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WO2017098731A1 - Dérivé d'acide 4-phényl-4-oxobutanoïque - Google Patents

Dérivé d'acide 4-phényl-4-oxobutanoïque Download PDF

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Publication number
WO2017098731A1
WO2017098731A1 PCT/JP2016/005097 JP2016005097W WO2017098731A1 WO 2017098731 A1 WO2017098731 A1 WO 2017098731A1 JP 2016005097 W JP2016005097 W JP 2016005097W WO 2017098731 A1 WO2017098731 A1 WO 2017098731A1
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WO
WIPO (PCT)
Prior art keywords
indol
oxobutanoic acid
acid
disease
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2016/005097
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English (en)
Japanese (ja)
Inventor
阿部　高明
恭次 石田
克志 北原
真由美 片岡
孝幸 深谷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tohoku Techno Arch Co Ltd
Sumitomo Pharma Co Ltd
Original Assignee
Tohoku Techno Arch Co Ltd
Sumitomo Dainippon Pharma Co Ltd
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Filing date
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Publication of WO2017098731A1 publication Critical patent/WO2017098731A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a 4-phenyl-4-oxobutanoic acid derivative useful as a medicine, or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a pharmaceutical composition containing a 4-phenyl-4-oxobutanoic acid derivative or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic and / or prophylactic agent containing a novel 4-phenyl-4-oxobutanoic acid derivative containing the compound or a pharmaceutically acceptable salt thereof.
  • Mitochondria is a major energy supply organ in cells, and is present in many tissues (for example, brain, skeletal muscle, heart muscle, kidney, etc.) that are actively active and have high energy requirements in human body tissues.
  • ⁇ Decreased mitochondrial function associated with genetic background and aging causes various diseases.
  • a typical example is known as a disease generally called mitochondrial disease.
  • An effective treatment for a patient suffering from mitochondrial disease has not yet been found, only symptomatic treatment is given to some symptoms, and treatment satisfaction is not high. Accordingly, there is a need for new drugs that improve mitochondrial dysfunction and thereby exert efficacy.
  • mitochondrial dysfunction inhibits the activities of energy-requiring tissues, and thus may cause various diseases other than mitochondrial diseases (for example, neurodegenerative diseases, muscle diseases, heart diseases, kidney diseases, etc.).
  • diseases for example, amyotrophic lateral sclerosis (ALS) is a disease with a poor prognosis in which the cause of its onset is still unknown and causes significant muscle atrophy as a symptom, resulting in movement disorders, difficulty swallowing, and respiratory failure.
  • riluzole is known as an ALS therapeutic agent, but it only shows the effect of delaying the progression of symptoms for several months.
  • diseases such as Parkinson's disease, Alzheimer's disease, muscular dystrophy, sarcopenia, and disuse muscle atrophy.
  • Patent Document 1 discloses an indole acetic acid derivative useful as a therapeutic agent for mitochondrial diseases and the like.
  • An object of the present invention is to provide a novel compound useful as a therapeutic and / or prophylactic agent for diseases associated with abnormal mitochondrial function.
  • the present inventors have found that a compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention” as necessary) have an effect of improving mitochondrial function.
  • the compound of the present invention is a cell that is prominent against cell death induced by oxidative stress load in patient cells with diseases involving mitochondrial dysfunction It has been found that it exhibits a death-inhibiting action, and the present invention has been completed.
  • X a , X b , X c and X d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C 1-4 alkyl group, or a C 1-4 alkoxy group;
  • A is (A) The following formula (II):
  • Y a , Y b , Y c , Y d and Y e , 1 to 3 are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, C 1
  • [4] 1-3 of Y a , Y b , Y c , Y d and Y e are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, or C
  • Y a , Y b , Y c , Y d and Y e are each independently a C 1-4 alkyl group; the rest are each independently a hydrogen atom, fluorine
  • [6] 1-3 of Y a , Y b , Y c , Y d and Y e are each independently a C 1-4 alkyl group; the rest are each independently a hydrogen atom or The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], which is a fluorine atom.
