JP2005089456A - Agent for treating and/or preventing mitochondrial encephalomyopathy - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new pharmaceutical for treating and/or preventing mitochondrial encephalomyopathy. <P>SOLUTION: This pharmaceutical contains a pyrazolone derivative expressed by formula (I) (R<SP>1</SP>is H, an aryl, an alkyl or an alkoxycarbonylalkyl; R<SP>2</SP>is H, an aryloxy, an arylmercapto, an alkyl or a hydroxyalkyl; and R<SP>3</SP>is H, an alkyl, a cycloalkyl, a hydroxyalkyl, benzyl, naphthyl, phenyl or a phenyl which is substituted with a substituent selected from an alkyl, an alkoxy, a hydroxyalkyl, an alkoxycarbonyl or the like), its physiologically acceptable salt, a hydrate thereof, or a solvate thereof as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a medicament for treatment and / or prevention of mitochondrial encephalomyopathy, which contains a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

  Mitochondria are important organelles of most eukaryotic cells that produce and supply the energy (ATP) that cells need. The size is 1 μm or less, and it has a double membrane structure consisting of an outer membrane and an inner membrane. In mammalian hepatocytes, there are 1,000 to 2,000 cells per cell, accounting for about 20% of the intracellular volume. It is about 4% for muscle fibers. Mitochondrial myopathy is a disease in which a large number of mitochondria showing abnormal morphology are found in skeletal muscle. Because many organs are chronically and progressively affected, especially in organs with high energy demand (muscles, central and peripheral nervous system, heart, kidneys), and various clinical symptoms including myopathy and central nervous system symptoms. Collectively named mitochondrial encephalomyopathy.

  Mitochondrial encephalomyopathy (1) Chronic progressive external ophthalmoplegia (CPEO) (Kearns-Sayre syndrome has three main features: extraocular muscle paralysis, retinitis pigmentosa, and cardiac conduction block (2) Myoclonus epilepsy associated with ragged-red fibers (MERRF), (3) Mitochondrial disease with stroke-like symptoms (MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode), (4) Leber's disease (Leber's hereditary optic neuropathy), (5) electron transport system abnormality complex I deficiency complex II deficiency complex III deficiency complex IV deficiency, (6) Classified into diabetes / deafness, (7) Pearson disease, and (8) mitochondrial DNA deficiency.

  Clinically, the presence of myopathy with a chronic course, short stature, and in some cases, extraocular palsy (CPEO), ptosis, clinical type of myoclonic epilepsy (MERRF), lactic acidosis, stroke-like symptoms (MELAS) Diagnosed as mitochondrial encephalomyopathy with characteristic clinical symptoms such as Furthermore, we consider the possibility of Leber's disease for an example of decreased visual acuity and optic nerve atrophy. Also, from a genetic standpoint, MERRF, MELAS, and Leber disease are strongly suspected if maternal inheritance is considered. There are many sporadic cases of CPEO, but there are rare cases of autosomal dominant inheritance.

  Moreover, as a laboratory finding, an increase in lactic acid and pyruvic acid in the blood or cerebrospinal fluid is a great basis for considering the possibility of mitochondrial encephalomyopathy. In particular, mitochondrial encephalomyopathy is strongly suspected if an increase in lactic acid and pyruvic acid is observed in a 15W ergometer exercise test (a test for examining aerobic oxidation ability in muscles). Furthermore, mitochondrial encephalomyopathy is diagnosed if a large number of ragged-red fibers (RRF) are observed in the muscle biopsy by modified Gomori-trichrome staining.

  Furthermore, in mitochondrial encephalomyopathy, there are mitochondrial DNA mutations unique to each disease. There are various sizes of deletions in CPEO. In MERRF, there are many cases in which the tRNALys gene of base number 8,344 has a mutation from A (adenine) to G (guanine), and other mutations are also found in the tRNALys gene. In MELAS, the tRNALeu (UUR) gene with base number 3,243 often has an A to G mutation, and other mutations are often found in the tRNALeu (UUR) gene. In Leber disease, there are many cases in which the ND4 gene is mutated.

