JP6845565B2 - Indoleacetic acid amide derivative - Google Patents

Description

The present invention relates to pharmaceutically useful indoleacetic acid amide derivatives, or pharmaceutically acceptable salts thereof. More specifically, it relates to a pharmaceutical composition containing an indoleacetic acid amide derivative or a pharmaceutically acceptable salt thereof. It relates to a therapeutic agent and / or a prophylactic agent containing a novel indoleacetic acid amide derivative containing the compound or a pharmaceutically acceptable salt thereof.

Mitochondria are the main energy supply organs in cells, and are abundant in human body tissues in tissues that are actively active and require high energy (for example, brain, skeletal muscle, myocardium, kidney, etc.).

Deterioration of mitochondrial function due to genetic background and aging causes various diseases. A typical example is known as a disease generally called mitochondrial disease. No effective treatment has yet been found for patients suffering from mitochondrial disease, and only symptomatic treatment is given for some symptoms, and treatment satisfaction is not high. Therefore, there is a long-awaited new drug that improves mitochondrial dysfunction and thereby exerts its effectiveness.

In addition, mitochondrial dysfunction inhibits the activity of tissues with high energy demand, and thus may cause various diseases other than mitochondrial diseases (for example, neurodegenerative diseases, muscle diseases, heart diseases, renal diseases, etc.). There are many known diseases for which there is no adequate cure.
For example, amyotrophic lateral sclerosis (ALS) is a disease with a poor prognosis that causes remarkable muscle atrophy of the whole body as a symptom, and causes movement disorder, dysphagia, and respiratory failure. As an ALS therapeutic agent, for example, riluzole and the like are known, but they only show an effect of delaying the progression of symptoms for several months. In addition, there is currently no effective treatment for diseases such as Parkinson's disease, Alzheimer's disease, muscular dystrophy, sarcopenia, and disused muscular atrophy.

Patent Document 1 discloses an indoleacetic acid derivative or the like useful as a therapeutic agent for mitochondrial diseases or the like, but does not specifically disclose the indoleacetic acid amide derivative of the present invention.

International Publication No. 2014/080640

An object of the present invention is to provide a novel compound useful as a therapeutic agent and / or a preventive agent for a disease associated with an abnormality in mitochondrial function.

The present inventors have a compound represented by the following formula (I) and a pharmaceutically acceptable salt thereof (hereinafter, may be abbreviated as "the compound of the present invention" as necessary) have an effect of improving mitochondrial function. As a result of diligent research to solve the above problems, focusing on the potential of the compound, the compound of the present invention is a cell that is prominent against cell death induced by oxidative stress loading in patient cells of diseases associated with mitochondrial dysfunction. They have found that they exhibit a death-suppressing effect, and have completed the present invention.

［式中、
Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄは、それぞれ独立して、水素原子、フッ素原子、塩素原子、シアノ基、Ｃ_１−３アルキル基、トリフルオロメチル基、メトキシ基、またはピリジル基を表すか、または；
Ｘ^ｂおよびＸ^ｃは、それらが結合する炭素原子と一緒になって１〜２個の酸素原子を含有する５員もしくは６員の飽和ヘテロ環を形成してもよく；
Ｚは、水素原子、メチル基、エチル基、シクロヘキシル基、またはフェニル基（該基は、フッ素またはメトキシで置換されていてもよい）を表し；
Ａは、
（１）３〜５個のフッ素原子で置換されているＣ_４−６アルキル基、
（２）ジフルオロシクロヘキシル−エチル基、
（３）下記式（II）：

（式中、
−ＣＨ_２−Ｗは、−ＣＨ_２−ＣＨ_２−、−ＣＨ_２−Ｃ（Ｏ）−、−ＣＨ_２−ＣＨ_２Ｏ−、または下記式（III）：

（式中、Ｌは、単結合または酸素原子を表す）で表される基を表し；
Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅは、それぞれ独立して、水素原子、フッ素原子、塩素原子、Ｃ_１−４アルキル基、メトキシ基、シクロヘキシル基、メチルチオ基、フェノキシ基、またはジメチルアミノ基を表すか、または；
Ｙ^ｂおよびＹ^ｃは、それらが結合する炭素原子と一緒になって１〜２個の酸素原子を含有する５員もしくは６員の飽和ヘテロ環を形成してもよい）で表される基、または
（４）下記式（IV）：

（式中、Ｑは、ピリジル基（該基は１〜３個のフッ素で置換されていてもよいメチルで置換されていてもよい）、チエニル基（該基はＣ_１−４アルキルまたはメトキシで置換されていてもよい）、またはピラゾリル基（該基は１〜３個のメチルで置換されていてもよい）を表す）で表される基を表す]で表される化合物またはその製薬学的に許容される塩。 That is, the present invention is as follows.
[1] The following formula (I):

[During the ceremony,
X ^a , X ^b , X ^c and X ^d independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a C _1-3 alkyl group, a trifluoromethyl group, a methoxy group, or a pyridyl group. Suka or;
X ^b and X ^c may be combined with the carbon atoms to which they are attached to form a 5- or 6-membered saturated heterocycle containing 1-2 oxygen atoms;
Z represents a hydrogen atom, a methyl group, an ethyl group, a cyclohexyl group, or a phenyl group (the group may be substituted with fluorine or methoxy);
A is
_{(1) C 4-6} alkyl group substituted with 3 to 5 fluorine atoms,
(2) Difluorocyclohexyl-ethyl group,
(3) The following formula (II):

(During the ceremony,
-CH ₂ -W _{is, -CH 2 -CH 2 -, -} CH 2 -C (O) -, - CH 2 -CH 2 O-, or formula (III):

(In the formula, L represents a single bond or an oxygen atom);
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are independently hydrogen atom, fluorine atom, chlorine atom, C _1-4 alkyl group, methoxy group, cyclohexyl group, methylthio group, phenoxy group, or Represents a dimethylamino group or;
Y ^b and Y ^c may form a 5- or 6-membered saturated heterocycle containing 1 to 2 oxygen atoms together with the carbon atoms to which they are attached). Or (4) The following formula (IV):

(In the formula, Q is a pyridyl group (the group may be substituted with 1-3 fluorine or methyl), a thienyl group (the group may be C _1-4 alkyl or methoxy). Represents a group represented by (which may be substituted) or a pyrazolyl group (which represents a group which may be substituted with 1 to 3 methyls)] or a compound thereof and pharmaceuticals thereof. Tolerant salt.

