to the LDH leakage value after ropinirole application (300 nM), with the LDH leakage value in the healthy control sample taken as the reference (100%). The LDH leakage improvement rate was calculated in the same manner as in Example 1 (1-2). The results are shown in Figure 10.

[0110] Figure 10 shows the results of measuring the improvement rate (%) of LDH leakage when various concentrations of ropinirole were added to the culture medium of frontal lobe-type cerebral cortical neurons differentiated from FTLD patient-derived iPS cells. In Figure 10, "*" and "**" indicate significant differences at a risk level of less than 5% or less than 1%, respectively, in one-way ANOVA with post-hoc Tukey's test.

[0111] As a result, the addition of ropinirole to frontal cortical neurons derived from iPS cells from multiple FTLD patients demonstrated neuroprotective effects (reduced LDH leakage), supporting the efficacy of ropinirole in treating not only the S116X mutation in the GRN gene, but also other familial (genetic mutation) and sporadic FTLD.

[0112] (3-2) Effect of ROPI on CatD Activity Because abnormalities in lysosome function occur in FTLD neuronal cells, the mechanism of action of ropinirole was analyzed by examining the activity of Cathepsin D, one of the major proteolytic enzymes present in lysosomes, upon addition of ropinirole. In this experiment, ropinirole treatment was performed in the same manner as in Example 1 (1-2), except that the timing of ropinirole addition was changed to days 8 to 13 after the start of differentiation induction.

[0113] Specifically, FTLD patients with a mutation (S116X) in the GRN gene (GRN S116X Ropinirole was added to the culture medium of frontal cortical neurons induced to differentiate from iPS cells derived from FTLD (Faculty of the Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease, Fibroblast Disease, and Fibroblast Disease and Fibroblast Disease, ... and Fibroblast Disease and Fibroblast Disease and Fibroblast Disease and Fibroblast Disease and Fibro

[0114] Figure 11 is a graph showing the results of measuring the SiR-lysosome fluorescence intensity in frontal cortical neurons differentiated from FTLD patient-derived iPS cells when various concentrations of ropinirole were added to the culture medium. In Figure 11, the vertical axis shows the SiR-lysosome fluorescence intensity (relative value) calculated based on the SiR-lysosome fluorescence intensity in the absence of ropinirole (0 nM). The horizontal axis shows the concentration of ropinirole added. "ROPI" indicates the results obtained when ropinirole was added to the culture medium. In Figure 11, "*" indicates a significant difference at a risk level of less than 5% based on one-way ANOVA with post-hoc Tukey's test.

[0115] As a result, the addition of ropinirole improved CatD activity (increased SiR-lysosome fluorescence intensity) even on days 8 to 13 after the start of differentiation induction.

[0116] (3-3) Analysis of the mechanism of neuroprotective action of ropinirole through DRD2-dependent / independent analysis Ropinirole was originally known to have dopamine D2 receptor (D2R) agonist activity in dopamine neurons. Therefore, we used bromocriptine, rotigotine, and sumanirole, which are also D2 receptor agonists, to compare the neuroprotective action of bromocriptine, rotigotine, and sumanirole with that of ropinirole.

[0117] As a parameter of neuroprotection, LDH leakage rate was measured after administration of ropinirole or various D2 receptor agonists (bromocriptine, rotigotine, sumanirole). LDH leakage rate was measured using a commercially available kit (model number "G7891", Promega) as in Example 1 (1-2). The results are shown in Figure 12.

[0118] Figure 12 shows the GRN S116X This graph shows the results of measuring LDH leakage rates in frontal cortical neurons differentiated from FTLD patient-derived iPS cells when various concentrations (10 nM, 30 nM, 100 nM, 300 nM) of bromocriptine, rotigotine, or sumanirole were added to the culture medium. In the right center of Figure 5, the vertical axis shows the LDH leakage rate (relative value) calculated based on the LDH leakage rate without the addition of each substance (0 nM), and the horizontal axis shows the results when bromocriptine, rotigotine, or sumanirole was added to the culture medium at 10 nM, 30 nM, 100 nM, or 300 nM.

[0119] As a result, when various D2 receptor agonists were added on days 8 to 13 after the start of differentiation induction, the neuroprotective effect (reduction in LDH leakage) seen when ropinirole was added was not observed.

[0120] (3-4) Analysis of the mechanism of neuroprotection by ropinirole using mTOR inhibitors The present inventors predicted that ropinirole exerts effects such as neuronal cell death suppression by inhibiting mTOR itself or its signaling pathway. To confirm this effect, it would be preferable to demonstrate that the effects of ropinirole, such as neuronal cell death suppression, are canceled when an mTOR activator is added. However, there is a problem that no suitable mTOR activator exists. Therefore, to help demonstrate the mechanism of action of ropinirole, we inferred that ropinirole indirectly inhibits mTOR based on whether an mTOR inhibitor has the same neuronal cell death suppression effect as ropinirole.