  As a treatment method for mitochondrial encephalomyopathy, for example, Neuquinone has been tried for MELAS, but its effect has not been confirmed, and symptomatic treatment with antiepileptic drugs is the main.

（式中、Ｒ¹は水素原子、アリール、炭素数１〜５のアルキル又は総炭素数３〜６のアルコキシカルボニルアルキルを表し、Ｒ²は、水素原子、アリールオキシ、アリールメルカプト、炭素数１〜５のアルキル又は１〜３のヒドロキシアルキルを表し、あるいは、Ｒ¹及びＲ²は、共同して炭素数３〜５のアルキレンを表し、Ｒ³は水素原子、炭素数１〜５のアルキル、炭素数５〜７のシクロアルキル、炭素数１〜３のヒドロキシアルキル、ベンジル、ナフチル又はフェニル、又は炭素数１〜５のアルコキシ、炭素数１〜３のヒドロキシアルキル、総炭素数２〜５のアルコキシカルボニル、炭素数１〜３のアルキルメルカプト、炭素数１〜４のアルキルアミノ、総炭素数２〜８のジアルキルアミノ、ハロゲン原子、トリフルオロメチル、カルボキシル、シアノ、水酸基、ニトロ、アミノ、及びアセトアミドからなる群から選ばれる同一若しくは異なる１〜３個の置換基で置換されたフェニルを表す。）で表されるピラゾロン誘導体については、医薬の用途として、脳機能正常化作用（特許文献１参照）、過酸化脂質生成抑制作用（特許文献２参照）、抗潰瘍作用（特許文献３参照）、及び血糖上昇抑制作用（特許文献４参照）等が知られている。 On the other hand, the following formula (I):

(In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms in total, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, 1 to 1 carbon atoms. 5 represents alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ represents a hydrogen atom, alkyl having 1 to 5 carbon atoms, carbon Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, or alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms in total , Alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms in total, halogen atom, trifluoromethyl, carboxyl A pyrazolone derivative represented by the same or different 1 to 3 substituents selected from the group consisting of sil, cyano, hydroxyl group, nitro, amino, and acetamide. , Brain function normalizing action (see Patent Document 1), lipid peroxide production inhibitory action (see Patent Document 2), anti-ulcer action (see Patent Document 3), blood glucose elevation inhibiting action (see Patent Document 4), etc. It has been.

  In addition, among the compounds of the above formula (I), a preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one as an active ingredient has been a brain protective agent (generic name “edaravone” since June 2001). The product name “Radicut” is manufactured and sold by Mitsubishi Pharma Corporation. This “edaravone” has been reported to have high reactivity to active oxygen (see Non-Patent Document 1; Non-Patent Document 2). Thus, edaravone is a free radical scavenger that works to prevent cell damage and the like by eliminating various free radicals including active oxygen. However, there has been no report on whether edaravone is effective for the treatment and / or prevention of mitochondrial encephalomyopathy so far.

Japanese Patent Publication No. 5-31523 Japanese Patent Publication No. 5-35128 Japanese Patent Laid-Open No. 3-215425 JP-A-3-215426 Kawai, H., et al., J. Phamacol. Exp. Ther., 281 (2), 921, 1997 Wu, TW. Et al., Life Sci, 67 (19), 2387, 2000

  An object of the present invention is to provide a medicament useful for the treatment and / or prevention of mitochondrial encephalomyopathy.

  In order to solve the above-mentioned problems, the present inventors examined the therapeutic effect on mitochondrial encephalomyopathy using a pyrazolone derivative represented by the formula (I). As a result, it has been found that administration of the above-mentioned pyrazolone derivative can stop the expansion of infarction in mitochondrial encephalomyopathy patients and can suppress edema, thereby completing the present invention.