[2] A is a group represented by the formula (II);
-CH ₂ -W _is, -CH 2 -C (O) - is a compound or a pharmaceutically acceptable salt thereof according to [1].

[3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein Z is a hydrogen atom.

[4] A drug containing the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient.

[5] A therapeutic agent and / or prevention of a disease caused by mitochondrial dysfunction, which contains the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.

[6] The therapeutic agent and the therapeutic agent according to [5], wherein the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease. / Or a preventive agent.

[7] Mitochondrial diseases include Lee encephalopathy, stroke-like attack syndrome (MELAS), chronic progressive external ocular muscle palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myokronus epilepsy syndrome with red rag fibers (MERRF), The therapeutic and / or prophylactic agent according to [6], which is Pearson's disease, Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acid acidosis.

[8] Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's atrophy, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, The therapeutic and / or prophylactic agent according to [6], which is spinal muscular atrophy, spinal and bulbar muscular atrophy, or Charcot-Marie-Tooth disease.

[9] The therapeutic agent and / according to [6], wherein the immune neurological disease is Guillain-Barré syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis. Or a preventive agent.

[10] The therapeutic agent and / or preventive agent according to [6], wherein the cerebral ischemic disease is cerebral infarction.

[11] Renal diseases include renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubule necrosis, nephrosis syndrome, diabetic nephropathy, gout kidney, renal edema, and kidney. The therapeutic and / or prophylactic agent according to [6], which is a tumor, renal ischemic disorder, renal ischemic reperfusion disorder, or cystic kidney.

[12] The muscle disease is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscular atrophy (sarcopenia), or disused muscle atrophy. , [6] The therapeutic agent and / or the preventive agent.

[13] The therapeutic agent and / or preventive agent according to [6], wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.

Further, as another embodiment of the present invention, the compound of the present invention is administered to a patient in need of treatment or prevention of a disease caused by mitochondrial dysfunction to treat a disease caused by mitochondrial dysfunction and /. Alternatively, a method for preventing the disease, a compound of the present invention for use as a therapeutic agent for a disease caused by mitochondrial dysfunction, a compound of the present invention for use in the treatment and / or prevention of a disease caused by mitochondrial dysfunction, or mitochondria. The use of the compounds of the present invention for producing therapeutic and / or prophylactic agents for diseases caused by dysfunction can be mentioned.

Since the compound of the present invention exhibits a remarkable inhibitory effect on cell death induced by oxidative stress in cells of patients with diseases associated with mitochondrial dysfunction, it is a therapeutic agent for diseases or symptoms associated with mitochondrial dysfunction and / Alternatively, a prophylactic agent can be provided. More specifically, it is useful as a therapeutic agent and / or a preventive agent for mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, and heart disease.

Hereinafter, the present invention will be described in more detail.
In the present specification, the number of substituents in the groups defined as "may be substituted" or "substituted" is not particularly limited as long as it can be substituted, and may be one or more.

In the present specification, the number of carbons in the definition of "substituent" may be expressed as _{, for example, "C 1-4".} Specifically, the _{notation "C 1-4} alkyl" is synonymous with a linear or branched alkyl group having 1 to 4 carbon atoms.

As used herein, the term "group" means a monovalent group. For example, "alkyl group" means a monovalent saturated hydrocarbon group. In addition, the term "group" may be omitted in the description of the substituent in the present specification.

"C _1-4 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. Specific examples of the "C _1-4 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

_{The "C 4-6} alkyl group" of the "C _4-6 alkyl group substituted with 3 to 5 fluorine atoms" is a linear or branched saturated hydrocarbon having 4 to 6 carbon atoms. It means a hydrogen group. Specific examples of the "C _4-6 alkyl group" include, for example, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, Examples thereof include 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. _{Specific examples of the "C 4-6} alkyl group substituted with 3 to 5 fluorine atoms" include, for example, a 4,4,4-trifluorobutyl group and a 3,3,4,5,4-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 can be mentioned. Preferably, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group or 5,5,6,6- Examples include pentafluorohexyl groups.

In the group represented by the formula (I) of the above [1], "X ^b and X ^c are 5 or 6 members containing 1 or 2 oxygen atoms together with the carbon atom to which they are bonded. As a specific example in the case of "may form a saturated heterocycle of", for example, a group represented by the following formula can be mentioned.

In the group represented by the formula (I) of the above [1], "Y ^b and Y ^c are 5 or 6 members containing 1 or 2 oxygen atoms together with the carbon atom to which they are bonded. As a specific example in the case of "may form a saturated heterocycle of", for example, a group represented by the following formula can be mentioned.

The compound of formula (I) may exist as multiple stereoisomers because it may have one or more asymmetric carbon atoms and may give rise to geometric isomerism or axial chirality. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compounds represented by the formula (I) of the present invention.

The present invention also presents the fact that one or more atoms in a compound that are identical to the compound of formula (I) are replaced by atoms that have an atomic mass or mass number that is different from the atomic mass or mass number normally found in nature. (Except for) isotope-labeled compounds, and pharmaceutically acceptable salts thereof are also included in the present invention. Examples of isotopes contained in the compounds of the present invention, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine, such as ^{2 H, 3 H, 11 C} , 13 C, 14 C, 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.} The present invention also includes compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof.

Further, substitution with deuterium, i.e. heavier isotopes such as ^{2 H} may be expected to afford certain therapeutic advantages resulting from increased metabolic stability. It may be suitable in some situations, for example as it results in an extended half-life or reduced dose requirement in vivo.

Pharmaceutically acceptable salts include acid-added salts and base-added salts.
Examples of acid addition salts 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-naphthate) ] And other organic acid salts.
Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. Can be mentioned.
Further, basic amino acid salts such as arginine salt, aspartate, glutamic acid and the like, or acidic amino acid salts can also be mentioned.
Preferred base addition salts include sodium salts, potassium salts, calcium salts and magnesium salts.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be present in the form of hydrates and / or pharmaceutically acceptable solvates thereof, and thus, for example, these. A solvate such as a hydrate or a solvate of ethanol is also included in the compound of the present invention. Furthermore, the compounds of the present invention also include those in crystalline form in all aspects.

