WO2018235728A1 - Medicinal composition for ameliorating neuropathy - Google Patents

Medicinal composition for ameliorating neuropathy Download PDF

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WO2018235728A1
WO2018235728A1 PCT/JP2018/022839 JP2018022839W WO2018235728A1 WO 2018235728 A1 WO2018235728 A1 WO 2018235728A1 JP 2018022839 W JP2018022839 W JP 2018022839W WO 2018235728 A1 WO2018235728 A1 WO 2018235728A1
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pharmaceutical composition
group
subject
hydrogen atom
composition according
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French (fr)
Japanese (ja)
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昌宏 石塚
高橋　究
直実 芳賀
倫史 塩田
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Ｓｂｉファーマ株式会社
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Priority to JP2019525547A priority Critical patent/JP7104037B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel use of 5-aminolevulinic acid or a derivative thereof (also referred to herein as simply "ALAs"), specifically, a subject having a neurological disorder resulting from the presence of triplet repeats on chromosomes.
  • ALAs 5-aminolevulinic acid or a derivative thereof
  • triplet repeat In the base sequence of a gene, the repeated arrangement of three base units (triplet, CAG, etc.) continuously is referred to as triplet repeat (hereinafter also referred to as "TR").
  • TR triplet repeat
  • the number of repetitions is variable even in normal people, but when it is repeated more than a certain number repeatedly, it may cause a neuropathy and is generically called triplet repeat disease (TR disease).
  • TR disease is based on the region on the gene where TR exists, a disease caused by the extension of TR present in the untranslated region at the 5 'end, a disease caused by the extension of TR present in the translation region, a non-translated region at the 3' end are classified as diseases due to the elongation of TR present in the disease and diseases due to the elongation of the TR present in the intron, Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration 1 Diseases such as type (SCA1), fragile X syndrome (FRAXA), fragile X-associated tremor / ataxia (FXTAS), and myotonic dystrophy are known.
  • FRDA Friedreich's ataxia
  • HD Huntington's disease
  • SCA1 fragile X syndrome
  • FXTAS fragile X-associated tremor / ataxia
  • myotonic dystrophy myotonic dystrophy
  • TR disease such as Huntington's disease and myotonic dystrophy
  • a 3-base repeat sequence such as CAG or CTG
  • the repeat length is proportional to the severity of the symptom.
  • the symptoms progress as the repeat length further extends with age, and development of gene therapy having an effect of suppressing the repeat elongation has been attempted in basic research, but has not been put into practical use.
  • symptomatic treatment is performed according to the symptoms (Non-patent Document 1).
  • Fragile X syndrome (FRAXA) and Fragile X-associated tremor / ataxia (FXTAS) involve the CGG repeat of the FMR1 gene located on the X chromosome.
  • FXTAS Fragile X-associated tremor / ataxia syndrome
  • mGluR glutamate receptor
  • ALAs may be useful for diseases caused by a decrease in the amount of frataxin protein including Friedreich's ataxia (FRDA), the effect on a subject having a triplet repeat or nerve The effect on the disorder is not shown (Patent Document 1).
  • FRDA Friedreich's ataxia
  • An object of the present invention is to provide a novel drug which can be used for the prevention or amelioration of neurological disorders caused by the presence of TR.
  • TR disease no fundamental treatment for TR disease has been established, and symptomatic treatments such as behavioral abnormalities and epilepsy have been performed.
  • the present inventors have surprisingly been able to morphologically and physiologically ameliorate neurological disorders caused by the presence of TR in the course of intensive studies to solve the above problems. It has been found that it is useful for treating the core symptoms of TR disease, and the present invention has been completed.
  • a pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder caused by the presence of a 3-base repeat sequence (triplet repeat) on a chromosome The following formula (I): (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group) And a salt or ester thereof, Pharmaceutical composition characterized by the above-mentioned.
  • FRDA Friedreich's ataxia
  • HD Huntington's disease
  • SCA1 spinocerebellar degeneration type 1
  • FXTAS fragile X-associated tremor / ataxia syndrome
  • FXTAS fragile X Subject suffering from triplet repeat disease selected from the group consisting of syndrome (FRAXA) and myotonic dystrophy
  • Pharmaceutical composition characterized by the above-mentioned Pharmaceutical composition characterized by the above-mentioned.
  • R 1 is selected from the group consisting of a hydrogen atom, an alkanoyl group having 1 to 8 carbon atoms, and an aroyl group having 7 to 14 carbon atoms
  • R 2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 14 carbon atoms, and an aralkyl having 7 to 15 carbon atoms Characterized in that it is selected from the group consisting of Pharmaceutical composition.
  • composition according to any one of [1] to [5], which It further contains one or more metal-containing compounds, Pharmaceutical composition.
  • the pharmaceutical composition according to [6], which is The metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt, Pharmaceutical composition.
  • the pharmaceutical composition according to [7], which is The metal-containing compound is a compound containing iron, magnesium or zinc, Pharmaceutical composition.
  • a pharmaceutical composition according to [9], which comprises The compound containing iron is sodium ferrous citrate, Pharmaceutical composition.
  • a method for preventing or treating a subject having a neurological disorder caused by the presence of a 3-base repeat sequence (triplet repeat) on a chromosome In a subject in need thereof, a therapeutically effective amount of Formula (I): (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group) Administering a compound of the formula: or a salt or ester thereof, It is characterized by Method.
  • a pharmaceutical composition for preventing or treating a subject having a neurological disorder caused by the presence of TR on a chromosome there is provided a pharmaceutical composition for preventing or treating a subject having a neurological disorder caused by the presence of TR on a chromosome.
  • FIG. 1 is a diagram showing electrophysiologically the nerve activity improvement effect in mouse cerebral cortex primary culture neurons.
  • FIG. 2 is a diagram showing the neuromorphologically the nerve activity improving effect in mouse cerebral cortex primary cultured neurons.
  • FIG. 3 shows the results of the Beam walking test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group.
  • FIG. 4 is a diagram showing the results of the novel object recognition test.
  • FIG. 5 shows the results of the number of arm penetrations in the Y-shaped maze test.
  • Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group.
  • FIG. 5 shows the results of the number of arm penetrations in the Y-shaped maze test.
  • Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group.
  • FIG. 5 shows the results of the number of arm penetrations in the Y-shaped maze test.
  • FIG. 6 is a figure which shows the result of the correct answer rate in a Y-shaped maze test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group.
  • the present invention relates to a pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder resulting from the presence of a 3-base repeat sequence (triplet repeat; TR) on a chromosome.
  • TR 3-base repeat sequence
  • the type of TR is not particularly limited as long as it is a TR that causes a neurological damage, morphologically or physiologically, such as neural damage or neural activity due to its presence on a chromosome.
  • the TR included in the present invention includes, but is not limited to, CGG repeat, CAG repeat, GAA repeat, CCG repeat, CTG repeat and the like.
  • the TR is a CGG repeat.
  • the TR repeat number may have a length that is sufficient to cause a morphologically or physiologically neurological disorder, such as a neurological injury, a decrease in neural activity, etc., as well as potentially a neurological disorder. Includes the number of repeats that can be triggered.
  • the repeat number of TR in the present invention is 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 1110 or more, 120 or more, 130 or more, 140 or more, 150 or more, 160 or more.
  • the above may be 170 or more, 180 or more, 190 or more, 200 or more.
  • subjects of prevention or treatment include Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration type 1 (SCA1), fragile X-associated tremors / ataxia It may be a subject suffering from a syndrome (FXTAS), fragile X syndrome (FRAXA) or myotonic dystrophy, or a subject at risk of developing these diseases.
  • FRDA Friedreich's ataxia
  • HD Huntington's disease
  • SCA1 spinocerebellar degeneration type 1
  • FXTAS fragile X-associated tremors / ataxia
  • FXTAS fragile X syndrome
  • FAAXA fragile X syndrome
  • myotonic dystrophy or a subject at risk of developing these diseases.
  • the subject is a subject suffering from fragile X-associated tremor / ataxia syndrome (FXTAS), or fragile X syndrome (FRAXA), or a subject at risk of developing these diseases.
  • FXTAS fragile X-associated tremor / ataxia syndrome
  • FXTAS fragile X syndrome
  • FXAXA Fragile X-Associated Tremor / Ataxia Syndrome
  • FMR1 fragile X mental retardation 1
  • FXTAS is a disease that requires differentiation from Parkinson's disease, intranuclear inclusion body disease, etc., and is said to occur in some carriers with CGG repeat 55-200.
  • FRAXA Philadelphia RAXA
  • the pharmaceutical composition of the present invention is characterized by containing ALAs as an active ingredient.
  • ALAs refer to ALA or derivatives thereof or salts or esters thereof.
  • ALA means 5-aminolevulinic acid.
  • ALA also referred to as ⁇ -aminolevulinic acid, is one of the amino acids.
  • R 1 represents a hydrogen atom or an acyl group
  • R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.
  • ALA corresponds to the case where R 1 and R 2 are hydrogen atoms.
  • ALAs may act as an active ingredient in the form of ALA of formula (I) or a derivative thereof in vivo, and can also be administered as a prodrug (precursor) that is degraded by enzymes in vivo.
  • the acyl group in R 1 of the formula (I) includes linear or branched C 1-8 straight or branched carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, benzylcarbonyl group and the like Examples thereof include an alkanoyl group, and an aroyl group having 7 to 14 carbon atoms such as benzoyl, 1-naphthoyl and 2-naphthoyl groups.
  • alkyl group in R 2 of the formula (I) linear such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl group or Examples thereof include branched alkyl groups having 1 to 8 carbon atoms.
  • cycloalkyl group in R 2 of formula (I) a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group and the like is present And a cycloalkyl group having 3 to 8 carbon atoms which may be mentioned.
  • Examples of the aryl group in R 2 of the formula (I) include aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl groups.
  • the aryl moiety may be the same as the above aryl group, and the alkyl moiety may be the same as the above alkyl group.
  • Preferred ALA derivatives include compounds in which R 1 is formyl, acetyl, propionyl, butyryl and the like.
  • Preferred examples of ALA derivatives include compounds in which R 2 is methyl, ethyl, propyl, butyl, pentyl and the like.
  • a combination of the R 1 and R 2 is (formyl and methyl), (acetyl and methyl), (propionyl and methyl), (butyryl and methyl), (formyl and ethyl), (acetyl And ethyl), (propionyl and ethyl), and (butyryl and ethyl) in combination.
  • each mineral acid salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and the like, formate, acetate, propionate, toluenesulfonic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc.
  • Organic acid addition salts can be exemplified.
  • metal salts include alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and metal salts such as aluminum and zinc.
  • ammonium salts include ammonium salts and alkyl ammonium salts such as tetramethyl ammonium salt.
  • organic amine salt include salts such as triethylamine salt, piperidine salt, morpholine salt, toluidine salt and the like. In addition, these salts can also be used as a solution at the time of use.
  • esters of ALAs include, but are not limited to, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester and the like.