  • At least one of X a , X b , X c and X d is a fluorine atom, a chlorine atom, a C 1-4 alkyl group or a C 1-4 alkoxy group, [1] to [9] Or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent and / or prevention of a disease caused by mitochondrial dysfunction comprising as an active ingredient the compound according to any one of [1] to [12] or a pharmaceutically acceptable salt thereof. Agent.
  • X a , X b , X c and X d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C 1-4 alkyl group, or a C 1-4 alkoxy group;
  • A is (A) The following formula (II):
  • the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease, [14] or [15] Therapeutic and / or prophylactic agent.
  • Mitochondrial diseases include Leigh's encephalopathy, stroke-like seizure syndrome (MELAS), chronic progressive extraocular muscle palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), The therapeutic and / or prophylactic agent according to [16], which is Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acidosis.
  • MELAS stroke-like seizure syndrome
  • CPEO chronic progressive extraocular muscle palsy syndrome
  • KSS Kearns-Sayer syndrome
  • MERRF myoclonic epilepsy syndrome with red rag fibers
  • Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich ataxia, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration,
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease Alzheimer's disease
  • Huntington's disease Friedreich ataxia
  • multiple system atrophy progressive supranuclear palsy
  • spinocerebellar degeneration The therapeutic and / or prophylactic agent according to [16], which is spinal muscular atrophy, bulbar spinal muscular atrophy, or Charcot-Marie-Tooth disease.
  • Renal diseases are renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, gout kidney, renal edema, kidney
  • the therapeutic and / or prophylactic agent according to [16] which is a tumor, renal ischemic injury, renal ischemia reperfusion injury, or cystic kidney.
  • Myopathy is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (sarcopenia), or disuse muscle atrophy [16] The therapeutic and / or prophylactic agent according to [16].
  • a method of treating a disease caused by mitochondrial dysfunction by administering the compound of the present invention to a patient in need of treatment of a disease caused by mitochondrial dysfunction, Production of the compound of the present invention for use as a therapeutic agent for diseases caused by dysfunction, the compound of the present invention for use in the treatment of diseases caused by mitochondrial dysfunction, and therapeutic agents for diseases caused by mitochondrial dysfunction.
  • the compound of the present invention exhibits a remarkable cell death inhibitory effect on cell death induced by oxidative stress in patient cells with diseases associated with mitochondrial dysfunction, and therefore a therapeutic agent for diseases or symptoms associated with mitochondrial dysfunction and / or Alternatively, a prophylactic agent can be provided. More specifically, it is useful as a therapeutic agent and / or preventive agent for mitochondrial diseases, or neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.
  • the number of carbons in the definition of “substituent” may be expressed as “C 1-4 ”, for example.
  • C 1-4 alkyl is synonymous with a linear or branched alkyl group having 1 to 4 carbon atoms.
  • group means a monovalent group.
  • alkyl group means a monovalent saturated hydrocarbon group.
  • group may be omitted.
  • C 1-4 alkyl group or “C 4-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 or 4 to 6 carbon atoms.
  • Specific examples of the “C 1-4 alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
  • a methyl group, an ethyl group, a propyl group, and an isopropyl group are mentioned.
  • C 4-6 alkyl group in addition to the above, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group and the like can be mentioned.
  • C 1-4 alkoxy group is synonymous with “C 1-4 alkyl group", the “C 1-4 alkyl group” moiety is the same as defined in the "C 1-4 alkyl group”.
  • Specific examples of “C 1-4 alkoxy group” include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group. It is done.
  • a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group is used.
  • C 4-6 alkyl group part of the “C 4-6 alkyl group substituted with 1 to 5 fluorine atoms” has the same meaning as the above “C 4-6 alkyl group”.
  • Specific examples of “C 4-6 alkyl group substituted with 1 to 5 fluorine atoms” include, for example, 4,4,4-trifluorobutyl group, 3,3,4,4,4-penta Fluorobutyl group, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group, 5,5,6,6,6 -Pentafluorohexyl group and the like.
  • 5,5,5-trifluoropentyl group 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group or 5,5,6,6,6- A pentafluorohexyl group may be mentioned.