[Manufacturing method]
Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto.

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 compound that can be produced by combining a commercially available compound or a known synthesis method from a known compound as a raw material. be able to.

[Manufacturing method 1]
Among the compounds represented by the formula (I), the compound represented by the formula (A1) can be produced, for example, by the following production method.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄ、Ｙ^ｅおよびＺは、前記〔１〕に定義されるとおりであり、Ｐ^１はアルキル等のカルボン酸の保護基である。）

^{(Wherein, X a, X b, X} c, X d, Y a, Y b, Y c, Y d, Y e and Z are as defined above [1], ^{P 1} is an alkyl It is a protecting group for carboxylic acids such as.)

Benzenes (a1) and acetophenones (a2) can be purchased as commercial products, for example, and indoles (a4) can be produced by the methods described in Org. Synth. 1985, 63, 214, etc., or are commercially available. Can be purchased as an item.

[Step A-1]
This step is a step of obtaining the compound (a3) by reacting the compound (a1) with maleic anhydride in the presence of various acids, in the absence of a solvent or in a suitable solvent. Examples of the acid used in this step include Lewis acid such as metal halide, and blended acid such as phosphoric acid, polyphosphoric acid, and trifluoromethanesulfonic acid, preferably aluminum chloride and iron (III) chloride. Titanium chloride (IV) can be mentioned. The solvent used in this step is, for example, aromatic hydrocarbons such as nitrobenzene, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, or a mixed solvent thereof. These include, preferably methylene chloride. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is usually −78 ° C. to 150 ° C., preferably −20 ° C. to 100 ° C.

[Step A-2]
This step is a step of obtaining the compound (a3) by reacting the compound (a2) with glyoxylic acid in the presence of various acids, in the absence of a solvent, or in a suitable solvent. Examples of the acid used in this step include Bronsted acids such as acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, and preferably acetic acid and hydrochloric acid. Examples of 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 (a3) obtained in the above steps A-1 or A-2 is reacted with the indole compound (a4) in a suitable solvent in the presence or absence of various acids. This is a step of obtaining (a5). When required in this step, examples of the acid used include blended acids such as acetic acid and Lewis acids such as aluminum chloride, iron (III) chloride and titanium (IV) chloride, preferably acetic acid and chloride. Iron (III) can be mentioned. Solvents used in this step are, for example, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, halogenated such as methylene chloride, chloroform and 1,2-dichloroethane. Hydrocarbons, or a mixed solvent thereof, are mentioned, and benzene or toluene is preferable. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour 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 A-1 or the compound obtained in step A-2 of the (a3) at P ^1. This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

For example, the compound (a6) can be produced as an ester by reacting the compound (a3) 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 the raw material compound and the like, and examples thereof include aromatic hydrocarbons such as toluene and benzene. Examples of the acid used in this step include hydrochloric acid, sulfuric acid, hydrofluoric acid, trifluoroacetic acid, methanesulfonic acid, blended acid such as trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron fluoride etherate and the like. Lewis acid can be mentioned. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

For example, the compound (a6) can be produced as an ester by reacting the compound (a3) with an alkyl halide in the presence of various bases in a suitable solvent or in the absence of a solvent. The solvent used in this step is selected depending on the type of the raw material compound and the like, and for example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, and 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 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

For example, compound (a6) can be produced as an ester by reacting compound (a3) with a diazo compound such as diazomethane or trimethylsilyldiazomethane in the presence of various inorganic salts in a suitable solvent or in the absence of a solvent. .. The solvent used in this step is selected depending on the type of the raw material compound and the like, and is, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or a mixed solvent thereof. Can be 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.

[A-5 step]
This step is a step of converting the compound (a6) obtained in the above A-4 step into the compound (a7) under the conditions according to the above A-3 step.

[A-6 process]
This step is a step for preparing the compound obtained in the above A-5 a protecting group P ¹ of (a7) is deprotected to a carboxylic acid (a5). This step is carried out by allowing compound (a7) to act in a suitable solvent under acidic or basic conditions. The solvent used in this step is selected depending on the type of the 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 include ethers, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, water, or 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 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

[A-7 process]
This step is a step of activating the carboxy group of the compound (a5) obtained in the above steps A-3 or A-6 and then reacting with ammonia or a salt thereof to produce the compound (A1). Examples of the method for activating the carboxy group include a method for converting a carboxy group into an acid anhydride, a mixed acid anhydride, an acid halide, an active ester, and an acid azide, or a method using a condensing agent.

When the acid halide method is used, the compound (a5) is reacted with a halogenating reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride to prepare an acid halide, and then the presence of a base. The compound (A1) can be obtained by reacting with ammonia or a salt thereof below. Examples of the base used in this step include triethylamine, diisopropylethylamine, tributylamine, and 1,5-diazabicyclo [4.3.0. ] Nona-5-en (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] Undec-7-en (DBU), pyridine, Examples thereof include organic bases such as dimethylaminopyridine, picolin or N-methylmorpholine (NMM), and inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. .. Examples of the solvent used in this step include halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride, and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane. , Aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate and methyl acetate, water, or a mixture thereof. The reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 5 hours. The reaction temperature is carried out from −78 ° C. under heating and reflux, and is usually from −20 ° C. to 0 ° C.

When the mixed acid anhydride method is used, the compound (a5) is reacted with an acid halide in the presence of a base to form a mixed acid anhydride, and then reacted with ammonia or a salt thereof to lead to the compound (A1). be able to. Examples of the acid halide include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride or tert-butylcarbonyl chloride. Examples of the base used in this step include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN), and 1,4-diazabicyclo [2.2]. .2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picolin or N-methylmorpholin (NMM), Alternatively, inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate can be mentioned. Examples of the solvent used in this step include halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride, and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane. , Aromatic hydrocarbons such as benzene, toluene or xylene, esters such as ethyl acetate and methyl acetate, water or mixtures thereof. The reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 5 hours. The reaction temperature is carried out from −78 ° C. under heating and reflux, and is usually from −20 ° C. to 0 ° C.