（式中、Ｒ¹は、水素原子、アリール基、炭素数１〜５のアルキル基又は総炭素数３〜６のアルコキシカルボニルアルキル基を表し；Ｒ²は、水素原子、アリールオキシ基、アリールメルカプト基、炭素数１〜５のアルキル基又は炭素数１〜３のヒドロキシアルキル基を表し；あるいは、Ｒ¹及びＲ²は、共同して炭素数３〜５のアルキレン基を表し；Ｒ³は、水素原子、炭素数１〜５のアルキル基、炭素数５〜７のシクロアルキル基、炭素数１〜３のヒドロキシアルキル基、ベンジル基、ナフチル基、フェニル基、又は炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜３のヒドロキシアルキル基、総炭素数２〜５のアルコキシカルボニル基、炭素数１〜３のアルキルメルカプト基、炭素数１〜４のアルキルアミノ基、総炭素数２〜８のジアルキルアミノ基、ハロゲン原子、トリフルオロメチル基、カルボキシル基、シアノ基、水酸基、ニトロ基、アミノ基及びアセトアミド基からなる群から選ばれる同一若しくは異なる１〜３個の置換基で置換されたフェニル基を表す。）
で示されるピラゾロン誘導体若しくはその生理学的に許容される塩、又はそれらの水和物若しくは溶媒和物を有効成分として含む、ミトコンドリア脳筋症の治療及び／又は予防のための医薬が提供される。 That is, according to the present invention, the following formula (I):

(In the formula, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms in total; R ² represents a hydrogen atom, an aryloxy group, or an aryl mercapto group. group, an alkyl group or hydroxyalkyl group having 1 to 3 carbon atoms of 1 to 5 carbon atoms; or, R ¹ and R ² are combined with each other to represent an alkylene group having 3 to 5 carbon atoms; R ³ is Hydrogen atom, alkyl group having 1 to 5 carbon atoms, cycloalkyl group having 5 to 7 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, benzyl group, naphthyl group, phenyl group, or alkyl group having 1 to 5 carbon atoms , An alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 total carbon atoms, an alkyl mercapto group having 1 to 3 carbon atoms, and an alkylamino group having 1 to 4 carbon atoms , Coal 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group having a prime number of 2 to 8, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group Represents a substituted phenyl group.)
The pharmaceutical for the treatment and / or prevention of mitochondrial encephalomyopathy which contains the pyrazolone derivative shown by these, its physiologically acceptable salt, or those hydrates or solvates as an active ingredient is provided.

According to a preferred embodiment of the present invention, the pyrazolone derivative represented by formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
According to a preferred embodiment of the present invention, the mitochondrial encephalomyopathy is mitochondrial disease (MERAS) with stroke-like symptoms.
According to another aspect of the present invention, a mitochondrial encephalomyopathy comprising the pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient A medicament is provided for stopping infarct expansion and / or suppressing edema in a patient.

  According to still another aspect of the present invention, there is provided a therapeutically and / or prophylactically effective amount of the pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. A method of treating and / or preventing mitochondrial encephalomyopathy is provided, comprising the step of administering to a mammal, including a human.

  According to yet another aspect of the present invention, a pyrazolone derivative of formula (I) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of mitochondrial encephalomyopathy, or Use of such hydrates or solvates is provided.

  The medicament according to the present invention can effectively treat and prevent mitochondrial encephalomyopathy.

  The medicament for the treatment and / or prevention of mitochondrial encephalomyopathy according to the present invention (hereinafter sometimes abbreviated as the medicament of the present invention) is a pyrazolone derivative represented by the formula (I) defined herein or a derivative thereof Including physiologically acceptable salts, or hydrates or solvates thereof.