  • ALA a monovalent fatty acid
  • various esters such as ALA methyl ester, ALA ethyl ester, ALA propyl ester, ALA butyl ester, ALA pentyl ester, and their hydrochlorides, phosphoric acid It is salt, sulfate.
  • ALA hydrochloride and ALA phosphate can be exemplified as particularly preferable ones.
  • the above-mentioned ALA can be produced by known methods such as chemical synthesis, production by microorganisms, production by enzymes, and the like.
  • the above ALAs may form hydrates or solvates, and may be used alone or in combination of two or more.
  • one or more metal-containing compounds are used in combination.
  • the pharmaceutical composition of the present invention may further contain one or more metal-containing compounds.
  • the metal part of such metal-containing compounds include iron, magnesium, zinc, nickel, vanadium, cobalt, copper, chromium and molybdenum.
  • the metal part of the metal-containing compound is iron, magnesium or zinc, in particular iron.
  • the iron compound may be an organic salt or an inorganic salt.
  • the inorganic salt include ferric chloride, ferric oxide, iron sulfate and ferrous pyrophosphate.
  • organic salts carboxylates such as hydroxycarboxylates, ferrous citrate, sodium ferrous citrate, sodium ferrous citrate (SFC), citrates such as ferric ammonium ammonium, pyrophosphate Diiron, heme iron, dextran iron, iron lactate, ferrous gluconate, sodium diethylene triamine pentaacetate, ammonium diethylenetriamine pentaacetate, iron sodium ethylenediaminetetraacetate, iron ethylenediaminepentaacetate, iron ammonium ethylenediaminepentaacetate, sodium dicarboxymethyl glutamate, disodium Organic acid salts such as ferric ammonium carboxymethyl glutamate, ferrous fumarate, iron acetate, iron oxalate, ferrous succinate, ferrous succinate, ferrous
  • examples of magnesium compounds include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium silicate, magnesium nitrate, diethylenetriaminepentaacetic acid magnesium diammonium, Mention may be made of ethylenediaminetetraacetate magnesium disodium and magnesium protoporphyrin.
  • examples of zinc compounds include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diethylenetriaminepentaacetic acid zinc diammonium, ethylenediaminetetraacetic acid zinc disodium, zinc protoporphyrin, zinc-containing yeast .
  • the dose of the metal-containing compound to the subject may be 0 to 100 times, preferably 0.01 to 10 times the molar dose of ALA to the subject, and preferably 0.1 to 8 times Is more desirable.
  • the ALAs and the metal-containing compound contained in the pharmaceutical composition of the present invention can be administered either as a composition containing the ALAs and the metal-containing compound, or each can be administered alone, but even when each is administered alone It is preferable to simultaneously administer, and not only simultaneous administration is performed at the same time, but administration of ALAs and the metal-containing compound exerts additive effects, preferably synergistic effects, even at the same time. In order to be able to, it means that it is done without a considerable interval between the two.
  • the administration route of the ALAs and the metal-containing compound in the present invention is not limited, and may be systemic administration or local administration.
  • the administration route may be, for example, oral administration including sublingual administration, or inhalation administration, intravenous administration including intravenous drip, transdermal administration by patch, etc., suppository, or naso-gastric tube, nasal intestinal tract, gastric fistula tube Or parenteral administration such as administration by forced enteral feeding using an intestinal fistula tube.
  • ALAs and metal-containing compounds may be administered from different routes.
  • the dosage form of the pharmaceutical composition of the present invention may be appropriately determined depending on the administration route, and is not limited to, but is not limited to injections, drips, tablets, capsules, fine granules, powders, solutions, syrups, etc. There may be mentioned dissolved solutions, patches, suppositories and the like.
  • the pharmaceutical composition according to the present invention may contain other optional ingredients such as other medicinal ingredients, nutritional agents, carriers and the like as needed.
  • optional ingredient for example, conventional pharmaceutically acceptable carriers, binders, such as crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats, oils and fats, gums, polyalkylene glycols, etc.
  • Additives such as stabilizers, solvents, dispersion media, bulking agents, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizers, isotonic agents, etc. it can.
  • the frequency and period of administration of the pharmaceutical composition of the present invention to a subject can be appropriately determined by those skilled in the art (for example, a physician) in consideration of the symptoms, conditions, etc. of the subject.
  • Example 1 Electrophysiological evaluation of the nerve activity improvement effect of ALA in mouse cerebral cortex primary cultured neurons
  • the plasmid purified using QIAGEN Plasmid Maxi Kit (QIAGEN) was used as a CGG 88-times repeated extension expression plasmid.
  • a plasmid in which only the GFP gene was inserted without inserting the CGG 88-times repeated sequence was used as a GFP expression plasmid.
  • the cells were cultured for 21 days. Medium, B-27 (R) supplement (2%) (Invitrogen) and GlutaMax TM supplement (1%) (Invitrogen) Neurobasal TM Medium (Invitrogen) supplemented with with (for neuronal medium) The cells were cultured at 37 ° C. in the presence of 5% CO 2 .
  • sEPSCs spontaneous excitatory postsynaptic currents
  • Whole-cell patch clamp method makes small glass electrode adhere to cell membrane with high resistance more than gigaohm and then sucks to make holes in cell membrane of the part where glass electrode adheres It is a method of recording the ion current flowing through the cell membrane.
  • Amplifier device EPC10 amplifier (HEKA, Lambrecht / Pfalz, Germany)
  • External solution in mM: 143 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 glucose, 10 HEPES, pH 7.4 with NaOH
  • Internal solution in mM: 135 CsMeS, 5 CsCl, 10 HEPES, 0.5 EGTA, 1 MgCl2, 4 Mg2 ATP, 0.4 NaGTP, 5 QX-314, pH 7.4 with CsOH.
  • Membrane potential fixed at -70mV.
  • each nerve cell used in ⁇ Example 1> is fixed with 4% paraformaldehyde after 21 days of culture, and an anti-MAP2 antibody (ab5392, Abcam, 1 / 1,000 dilution) as a nerve cell marker, and an anti Cell staining was performed using a GFP antibody (ab290, Abcam, 1 / 1,000 dilution).
  • the fixed cells were washed with PBS containing Triton X-100 (0.1%) for 10 minutes, and incubated at 4 ° C. in the presence of the above antibody (primary antibody).
  • the present model mouse is a mouse in which a CGG repeat mutation of 98 times has been introduced into the Fmrl gene of mouse C57BL6 / J strain, and is characterized by exhibiting neuropathic symptoms of FXTAS from the age of 5 months.
  • a drug administration group (administered with ALA hydrochloride and SFC in combination) and a Vehicle group (administered with SFC alone) were respectively set for wild-type mice and the above-mentioned model mice, and a total of 4 groups were used as test groups.
  • the dose of ALA hydrochloride was used as 3 mg / kg per dose.
  • an aqueous solution containing ALA and SFC in a molar ratio of 20: 1 was prepared and used for the test. Specifically, SFC 0.47 mg / kg was used for ALA hydrochloride 3 mg / kg.
  • test drug thus prepared was orally administered using a sonde.
  • the administration period was once a day for 5 months of age to 1 month.
  • the behavioral test mentioned later was implemented. Administration continued during the behavioral test.
  • mice were walked on an elongated plate (length 80 cm, width 5 mm), and the number of times of slipping on the elongated plate was counted.
  • the new object recognition test is a learning / memory ability test using the habit of a mouse that the search behavior for old knowledge objects is lower than that for new objects by memory.
  • the mouse searches for the object. If the novelty is reduced by recognizing the object, the search behavior for the object also decreases. If two objects are placed in the cage and the search action is performed, then if one object is changed to a new one and the search action is performed, the search behavior for the old knowledge object is lower than that for the new object by memory It is observed.
  • the proportion of the search action time showed a smaller value than that in the WT group.
  • the ratio of the search action time shows a large value as compared with the CGG KI group. That is, improvement of the learning and memory function by ALA was confirmed.
  • mice It is a test well known to those skilled in the art for testing spontaneous alternation behavior of Y-shaped maze test mice. Specifically, it is a test method that takes advantage of the nature of mice that spontaneously enter different arms of a Y-maze in exploratory behavior, allowing the mice to freely move in the Y-maze and evaluating the memory about the arms that have already entered. By doing this, we evaluate the attention and spatial memory of the mouse.
  • a Y-maze in which all three arms have the same size and the angle between the arms is 120 degrees is used to test the spontaneous alternation behavior of mice.
  • Spontaneous alternation is a test method that takes advantage of the ability of mice to spontaneously enter different arms in an exploratory behavior, and is an action that is made possible by storing arm that has already entered.
  • For measurement record the order in which the mice enter the three arms for 8 minutes. Count the number of times of entry into all arms and the number of consecutive entry into 3 different arms (the number of times of entry into all arms with a minimum of 3 times: number of alternations) The value divided by is evaluated as the replacement activity rate.
  • the number of alternations in the CGG + ALA group is not different from that in the other groups, and in addition, the accuracy rate of the CGG + ALA group recovers compared to the CGG KI group, and further to the level of the WT group. Was confirmed. That is, improvement of the learning and memory function by ALA was confirmed.
  • a pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder resulting from the presence of TR on a chromosome Since the pharmaceutical composition of the present invention can be effectively used for the core symptoms of TR disease, it is expected as a means to fundamentally treat TR disease.

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Abstract

[Problem] To provide a novel medicine that is usable for preventing or treating neuropathy caused by the presence of a triplet repeat (TR) on chromosome. [Solution] A medicinal composition to be used for treating a subject with neuropathy caused by the presence of a TR on chromosome or preventing the neuropathy, said medicinal composition comprising 5-aminolevulinic acid (ALA) or a derivative thereof as an active ingredient.

Description

神経障害を改善するための医薬組成物Pharmaceutical composition for improving neurological disorders
　本発明は、５－アミノレブリン酸またはその誘導体（本明細書中、単に「ＡＬＡ類」とも称する）の新規用途、具体的には、染色体上のトリプレットリピートの存在に起因する神経障害を有する対象の治療におけるＡＬＡ類の使用に関する。 The present invention relates to a novel use of 5-aminolevulinic acid or a derivative thereof (also referred to herein as simply "ALAs"), specifically, a subject having a neurological disorder resulting from the presence of triplet repeats on chromosomes. Use of ALAs in the treatment.
　遺伝子の塩基配列において、３塩基単位（トリプレット、ＣＡＧなど）が連続して繰り返し配列することをトリプレットリピート（以下「ＴＲ」とも称する）という。この繰り返し回数は、正常人でも多様であるが、一定以上に多く繰り返して過伸長すると神経障害を惹起する場合があり、総称してトリプレットリピート病（ＴＲ病）と称されている。 In the base sequence of a gene, the repeated arrangement of three base units (triplet, CAG, etc.) continuously is referred to as triplet repeat (hereinafter also referred to as "TR"). The number of repetitions is variable even in normal people, but when it is repeated more than a certain number repeatedly, it may cause a neuropathy and is generically called triplet repeat disease (TR disease).