  • the compound of the formula (I) may have one or more asymmetric carbon atoms, and may cause geometric isomerism and axial chirality, and therefore may exist as a plurality of stereoisomers.
  • these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
  • the present invention also includes the fact that one or more atoms in the compound of formula (I) are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature.
  • Isotope-labeled compounds, and pharmaceutically acceptable salts thereof are also included in the present invention.
  • isotopes contained in the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine isotopes such as 2 H, 3 H, 11 C, 13 C, 14 C, It includes isotopes such as 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 75 Br, 76 Br, 77 Br, 82 Br, and 36 Cl.
  • compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof.
  • a heavy isotope such as 2 H
  • a heavy isotope such as 2 H
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydroiodide, nitrate and phosphate; citrate, oxalate and acetic acid Salt, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, hydrogen tartrate, lactate, malate, pyruvate Salt, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate [1,1'-methylene-bis- (2-hydroxy-3-naphthoate) ] Organic acid salt, such as].
  • base addition salt examples include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. Can be mentioned. Furthermore, basic amino acid salts or acidic amino acid salts such as arginine salt, aspartate and glutamate can also be mentioned. Preferred base addition salts include sodium, potassium, calcium and magnesium salts.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a pharmaceutically acceptable solvate. Also included in the compounds of the present invention are solvates such as hydrates or ethanolates. Furthermore, the compounds of the present invention include all forms of crystal forms.
  • the compound of the present invention represented by the formula (I) is produced by the following method using a commercially available compound, a known compound, or a commercially available compound or a compound that can be produced by combining known synthesis methods from known compounds as raw materials. be able to.
  • the compound represented by the formula (A1) can be produced, for example, by the following production method.
  • X a , X b , X c , X d , Y a , Y b , Y c , Y d and Y e are as defined in the above [1], and P 1 is alkyl or the like (Protecting group for carboxylic acid.)
  • the benzenes (a1) and acetophenones (a3) can be purchased as, for example, commercial products, and the indoles (a4) can be produced by the method described in Org. Synth. 1985, 63, 214, etc. It can be purchased as a product.
  • Step A-1 This step is a step of obtaining compound (a2) by reacting maleic anhydride with compound (a1) in the presence of various acids, in the absence of a solvent, or in a suitable solvent.
  • the acid used in this step include Lewis acids such as metal halides, Bronsted acids such as phosphoric acid, polyphosphoric acid, and trifluoromethanesulfonic acid, preferably aluminum chloride and iron (III) chloride, Titanium chloride (IV) is mentioned.
  • the solvent used in this step include aromatic hydrocarbons such as nitrobenzene, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, or a mixed solvent thereof. And methylene chloride is preferable.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the reaction temperature is generally ⁇ 78 ° C. to 150 ° C., preferably ⁇ 20 ° C. to 100 ° C
  • Step A-2 This step is a step of obtaining compound (a2) by reacting glyoxylic acid with compound (a3) in the presence of various acids, in the absence of a solvent, or in a suitable solvent.
  • the acid used in this step include Bronsted acids such as acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, and preferably include acetic acid and hydrochloric acid.
  • the solvent include ethers such as 1,4-dioxane, water, or a mixed solvent thereof.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • Step A-3 In this step, the compound (a2) obtained in the above step A-1 or A-2 is reacted with the indole compound (a4) in a suitable solvent in the presence or absence of various acids.
  • the acid used in this step include Bronsted acid such as acetic acid, Lewis acid such as aluminum chloride, iron chloride (III) and titanium chloride (IV), preferably acetic acid and chloride. Iron (III) is mentioned.
  • Solvents used in this step are, for example, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, halogenated compounds such as methylene chloride, chloroform and 1,2-dichloroethane. Examples thereof include hydrocarbons or a mixed solvent thereof, preferably benzene or toluene.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.
  • Step A-4 This step is a step of protecting the compound (a2) obtained in the above step A-1 or A-2 with P 1 .
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the compound (a5) can be produced as an ester by reacting the compound (a2) with an alcohol in the presence of an acid, in the absence of a solvent or in a suitable solvent.
  • the solvent used in this step is selected depending on the type of raw material compound and the like, and examples thereof include aromatic hydrocarbons such as toluene and benzene.