  The compound represented by the formula (I) used in the present invention can also have a structure represented by the following formula (I ′) or (I ″) due to tautomerism. In the formula (I) in the present specification, For convenience, one of the tautomers is shown, but the existence of the following tautomers is obvious to those skilled in the art: As an active ingredient of the medicament of the present invention, the following formula (I ′) Alternatively, a compound represented by (I ″) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be used.

In the formula (I), the aryl group in the definition of R ¹ may be either a monocyclic or polycyclic aryl group. For example, in addition to a phenyl group, a naphthyl group, etc., an alkyl group such as a methyl group or a butyl group, an alkoxy group such as a methoxy group or a butoxy group, a halogen atom such as a chlorine atom, or a phenyl group substituted with a substituent such as a hydroxyl group Etc. The same applies to the aryl moiety in other substituents having an aryl moiety (such as an aryloxy group).

The alkyl group having 1 to 5 carbon atoms in the definitions of R ¹ , R ² and R ³ may be either linear or branched. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a pentyl group. The same applies to the alkyl moiety in other substituents (alkoxycarbonylalkyl group) having an alkyl moiety.

Examples of the alkoxycarbonylalkyl group having 3 to 6 carbon atoms in total in the definition of R ¹ include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a methoxycarbonylethyl group, and a methoxycarbonylpropyl group.

Examples of the aryloxy group in the definition of R ² include a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy group, a p-hydroxyphenoxy group, and the aryl mercapto group includes a phenyl mercapto group, p -Methylphenyl mercapto group, p-methoxyphenyl mercapto group, p-chlorophenyl mercapto group, p-hydroxyphenyl mercapto group and the like.

Examples of the hydroxyalkyl group having 1 to 3 carbon atoms in the definition of R ² and R ³ include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group. Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R ³ include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

In the definition of R ³ , examples of the alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, and the like. Examples of the alkoxycarbonyl group having 2 to 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. Examples of the alkyl mercapto group having 1 to 3 carbon atoms include a methyl mercapto group, an ethyl mercapto group, Propyl mercapto group and the like, and examples of the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like, and a dialkylamino group having a total carbon number of 2 to 8 As dimethylamino group, diethylamino group, dipropylamino group, dibutylamino Etc. The.

Examples of the compound (I) suitably used as the active ingredient of the medicament of the present invention include the compounds shown below.
3-methyl-1-phenyl-2-pyrazolin-5-one;
3-methyl-1- (2-methylphenyl) -2-pyrazolin-5-one;
3-methyl-1- (3-methylphenyl) -2-pyrazolin-5-one;
3-methyl-1- (4-methylphenyl) -2-pyrazolin-5-one;
3-methyl-1- (3,4-dimethylphenyl) -2-pyrazolin-5-one;
1- (4-ethylphenyl) -3-methyl-2-pyrazolin-5-one;
3-methyl-1- (4-propylphenyl) -2-pyrazolin-5-one;
1- (4-butylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-trifluoromethylphenyl) -3-methyl-2-pyrazolin-5-one;

1- (4-trifluoromethylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (2-methoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-methoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-methoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3,4-dimethoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-ethoxyphenyl) -3-methyl-2-pyrazolin-5-one;
3-methyl-1- (4-propoxyphenyl) -2-pyrazolin-5-one;
1- (4-butoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (2-chlorophenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-chlorophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one;
1- (3,4-dichlorophenyl) -3-methyl-2-pyrazolin-5-one;

1- (4-bromophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-fluorophenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-chloro-4-methylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-methylmercaptophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-methylmercaptophenyl) -3-methyl-2-pyrazolin-5-one;
4- (3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid;
1- (4-ethoxycarbonylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-nitrophenyl) -3-methyl-2-pyrazolin-5-one;
3-ethyl-1-phenyl-2-pyrazolin-5-one;
1-phenyl-3-propyl-2-pyrazolin-5-one;