Compound (A1) can also be produced by reacting compound (a5) with ammonia or a salt thereof with a condensing agent in the presence or absence of a base. Examples of the condensing agent used in this step include phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC / HCl), and the like. Carbodiimides such as dicyclohexylcarbodiimide (CDI), imidazoles such as 1,1'-carbonyldiimidazole (CDI), hexafluorophosphate O- (7-aza-1H-benzotriazole-1-yl) -N, N , N', N'-tetramethyluronium (HATU), hexafluorophosphate O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium (HBTU), etc. Examples include phosphoniums such as 1H-benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate. The solvent used in this step is, for example, the same solvent as when the acid halide method is used, or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3. -Dimethyl-2-imidazolidinone, an aprotic polar solvent such as dimethyl sulfoxide, water, or a mixed solvent thereof is used. The base used in this step is not particularly limited, but for example, triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN), 1,4- Diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picolin or N-methylmorpholin (NMM), etc. Organic bases can be mentioned. The reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 10 hours. The reaction temperature is −78 ° C. under heating and reflux, and is usually 0 ° C. to 100 ° C.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、ＡおよびＺは、前記〔１〕に定義されるとおりであり、Ｐ^１はカルボン酸の保護基であり、Ｐ^２はアミノ基の保護基であり、ＬＧは脱離基（例えば塩素、臭素、ヨウ素のようなハロゲン原子、メタンスルホニルオキシ基のようなアルキルスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基のようなトリハロゲノメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基のようなアリールスルホニルオキシ基など）である。） [Manufacturing method 2]
Among the compounds represented by the formula (I), the compound represented by the formula (A2) can be produced, for example, by the following production method.

(In the formula, X ^a , X ^b , X ^c , X ^d , A and Z are as defined in the above [1], P ¹ is a protecting group for a carboxylic acid, and P ² is an amino group. Protecting groups, LG is a leaving group (eg, halogen atoms such as chlorine, bromine, iodine, alkylsulfonyloxy groups such as methanesulfonyloxy groups, trihalogenomethanesulfonyloxy groups such as trifluoromethanesulfonyloxy groups, Benzenesulfonyloxy group, arylsulfonyloxy group such as p-toluenesulfonyloxy group, etc.).

The indoleacetic acid (a8) can be produced, for example, by the method described in US Patent Application Publication No. 5684034 and a method similar thereto, or can be purchased as a commercial product. It can be manufactured by the method described in Journal of the Chemical Society --Perkin Transactions 1, 1996, 2303 --2308, Journal of Organic Chemistry, 1984, 438 --442, etc. ..

[A-8 process]
This step is a step of introducing a protective group P ² relative to compound (a8). This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

When a tert-butoxycarbonyl group is introduced, compound (a9) can be produced by reacting compound (a8) with di-tert-butyl dicarbonate in a suitable solvent in the presence of a base.

When a benzyloxycarbonyl group is introduced, the compound (a9) can be produced by reacting the compound (a8) with benzyloxycarbonyl chloride in a suitable solvent in the presence of a base.

When a p-toluenesulfonyl group is introduced, the compound (a9) can be produced by reacting the p-toluenesulfonyl chloride in a suitable solvent in the presence of a base in the compound (a8).

Solvents used in this step are, for example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide and N-methyl-2-. Examples include amides such as pyrrolidone, water or a mixed solvent thereof, preferably tetrahydrofuran, methylene chloride, N, N-dimethylformamide. The bases used in this step are, for example, sodium carbonate, alkali carbonates such as potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and 4-dimethylamino. Included are organic bases such as pyridine (DMAP), 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU), preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP). ). 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.

[A-9 process]
In this step, the compound (a11) is reacted with the compound (a9) obtained in the above step A-7 in a suitable solvent in the presence or absence of an additive together with the base. ) Is the process of manufacturing. Examples of 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. However, tetrahydrofuran and N, N-dimethylformamide are preferable. Examples of the base used in this step include organic metal bases such as butyllithium, lithium diisopropylamide, and lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide and lithium diisopropylamide, which are more preferable. Examples include lithium hexamethyldisilazide. Examples of the additive used when necessary in this step include hexamethylphosphoric acid triamide and N, N-dimethylpropylene urea, and more preferably hexamethylphosphoric acid 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.

[A-10 process]
This step is the A-9 The compound obtained in step a protective group P ² of (a11), by deprotection, to produce compound (a12). This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

When the protecting group P ² is a tert-butoxycarbonyl group, the compound (a11) is mixed with a blended acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid in a suitable solvent, or aluminum chloride, zinc bromide or trifluoride. Compound (a12) 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. , 1,2-Dichloroethane and other halogenated hydrocarbons, mixed solvents thereof and the like. In the case of Bronsted acid, water can also be used alone or in admixture with the solvent described. The reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours. The reaction temperature is usually −20 ° C. to 100 ° C., preferably −20 ° C. to 40 ° C.

For protecting group P ² is benzyloxycarbonyl group of the compound (a11), in a suitable solvent, for example, palladium / carbon, palladium hydroxide, in the presence of a metal catalyst such as nickel, ammonium formate and the like, if necessary Can be added and reacted in a hydrogen gas atmosphere to produce compound (a12). 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 and heptane. Examples thereof include aliphatic hydrocarbons such as, ethyl acetate, esters such as propyl acetate, organic acids such as acetic acid, and mixed solvents thereof.

[Step A-11]
This step is a step of producing the compound (a13) from the compound (a12) obtained in the above step A-10 by the same method as in the above step A-6.

[Step A-12]
This step is a step of producing the compound (A2) from the compound (a13) obtained in the above step A-11 by the same method as in the above step A-7.

The compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by a method known to those skilled in the art. For example, extraction, partitioning, reprecipitation, column chromatography (eg, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization can be mentioned.

Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol or isopropanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, and acetone. A ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aproton solvent such as N, N-dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used. As another purification method, the method described in the Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen), 5th edition, Volume 1 and the like can be used. Further, in determining the molecular structure of the compound of the present invention, spectroscopic methods such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, and spectroscopic methods, with reference to the structure derived from each raw material compound, and It can be done by mass spectrometry.