  • the acid used in this step include Bronsted acid such as hydrochloric acid, sulfuric acid, hydrofluoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron fluoride etherate, etc. Of Lewis acids.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.
  • the compound (a5) can be produced as an ester by reacting the compound (a2) with an alkyl halide in the presence of various bases in an appropriate solvent or in the absence of a solvent.
  • the solvent used in this step is selected depending on the type of raw material compound, etc., for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, aromatics such as toluene and benzene. Examples thereof include hydrocarbons, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, and mixed solvents of these solvents.
  • Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the compound (a5) can be produced as an ester by reacting the compound (a2) with a diazo compound such as diazomethane or trimethylsilyldiazomethane in the presence of various inorganic salts in an appropriate solvent or without a solvent.
  • the solvent used in this step is selected depending on the kind of the raw material compound, etc., for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or a mixed solvent thereof. Is mentioned.
  • the reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 5 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to 40 ° C.
  • Step A-5 This step is a step of converting the compound (a5) obtained in the above step A-4 into the compound (a6) under the conditions according to the above step A-3.
  • Step A-6 This step is a step for preparing the compound obtained in the above A-5 a protecting group P 1 of (a6) is deprotected to a carboxylic acid (A1). This step is performed by reacting compound (a6) in an appropriate solvent under acidic or basic conditions.
  • the solvent used in this step is selected depending on the type of raw material compound and the like, and for example, alcohols such as methanol, ethanol and isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • Examples thereof include ethers, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, water, and a mixed solvent thereof.
  • Examples of the acid used in this step include Bronsted acids such as hydrochloric acid and sulfuric acid.
  • Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the compound represented by the formula (A2) can be produced, for example, by the following production method.
  • P 1 is a protecting group for carboxylic acid
  • P 2 is an amino group.
  • LG is a protecting group
  • LG is a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, an alkylsulfonyloxy group such as methanesulfonyloxy group, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy group, Benzenesulfonyloxy group, arylsulfonyloxy group such as p-toluenesulfonyloxy group, etc.)
  • Indole acetic acid (a7) can be produced, for example, by the method described in US Patent Application Publication No. 5684034 and the like, or can be purchased as a commercial product, and compound (a9) is, for example, Journal of the Chemical Society-Perkin Transactions 1, 1996, 2303-2308, Journal of Organic Chemistry, 1984, 438-442, etc. .
  • Step A-7 This step is a step of introducing a protecting group P 2 into the compound (a7).
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • compound (a8) can be produced by reacting compound (a7) with di-tert-butyldicarbonate in a suitable solvent in the presence of a base.
  • compound (a8) can be produced by reacting compound (a7) with benzyloxycarbonyl chloride in a suitable solvent in the presence of a base.
  • compound (a8) can be produced by reacting compound (a7) with p-toluenesulfonyl chloride in a suitable solvent in the presence of a base.
  • Examples of the solvent used in this step include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, N-methyl-2- Amides such as pyrrolidone, water or a mixed solvent thereof can be mentioned, and tetrahydrofuran, methylene chloride and N, N-dimethylformamide are preferred.
  • Examples of the base used in this step include alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and 4-dimethylamino.
  • Organic bases such as pyridine and 1,8-diazabicyclo [5.4.0] -undec-7-ene are exemplified, and triethylamine, diisopropylethylamine and 4-dimethylaminopyridine are preferred.
  • the reaction time is usually 5 minutes to about 48 hours, preferably 10 minutes to 10 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 40 ° C.
  • Step A-8 In this step, compound (a10) is reacted with compound (a9) with compound (a8) obtained in step A-7 in the presence of an additive or in the presence of an additive in a suitable solvent.
  • the solvent used in this step include ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone
  • mixed solvents thereof Preferably, tetrahydrofuran and N, N-dimethylformamide are used.
  • Examples of the base used in this step include organometallic bases such as butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide and lithium diisopropylamide, and more preferably. Examples include lithium hexamethyldisilazide.
  • Examples of the additive used when necessary in this step include hexamethyl phosphate triamide and N, N-dimethylpropylene urea, and more preferably hexamethyl phosphate triamide.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably ⁇ 78 ° C. to 20 ° C.