[0121] Rapamycin is well known in the art as an mTOR inhibitor, but it is known that it can only partially inhibit mTOR function (i.e., it can completely inhibit S6K, a downstream protein of mTOR, but cannot completely inhibit 4EBP, another downstream protein). This is thought to depend on the mechanism of mTOR inhibitory action by rapamycin.

[0122] On the other hand, second-generation mTOR inhibitors are known to competitively bind to the ATP-binding site required for mTOR kinase activity, thereby almost completely suppressing mTOR kinase activity. Therefore, in this example, we conducted experiments using TORIN1, a second-generation mTOR inhibitor.

[0123] As a parameter of neuroprotective effect, the following chemical formula:

[0124]

[0125] The LDH leakage rate due to neuronal cell death was measured when Torin1 containing the α-aminobutyric acid (α-aminobutyric acid) was administered. Measurements of LDH leakage were performed in triplicate for each experimental condition. Based on these results, the LDH leakage value in healthy control samples was used as the reference (100%), and the improvement rate of LDH leakage (relative value) was calculated from the LDH leakage value before Torin1 application (0 nM) to the LDH leakage value after Torin1 application (300 nM). Measurement of the LDH leakage rate was performed using a commercially available kit (model number "G7891", Promega) as in Example 1 (1-2). The results are shown in Figure 13.

[0126] Figure 13 shows the GRN S116X 13 shows the results of measuring the percentage improvement in LDH leakage in frontal cortical neurons differentiated from FTLD patient-derived iPS cells when various concentrations of Torin1 (Selleck) were added to the culture medium (3 nM, 10 nM, 30 nM, 100 nM). In Figure 13, "*" indicates a significant difference at a risk level of less than 5% based on one-way ANOVA with post-hoc Tukey's test.

[0127] The results showed that the addition of Torin1 on days 8 to 13 after the start of differentiation induction had a neuroprotective effect (reduced LDH leakage) comparable to that of ropinirole, suggesting that the mechanism of action of ropinirole is via mTOR inhibition.

[0128] According to the present invention, it is possible to provide a therapeutic agent for FTLD and a therapeutic composition for FTLD. The therapeutic agent for FTLD or the therapeutic composition for FTLD of the present invention can treat not only familial FTLD but also sporadic FTLD. Furthermore, by analyzing the mechanism of efficacy of the therapeutic agent for FTLD of the present invention on frontal cortical neurons differentiated from iPS cells derived from FTLD patients, it is possible to elucidate the pathological mechanism of FTLD.

Claims

1. A compound represented by the following formula (1-1): [In formula (1-1), R 1 each independently represents an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1 to 3. A compound represented by the following formula (2-1): [In formula (2-1), R 21 is selected from the group consisting of hydrogen, fatty acid acyl groups having 2 to 18 carbon atoms, and aromatic carboxylic acid acyl groups having 7 to 9 carbon atoms], a compound represented by the following formula (3): [In formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, and CF3; R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group and an optionally substituted nitrogen-containing aromatic heterocycle; R 33 is selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms; R 34 is selected from the group consisting of a carboxy group, a cyano group, and a 1H-tetrazolyl group, a pharma- ceutically acceptable salt thereof, or a solvate thereof.

2. The FTLD therapeutic agent according to claim 1, wherein the FTLD is one or more symptoms selected from behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA).

3. The FTLD therapeutic agent according to claim 1 or 2, wherein in formula (1-1), n ​​is 2.

4. In the above formula (1-1), R 1 The FTLD therapeutic agent according to claim 1 or 2, wherein is an n-propyl group.

5. In the above formula (1-1), R 1 The FTLD therapeutic agent according to claim 3, wherein is an n-propyl group.

6. The compound represented by the formula (1-1) is a compound represented by the following formula (1-2): The FTLD therapeutic agent according to claim 1 or 2, which is (4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one).

7. The pharma- ceutically acceptable salt of the compound represented by the formula (1-1) is a compound represented by the following formula (1-2): The method of claim 1 or 2, wherein the compound is the hydrochloride salt of (4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride).

8. The compound represented by the formula (2-1) is a compound represented by the following formula (2-2): The FTLD therapeutic agent according to claim 1 or 2, which is 4-amino-N-(3,4-dimethyl-5-isoxazoyl)benzenesulfonamide.

9. The compound represented by the formula (3-1) is a compound represented by the following formula (3-2): The FTLD therapeutic agent according to claim 1 or 2, which is (4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl 1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid).

10. A compound represented by the following formula (1-1): [In formula (1-1), R 1 each independently represents an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1 to 3. A compound represented by the following formula (2-1): [In formula (2-1), R 21 is selected from the group consisting of hydrogen, fatty acid acyl groups having 2 to 18 carbon atoms, and aromatic carboxylic acid acyl groups having 7 to 9 carbon atoms], a compound represented by the following formula (3-1): [In formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms, and CF3; R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group and an optionally substituted nitrogen-containing aromatic heterocycle; R 33 is selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms; R 34 is selected from the group consisting of a carboxy group, a cyano group, and a 1H-tetrazolyl group, a pharma- ceutical acceptable salt thereof, or a solvate thereof as an active ingredient.

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