Further, the intermediate or final product in the above production method is appropriately converted from its functional group, and in particular, various side chains are extended by using an amino group, a hydroxyl group, a carbonyl group, a halogen group, etc. as a foothold, and At that time, by performing the above-mentioned protection and deprotection as necessary, it is possible to lead to another compound contained in the present invention. Functional group transformation and side chain extension can be performed by conventional methods (see, eg, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may be asymmetric or may have a substituent having an asymmetric carbon, and such compounds have Has optical isomers. The compounds of the present invention also include mixtures and isolated compounds of each of these isomers. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing an asymmetry in an intermediate stage. Alternatively, for example, an optical isomer can be obtained by carrying out a separation step such as a method using an optically active column or a fractional crystallization method at an appropriate stage in the manufacturing process. As an optical division method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is contained in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or isopropanol, diethyl. Ether-based solvent such as ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aproton solvent such as acetonitrile, water or a mixed solvent of two or more kinds selected from the above solvents), optically active. Acids (eg, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartrate, dicarboxylic acids such as o-diisopropyridene tartrate, malic acid, sulfonic acids such as camphorsulfonic acid, bromocamparsulfonic acid) A diastereomer method is used to form a salt. When the compound of the present invention represented by the formula (I) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strikinine) It is also possible to perform optical resolution by forming a salt using (organic amines such as).

The temperature at which the salt is formed is selected from the range of −50 ° C. to the boiling point of the solvent, preferably the range of 0 ° C. to the boiling point, and more preferably the range of 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. When the precipitated salt is collected by filtration, it can be cooled if necessary to improve the yield. The amount of the optically active acid or amine used is appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent with respect to the substrate. If necessary, salt is added to 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, and a non-nitrile solvent such as acetonitrile. It can also be recrystallized in a proton-based solvent or a mixed solvent of two or more kinds selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, the optically resolution salt can be treated with an acid or a base by a usual method to obtain an optically active compound of the present invention represented by the formula (I) as a free form.

Of the raw materials and intermediates in each of the production methods described above, those for which the production method is not described are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or methods similar thereto. Can be synthesized by.

Since the compound of the present invention has an effect of improving mitochondrial function, it is possible to provide a therapeutic agent and / or a preventive agent for a disease or symptom associated with mitochondrial dysfunction. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease.

In the present invention, "prevention" is an act of administering the active ingredient of the present invention to a person who has not developed a disease, and aims to prevent / or delay the onset of the disease, for example. It is a thing. "Treatment" is an act of administering the active ingredient of the present invention to a person (patient) who has been diagnosed as having a disease by a doctor.

Mitochondrial disease is a disease in which mitochondrial functions such as ATP production, regulation of apoptosis, and regulation of intracellular concentrations of calcium ions and iron occur due to mutation or deletion of cell nucleus DNA or mitochondrial DNA.

Leigh's encephalopathy is one of the symptoms of mitochondrial disease that can be treated or prevented by the compound of the present invention. Leigh's encephalopathy is a serious congenital disorder that begins in infancy and is characterized by symmetric degenerative loss of the basal ganglia and brain stem, with intellectual disability, muscular movement disorders, and respiratory disorders as the main symptoms.

Other mitochondrial disease symptoms that can be treated or prevented by the compounds of the present invention include, for example, mitochondrial encephalomyopathy, lactic acidosis, stroke-like attack syndrome (MELAS), chronic progressive external ocular muscle palsy syndrome (CPEO), Kearns-Sayer. Syndrome (KSS), Myocronus epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, lactate acidosis and the like.

Neurodegenerative diseases that can be treated or prevented by the compounds of the present invention include, for example, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's atrophy, multiple system atrophy, and progressive supranuclear disease. Examples include sexual palsy, spinocerebellar degeneration, spinal muscular atrophy, spinal and bulbar muscular atrophy, and Charcot-Marie-Tooth disease.

Immunological neurological disorders that can be treated or prevented by the compounds of the present invention include, for example, Guillain-Barré syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, myasthenia gravis and the like.

Examples of cerebral ischemic diseases that can be treated or prevented by the compound of the present invention include cerebral infarction and the like.

Renal diseases that can be treated or prevented by the compound of the present invention include, for example, renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubule necrosis, nephrosis syndrome, diabetic nephropathy, etc. Gouty kidney, renal edema, renal tumor, renal ischemic disorder, renal ischemic reperfusion disorder, cystic kidney and the like can be mentioned.

Muscle diseases that can be treated or prevented by the compounds of the present invention include, for example, progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscular atrophy (sarcopenia), and the like. Examples include disused muscular atrophy.

Examples of heart diseases that can be treated or prevented by 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 oral administration, parenteral administration or rectal administration, and the daily dose thereof varies depending on the type of compound, administration method, patient's symptom / age and the like. For example, in the case of 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 a non-human mammal can be administered in one to several divided doses. In the case of parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of human or non-human mammal can be administered.

The compound of the present invention can be prepared and administered directly or by using an appropriate dosage form by oral administration or parenteral administration. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, haptics and the like. Formulations are prepared by known methods using pharmaceutically acceptable additives.

Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Perfume and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, stear. Examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

Examples of other agents 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.

Examples of the mitochondrial function improving agent include Bendavia and idebenone.

Examples of therapeutic agents for neurodegenerative diseases include ALS therapeutic agents (rilzole, edaravon, etc.), Parkinson's disease therapeutic agents (levodopa, carvidopa, zonisamide, droxydopa, pramipexole, ropinirole, etc.), and Alzheimer's disease therapeutic agents (donepezil, memantine, rivastigmin, galantamine, etc.). Etc.) etc.

Examples of the therapeutic agent for muscle diseases include anti-activin antibodies (bimaglumab and the like), steroidal anti-inflammatory agents (prednisolone, triamcinolone and the like) and the like.

Examples of therapeutic agents for heart disease and renal disease include angiotensin II receptor blockers (candesartan, valsartan, etc.), ACE inhibitors (captopril, enalapril, etc.), diuretics (furosemide, tolvaptan, etc.) and the like.