  • Step A-9 This step is the A-8 The compound obtained in step a protective group P 2 of (a10), by deprotection, to produce compound (a11).
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the compound (a10) is subjected to Bronsted acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, or aluminum chloride, zinc bromide, trifluoride in a suitable solvent.
  • Bronsted acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, or aluminum chloride, zinc bromide, trifluoride in a suitable solvent.
  • Compound (a11) can be produced by using a Lewis acid such as boron.
  • Solvents used in this step are, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, aromatic hydrocarbons such as toluene and benzene, methylene chloride, chloroform.
  • Halogenated hydrocarbons such as 1,2-dichloroethane, mixed solvents thereof and the like.
  • water can be used alone or mixed with the described solvent.
  • the reaction time is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 40 ° C.
  • the compound (a10) can be used in an appropriate solvent, for example, in the presence of a metal catalyst such as palladium / carbon, palladium hydroxide, nickel, and ammonium formate if necessary. Can be added and reacted in a hydrogen gas atmosphere to produce the compound (a11).
  • a metal catalyst such as palladium / carbon, palladium hydroxide, nickel, and ammonium formate if necessary. Can be added and reacted in a hydrogen gas atmosphere to produce the compound (a11).
  • Solvents used in this step are, for example, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as toluene and benzene, hexane, heptane Aliphatic hydrocarbons such as, esters such as ethyl acetate and propyl acetate, organic acids such as acetic acid, and mixed solvents thereof.
  • alcohols such as methanol, ethanol and isopropanol
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • aromatic hydrocarbons such as toluene and benzene
  • hexane hexane
  • heptane Aliphatic hydrocarbons such as, esters such as ethyl acetate and propyl acetate, organic acids such as acetic acid, and mixed solvents thereof.
  • Step A-10 This step is a step of producing compound (A2) from compound (a11) obtained in the above step A-9 by the same method as in the above step A-6.
  • the compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. For example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned.
  • column chromatography for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography
  • recrystallization may be mentioned.
  • recrystallization solvent examples include alcohol solvents such as methanol, ethanol and isopropanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • a ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aprotic solvent such as N, N-dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used.
  • alcohol solvents such as methanol, ethanol and isopropanol
  • ether solvents such as diethyl ether
  • ester solvents such as ethyl acetate
  • aromatic hydrocarbon solvents such as benzene and toluene
  • acetone and the like aromatic hydrocarbon solvents
  • the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, a spectroscopic method such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, and the like. Can be done by mass spectrometry.
  • a spectroscopic method such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, and the like. Can be done by mass spectrometry.
  • the intermediate or final product in the above production method is appropriately converted in its functional group, in particular, extending various side chains based on amino groups, hydroxyl groups, carbonyl groups, halogen groups, etc., and In this case, if necessary, the above-mentioned protection and deprotection can be performed to lead to another compound included in the present invention.
  • the transformation of the functional group and the extension of the side chain can be performed by a commonly used general method (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • Has optical isomers The compounds of the present invention include mixtures of these isomers and isolated ones.
  • Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage.
  • an optical isomer can be obtained by performing a separation step such as a method using an optically active column or a fractional crystallization method at an appropriate stage of the production process.
  • optical resolution method for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is used in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, isopropanol, diethyl An ether solvent such as ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, water or a mixed solvent of two or more selected from the above solvents), optically active Acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) And a diastereomeric method in which a salt is formed.
  • an inert solvent
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine
  • the optical resolution can also be carried out by forming a salt using an organic amine).
  • the temperature at which the salt is formed is selected from the range from ⁇ 50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point, and more preferably from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is often desirable to raise the temperature to near the boiling point of the solvent once. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • a salt in an inert solvent for example, an alcohol solvent such as methanol, ethanol, isopropanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, a non-aqueous solvent such as acetonitrile, etc. It can also be recrystallized with a proton solvent or a mixed solvent of two or more selected from the above-mentioned solvents to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain the optically active compound of the present invention represented by formula (I) as a free form.