　ＴＲ病は、ＴＲが存在する遺伝子上の領域に基づいて、５’末端の非翻訳領域に存在するＴＲの伸長による疾患、翻訳領域に存在するＴＲの伸長による疾患、３’末端の非翻訳領域に存在するＴＲの伸長による疾患、およびイントロン内に存在するＴＲの伸長による疾患に分類され、フリードライヒ失調症（ＦＲＤＡ）、球脊髄性筋委縮症、ハンチントン病（ＨＤ）、脊髄小脳変性症１型（ＳＣＡ１）、脆弱Ｘ症候群（ＦＲＡＸＡ）、脆弱Ｘ随伴振戦／失調症候群（ＦＸＴＡＳ）、筋緊張性ジストロフィーなどの疾患が知られている。 TR disease is based on the region on the gene where TR exists, a disease caused by the extension of TR present in the untranslated region at the 5 'end, a disease caused by the extension of TR present in the translation region, a non-translated region at the 3' end Are classified as diseases due to the elongation of TR present in the disease and diseases due to the elongation of the TR present in the intron, Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration 1 Diseases such as type (SCA1), fragile X syndrome (FRAXA), fragile X-associated tremor / ataxia (FXTAS), and myotonic dystrophy are known.
　ハンチントン病や筋強直性ジストロフィーなどのＴＲ病では、ＣＡＧやＣＴＧといった３塩基繰り返し配列（リピート）が異常に伸長しており、そのリピート長は症状の重症度と比例する。これらＴＲ病患者では、年齢とともにリピート長がさらに伸長することにより、症状が進行するとされ、リピート伸長抑制効果のある遺伝子治療の開発が基礎研究で試みられているが実用化には至っていない。実際の臨床現場では、症状に応じた対症療法が行われている（非特許文献１）。 In TR disease such as Huntington's disease and myotonic dystrophy, a 3-base repeat sequence (repeat) such as CAG or CTG is abnormally extended, and the repeat length is proportional to the severity of the symptom. In these patients with TR disease, it is considered that the symptoms progress as the repeat length further extends with age, and development of gene therapy having an effect of suppressing the repeat elongation has been attempted in basic research, but has not been put into practical use. At the actual clinical site, symptomatic treatment is performed according to the symptoms (Non-patent Document 1).
　脆弱Ｘ症候群（ＦＲＡＸＡ）、脆弱Ｘ随伴振戦／失調症候群（ＦＸＴＡＳ）は、Ｘ染色体に位置するＦＭＲ１遺伝子のＣＧＧリピートが関与している。脆弱Ｘ症候群（ＦＲＡＸＡ）、脆弱Ｘ随伴振戦／失調症候群（ＦＸＴＡＳ）に対する治療法としては、薬剤により、ＦＭＲ遺伝子調節を変化させ、ＦＭＲ遺伝子の発現を回復させる方法、神経細胞間の興奮性神経伝達に重要な役割を担う、グルタミン酸を認識する受容体（ｍＧｌｕＲ）の阻害剤を用いる方法、ＦＸＳで抑制されているとされているＧＡＢＡシステムにおけるＧＡＢＡ受容体の作動薬を用いる方法、ＦＭＲタンパクが制御する遺伝子を薬剤で抑制する方法などが報告されているが、いずれも研究段階であり、治療法の確立には至っていない（非特許文献２）。 Fragile X syndrome (FRAXA) and Fragile X-associated tremor / ataxia (FXTAS) involve the CGG repeat of the FMR1 gene located on the X chromosome. As a treatment for fragile X syndrome (FRAXA) and fragile X-associated tremor / ataxia syndrome (FXTAS), a method of changing FMR gene regulation by a drug and restoring the expression of FMR gene, excitatory nerve between neurons A method that uses an inhibitor of glutamate receptor (mGluR) that plays an important role in transmission, a method that uses an agonist of a GABA receptor in the GABA system that is believed to be inhibited by FXS, an FMR protein Although a method for suppressing a gene to be controlled by a drug and the like have been reported, all of them are in the research stage and have not established a therapeutic method (Non-patent Document 2).
　また、フリードライヒ失調症（ＦＲＤＡ）を含むフラタキシンタンパク質量の低下に起因する疾患に対して、ＡＬＡ類が有用であり得ることが報告されているが、トリプレットリピートを有する対象に対する効果や、神経障害に対する効果は示されていない（特許文献１）。 In addition, although it has been reported that ALAs may be useful for diseases caused by a decrease in the amount of frataxin protein including Friedreich's ataxia (FRDA), the effect on a subject having a triplet repeat or nerve The effect on the disorder is not shown (Patent Document 1).
ＷＯ２０１５／０６４４４７WO 2015/064447
　本発明は、ＴＲの存在に起因する神経障害の予防または改善に使用することができる新規薬剤を提供することを目的とする。 An object of the present invention is to provide a novel drug which can be used for the prevention or amelioration of neurological disorders caused by the presence of TR.
　現在までに、ＴＲ病の根本的な治療法が確立されておらず、行動異常やてんかんなど、症状に応じた対症療法が行われている。本発明者らは、上記課題を解決するために鋭意検討する過程で、驚くべきことに、ＡＬＡ類が、ＴＲの存在に起因する神経障害を形態学的および生理学的に改善することができ、ＴＲ病の中核症状の治療に有用であることを見出し、本発明を完成させるに至った。 To date, no fundamental treatment for TR disease has been established, and symptomatic treatments such as behavioral abnormalities and epilepsy have been performed. The present inventors have surprisingly been able to morphologically and physiologically ameliorate neurological disorders caused by the presence of TR in the course of intensive studies to solve the above problems. It has been found that it is useful for treating the core symptoms of TR disease, and the present invention has been completed.
　具体的に、本発明は、以下の特徴を包含する。
　［１］　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物であって、
　下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000004
 （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
で示される化合物またはその塩もしくはエステルを含有する、
ことを特徴とする
医薬組成物。 Specifically, the present invention includes the following features.
[1] A pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder caused by the presence of a 3-base repeat sequence (triplet repeat) on a chromosome,
The following formula (I):
Figure JPOXMLDOC01-appb-C000004
 (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
And a salt or ester thereof,
Pharmaceutical composition characterized by the above-mentioned.
　［２］　［１］に記載の医薬組成物であって、
　前記対象は、フリードライヒ失調症（ＦＲＤＡ）、球脊髄性筋委縮症、ハンチントン病（ＨＤ）、脊髄小脳変性症１型（ＳＣＡ１）、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）、脆弱Ｘ症候群（ＦＲＡＸＡ）、筋緊張性ジストロフィーからなる群から選択されるトリプレットリピート病を患う対象である、
ことを特徴とする
医薬組成物。 [2] The pharmaceutical composition according to [1], wherein
The subject includes Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration type 1 (SCA1), fragile X-associated tremor / ataxia syndrome (FXTAS), fragile X Subject suffering from triplet repeat disease selected from the group consisting of syndrome (FRAXA) and myotonic dystrophy,
Pharmaceutical composition characterized by the above-mentioned.
　［３］　［１］または［２］に記載の医薬組成物であって、
　前記対象は、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）または脆弱Ｘ症候群（ＦＲＡＸＡ）を患う対象である、
ことを特徴とする
医薬組成物。 [3] The pharmaceutical composition according to [1] or [2], which
The subject is a subject suffering from fragile X-associated tremor / ataxia syndrome (FXTAS) or fragile X syndrome (FRAXA),
Pharmaceutical composition characterized by the above-mentioned.
　［４］　［１］～［３］のいずれかに記載の医薬組成物であって、
　Ｒ１が、水素原子、炭素数１～８のアルカノイル基、および、炭素数７～１４のアロイル基からなる群から選択され、
　Ｒ２が、水素原子、直鎖または分岐状の炭素数１～８のアルキル基、炭素数３～８のシクロアルキル基、炭素数６～１４のアリール基、および、炭素数７～１５のアラルキル基からなる群から選択される
ことを特徴とする、
医薬組成物。 [4] The pharmaceutical composition according to any one of [1] to [3], which
R 1 is selected from the group consisting of a hydrogen atom, an alkanoyl group having 1 to 8 carbon atoms, and an aroyl group having 7 to 14 carbon atoms,
R 2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 14 carbon atoms, and an aralkyl having 7 to 15 carbon atoms Characterized in that it is selected from the group consisting of
Pharmaceutical composition.
　［５］　［１］～［４］のいずれかに記載の医薬組成物であって、
　Ｒ１およびＲ２が、水素原子である、
医薬組成物。 [5] The pharmaceutical composition according to any one of [1] to [4], which
R 1 and R 2 are hydrogen atoms,
Pharmaceutical composition.
　［６］　［１］～［５］のいずれかに記載の医薬組成物であって、
　一種または二種以上の金属含有化合物をさらに含有する、
医薬組成物。 [6] The pharmaceutical composition according to any one of [1] to [5], which
It further contains one or more metal-containing compounds,
Pharmaceutical composition.
　［７］　［６］に記載の医薬組成物であって、
　金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデンまたはコバルトを含有する化合物である、
医薬組成物。 [7] The pharmaceutical composition according to [6], which is
The metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt,
Pharmaceutical composition.
　［８］　［７］に記載の医薬組成物であって、
　金属含有化合物が、鉄、マグネシウムまたは亜鉛を含有する化合物である、
医薬組成物。 [8] The pharmaceutical composition according to [7], which is
The metal-containing compound is a compound containing iron, magnesium or zinc,
Pharmaceutical composition.
　［９］　［８］に記載の医薬組成物であって、
　金属含有化合物が、鉄を含有する化合物である、
医薬組成物。 [9] The pharmaceutical composition according to [8], which
The metal-containing compound is a compound containing iron,
Pharmaceutical composition.
　［１０］　［９］に記載の医薬組成物であって、
　前記鉄を含有する化合物が、クエン酸第一鉄ナトリウムである、
医薬組成物。 [10] A pharmaceutical composition according to [9], which comprises
The compound containing iron is sodium ferrous citrate,
Pharmaceutical composition.
　［１１］　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象を予防または治療するための医薬の製造における下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000005
 （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
で示される化合物またはその塩もしくはエステルの使用。 [11] The following formula (I) in the manufacture of a medicament for preventing or treating a subject having a neurological disorder caused by the presence of a 3-base repeat sequence (triplet repeat) on a chromosome:
Figure JPOXMLDOC01-appb-C000005
 (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
Use of a compound represented by or a salt or ester thereof.
　［１２］　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象を予防または治療する方法であって、
　それを必要とする対象に、治療上有効量の下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000006
 （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
で示される化合物またはその塩もしくはエステルを投与することを含む、
ことを特徴とする、
方法。 [12] A method for preventing or treating a subject having a neurological disorder caused by the presence of a 3-base repeat sequence (triplet repeat) on a chromosome,
In a subject in need thereof, a therapeutically effective amount of Formula (I):
Figure JPOXMLDOC01-appb-C000006
 (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
Administering a compound of the formula: or a salt or ester thereof,
It is characterized by
Method.