1,3-diphenyl-2-pyrazolin-5-one;
3-phenyl-1- (p-tolyl) -2-pyrazolin-5-one;
1- (4-methoxyphenyl) -3-phenyl-2-pyrazolin-5-one;
1- (4-chlorophenyl) -3-phenyl-2-pyrazolin-5-one;
3,4-dimethyl-1-phenyl-2-pyrazolin-5-one;
4-isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;
4- (2-hydroxyethyl) -3-methyl-1-phenyl-2-pyrazolin-5-one;
3-methyl-4-phenoxy-1-phenyl-2-pyrazolin-5-one;
3-methyl-4-phenylmercapto-1-phenyl-2-pyrazolin-5-one;

3,3 ′, 4,5,6,7-hexahydro-2-phenyl-2H-indazol-3-one;
3- (ethoxycarbonylmethyl) -1-phenyl-2-pyrazolin-5-one;
1-phenyl-2-pyrazolin-5-one;
3-methyl-2-pyrazolin-5-one;
1,3-dimethyl-2-pyrazolin-5-one;
1-ethyl-3-methyl-2-pyrazolin-5-one;
1-butyl-3-methyl-2-pyrazolin-5-one;
1- (2-hydroxyethyl) -3-methyl-2-pyrazolin-5-one;
1-cyclohexyl-3-methyl-2-pyrazolin-5-one;
1-benzyl-3-methyl-2-pyrazolin-5-one;

1- (α-naphthyl) -3-methyl-2-pyrazolin-5-one;
1-methyl-3-phenyl-2-pyrazolin-5-one;
3-methyl-1- (4-methylphenyl) -2-pyrazolin-5-one;
1- (4-butylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-methoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-butoxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3,4-dihydroxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (2-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one;

1- (4-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (3,4-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-hydroxyphenyl) -3-phenyl-2-pyrazolin-5-one;
1- (4-hydroxymethylphenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-aminophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-methylaminophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-ethylaminophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-butylaminophenyl) -3-methyl-2-pyrazolin-5-one;
1- (4-dimethylaminophenyl) -3-methyl-2-pyrazolin-5-one;
1- (acetamidophenyl) -3-methyl-2-pyrazolin-5-one; and 1- (4-cyanophenyl) -3-methyl-2-pyrazolin-5-one

  As an active ingredient of the medicament of the present invention, a physiologically acceptable salt may be used in addition to the free form compound represented by the formula (I). Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrobromide, phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid , Maleic acid, fumaric acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, nicotinic acid, salts with organic acids such as tartaric acid; salts with alkali metals such as sodium and potassium; alkaline earth metals such as magnesium and calcium Salt of ammonia, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglutamine, L-glutamine, etc. Examples include salts with amines. A salt with an amino acid such as glycine may also be used.

  The active ingredient of the medicament of the present invention includes a compound represented by the above formula (I) or a hydrate of a physiologically acceptable salt thereof, a compound represented by the above formula (I) or a physiologically Acceptable salt solvates may be used. Although the kind of organic solvent which forms a solvate is not specifically limited, For example, methanol, ethanol, ether, dioxane, tetrahydrofuran etc. can be illustrated. In addition, the compound represented by the above formula (I) may have one or more asymmetric carbons depending on the type of substituent, and may have a stereoisomer such as an optical isomer or a diastereoisomer. . As the active ingredient of the medicament of the present invention, a stereoisomer in a pure form, an arbitrary mixture of stereoisomers, a racemate and the like may be used.

  All of the compounds represented by the formula (I) are known compounds and can be easily synthesized by those skilled in the art by the method described in JP-B-5-31523.

  The dose of the medicament of the present invention is not particularly limited, but usually the weight of the compound represented by the formula (I) as an active ingredient is generally 0.1 to 1000 mg / kg body weight per day in the case of oral administration, preferably 0.5 to 50 mg / kg body weight per day, and 0.01 to 100 mg / kg body weight per day for parenteral administration, preferably 0.1 to 10 mg / kg body weight. The above dose is preferably administered once a day or divided into 2 to 3 times a day, and may be increased or decreased as appropriate according to age, disease state, and symptoms.