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol, isopropanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene
  • the compound of the present invention has an action for improving mitochondrial function, it can provide a therapeutic and / or preventive agent for diseases or symptoms associated with abnormal mitochondrial function. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, or heart diseases.
  • prevention is an act of administering the active ingredient of the present invention to a person who has not developed a disease, for example, for the purpose of preventing or delaying the onset of the disease. It is. “Treatment” is an act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor.
  • Mitochondrial disease is a disease in which mitochondrial function decreases such as ATP production, regulation of apoptosis, regulation of intracellular concentrations of calcium ions and iron, etc. due to mutation or deletion of nuclear DNA or mitochondrial DNA.
  • Leigh's encephalopathy is a serious congenital disease that begins in early childhood and is characterized by symmetric degeneration of the basal ganglia and brainstem, with intellectual disability, muscle movement disorder, and respiratory disorder as the main symptoms.
  • mitochondrial diseases that can be treated or prevented by the compounds of the present invention include, for example, mitochondrial encephalomyopathy, lactic acidosis, stroke-like seizure syndrome (MELAS), chronic progressive extraocular muscular palsy syndrome (CPEO), Kearns Sayre Syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, lactic acidosis and the like.
  • MELAS stroke-like seizure syndrome
  • CPEO chronic progressive extraocular muscular palsy syndrome
  • KSS Kearns Sayre Syndrome
  • MERRF myoclonic epilepsy syndrome with red rag fibers
  • Pearson's disease Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, lactic acidosis and the like.
  • neurodegenerative diseases that can be treated or prevented by the compounds of the present invention include amyotropic axillary lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, multiple system atrophy, progressive nuclear supra Include paralysis, spinocerebellar degeneration, spinal muscular atrophy, bulbar spinal muscular atrophy, Charcot-Marie-Tooth disease.
  • ALS amyotropic axillary lateral sclerosis
  • Parkinson's disease Alzheimer's disease
  • Huntington's disease Huntington's disease
  • Friedreich's ataxia multiple system atrophy
  • progressive nuclear supra Include paralysis, spinocerebellar degeneration, spinal muscular atrophy, bulbar spinal muscular atrophy, Charcot-Marie-Tooth disease.
  • immune neurological diseases examples include Guillain-Barre syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, myasthenia gravis, and the like.
  • cerebral ischemic diseases examples include cerebral infarction and the like.
  • renal diseases that can be treated or prevented by the compound of the present invention include renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, Examples include gout kidney, renal edema, renal tumor, renal ischemic injury, renal ischemia reperfusion injury, cystic kidney and the like.
  • Examples of the muscular disease that can be treated or prevented by the compound of the present invention include progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (Sarcopenia), Examples include disuse muscle atrophy.
  • Examples of heart diseases that can be treated or prevented with the compound of the present invention include myocardial infarction, heart failure, ischemic heart disease, cardiomyopathy and the like.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, the administration method, the symptom / age of the patient and the like.
  • oral administration usually about 0.01 mg to 5000 mg, more preferably about 0.1 mg to 3000 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • the compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using a suitable dosage form.
  • suitable dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and haptics.
  • the preparation is produced by a known method using a pharmaceutically acceptable additive.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • lactose lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin
  • examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • Examples of other drugs that can be used in combination with the compound of the present invention include mitochondrial function improving agents, neurodegenerative disease therapeutic agents, muscle disease therapeutic agents, heart disease therapeutic agents, renal disease therapeutic agents, and the like.
  • mitochondrial function improving agent examples include Bendavia and idebenone.
  • therapeutic agents for neurodegenerative diseases include ALS therapeutic agents (riluzole, edaravone, etc.), Parkinson's disease therapeutic agents (levodopa, carbidopa, zonisamide, droxidopa, pramipexole, ropinirole, etc.), Alzheimer's disease therapeutic agents (donepezil, memantine, rivastigmine, Galantamine, etc.).
  • muscular disease therapeutic agent examples include anti-activin antibodies (bimaglumab etc.), steroidal anti-inflammatory drugs (prednisolone, triamcinolone etc.) and the like.