　なお、上記に述べた本発明の一または複数の特徴を任意に組み合わせた発明も、本発明の範囲に含まれる。 In addition, invention which combined arbitrarily the one or several characteristic of this invention described above is also contained in the scope of the present invention.
　本発明によれば、染色体上のＴＲの存在に起因する神経障害を有する対象を予防または治療するための医薬組成物が提供される。 According to the present invention, there is provided a pharmaceutical composition for preventing or treating a subject having a neurological disorder caused by the presence of TR on a chromosome.
図１は、マウス大脳皮質初代培養神経細胞における神経活動改善効果を電気生理学的に示す図である。FIG. 1 is a diagram showing electrophysiologically the nerve activity improvement effect in mouse cerebral cortex primary culture neurons. 図２は、マウス大脳皮質初代培養神経細胞における神経活動改善効果を神経形態学的に示す図である。FIG. 2 is a diagram showing the neuromorphologically the nerve activity improving effect in mouse cerebral cortex primary cultured neurons. 図３は、Ｂｅａｍ　ｗａｌｋｉｎｇ試験の結果を示す図である。図中の各符号は、それぞれ以下を示している：ＷＴ、ｗｉｌｄ－ｔｙｐｅ；ＷＴ＋ＡＬＡ、ｗｉｌｄ－ｔｙｐｅ薬剤（ＡＬＡ塩酸塩＋ＳＦＣ）投与群；ＣＧＧ　ＫＩ、ＦＸＴＡＳ　Ｖｅｈｉｃｌｅ（ＳＦＣ）投与群；ＣＧＧ＋ＡＬＡ、ＦＸＴＡＳ　薬剤（ＡＬＡ＋ＳＦＣ）投与群。FIG. 3 shows the results of the Beam walking test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group. 図４は、新規物体認識試験の結果を示す図である。図中の各符号は、それぞれ以下を示している：ＷＴ、ｗｉｌｄ－ｔｙｐｅ；ＷＴ＋ＡＬＡ、ｗｉｌｄ－ｔｙｐｅ薬剤（ＡＬＡ塩酸塩＋ＳＦＣ）投与群；ＣＧＧ　ＫＩ、ＦＸＴＡＳ　Ｖｅｈｉｃｌｅ（ＳＦＣ）投与群；ＣＧＧ＋ＡＬＡ、ＦＸＴＡＳ　薬剤（ＡＬＡ＋ＳＦＣ）投与群。FIG. 4 is a diagram showing the results of the novel object recognition test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group. 図５は、Ｙ字迷路試験におけるアーム侵入回数の結果を示す図である。図中の各符号は、それぞれ以下を示している：ＷＴ、ｗｉｌｄ－ｔｙｐｅ；ＷＴ＋ＡＬＡ、ｗｉｌｄ－ｔｙｐｅ薬剤（ＡＬＡ塩酸塩＋ＳＦＣ）投与群；ＣＧＧ　ＫＩ、ＦＸＴＡＳ　Ｖｅｈｉｃｌｅ（ＳＦＣ）投与群；ＣＧＧ＋ＡＬＡ、ＦＸＴＡＳ　薬剤（ＡＬＡ＋ＳＦＣ）投与群。FIG. 5 shows the results of the number of arm penetrations in the Y-shaped maze test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group. 図６は、Ｙ字迷路試験における正解率の結果を示す図である。図中の各符号は、それぞれ以下を示している：ＷＴ、ｗｉｌｄ－ｔｙｐｅ；ＷＴ＋ＡＬＡ、ｗｉｌｄ－ｔｙｐｅ薬剤（ＡＬＡ塩酸塩＋ＳＦＣ）投与群；ＣＧＧ　ＫＩ、ＦＸＴＡＳ　Ｖｅｈｉｃｌｅ（ＳＦＣ）投与群；ＣＧＧ＋ＡＬＡ、ＦＸＴＡＳ　薬剤（ＡＬＡ＋ＳＦＣ）投与群。FIG. 6 is a figure which shows the result of the correct answer rate in a Y-shaped maze test. Each symbol in the figure indicates the following: WT, wild-type; WT + ALA, wild-type drug (ALA hydrochloride + SFC) administration group; CGG KI, FXTAS Vehicle (SFC) administration group; CGG + ALA, FXTAS agent (ALA + SFC) administration group.
　以下、本発明を詳細に説明する。
　本発明は、染色体上の３塩基繰り返し配列（トリプレットリピート；ＴＲ）の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物に関する。 Hereinafter, the present invention will be described in detail.
The present invention relates to a pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder resulting from the presence of a 3-base repeat sequence (triplet repeat; TR) on a chromosome.
　本発明において、ＴＲは、染色体上のその存在に起因して、神経損傷、神経活動低下など、形態学的または生理学的に神経障害を引き起こすＴＲである限り、その種類は特に制限されない。例えば、本発明に含まれるＴＲには、これに限定されるものではないが、ＣＧＧリピート、ＣＡＧリピート、ＧＡＡリピート、ＣＣＧリピート、ＣＴＧリピート等を挙げることができる。本発明の一実施形態において、ＴＲは、ＣＧＧリピートである。 In the present invention, the type of TR is not particularly limited as long as it is a TR that causes a neurological damage, morphologically or physiologically, such as neural damage or neural activity due to its presence on a chromosome. For example, the TR included in the present invention includes, but is not limited to, CGG repeat, CAG repeat, GAA repeat, CCG repeat, CTG repeat and the like. In one embodiment of the invention, the TR is a CGG repeat.
　また、本発明において、ＴＲのリピート数は、神経損傷、神経活動低下など、形態学的または生理学的に神経障害を引き起こすのに十分な長さである場合のほか、潜在的に、神経障害を引き起こし得るリピート数を含む。具体的に、本発明におけるＴＲのリピート数は、４０以上、５０以上、６０以上、７０以上、８０以上、９０以上、１００以上、１１１０以上、１２０以上、１３０以上、１４０以上、１５０以上、１６０以上、１７０以上、１８０以上、１９０以上、２００以上であり得る。 Furthermore, in the present invention, the TR repeat number may have a length that is sufficient to cause a morphologically or physiologically neurological disorder, such as a neurological injury, a decrease in neural activity, etc., as well as potentially a neurological disorder. Includes the number of repeats that can be triggered. Specifically, the repeat number of TR in the present invention is 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 1110 or more, 120 or more, 130 or more, 140 or more, 150 or more, 160 or more. The above may be 170 or more, 180 or more, 190 or more, 200 or more.
　本発明において、予防または治療の対象は、フリードライヒ失調症（ＦＲＤＡ）、球脊髄性筋委縮症、ハンチントン病（ＨＤ）、脊髄小脳変性症１型（ＳＣＡ１）、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）、脆弱Ｘ症候群（ＦＲＡＸＡ）、または筋緊張性ジストロフィーを患う対象、またはこれらの疾患を発症するおそれのある対象であり得る。 In the present invention, subjects of prevention or treatment include Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration type 1 (SCA1), fragile X-associated tremors / ataxia It may be a subject suffering from a syndrome (FXTAS), fragile X syndrome (FRAXA) or myotonic dystrophy, or a subject at risk of developing these diseases.
　本発明の一実施形態において、前記対象は、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）、または脆弱Ｘ症候群（ＦＲＡＸＡ）を患う対象、またはこれらの疾患を発症するおそれのある対象である。脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）、および脆弱Ｘ症候群（ＦＲＡＸＡ）は、いずれもｆｒａｇｉｌｅ　Ｘ　ｍｅｎｔａｌ　ｒｅｔａｒｄａｔｉｏｎ　１（ＦＭＲ１）遺伝子の５’非翻訳領域におけるＣＧＧリピートの異常な延長によって特徴付けられる。ＦＸＴＡＳは、パーキンソン病、神経核内封入体病などとの鑑別が必要な疾患で、ＣＧＧリピート５５～２００を持つ保因者の一部に発症するとされている。世界的な保因者数は男性の８５０人に１人、女性の３００人に１人とされ、この保因者男性の４０％、保因者女性の１６％程度が発症するとされている。また、ＦＲＡＸＡはＣＧＧリピート２００以上で発症するといわれている。現時点で、ＦＸＴＡＳ、ＦＲＡＸＡともに確立された治療法は存在しない。 In one embodiment of the present invention, the subject is a subject suffering from fragile X-associated tremor / ataxia syndrome (FXTAS), or fragile X syndrome (FRAXA), or a subject at risk of developing these diseases. Fragile X-Associated Tremor / Ataxia Syndrome (FXTAS), and Fragile X Syndrome (FRAXA) are both characterized by abnormal elongation of the CGG repeat in the 5 'untranslated region of the fragile X mental retardation 1 (FMR1) gene . FXTAS is a disease that requires differentiation from Parkinson's disease, intranuclear inclusion body disease, etc., and is said to occur in some carriers with CGG repeat 55-200. The worldwide number of carriers is 1 in 850 males and 1 in 300 females. It is estimated that 40% of male carriers and 16% of female carriers will develop. In addition, FRAXA is said to develop at CGG repeat 200 or more. At the moment, there are no established therapies for both FXTAS and FRAXA.
　本発明の医薬組成物は、ＡＬＡ類を有効成分とすることを特徴とする。
　本明細書において、ＡＬＡ類とは、ＡＬＡ若しくはその誘導体またはそれらの塩またはエステルをいう。 The pharmaceutical composition of the present invention is characterized by containing ALAs as an active ingredient.
As used herein, ALAs refer to ALA or derivatives thereof or salts or esters thereof.
　本明細書において、ＡＬＡは、５－アミノレブリン酸を意味する。ＡＬＡは、δ－アミノレブリン酸ともいい、アミノ酸の１種である。 As used herein, ALA means 5-aminolevulinic acid. ALA, also referred to as δ-aminolevulinic acid, is one of the amino acids.
　ＡＬＡの誘導体としては、下記式（Ｉ）で表される化合物を例示することができる。式（Ｉ）において、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す。なお、式（Ｉ）において、ＡＬＡは、Ｒ１およびＲ２が水素原子の場合に相当する。
Figure JPOXMLDOC01-appb-C000007
 As a derivative of ALA, a compound represented by the following formula (I) can be exemplified. In formula (I), R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group. In Formula (I), ALA corresponds to the case where R 1 and R 2 are hydrogen atoms.
Figure JPOXMLDOC01-appb-C000007
　ＡＬＡ類は、生体内で式（Ｉ）のＡＬＡまたはその誘導体の状態で有効成分として作用すればよく、生体内の酵素で分解されるプロドラッグ（前駆体）として投与することもできる。 ALAs may act as an active ingredient in the form of ALA of formula (I) or a derivative thereof in vivo, and can also be administered as a prodrug (precursor) that is degraded by enzymes in vivo.