In the combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and other concomitant agents, these plurality of agents may be administered separately or together as one pharmaceutical composition. .. In addition, one active ingredient of the combination of the present invention may be administered first, simultaneously, or later with respect to the other active ingredient. These active ingredients may be prepared as a pharmaceutical preparation in a single preparation form or a separate preparation form.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to this. The compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description of the specification, the abbreviations shown below may be used in Reference Examples and Examples.
Me: Methyl Et: Ethyl
^t Bu: tert-butyl TFA: trifluoroacetate THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMSO-D ₆ : didimethyl sulfoxide Boc: tert-butoxycarbonyl (Boc) ₂ O: di-tert-butyl dicarbonate DMAP: 4-dimethyl Aminopyridine LHMDS: Lithium hexamethyldisilazide HMPA: Hexamethylphosphoric acid triamide

As symbols used in NMR, s means a single line, d means a double line, dd means a double double line, m means a multiple line, and J means a coupling constant.

The proton nuclear magnetic resonance spectrum was measured using an FT-NMR measuring device (270 MHz, 300 MHz or 400 MHz) manufactured by JEOL Ltd. The chemical shift value is described as a δ value (ppm).

High performance liquid chromatograph mass spectrometer; The measurement conditions of LCMS are as follows, and the observed mass spectrometric value [MS (m / z)] is ^{indicated by [M + H] +} , and the retention time is indicated by Rt (min). .. In each measured value, the measurement conditions used for the measurement are added with A, B, C and D.

[Measurement condition A]
Detection device: Shimadzu LCMS-2020
Volume: Phenomenex Kinetex (1.7 μm C18, 50 mm x 2.10 mm)
Solvent: Solution A: 0.05% TFA / H ₂ O, Solution B: CH ₃ CN
Gradient Condition:
0.0-1.7 minutes; A / B = 90: 10: 10: 99 (liner gradient)
1.7-1.9 minutes; A / B = 1:99
1.9-3.0 minutes; A / B = 90:10
Flow rate: 0.5 mL / min UV: 220 nm
Column temperature: 40 ° C

[Measurement condition B]
Measuring equipment: Water2695
Column: Yamato Scientific Prima Sil C18HC (5 μm, 4.6 x 75 mm)
Solvent: Solution A: 0.1% formic acid / H ₂ O, Solution B: 0.1% formic acid / CH ₃ CN
Gradient Condition:
0.0-6.0 minutes; A / B = 90: 10-0: 100 (liner gradient) 6.0-8.0 minutes; A / B = 0: 100
Flow rate: 1.0 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

[Measurement condition C]
Measuring equipment: Waters ACQUITY Ultra Performance LC H-Class System
Column: Waters ACQUITYTM UPLC HSS T3
(1.8 μm, 2.1 x 50 mm)
Solvent: Solution A: 0.1% formic acid / H ₂ O, Solution B: 0.1% formic acid / CH ₃ CN
Gradient Condition:
0.0-2.4 minutes; A / B = 90: 10-0: 100 (liner gradient)
2.4-3.2 minutes; A / B = 0: 100
Flow rate: 1.0 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

[Measurement condition D]
Measuring equipment: Waters ACQUITYTM UltraPerformance LC
Column: Waters ACQUITYTM UPLC BEH C18
(1.7 μm, 2.1 x 30 mm)
Solvent: Solution A: 0.05% formic acid / H ₂ O, Solution B: CH ₃ CN
Gradient Condition:
0.0-1.3 minutes; A / B = 90: 10-5: 95 (liner gradient)
1.3-1.5 minutes; A / B = 90:10
Flow rate: 0.80 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

化合物１Ａ（１．２５ｇ）、化合物１Ｂ（２．００ｇ）、トルエン（２０ｍＬ）、酢酸（２．０ｍＬ）の混合物を９０℃にて６時間撹拌した。室温に冷却し、析出した固体をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール）で精製することにより表題化合物１Ｃ（１．３２ｇ）を得た。
ＬＣ−ＭＳ：測定法Ｃ、[M+H]^＋=324.2、Rt=1.78min [Reference example 1]
Production of 2- (2H-Indole-3-yl) -4- (4-Methoxyphenyl) -4-oxobutanoic acid (Compound 1C)

A mixture of compound 1A (1.25 g), compound 1B (2.00 g), toluene (20 mL) and acetic acid (2.0 mL) was stirred at 90 ° C. for 6 hours. The mixture was cooled to room temperature and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol) to give the title compound 1C (1.32 g).
LC-MS: Measurement method C, [M + H] ⁺ = 324.2, Rt = 1.78min

[Reference Examples 2-56]
Using the corresponding raw material compounds, the compounds of Reference Examples 2 to 56 were obtained in the same manner as in Reference Example 1.

[Reference Example 57]
Preparation of 2- (1H-indole-3-yl) -4-oxo-4- [5-trifluoromethyl) pyridin-2-yl] butanoic acid (Compound 2D)

Step 1:
A mixture of compound 2A (199 mg), compound 2B (465 mg), toluene (3.4 mL) and acetic acid (0.34 mL) was heated to reflux for 13 hours. After distilling off the solvent under reduced pressure, diisopropyl ether (5.0 mL) was added to the obtained residue, and the precipitated solid was collected by filtration, washed with diisopropyl ether and dried to obtain compound 2C (593 mg).
LC-MS: Measurement method B, [M + H] ⁺ = 391.3, Rt = 6.44min

Step 2:
Lithium hydroxide monohydrate (70.1 mg) was added to a mixed solution of compound 2C (593 mg), THF (15 mL) and water (7.5 mL), and the mixture was stirred at 60 ° C. for 1.5 hours. After cooling the reaction solution to room temperature, THF was removed by distillation under reduced pressure, 2 mol / L hydrochloric acid was added to adjust the pH of the solution to 4, and then the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol). Acetone (4.0 mL) was added to the obtained solid to dissolve it, water (3.0 mL) was added, and the precipitated solid was collected by filtration, washed with acetone and dried to obtain the title compound 2D (245 mg).
LC-MS: Measurement method B, [M + H] ⁺ = 363.2, Rt = 5.52min

[Reference Examples 58-60]
Using the corresponding raw material compounds, the compounds of Reference Examples 58 to 60 were obtained in the same manner as in Reference Example 57.