  • therapeutic agents for heart diseases and renal diseases include angiotensin II receptor antagonists (candesartan, valsartan, etc.), ACE inhibitors (captopril, enalapril, etc.), diuretics (furosemide, tolvaptan, etc.) and the like.
  • the plurality of drugs may be administered separately or may be administered together as a single pharmaceutical composition.
  • one active ingredient of the combination of the present invention may be administered prior to, simultaneously with, or after other active ingredients.
  • These active ingredients may be prepared in a pharmaceutical formulation in a single dosage form or in a separate dosage form.
  • s is a single line
  • d is a double line
  • dd is a double double line
  • t is a triple line
  • q is a quadruple line
  • m is a multiple line
  • br is wide
  • brs is Wide single line
  • J mean coupling constant
  • the proton nuclear magnetic resonance spectrum was measured using an FT-NMR measuring apparatus (270 MHz, 300 MHz or 400 MHz) manufactured by JEOL.
  • the chemical shift value was described in ⁇ value (ppm).
  • Reference Examples 2 to 6 The compounds of Reference Examples 2 to 6 were obtained in the same manner as in Reference Example 1 using the corresponding starting compounds.
  • Reference Examples 8 to 10 The compounds of Reference Examples 8 to 10 were obtained in the same manner as in Reference Example 7 using the corresponding starting compounds.
  • Example 2 to 29 The compounds of Examples 2 to 29 were obtained in the same manner as in Example 1, using the corresponding starting compounds.
  • Examples 31 to 35 The compounds of Examples 31 to 35 were obtained in the same manner as in Example 30 using the corresponding starting compounds.
  • Example 37 to 40 The compounds of Examples 37 to 40 were obtained in the same manner as in Example 36 using the corresponding starting compounds.
  • Example 41 Production of 4- (4-tert-butylphenyl) -2- (5,6-difluoro-1H-indol-3-yl) -4-oxobutanoic acid Same as Example 1 using the corresponding starting compound The following compounds were obtained by this method.
  • Test example The pharmacological test results of the representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.
  • a glutathione synthesis inhibitor BSO (manufactured by Sigma-Aldrich) was added at 100 ⁇ mol / L. It mixed in the culture solution so that it might become.
  • BSO glutathione synthesis inhibitor
  • the Example compounds were mixed in the culture solution to 3 or 10 ⁇ mol / L. After culturing for 3 days in the presence of the compound, the number of viable cells was measured using Cell Count Reagent SF (Nacalai Tesque), and the cell viability was calculated.
  • a control for the oxidative stress load a well to which both BSO and the compound were not added was used, and as a control for the effect of the compound, a BSO added well was used.
  • Table 6 shows the inhibitory effect of each compound on cell death due to oxidative stress in KSS patient-derived fibroblasts.
  • the compound concentration of each compound showing the inhibitory effect on cell death due to oxidative stress in KSS patient-derived fibroblasts is 3 ⁇ mol / L, it is expressed as ++, and when it is 10 ⁇ mol / L, it is expressed as +.
  • This result shows that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as KSS, suggesting that the compounds of the present invention can treat mitochondrial diseases such as KSS.
  • Table 7 shows the inhibitory effect of each compound on cell death due to oxidative stress in LHON patient-derived fibroblasts.
  • the compound concentration at which each compound has an inhibitory effect on cell death due to oxidative stress in LHON patient-derived fibroblasts is 3 ⁇ mol / L, it is expressed as ++, and when it is 10 ⁇ mol / L, it is expressed as +.
  • This result indicates that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as LHON, suggesting that the compounds of the present invention can treat mitochondrial diseases such as LHON.
  • Example 3 Inhibitory effect on cell death due to oxidative stress in ALS patient-derived fibroblasts.
  • ALS patient-derived fibroblasts treated with BSO were cultured in the presence of Example 1 and the cell viability was measured.
  • a 96-well cell culture plate was seeded with 6.4 ⁇ 10 3 ALS patient-derived fibroblasts per well using DMEM medium containing 1% FBS.
  • the glutathione synthesis inhibitor BSO was mixed in the culture solution to 100 ⁇ mol / L.
  • the compound of Example 1 was mixed in the culture solution so as to be 1, 3, 10 or 30 ⁇ mol / L.