　式（Ｉ）のＲ１におけるアシル基としては、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、オクタノイル、ベンジルカルボニル基等の直鎖または分岐状の炭素数１～８のアルカノイル基や、ベンゾイル、１－ナフトイル、２－ナフトイル基等の炭素数７～１４のアロイル基を挙げることができる。 The acyl group in R 1 of the formula (I) includes linear or branched C 1-8 straight or branched carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, benzylcarbonyl group and the like Examples thereof include an alkanoyl group, and an aroyl group having 7 to 14 carbon atoms such as benzoyl, 1-naphthoyl and 2-naphthoyl groups.
　式（Ｉ）のＲ２におけるアルキル基としては、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル基等の直鎖または分岐状の炭素数１～８のアルキル基を挙げることができる。 As the alkyl group in R 2 of the formula (I), linear such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl group or Examples thereof include branched alkyl groups having 1 to 8 carbon atoms.
　式（Ｉ）のＲ２におけるシクロアルキル基としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロドデシル、１－シクロヘキセニル基等の飽和、または一部不飽和結合が存在してもよい、炭素数３～８のシクロアルキル基を挙げることができる。 As the cycloalkyl group in R 2 of formula (I), a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group and the like is present And a cycloalkyl group having 3 to 8 carbon atoms which may be mentioned.
　式（Ｉ）のＲ２におけるアリール基としては、フェニル、ナフチル、アントリル、フェナントリル基等の炭素数６～１４のアリール基を挙げることができる。 Examples of the aryl group in R 2 of the formula (I) include aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl groups.
　式（Ｉ）のＲ２におけるアラルキル基としては、アリール部分は上記アリール基と同じ例示ができ、アルキル部分は上記アルキル基と同じ例示ができ、具体的には、ベンジル、フェネチル、フェニルプロピル、フェニルブチル、ベンズヒドリル、トリチル、ナフチルメチル、ナフチルエチル基等の炭素数７～１５のアラルキル基を挙げることができる。 As the aralkyl group in R 2 of the formula (I), the aryl moiety may be the same as the above aryl group, and the alkyl moiety may be the same as the above alkyl group. Specifically, benzyl, phenethyl, phenylpropyl, phenyl Examples thereof include aralkyl groups having 7 to 15 carbon atoms such as butyl, benzhydryl, trityl, naphthylmethyl and naphthylethyl groups.
　好ましいＡＬＡ誘導体としては、Ｒ１が、ホルミル、アセチル、プロピオニル、ブチリル基等である化合物が挙げられる。また、好ましいＡＬＡ誘導体としては、上記Ｒ２が、メチル、エチル、プロピル、ブチル、ペンチル基等である化合物が挙げられる。また、好ましいＡＬＡ誘導体としては、上記Ｒ１とＲ２の組合せが、（ホルミルとメチル）、（アセチルとメチル）、（プロピオニルとメチル）、（ブチリルとメチル）、（ホルミルとエチル）、（アセチルとエチル）、（プロピオニルとエチル）、（ブチリルとエチル）の各組合せである化合物が挙げられる。 Preferred ALA derivatives include compounds in which R 1 is formyl, acetyl, propionyl, butyryl and the like. Preferred examples of ALA derivatives include compounds in which R 2 is methyl, ethyl, propyl, butyl, pentyl and the like. Moreover, as a preferable ALA derivative, a combination of the R 1 and R 2 is (formyl and methyl), (acetyl and methyl), (propionyl and methyl), (butyryl and methyl), (formyl and ethyl), (acetyl And ethyl), (propionyl and ethyl), and (butyryl and ethyl) in combination.
　ＡＬＡ類のうち、ＡＬＡまたはその誘導体の塩としては、薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩等を挙げることができる。酸付加塩としては、例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硝酸塩、硫酸塩等の各無機酸塩、ギ酸塩、酢酸塩、プロピオン酸塩、トルエンスルホン酸塩、コハク酸塩、シュウ酸塩、乳酸塩、酒石酸塩、グリコール酸塩、メタンスルホン酸塩、酪酸塩、吉草酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩等の各有機酸付加塩を例示することができる。金属塩としては、リチウム塩、ナトリウム塩、カリウム塩等の各アルカリ金属塩、マグネシウム、カルシウム塩等の各アルカリ土類金属塩、アルミニウム、亜鉛等の各金属塩を例示することができる。アンモニウム塩としては、アンモニウム塩、テトラメチルアンモニウム塩等のアルキルアンモニウム塩等を例示することができる。有機アミン塩としては、トリエチルアミン塩、ピペリジン塩、モルホリン塩、トルイジン塩等の各塩を例示することができる。なお、これらの塩は使用時において溶液としても用いることができる。 Among the ALAs, as salts of ALA or derivatives thereof, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like can be mentioned. As the acid addition salt, for example, each mineral acid salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and the like, formate, acetate, propionate, toluenesulfonic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc. Organic acid addition salts can be exemplified. Examples of metal salts include alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and metal salts such as aluminum and zinc. Examples of ammonium salts include ammonium salts and alkyl ammonium salts such as tetramethyl ammonium salt. Examples of the organic amine salt include salts such as triethylamine salt, piperidine salt, morpholine salt, toluidine salt and the like. In addition, these salts can also be used as a solution at the time of use.
　ＡＬＡ類のエステルとしては、これに限定されるものではないが、メチルエステル、エチルエステル、プロピルエステル、ブチルエステル、ペンチルエステル等を挙げることができる。 Examples of esters of ALAs include, but are not limited to, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester and the like.
　以上のＡＬＡ類のうち、もっとも望ましいものは、ＡＬＡ、および、ＡＬＡメチルエステル、ＡＬＡエチルエステル、ＡＬＡプロピルエステル、ＡＬＡブチルエステル、ＡＬＡペンチルエステル等の各種エステル類、並びに、これらの塩酸塩、リン酸塩、硫酸塩である。とりわけ、ＡＬＡ塩酸塩、ＡＬＡリン酸塩を特に好適なものとして例示することができる。 Among the above ALAs, the most desirable ones are ALA and various esters such as ALA methyl ester, ALA ethyl ester, ALA propyl ester, ALA butyl ester, ALA pentyl ester, and their hydrochlorides, phosphoric acid It is salt, sulfate. Among them, ALA hydrochloride and ALA phosphate can be exemplified as particularly preferable ones.
　上記ＡＬＡ類は、例えば、化学合成、微生物による生産、酵素による生産など公知の方法によって製造することができる。また、上記ＡＬＡ類は、水和物または溶媒和物を形成していてもよく、またＡＬＡ類を単独でまたは２種以上を適宜組み合わせて用いることもできる。 The above-mentioned ALA can be produced by known methods such as chemical synthesis, production by microorganisms, production by enzymes, and the like. The above ALAs may form hydrates or solvates, and may be used alone or in combination of two or more.
　上記ＡＬＡ類を水溶液として調製する場合には、ＡＬＡ類の分解を防ぐため、水溶液がアルカリ性とならないように留意する必要がある。アルカリ性となってしまう場合は、酸素を除去することによって分解を防ぐことができる。 When preparing the above-mentioned ALAs as an aqueous solution, care must be taken so that the aqueous solution does not become alkaline in order to prevent the decomposition of ALAs. If it becomes alkaline, decomposition can be prevented by removing oxygen.
　本発明の医薬組成物は、一実施形態において、一種または二種以上の金属含有化合物が併用される。したがって、本発明の医薬組成物は、一種または二種以上の金属含有化合物をさらに含有することができる。かかる金属含有化合物の金属部分としては、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、コバルト、銅、クロム、モリブデンを挙げることができる。好ましい実施形態では、金属含有化合物の金属部分は、鉄、マグネシウムまたは亜鉛であり、特に鉄であることが好ましい。 In one embodiment of the pharmaceutical composition of the present invention, one or more metal-containing compounds are used in combination. Thus, the pharmaceutical composition of the present invention may further contain one or more metal-containing compounds. Examples of the metal part of such metal-containing compounds include iron, magnesium, zinc, nickel, vanadium, cobalt, copper, chromium and molybdenum. In a preferred embodiment, the metal part of the metal-containing compound is iron, magnesium or zinc, in particular iron.
　本発明において、鉄化合物は、有機塩でも無機塩でもよい。無機塩としては、塩化第二鉄、三二酸化鉄、硫酸鉄、ピロリン酸第一鉄を挙げることができる。有機塩としては、ヒドロキシカルボン酸塩等のカルボン酸塩、クエン酸第一鉄、クエン酸鉄ナトリウム、クエン酸第一鉄ナトリウム（ＳＦＣ）、クエン酸鉄アンモニウム等のクエン酸塩や、ピロリン酸第二鉄、ヘム鉄、デキストラン鉄、乳酸鉄、グルコン酸第一鉄、ジエチレントリアミン五酢酸鉄ナトリウム、ジエチレントリアミン五酢酸鉄アンモニウム、エチレンジアミン四酢酸鉄ナトリウム、エチレンジアミン五酢酸鉄アンモニウム、ジカルボキシメチルグルタミン酸鉄ナトリウム、ジカルボキシメチルグルタミン酸鉄アンモニウム、フマル酸第一鉄、酢酸鉄、シュウ酸鉄、コハク酸第一鉄、コハク酸クエン酸鉄ナトリウム等の有機酸塩や、トリエチレンテトラアミン鉄、ラクトフェリン鉄、トランスフェリン鉄、鉄クロロフィリンナトリウム、フェリチン鉄、含糖酸化鉄、グリシン第一鉄硫酸塩を挙げることができる。 In the present invention, the iron compound may be an organic salt or an inorganic salt. Examples of the inorganic salt include ferric chloride, ferric oxide, iron sulfate and ferrous pyrophosphate. As organic salts, carboxylates such as hydroxycarboxylates, ferrous citrate, sodium ferrous citrate, sodium ferrous citrate (SFC), citrates such as ferric ammonium ammonium, pyrophosphate Diiron, heme iron, dextran iron, iron lactate, ferrous gluconate, sodium diethylene triamine pentaacetate, ammonium diethylenetriamine pentaacetate, iron sodium ethylenediaminetetraacetate, iron ethylenediaminepentaacetate, iron ammonium ethylenediaminepentaacetate, sodium dicarboxymethyl glutamate, disodium Organic acid salts such as ferric ammonium carboxymethyl glutamate, ferrous fumarate, iron acetate, iron oxalate, ferrous succinate, ferrous succinate, sodium ferric succinate, triethylenetetraamine iron, lactoferrin iron, transferrin iron, Iron chlorophyllinato Um, it can be cited ferritin iron, saccharated iron oxide, glycine ferrous sulphate.
　本発明において、マグネシウム化合物としては、クエン酸マグネシウム、安息香酸マグネシウム、酢酸マグネシウム、酸化マグネシウム、塩化マグネシウム、水酸化マグネシウム、炭酸マグネシウム、硫酸マグネシウム、ケイ酸マグネシウム、硝酸マグネシウム、ジエチレントリアミン五酢酸マグネシウムジアンモニウム、エチレンジアミン四酢酸マグネシウムジナトリウム、マグネシウムプロトポルフィリンを挙げることができる。 In the present invention, examples of magnesium compounds include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium silicate, magnesium nitrate, diethylenetriaminepentaacetic acid magnesium diammonium, Mention may be made of ethylenediaminetetraacetate magnesium disodium and magnesium protoporphyrin.