  As the medicament of the present invention, the compound represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be administered as it is. It is preferable to prepare and administer a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmacologically and pharmaceutically acceptable additive.

  Examples of pharmacologically and pharmaceutically acceptable additives include excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or Solubilizers, tonicity agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be used.

  For pharmaceutical compositions suitable for oral administration, as additives, for example, excipients such as glucose, lactose, D-mannitol, starch or crystalline cellulose; disintegrants or disintegrations such as carboxymethylcellulose, starch or carboxymethylcellulose calcium Adjuvants; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol or titanium oxide; petrolatum, Bases such as liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.

  Pharmaceutical compositions suitable for injection or infusion include aqueous solutions such as distilled water for injection, physiological saline, propylene glycol, or solubilizers or solubilizers that can constitute soluble injections for use; glucose, sodium chloride, D -Additives such as isotonic agents such as mannitol and glycerin; pH adjusters such as inorganic acids, organic acids, inorganic bases and organic bases can be used.

  The form of the medicament of the present invention is not particularly limited, and can take various forms that can be used by those skilled in the art. As pharmaceuticals suitable for oral administration, for example, tablets, powders, granules, hard gelatin capsules, suppositories, or lozenges can be prepared using solid pharmaceutical additives, and liquid pharmaceutical additives Can be used to prepare syrups, emulsions, soft gelatin capsules and the like. In addition, injections, infusions, inhalants, suppositories, transdermal absorption agents, transmucosal absorption agents, and the like can be prepared as medicaments suitable for parenteral administration. In addition, since a brain protective agent (instillation) containing the compound of the above formula (I) as an active ingredient has already been used in clinical practice (generic name “Edaravone”, trade name “Radicut”: manufactured by Mitsubishi Pharma Corporation) -Sales) The above-mentioned commercial preparation can be used as it is in the medicament of the present invention.

  The administration route of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally. The administration route for parenteral administration is not particularly limited, and can be administered intravenously, intramuscularly, intradermally or subcutaneously.

  The medicament of the present invention can also be administered prophylactically prior to the onset of mitochondrial encephalomyopathy. In addition, to the patient who has developed mitochondrial encephalomyopathy, the medicament of the present invention can be administered to the patient for the purpose of preventing the deterioration of the symptoms or reducing the symptoms.

  Mitochondrial encephalomyopathy for which the medicament of the present invention is administered is interpreted in the broadest sense. Mitochondrial encephalomyopathy includes: (1) Chronic progressive external ophthalmoplegia (CPEO) (Kearns-Sayre syndrome is a triad of retinal pigment degeneration and cardiac conduction block in addition to extraocular muscle paralysis (2) Myoclonus epilepsy associated with ragged-red fibers (MERRF), (3) Mitochondrial disease with stroke-like symptoms (MELAS: mitochondrial myopathy , encephalopathy, lactic acidosis and stroke-like episode), (4) Leber's disease (Leber's hereditary optic neuropathy), (5) Electron transport system abnormality complex I deficiency complex II deficiency complex III deficiency complex IV deficiency, (6 ) Diabetes / Hearing loss, (7) Pearson's disease, and (8) Mitochondrial DNA deficiency.

  Particularly preferably, the medicament of the present invention can be used for the treatment and / or prevention of mitochondrial disease (MERAS) with stroke-like symptoms. Mitochondrial disease with stroke-like symptoms (MELAS) is a clinical unit of mitochondrial encephalomyopathy proposed by Pavlakis et al. (Pavlakis et al. Mitochodrial myopathy, encephalopathy, lactic acidosis and stroke-like episode: a distinct clinical syndrome Ann. Neurol. 16: 481-488, 1984), a metastatic disease that is relatively common in the pediatric field. As clinical symptoms, the age of onset is often less than 15 years old, and the first symptoms are headache and vomiting attacks, followed by fatigue and seizures. Although it is slowly progressive, there are cases where it progresses rapidly with stroke-like seizures and convulsive status. Recently, it has been attracting attention as a cause of hearing loss and diabetes.