  • the number of viable cells in each well was measured using Cell Counting Kit-8 (Dojindo Laboratories) and the cell viability was calculated.
  • a well to which both BSO and the compound were not added was used as a control for oxidative stress load, and a BSO-added well was used as a control for the effect of the compound.
  • Example 1 The compound of Example 1 was statistically detected at 3, 10, and 30 ⁇ mol / L in Dunnett's multiple comparison test for cell death induced by 100 ⁇ mol / L BSO in the group added with BSO and DMSO. It showed a significant inhibitory effect. From these results, it was suggested that the compound of the present invention may be able to improve the pathology of ALS patients by suppressing the damage to cells caused by oxidative stress.
  • the EC50 value of the cell death inhibitory effect of the compound of the present invention can be calculated using statistical analysis software Stat Preclinica (Takumi Information Technology). Specifically, the EC50 value is obtained by analyzing the data using a technique such as “Dx calculation (logistic curve fitting): response rate input” included in the dose-response data analysis.
  • the compound of Example 41 showed an inhibitory effect at 10 ⁇ mol / L against cell death induced by 10 ⁇ mol / L BSO. This result indicates that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as Leigh encephalopathy, suggesting that the compounds of the present invention can treat mitochondrial diseases such as Leigh encephalopathy.
  • a therapeutic agent for a disease or condition associated with abnormal mitochondrial function and / or A prophylactic agent can be provided. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.

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Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable correspondant, qui est utilisé en tant qu'agent thérapeutique et/ou agent prophylactique pour des maladies associées à des anomalies des fonctions mitochondriales, par exemple les maladies mitochondriales, les maladies neurodégénératives, les maladies neurologiques immunitaires, les maladies ischémiques cérébrales, les maladies rénales, les maladies musculaires ou les maladies cardiaques. [Dans la formule (I), Xa, Xb, Xc et Xd représentent chacun indépendamment, par exemple, un atome d'hydrogène, un atome de chlore, un atome de fluor, un groupe méthyle, un groupe éthyle ou un groupe méthoxy ; et A est, par exemple, un groupe de formule (II) (dans les formules, Ya, Yb, Yc, Yd et Ye représentent chacun, par exemple, un atome d'hydrogène, un atome de chlore, un atome de fluor, un groupe méthyle, ou un groupe t-butyle)].
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080640A1 (fr) * 2012-11-26 2014-05-30 国立大学法人東北大学 Promoteur d'expression de l'érythropoïétine
JP2015189670A (ja) * 2014-03-27 2015-11-02 国立大学法人東北大学 臓器線維化抑制剤

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* Cited by examiner, † Cited by third party
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WO2014080640A1 (fr) * 2012-11-26 2014-05-30 国立大学法人東北大学 Promoteur d'expression de l'érythropoïétine
JP2015189670A (ja) * 2014-03-27 2015-11-02 国立大学法人東北大学 臓器線維化抑制剤

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HAYASHI, KEN-ICHIRO ET AL.: "Rational Design of an Auxin Antagonist of the SCFTIR1 Auxin Receptor Complex", ACS CHEMICAL BIOLOGY, vol. 7, no. 3, 2012, pages 590 - 598, XP055287676, DOI: doi:10.1021/cb200404c *
SAYED, G. H. ET AL.: "Nucleophilic addition of indoles to beta-aroylacrylic acids and some reactions with the adducts", INDIAN JOURNAL OF CHEMISTRY , SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 20 B, no. 5, 1981, pages 424 - 426 *
SAYED, G. H. ET AL.: "Synthesis and reactions of some beta -aroyl- a - (indol-3-yl) propionic acids", JOURNAL OF THE CHEMICAL SOCIETY OF PAKISTAN, vol. 7, no. 4, 1985, pages 263 - 272 *
SUZUKI, TAKEHIRO ET AL.: "Mitochonic acid 5 (MA-5), a derivative of the plant hormone indole-3-acetic acid, improves survival of fibroblasts from patients with mitochondrial diseases", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 236, no. 3, 2015, pages 225 - 232, XP055379205, DOI: doi:10.1620/tjem.236.225 *

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