　本発明において、亜鉛化合物としては、塩化亜鉛、酸化亜鉛、硝酸亜鉛、炭酸亜鉛、硫酸亜鉛、ジエチレントリアミン五酢酸亜鉛ジアンモニウム、エチレンジアミン四酢酸亜鉛ジナトリウム、亜鉛プロトポルフィリン、亜鉛含有酵母を挙げることができる。 In the present invention, examples of zinc compounds include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diethylenetriaminepentaacetic acid zinc diammonium, ethylenediaminetetraacetic acid zinc disodium, zinc protoporphyrin, zinc-containing yeast .
　対象への金属含有化合物の投与量は、対象へのＡＬＡの投与量に対してモル比で０～１００倍であればよく、０．０１倍～１０倍が望ましく、０．１倍～８倍がより望ましい。 The dose of the metal-containing compound to the subject may be 0 to 100 times, preferably 0.01 to 10 times the molar dose of ALA to the subject, and preferably 0.1 to 8 times Is more desirable.
　本発明の医薬組成物に含有されるＡＬＡ類と金属含有化合物は、ＡＬＡ類と金属含有化合物とを含む組成物としても、あるいは、それぞれ単独でも投与することできるが、それぞれ単独で投与する場合でも同時に投与することが好ましく、ここで同時とは、同時刻に行われることのみならず、同時刻でなくともＡＬＡ類と金属含有化合物との投与が相加的効果、好ましくは相乗的効果を奏することができるように、両者間で相当の間隔をおかずに行われることを意味する。 The ALAs and the metal-containing compound contained in the pharmaceutical composition of the present invention can be administered either as a composition containing the ALAs and the metal-containing compound, or each can be administered alone, but even when each is administered alone It is preferable to simultaneously administer, and not only simultaneous administration is performed at the same time, but administration of ALAs and the metal-containing compound exerts additive effects, preferably synergistic effects, even at the same time. In order to be able to, it means that it is done without a considerable interval between the two.
　本発明におけるＡＬＡ類と金属含有化合物の投与経路は限定されず、全身投与であっても、局所投与であってもよい。投与経路としては、例えば、舌下投与も含む経口投与、あるいは吸入投与、点滴を含む静脈内投与、貼付剤等による経皮投与、座薬、または、経鼻胃管、経鼻腸管、胃ろうチューブ若しくは腸ろうチューブを用いる強制的経腸栄養法による投与等の非経口投与などを挙げることができる。また、上述のとおり、ＡＬＡ類と、金属含有化合物とを、別々の経路から投与してもよい。 The administration route of the ALAs and the metal-containing compound in the present invention is not limited, and may be systemic administration or local administration. The administration route may be, for example, oral administration including sublingual administration, or inhalation administration, intravenous administration including intravenous drip, transdermal administration by patch, etc., suppository, or naso-gastric tube, nasal intestinal tract, gastric fistula tube Or parenteral administration such as administration by forced enteral feeding using an intestinal fistula tube. Also, as described above, ALAs and metal-containing compounds may be administered from different routes.
　本発明の医薬組成物の剤型は、前記投与経路に応じて適宜決定してよく、限定はされないが、注射剤、点滴剤、錠剤、カプセル剤、細粒剤、散剤、液剤、シロップ等に溶解した水剤、貼付剤、座薬剤等を挙げることができる。 The dosage form of the pharmaceutical composition of the present invention may be appropriately determined depending on the administration route, and is not limited to, but is not limited to injections, drips, tablets, capsules, fine granules, powders, solutions, syrups, etc. There may be mentioned dissolved solutions, patches, suppositories and the like.
　本発明に係る医薬組成物は、必要に応じて他の薬効成分、栄養剤、担体等の他の任意成分を加えることができる。任意成分として、例えば結晶性セルロース、ゼラチン、乳糖、澱粉、ステアリン酸マグネシウム、タルク、植物性および動物性脂肪、油脂、ガム、ポリアルキレングリコール等の、薬学的に許容される通常の担体、結合剤、安定化剤、溶剤、分散媒、増量剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤などの各種調剤用配合成分を添加することができる。 The pharmaceutical composition according to the present invention may contain other optional ingredients such as other medicinal ingredients, nutritional agents, carriers and the like as needed. As an optional ingredient, for example, conventional pharmaceutically acceptable carriers, binders, such as crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats, oils and fats, gums, polyalkylene glycols, etc. Additives, such as stabilizers, solvents, dispersion media, bulking agents, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizers, isotonic agents, etc. it can.
　本発明の医薬組成物の対象への投与頻度や投与期間は、対象の症状や状態等を考慮して、当業者（例えば、医師）が適宜決定することができる。 The frequency and period of administration of the pharmaceutical composition of the present invention to a subject can be appropriately determined by those skilled in the art (for example, a physician) in consideration of the symptoms, conditions, etc. of the subject.
　本明細書において用いられる用語は、特に定義されたものを除き、特定の実施態様を説明するために用いられるのであり、発明を限定する意図ではない。 The terms used herein, except as specifically defined, are used to describe particular embodiments and are not intended to limit the invention.
　また、本明細書において用いられる「含む」との用語は、文脈上明らかに異なる理解をすべき場合を除き、記述された事項（部材、ステップ、要素、数字など）が存在することを意図するものであり、それ以外の事項（部材、ステップ、要素、数字など）が存在することを排除しない。 In addition, the term "including" as used herein is intended to include the described items (members, steps, elements, numbers, etc.) unless clearly understood in context. It does not exclude the existence of other matters (members, steps, elements, numbers, etc.).
　異なる定義が無い限り、ここに用いられるすべての用語（技術用語および科学用語を含む。）は、本発明が属する技術の当業者によって広く理解されるのと同じ意味を有する。ここに用いられる用語は、異なる定義が明示されていない限り、本明細書および関連技術分野における意味と整合的な意味を有するものとして解釈されるべきであり、理想化され、または、過度に形式的な意味において解釈されるべきではない。 Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used herein should be construed as having a meaning consistent with that in the present specification and related art, unless a different definition is explicitly stated, and are idealized or excessively formalized. It should not be interpreted in the sense of meaning.
　以下において、本発明を、実施例を参照してより詳細に説明する。しかしながら、本発明はいろいろな態様により具現化することができ、ここに記載される実施例に限定されるものとして解釈されてはならない。 In the following, the invention is described in more detail with reference to the examples. However, the present invention can be embodied in various aspects and should not be construed as limited to the embodiments set forth herein.
＜実施例１＞マウス大脳皮質初代培養神経細胞におけるＡＬＡの神経活動改善効果の電気生理学的評価 <Example 1> Electrophysiological evaluation of the nerve activity improvement effect of ALA in mouse cerebral cortex primary cultured neurons
　本実施例では、ＣＧＧリピートを神経細胞に導入することで低下した神経活動が、ＡＬＡによって改善するかどうかを電気生理学的に評価した。
　マウス大脳皮質初代培養神経細胞に、ＣＧＧ８８回反復伸長発現プラスミドまたはコントロールとしてのＧＦＰ発現プラスミドを発現させた各神経細胞を作製した。
　プラスミドの細胞へのトランスフェクションは、ＮＥＰＡ２１エレクトロポレーター（ネッパジーン社）を用い、エレクトロポレーション法にて行った。
　ヒト由来ゲノムからＣＧＧ８８回反復配列を含むＤＮＡを取得し、ｐＣＡＧ－ｎｅｏベクター（Ｗａｋｏ社）に挿入し、さらに、ＣＧＧ８８回反復配列の下流にｐＥＧＦＰ－Ｃ１　Ｖｅｃｔｏｒ（ｃｌｏｎｔｅｃｈ社）由来のＧＦＰ遺伝子を挿入した。ＱＩＡＧＥＮ　Ｐｌａｓｍｉｄ　Ｍａｘｉ　Ｋｉｔ（キアゲン社）を用いて精製したプラスミドを、ＣＧＧ８８回反復伸長発現プラスミドとして用いた。また、ＣＧＧ８８回反復配列を挿入せずに、ＧＦＰ遺伝子のみを挿入したプラスミドを、ＧＦＰ発現プラスミドとして用いた。前記各細胞は２１日間培養した。培地は、Ｂ－２７（登録商標）サプリメント（２％）（インビトロジェン社）およびＧｌｕｔａＭａｘＴＭサプリメント（１％）（インビトロジェン社）を添加したＮｅｕｒｏｂａｓａｌＴＭ　Ｍｅｄｉｕｍ（インビトロジェン社）（神経細胞用メディウム）を用いて、３７℃、５％ＣＯ２存在下で培養した。１μＭ　ＡＬＡ＋０．０５μＭ　ＳＦＣ（ＡＬＡとＳＦＣをモル比で２０：１の割合で混合）を培養１４日目から１週間培養液中に投与した。
　培養２１日後の各神経細胞に対して、ホールセルパッチクランプ法にて自発性の興奮性シナプス後電流（ｓｐｏｎｔａｎｅｏｕｓ　ｅｘｃｉｔａｔｏｒｙ　ｐｏｓｔｓｙｎａｐｔｉｃ　ｃｕｒｒｅｎｔｓ（ｓＥＰＳＣｓ））を神経活動の指標として測定した。 In this example, it was electrophysiologically evaluated whether neural activity reduced by introducing CGG repeats into neurons was improved by ALA.
Each neuronal cell in which a CGG 88-times repeated extension expression plasmid or a GFP expression plasmid as a control was expressed in mouse cerebral cortex primary cultured neurons was prepared.
Transfection of the plasmid into cells was carried out by electroporation using a NEPA 21 electroporator (Nepagene).
Obtain DNA containing CGG 88 repeats from human-derived genome, insert into pCAG-neo vector (Wako), and insert the GFP gene from pEGFP-C1 Vector (clontech) downstream of CGG 88 repeats did. The plasmid purified using QIAGEN Plasmid Maxi Kit (QIAGEN) was used as a CGG 88-times repeated extension expression plasmid. In addition, a plasmid in which only the GFP gene was inserted without inserting the CGG 88-times repeated sequence was used as a GFP expression plasmid. The cells were cultured for 21 days. Medium, B-27 (R) supplement (2%) (Invitrogen) and GlutaMax TM supplement (1%) (Invitrogen) Neurobasal TM Medium (Invitrogen) supplemented with with (for neuronal medium) The cells were cultured at 37 ° C. in the presence of 5% CO 2 . 1 μM ALA + 0.05 μM SFC (mixture of ALA and SFC at a molar ratio of 20: 1) was administered to the culture for one week starting on the 14th day of culture.
For each neuron after 21 days of culture, spontaneous excitatory postsynaptic currents (sEPSCs) were measured as an index of nerve activity by whole cell patch clamp method.