[Reference Example 61]
Production of 6,6,7,7,7-Pentafluoro-2- (5-Methoxy-1H-Indole-3-yl) Heptanoic Acid (Compound 3E)

Step 1:
To a tert-butyl alcohol solution (65 mL) of compound 3A (4.00 g), (Boc) ₂ O (12.8 g) and DMAP (238 mg) were added, and the mixture was stirred at room temperature for 1 hour and then DMAP (2). .38 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. .. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate) to give the title compound 3B (4.60 g).
LC-MS: Measurement method D, [M + H] ⁺ = 362.1, Rt = 1.29min

Step 2:
LHMDS / THF solution (1.0 mol / L, 6.23 mL) was added to a THF solution (30 mL) of compound 3B (1.50 g) and HMPA (1.45 mL) at −78 ° C., and the mixture was stirred for 30 minutes. At −78 ° C., a THF solution (15 mL) of compound 3C (1.20 g) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate) to obtain the title compound 3D (1.57 g).
LC-MS: Measurement method D, [M + H] ⁺ = 522.5, Rt = 1.45min

Step 3:
A mixture of compound 3D (1.10 g) and hydrogen chloride-ethyl acetate solution (4 mol / L, 80 mL) was stirred at room temperature for 3 hours, and the reaction solution was concentrated under reduced pressure. A 4 mol / L sodium hydroxide aqueous solution (50 mL) was added to a solution of the obtained residue (1.10 g) in methanol (20 mL), and the mixture was stirred at room temperature for 8 hours. Under ice-cooling, 4 mol / L hydrochloric acid was added to the reaction mixture, the mixture was separated and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue (929 mg). Obtained. The obtained residue was dissolved in methanol (30 mL) and stirred at 50 ° C. for 1.5 hours and then at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and dried to give the title compound 3E (618 mg).
LC-MS: Measurement method D, [M + H] ⁺ = 366.1, Rt = 0.88min

[Reference Examples 62 to 71]
Using the corresponding raw material compounds, the compounds of Reference Examples 62 to 71 were obtained in the same manner as in Reference Example 61.

[Reference example 72]
Production of 4- (4-tert-butylphenyl) -2- (1H-indole-3-yl) butanoic acid (Compound 4D)

Step 1:
LHMDS / THF solution (1.0 mol / L, 2.10 mL) was added to a THF solution (10 mL) of compound 4A (500 mg) and HMPA (0.600 mL) at −78 ° C., and the mixture was stirred for 5 minutes. At −78 ° C., a THF solution (2.0 mL) of compound 4B (598 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate) to obtain compound 4C (420 mg).
^{1 1} H-NMR (300MHz, CDCl ₃ ) δ: 8.14 (1H, d, J = 8.1 Hz), 7.57-7.53 (2H, m), 7.34-7.20 (4H, m), 7.11 (2H, d, J = 8.1 Hz), 3.84 (1H, t, J = 7.4 Hz), 3.67 (3H, s), 2.64 (2H, t, J = 7.7 Hz), 2.55-2.43 (1H, m), 2.29-2.17 (1H, s) m), 1.67 (9H, s), 1.31 (9H, s)

Step 2:
A mixture of compound 4C (450 mg) and hydrogen chloride-ethyl acetate solution (4 mol / L, 10 mL) was stirred at room temperature for 3 hours, and the reaction solution was concentrated under reduced pressure. Lithium hydroxide monohydrate (126 mg) was added to the obtained mixed solution of THF (5.0 mL) and water (5.0 mL), and the mixture was stirred at room temperature for 7 hours. Under ice-cooling, 2 mol / L hydrochloric acid was added to the reaction mixture, the mixture was separated and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried. 4D (180 mg) was obtained.
LC-MS: Measurement method A, [M + H] ⁺ = 336.2, Rt = 2.14min

[Reference Examples 73 to 75]
Using the corresponding raw material compounds, the compounds of Reference Examples 73 to 75 were obtained in the same manner as in Reference Example 72.

[Reference example 76]
Production of 2- (1H-Indole-3-yl) -3- (3-Phenyloxetane-3-yl) propanoic acid (Compound 5D)

Step 1:
A LHMDS / THF solution (1.3 mol / L, 0.957 mL) was added to a THF solution (10 mL) of compound 5A (300 mg) and HMPA (0.361 mL) at −78 ° C., and the mixture was stirred for 30 minutes. At −78 ° C., a THF solution (3.0 mL) of compound 5B (184 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate) to obtain compound 5C (420 mg).
LC-MS: Measurement method C, [M + H] ⁺ = 436.7, Rt = 2.59min

Step 2:
Potassium carbonate (48.0 mg) was added to a mixed solution of compound 5C (50.0 mg) in methanol (5.7 mL) and water (1.7 mL), and the mixture was stirred at 60 ° C. for 92 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: methyl chloride / methanol) to obtain compound 5D (23.4 mg).
LC-MS: Measurement method C, [M + H] ⁺ = 322.3, Rt = 1.73min

[Reference example 77]
Production of 4- (2,4-difluorophenyl) -2- (2-phenyl-1H-indole-3-yl) butanoic acid (Compound 6B)

Zinc (645 mg) and chlorotrimethylsilane (0.626 mL) were added to a mixed solution of Compound 6A (200 mg, Reference Example 51) in THF (2.5 mL) and water (0.027 mL), and the mixture was stirred for 2 hours. With ice cooling, 2 mol / L hydrochloric acid was added to the reaction mixture, the mixture was separated and extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol). Acetone (5.0 mL) was added to the obtained solid, and the mixture was heated and dissolved, cooled to room temperature, and the precipitated solid was collected by filtration, washed with acetone and dried to obtain the title compound 6B (757 mg).
LC-MS: Measurement method A, [M + H] ⁺ = 392.2, Rt = 2.05min

[Example 1]
Production of 2- (1H-indole-3-yl) -4- (4-methoxyphenyl) -4-oxobutaneamide (1D)

N, N-diisopropylethylamine (0.939 mL), hexafluorophosphate O- (7-azabenzotriazole-1-yl) -N, in a solution of compound 1C (1.19 g, Reference Example 1) in DMF (12 mL), N, N', N'-tetramethyluronium (1.68 g) was added, and the mixture was stirred at room temperature for 7 hours. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol) to give the title compound 1D (26 mg).
^{1 1} H-NMR (DMSO-D ₆ ) δ: 10.89 (1H, s), 8.00-7.93 (2H, m), 7.74 (1H, d, J = 7.6 Hz), 7.33 (2H, d, J = 8.2 Hz) ), 7.22 (1H, d, J = 2.3 Hz), 7.10-6.93 (4H, m), 6.75 (1H, s), 4.31 (1H, dd, J = 9.7, 4.5 Hz), 3.97-3.84 (1H, s) m), 3.83 (3H, s), 3.23-3.12 (1H, m).