ホールセルパッチクランプ法
　ホールセルパッチクランプ法は、細胞膜に微小ガラス電極をギガオーム以上の高抵抗で密着させた後、さらに吸引することでガラス電極が密着している部分の細胞膜に穴をあけ、全細胞膜を流れるイオン電流を記録する方法である。本実施例においては、以下の装置、試薬、条件を用いた：
　アンプ装置：ＥＰＣ１０　ａｍｐｌｉｆｉｅｒ（ＨＥＫＡ，Ｌａｍｂｒｅｃｈｔ／Ｐｆａｌｚ，Ｇｅｒｍａｎｙ）
　外液（ｉｎ　ｍＭ）：１４３　ＮａＣｌ，５　ＫＣｌ，２　ＣａＣｌ２，１　ＭｇＣｌ２，１０ｇｌｕｃｏｓｅ，１０　ＨＥＰＥＳ，ｐＨ７．４　ｗｉｔｈ　ＮａＯＨ；
　内液（ｉｎ　ｍＭ）：１３５　ＣｓＭｅＳ，５　ＣｓＣｌ，１０　ＨＥＰＥＳ，０．５　ＥＧＴＡ，１　ＭｇＣｌ２，４　Ｍｇ２ＡＴＰ，０．４　ＮａＧＴＰ，５　ＱＸ－３１４，ｐＨ７．４　ｗｉｔｈ　ＣｓＯＨ．
　膜電位：－７０ｍＶに固定し測定。 Whole-cell patch clamp method Whole-cell patch clamp method makes small glass electrode adhere to cell membrane with high resistance more than gigaohm and then sucks to make holes in cell membrane of the part where glass electrode adheres It is a method of recording the ion current flowing through the cell membrane. The following apparatus, reagents and conditions were used in this example:
Amplifier device: EPC10 amplifier (HEKA, Lambrecht / Pfalz, Germany)
External solution (in mM): 143 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 glucose, 10 HEPES, pH 7.4 with NaOH;
Internal solution (in mM): 135 CsMeS, 5 CsCl, 10 HEPES, 0.5 EGTA, 1 MgCl2, 4 Mg2 ATP, 0.4 NaGTP, 5 QX-314, pH 7.4 with CsOH.
Membrane potential: fixed at -70mV.
　＜結果＞
　図１から分かるとおり、ＣＧＧ８８回反復伸長発現神経細胞において低下した神経活動（図１内「ＣＧＧ　ｒｅｐｅａｔ」）がＡＬＡ＋ＳＦＣ処置により改善した（図１内「ＣＧＧ　ｒｅｐｅａｔ　＋　５－ＡＬＡ」）。
＜実施例２＞マウス大脳皮質初代培養神経細胞におけるＡＬＡの神経活動改善効果の神経形態学的評価 <Result>
As can be seen from FIG. 1, the neural activity (“CGG repeat” in FIG. 1) decreased in CGG 88-times repeated expansion expressing neurons was improved by ALA + SFC treatment (“CGG repeat + 5-ALA” in FIG. 1).
<Example 2> Neuromorphological evaluation of neural activity improvement effect of ALA in mouse cerebral cortex primary cultured neurons
　本実施例では、ＣＧＧリピートを神経細胞に導入することで低下した神経活動が、ＡＬＡによって改善するかどうかを神経形態学的に評価した。
　＜実施例１＞で使用した各神経細胞について、培養２１日後に、４％パラホルムアルデヒドで固定し、神経細胞マーカーとしての抗ＭＡＰ２抗体（ａｂ５３９２、アブカム社、１／１，０００希釈）、および抗ＧＦＰ抗体（ａｂ２９０、アブカム社、１／１，０００希釈）を用いて細胞染色を行った。固定した細胞をＴｒｉｔｏｎ　Ｘ－１００（０．１％）を含むＰＢＳで１０分間洗浄し、上記抗体（１次抗体）存在下、４℃でインキュベートした。その後、ＰＢＳで洗浄し、蛍光標識された２次抗体（ＤｙＬｉｇｈｔ　４０５‐ＡｆｆｉｎｉＰｕｒｅ　Ｄｏｎｋｅｙ　Ａｎｔｉ－Ｃｈｉｃｋｅｎ　ＩｇＹ（Ｊａｃｋｓｏｎ　ＩｍｍｕｎｏＲｅｓｅａｒｃｈ社、１／５００希釈）およびＡｌｅｘａ　Ｆｌｕｏｒ　４８８‐ｃｏｎｊｕｇａｔｅｄ　ｄｏｎｋｅｙ　ａｎｔｉ－ｒａｂｂｉｔ　ＩｇＧ（インビトロジェン社、１／５００希釈））で染色した。染色後、ＰＢＳで洗浄し、共焦点顕微鏡（ＬＳＭ７００、カールツァイス社）で撮影した。 In this example, it was neuromorphologically evaluated whether the neural activity reduced by introducing CGG repeats into neurons was improved by ALA.
Each nerve cell used in <Example 1> is fixed with 4% paraformaldehyde after 21 days of culture, and an anti-MAP2 antibody (ab5392, Abcam, 1 / 1,000 dilution) as a nerve cell marker, and an anti Cell staining was performed using a GFP antibody (ab290, Abcam, 1 / 1,000 dilution). The fixed cells were washed with PBS containing Triton X-100 (0.1%) for 10 minutes, and incubated at 4 ° C. in the presence of the above antibody (primary antibody). After washing with PBS, fluorescently labeled secondary antibody (DyLight 405-AffiniPure Donkey Anti-Chicken IgY (Jackson ImmunoResearch, 1/500 dilution) and Alexa Fluor 488-conjugated donkey anti-rabbit IgG (Invitrogen, 1) / 500 dilution)). After staining, the cells were washed with PBS and photographed with a confocal microscope (LSM700, Carl Zeiss).
　＜結果＞
　図２から分かるとおり、ＣＧＧ８８回反復伸長発現神経細胞において低下した神経細胞突起分岐数（図２内「ＣＧＧ　ｒｅｐｅａｔ」）が、ＡＬＡ＋ＳＦＣ処置により改善した（図２内「ＣＧＧ　ｒｅｐｅａｔ　＋　ＡＬＡ」）。
＜実施例３＞脆弱Ｘ随伴振戦／失調症候群（ＦＸＴＡＳ）モデルマウスに対するＡＬＡの行動改善効果の評価 <Result>
As can be seen from FIG. 2, the number of neurite bifurcations (“CGG repeat” in FIG. 2) reduced in CGG 88-times repeat-elongated neurons was improved by ALA + SFC treatment (“CGG repeat + ALA” in FIG. 2).
<Example 3> Evaluation of behavioral improvement effect of ALA on fragile X-associated tremor / ataxia (FXTAS) model mouse
　ＦＸＴＡＳの症状に対するＡＬＡの効果を評価するために、確立されたＦＸＴＡＳモデルマウスを本試験に用いた。なお、本モデルマウスは、マウスＣ５７ＢＬ６／Ｊ系統のＦｍｒ１遺伝子にＣＧＧの９８回リピート変異が導入されたマウスであり、５か月齢から、ＦＸＴＡＳの神経障害症状を呈していることによって特徴付けられる。 To evaluate the effect of ALA on FXTAS symptoms, established FXTAS model mice were used in this study. The present model mouse is a mouse in which a CGG repeat mutation of 98 times has been introduced into the Fmrl gene of mouse C57BL6 / J strain, and is characterized by exhibiting neuropathic symptoms of FXTAS from the age of 5 months.
　なお、本試験では、コントロール群として、同腹仔のｗｉｌｄ－ｔｙｐｅマウスを使用した。 In this test, littermate wild-type mice were used as a control group.
＜試験薬および投与＞
　ｗｉｌｄ－ｔｙｐｅマウスおよび上記のモデルマウスに対し、薬剤投与群（ＡＬＡ塩酸塩とＳＦＣ併用投与）、Ｖｅｈｉｃｌｅ群（ＳＦＣのみを投与）をそれぞれ設定し、試験群として計４群を用いた。また、ＡＬＡ塩酸塩の投与量は、１回投与あたり３ｍｇ／ｋｇとして用いた。
　薬剤投与群においては、ＡＬＡとＳＦＣとがモル比で２０：１の割合で含む水溶液を調製し、試験に用いた。具体的には、ＡＬＡ塩酸塩３ｍｇ／ｋｇに対して、ＳＦＣ０．４７ｍｇ／ｋｇを使用した。 <Test drug and administration>
A drug administration group (administered with ALA hydrochloride and SFC in combination) and a Vehicle group (administered with SFC alone) were respectively set for wild-type mice and the above-mentioned model mice, and a total of 4 groups were used as test groups. In addition, the dose of ALA hydrochloride was used as 3 mg / kg per dose.
In the drug administration group, an aqueous solution containing ALA and SFC in a molar ratio of 20: 1 was prepared and used for the test. Specifically, SFC 0.47 mg / kg was used for ALA hydrochloride 3 mg / kg.
　こうして調製した試験薬は、ゾンデを使用し経口投与した。投与期間は、５か月齢から１ヶ月間にわたり、１日あたり１回投与した。その後、後述する行動試験を実施した。なお、投与は行動試験中も継続した。 The test drug thus prepared was orally administered using a sonde. The administration period was once a day for 5 months of age to 1 month. Then, the behavioral test mentioned later was implemented. Administration continued during the behavioral test.
Ｂｅａｍ　Ｗａｌｋｉｎｇ試験による運動機能確認
　各群のマウスを細長い板の上（長さ８０ｃｍ、幅５ｍｍ）で歩かせ、この細長い板上で足を滑らせる（スリップ）回数を数えた。 Motor Function Confirmation by Beam Walking Test Each group of mice was walked on an elongated plate (length 80 cm, width 5 mm), and the number of times of slipping on the elongated plate was counted.
　図３からわかるとおり、薬剤投与（ＣＧＧ＋ＡＬＡ）群は、Ｖｅｈｉｃｌｅ（ＣＧＧ　ＫＩ）群に比べ、足を滑らせる回数が少なく、ＡＬＡにより運動機能が改善されていることが確認された。 As can be seen from FIG. 3, in the drug administration (CGG + ALA) group, the number of times of sliding on the foot was smaller than that in the Vehicle (CGG KI) group, and it was confirmed that the motor function was improved by ALA.
新規物体認識試験
　新規物体認識試験とは、記憶により旧知物体に対する探索行動が新規物体に対するものより低下するというマウスの習性を利用した学習・記憶能力試験である。 New Object Recognition Test The new object recognition test is a learning / memory ability test using the habit of a mouse that the search behavior for old knowledge objects is lower than that for new objects by memory.
　すなわち、マウスはケージ内に新規物体があれば物体に対する探索行動を行う。物体を認識することにより新規性が低下すれば物体に対する探索行動も低下する。２個の物体をケージ内に置き探索行動をさせた後、１個の物体を新規のものに替えて探索行動をさせると、記憶により旧知物体に対する探索行動が新規物体に対するものより低下していることが観察される。 That is, if there is a new object in the cage, the mouse searches for the object. If the novelty is reduced by recognizing the object, the search behavior for the object also decreases. If two objects are placed in the cage and the search action is performed, then if one object is changed to a new one and the search action is performed, the search behavior for the old knowledge object is lower than that for the new object by memory It is observed.