[Examples 2-77]
The compounds of Examples 2 to 77 were obtained from the compounds of Reference Examples 2 to 77 in the same manner as in Example 1.

[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.

[Test Example 1: Suppressive effect on cell death due to oxidative stress of fibroblasts derived from patients with Leigh's encephalopathy]
In order to investigate the effect of suppressing cell death of fibroblasts derived from Lee encephalopathy patients due to oxidative stress with respect to the compound of the present invention, fibroblasts derived from Lee encephalopathy patients treated with glutathione synthesis inhibitor BSO (L-Buthionine sulphoximine) were used. The cells were cultured in the presence of the compound, and the cell viability was measured.

[Method]
^{6.4 × 10 3} fibroblasts derived from Leigh's encephalopathy patient per well were sprinkled on a 96-well cell culture plate, and then cultured for 24 hours to bring the glutathione synthesis inhibitor BSO to 10 μmol / L. Mixed inside. After culturing for 24 hours in the presence of BSO, each Example compound was mixed in the culture broth to a concentration of 3 or 10 μmol / L. After culturing in the presence of the compound for 2 days (evaluation of Examples 74 and 77) or 3 days (evaluation of Examples 1, 6, 11, 12, 19, 20, 23, 61 and 70), the number of viable cells was determined to be Cell. The cell viability was calculated by measuring using Counting Kit-8 (manufactured by Dojin Chemical Research Institute). Wells to which both BSO and compound were not added were used to control the oxidative stress load, and wells to which BSO was added were used to control the effect of the compound.

[result]
Table 6 shows the inhibitory effect of each compound on cell death due to oxidative stress of fibroblasts derived from Leigh's encephalopathy patients. When the compound concentration showing the inhibitory effect on cell death of fibroblasts derived from Leigh's encephalopathy patients due to oxidative stress of each compound is 3 μmol / L, it is represented by ++, and when it is 10 μmol / L, it is represented by +. This result indicates that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as Leigh's encephalopathy, and suggests that the compounds of the present invention can treat mitochondrial diseases such as Leigh's encephalopathy.

In addition to mitochondrial diseases such as Lee's encephalopathy, patients-derived fibroblasts from other diseases (neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, heart diseases) were used as described above. By the same method or a method similar to the above, the inhibitory effect of the compound of the present invention on cell death due to oxidative stress of various fibroblasts can be confirmed.

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 Co., Ltd.). Specifically, the EC50 value is obtained by analyzing the data using the method of "Dx calculation (fitting of logistic curve): reaction rate input" included in the dose-response data analysis.

Since the compound of the present invention exhibits a remarkable inhibitory effect on cell death induced in cells of patients with diseases associated with mitochondrial dysfunction, it is a therapeutic agent and / or a therapeutic agent for diseases or symptoms associated with mitochondrial dysfunction. Prophylactic agents can be provided. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, and heart disease.

Claims (13)

The following formula (I):

[During the ceremony,
X ^a , X ^b , X ^c and X ^d independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a C _1-3 alkyl group, a trifluoromethyl group, a methoxy group, or a pyridyl group. Suka or;
X ^b and X ^c may be combined with the carbon atoms to which they are attached to form a 5- or 6-membered saturated heterocycle containing 1-2 oxygen atoms;
Z represents a hydrogen atom, a methyl group, an ethyl group, a cyclohexyl group, or a phenyl group (the group may be substituted with fluorine or methoxy);
A is
_{(1) C 4-6} alkyl group substituted with 3 to 5 fluorine atoms,
(2) Difluorocyclohexyl-ethyl group,
(3) The following formula (II):

(During the ceremony,
-CH ₂ -W _{is, -CH 2 -CH 2 -, -} CH 2 -C (O) -, - CH 2 -CH 2 O-, or formula (III):

(In the formula, L represents a single bond or an oxygen atom);
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are independently hydrogen atom, fluorine atom, chlorine atom, C _1-4 alkyl group, methoxy group, cyclohexyl group, methylthio group, phenoxy group, or Represents a dimethylamino group or;
Y ^b and Y ^c may form a 5- or 6-membered saturated heterocycle containing 1 to 2 oxygen atoms together with the carbon atoms to which they are attached). Or (4) The following formula (IV):

(In the formula, Q is a pyridyl group (the group may be substituted with 1-3 fluorine or methyl), a thienyl group (the group may be C _1-4 alkyl or methoxy). Represents a group represented by (which may be substituted) or a pyrazolyl group (which represents a group which may be substituted with 1 to 3 methyls)] or a compound thereof and pharmaceuticals thereof. Tolerant salt. A is the group represented by equation (II);
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -CH _2- W is -CH _{2-C (O)-.} The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is a hydrogen atom. A pharmaceutical product containing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a disease caused by mitochondrial dysfunction, which comprises the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. The therapeutic agent and / or prevention according to claim 5, wherein the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease. Agent. Mitochondrial diseases include Lee encephalopathy, stroke-like attack syndrome (MELAS), chronic progressive external ocular muscle palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myokronus epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, The therapeutic and / or prophylactic agent according to claim 6, which is Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acid acidosis. Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's atrophy, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, spinal muscle The therapeutic and / or prophylactic agent according to claim 6, which is atrophy, spinal and bulbar muscular atrophy, or Charcot-Marie-Tooth disease. The therapeutic and / or prophylactic agent according to claim 6, wherein the immune neurological disorder is Guillain-Barré syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis. .. The therapeutic agent and / or preventive agent according to claim 6, wherein the cerebral ischemic disease is cerebral infarction. Renal diseases include renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubule necrosis, nephropathy syndrome, diabetic nephropathy, gout kidney, renal edema, renal tumor, kidney The therapeutic and / or prophylactic agent according to claim 6, which is an ischemic disorder, a renal ischemia-reperfusion disorder, or a cystic kidney. Claim that the muscle disease is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscular atrophy (sarcopenia), or disused muscle atrophy. The therapeutic agent and / or preventive agent according to 6. The therapeutic and / or prophylactic agent according to claim 6, wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.