　具体的には、物体のないケージに馴化させた後、２個の同じ物体をケージ内で離して置き、マウスをケージに入れて１０分間、物体への探索行動をさせる。それぞれの物体への探索行動（臭いを嗅ぐ、前肢で触れるなど）の時間を測定し、飼育ケージへ戻す。２４時間後に一つの物体を形状の異なる新規物体にして同様にマウスの探索行動の時間を測定する。両物体への探索時間の合計に対する新規物体に対する探索時間の割合を学習・記憶の指標とする。学習・記憶が障害されていれば、０に近くなり、物体に対する記憶があれば、より大きな値となる。 Specifically, after being acclimatized in an object-free cage, two identical objects are placed apart in the cage, and the mouse is put in the cage to make the object explore for 10 minutes. Measure the time of the exploratory behavior (smelling smell, touching with forelimb etc.) to each object, and return to the rearing cage. After 24 hours, one object is made into a new object with a different shape, and the time of exploratory behavior of the mouse is similarly measured. The ratio of the search time to the new object to the total of the search time to both objects is used as a learning / memory index. If learning and memory are impaired, it will be close to 0, and if there is memory for the object, it will be a larger value.
　図４からわかるとおり、ＣＧＧ　ＫＩ群では探索行動時間の割合がＷＴ群のそれに比べて小さい値を示した。これに対して、ＣＧＧ＋ＡＬＡ群では探索行動時間の割合がＣＧＧ　ＫＩ群に比して大きい値を示すことが確認された。すなわち、ＡＬＡによる学習・記憶機能の改善が確認された。 As can be seen from FIG. 4, in the CGG KI group, the proportion of the search action time showed a smaller value than that in the WT group. On the other hand, it was confirmed that in the CGG + ALA group, the ratio of the search action time shows a large value as compared with the CGG KI group. That is, improvement of the learning and memory function by ALA was confirmed.
Ｙ字迷路試験
　マウスの自発的交替行動を試験する当業者に周知の試験である。具体的に、探索行動で自発的にＹ字迷路の異なるアームに入るマウスの性質を利用した試験方法であり、マウスをＹ字迷路中で自由に行動させ、既に入ったアームについての記憶を評価することで、マウスの注意力、空間記憶を評価するものである。 It is a test well known to those skilled in the art for testing spontaneous alternation behavior of Y-shaped maze test mice. Specifically, it is a test method that takes advantage of the nature of mice that spontaneously enter different arms of a Y-maze in exploratory behavior, allowing the mice to freely move in the Y-maze and evaluating the memory about the arms that have already entered. By doing this, we evaluate the attention and spatial memory of the mouse.
　具体的には、３本のａｒｍをすべて同じ大きさにしてａｒｍ間の角度を１２０度としたＹ迷路がマウスの自発的交替行動の試験に用いられる。自発的交替行動はマウスが探索行動で自発的に異なるａｒｍに入る性質を利用した試験方法で、既に入ったａｒｍを記憶していることにより可能となる行動である。
　測定では、８分間マウスが３本のａｒｍに入る順序を記録する。すべてのａｒｍに侵入した回数と続けて３回異なるａｒｍに入った回数（最少回数３回ですべてのａｒｍに侵入した回数：交替行動数）を数え、交替行動数をａｒｍの総侵入回数引く２で割った値を交替行動率として評価する。 Specifically, a Y-maze in which all three arms have the same size and the angle between the arms is 120 degrees is used to test the spontaneous alternation behavior of mice. Spontaneous alternation is a test method that takes advantage of the ability of mice to spontaneously enter different arms in an exploratory behavior, and is an action that is made possible by storing arm that has already entered.
For measurement, record the order in which the mice enter the three arms for 8 minutes. Count the number of times of entry into all arms and the number of consecutive entry into 3 different arms (the number of times of entry into all arms with a minimum of 3 times: number of alternations) The value divided by is evaluated as the replacement activity rate.
　図５及び図６からわかるとおり、ＣＧＧ＋ＡＬＡ群の交替行動数は、他の群と差がなく、加えてＣＧＧ＋ＡＬＡ群の正解率がＣＧＧ　ＫＩ群よりも回復し、さらにはＷＴ群の水準まで回復していることが確認された。すなわち、ＡＬＡによる学習・記憶機能の改善が確認された。 As can be seen from FIGS. 5 and 6, the number of alternations in the CGG + ALA group is not different from that in the other groups, and in addition, the accuracy rate of the CGG + ALA group recovers compared to the CGG KI group, and further to the level of the WT group. Was confirmed. That is, improvement of the learning and memory function by ALA was confirmed.
　本発明によれば、染色体上のＴＲの存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物が提供される。本発明の医薬組成物は、ＴＲ病の中核症状に対して効果的に使用することができると考えられるため、ＴＲ病を根本的に治療する手段として期待される。 According to the present invention, there is provided a pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder resulting from the presence of TR on a chromosome. Since the pharmaceutical composition of the present invention can be effectively used for the core symptoms of TR disease, it is expected as a means to fundamentally treat TR disease.

Claims (12)

  1. 　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物であって、
    　下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
    で示される化合物またはその塩もしくはエステルを含有する、
    ことを特徴とする
    医薬組成物。     A pharmaceutical composition for use in the prevention or treatment of a subject having a neurological disorder caused by the presence of a triple nucleotide repeat sequence (triplet repeat) on a chromosome,
    The following formula (I):
    Figure JPOXMLDOC01-appb-C000001
     (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
    And a salt or ester thereof,
    Pharmaceutical composition characterized by the above-mentioned.
  2. 　請求項１に記載の医薬組成物であって、
    　前記対象は、フリードライヒ失調症（ＦＲＤＡ）、球脊髄性筋委縮症、ハンチントン病（ＨＤ）、脊髄小脳変性症１型（ＳＣＡ１）、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）、脆弱Ｘ症候群（ＦＲＡＸＡ）、筋緊張性ジストロフィーからなる群から選択されるトリプレットリピート病を患う対象である、
    ことを特徴とする
    医薬組成物。     The pharmaceutical composition according to claim 1, wherein
    The subject includes Friedreich's ataxia (FRDA), bulbar and spinal muscular atrophy, Huntington's disease (HD), spinocerebellar degeneration type 1 (SCA1), fragile X-associated tremor / ataxia syndrome (FXTAS), fragile X Subject suffering from triplet repeat disease selected from the group consisting of syndrome (FRAXA) and myotonic dystrophy,
    Pharmaceutical composition characterized by the above-mentioned.
  3. 　請求項１または２に記載の医薬組成物であって、
    　前記対象は、脆弱Ｘ随伴振戦／運動失調症候群（ＦＸＴＡＳ）または脆弱Ｘ症候群（ＦＲＡＸＡ）を患う対象である、
    ことを特徴とする
    医薬組成物。     The pharmaceutical composition according to claim 1 or 2, wherein
    The subject is a subject suffering from fragile X-associated tremor / ataxia syndrome (FXTAS) or fragile X syndrome (FRAXA),
    Pharmaceutical composition characterized by the above-mentioned.
  4. 　請求項１～３のいずれか１項に記載の医薬組成物であって、
    　Ｒ１が、水素原子、炭素数１～８のアルカノイル基、および、炭素数７～１４のアロイル基からなる群から選択され、
    　Ｒ２が、水素原子、直鎖または分岐状の炭素数１～８のアルキル基、炭素数３～８のシクロアルキル基、炭素数６～１４のアリール基、および、炭素数７～１５のアラルキル基からなる群から選択される
    ことを特徴とする、
    医薬組成物。     A pharmaceutical composition according to any one of claims 1 to 3 comprising
    R 1 is selected from the group consisting of a hydrogen atom, an alkanoyl group having 1 to 8 carbon atoms, and an aroyl group having 7 to 14 carbon atoms,
    R 2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 14 carbon atoms, and an aralkyl having 7 to 15 carbon atoms Characterized in that it is selected from the group consisting of
    Pharmaceutical composition.
  5. 　請求項１～４のいずれか１項に記載の医薬組成物であって、
    　Ｒ１およびＲ２が、水素原子である、
    医薬組成物。     A pharmaceutical composition according to any one of claims 1-4,
    R 1 and R 2 are hydrogen atoms,
    Pharmaceutical composition.
  6. 　請求項１～５のいずれか１項に記載の医薬組成物であって、
    　一種または二種以上の金属含有化合物をさらに含有する、
    医薬組成物。     The pharmaceutical composition according to any one of claims 1 to 5, wherein
    It further contains one or more metal-containing compounds,
    Pharmaceutical composition.
  7. 　請求項６に記載の医薬組成物であって、
    　金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデンまたはコバルトを含有する化合物である、
    医薬組成物。     The pharmaceutical composition according to claim 6, wherein
    The metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt,
    Pharmaceutical composition.
  8. 　請求項７に記載の医薬組成物であって、
    　金属含有化合物が、鉄、マグネシウムまたは亜鉛を含有する化合物である、
    医薬組成物。     The pharmaceutical composition according to claim 7, which is
    The metal-containing compound is a compound containing iron, magnesium or zinc,
    Pharmaceutical composition.
  9. 　請求項８に記載の医薬組成物であって、
    　金属含有化合物が、鉄を含有する化合物である、
    医薬組成物。     The pharmaceutical composition according to claim 8, which is
    The metal-containing compound is a compound containing iron,
    Pharmaceutical composition.
  10. 　請求項９に記載の医薬組成物であって、
    　前記鉄を含有する化合物が、クエン酸第一鉄ナトリウムである、
    医薬組成物。     The pharmaceutical composition according to claim 9, which is
    The compound containing iron is sodium ferrous citrate,
    Pharmaceutical composition.
  11. 　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象を予防または治療するための医薬の製造における下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
    で示される化合物またはその塩もしくはエステルの使用。     The following formula (I) in the manufacture of a medicament for preventing or treating a subject having a neurological disorder caused by the presence of a triple nucleotide repeat sequence (triplet repeat) on a chromosome:
    Figure JPOXMLDOC01-appb-C000002
     (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
    Use of a compound represented by or a salt or ester thereof.
  12. 　染色体上の３塩基繰り返し配列（トリプレットリピート）の存在に起因する神経障害を有する対象を予防または治療する方法であって、
    　それを必要とする対象に、治療上有効量の下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ１は、水素原子またはアシル基を表し、Ｒ２は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基またはアラルキル基を表す）
    で示される化合物またはその塩もしくはエステルを投与することを含む、
    ことを特徴とする、
    方法。

          A method for preventing or treating a subject having a neurological disorder caused by the presence of a triple nucleotide repeat sequence (triplet repeat) on a chromosome,
    In a subject in need thereof, a therapeutically effective amount of Formula (I):
    Figure JPOXMLDOC01-appb-C000003
     (Wherein, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group)
    Administering a compound of the formula: or a salt or ester thereof,
    It is characterized by
    Method.

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