  The frequency of the main symptoms of MELAS were stroke-like seizures (100%), impaired consciousness (94%), visual and visual impairment (57%), unilateral convulsions (50%), hemiplegia (25%), aphasia (3 %), Headache / vomiting attacks (95%), muscle weakness (90%), convulsions (87%), intelligence impairment (74%), short stature (55%), hearing loss (28%), myocardial injury (10%) ), Drooping eyelids (8%), myoclonus (3%), cardiac conduction disorder (3%). As laboratory findings, high blood and lactic acid levels are observed in almost all cases. Half of the CK increases, and as the course progresses, it begins to show atrophy. Pathological findings include abnormally mitochondrial accumulation of ragged-red fiber (RRF) in 80% of cases, and mitochondrial abnormalities in small arteries, especially abnormalities in vascular smooth muscle cells, are characteristic in MELAS. Such abnormalities of vascular smooth muscle cells have also been confirmed in the central nervous system. Strongly SDH-reactive vessels (SSV) reflecting abnormal mitochondrial accumulation in small arteries are also observed in about 90% of cases. In addition, as a genetic abnormality, in 80% of the cases, a mutation from A to G in base number 3,243 of the tRNALeu (UUR) gene is 10%, and a T to C mutation in base number 3,271 of the tRNALeu (UUR) gene or Deletions have been found and in the remaining 10% no genetic abnormalities have yet been identified. These mutations can usually be detected by DNA diagnosis of peripheral blood leukocytes, but in some cases, the abundance of mutated mitochondria differs greatly between leukocytes and muscles, and there are rare cases in which diagnosis cannot be made without muscles.

  A mitochondrial disease having a stroke-like symptom is referred to as a mitochondrial disease with a stroke-like symptom (MELAS), which is a disease distinct from cerebral infarction. Mitochondrial encephalomyopathy is a genetic disease caused by abnormal mitochondrial function due to DNA deficiency. The cerebral pathology is a softened and necrotic layer and differs from cerebral infarction in that it does not coincide with a specific vascular area. As described above, as symptoms of MELAS, in addition to stroke-like symptoms, muscle weakness, easy fatigue, dementia, short stature, hearing loss, heart disease and the like are observed.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited by the following Example.
In addition, "Radicut (registered trademark) Note 30 mg" sold by Mitsubishi Pharma Corporation was used as the Radicut (registered trademark) used in the following examples.

Example 1:
In this example, the chief complaint was a patient who cannot see both eyes. The patient's medical history is as follows. Deafness appeared in both ears about 10 years ago, headache and speech difficulty appeared 7 years ago, and left temporal lobe lesions were observed by MRI. Later, the symptoms worsened and disturbances of consciousness appeared. A diagnosis of mitochondrial encephalomyopathy (MELAS) due to A3243G mutation was made by genetic diagnosis. Neuquinone high-dose therapy alleviated the symptoms, but remained intellectually impaired. Three years ago, headache, tinnitus, fever, seizures appeared, MRI confirmed a new lesion, and MELAS recurred. At this time, the symptoms improved with high dose Neuquinone therapy. Symptoms such as nausea, headache, and uncertain location appeared this time, and he noticed a decrease in vision on both sides. There was no increase in blood lactic acid level and no abnormal findings on head CT, but MELAS reoccurrence was suspected.

Physical findings on admission: Clearness of consciousness, visual acuity for both eyes, light valves, pupils of the same size, light reflection, high hearing loss, no abnormalities in other cranial nerve areas, no decrease in gross muscle strength, walking alone, table No decrease in perception and depth perception, normal deep tendon reflexes, no pathological reflexes General blood test at visit, emergency biochemistry, no abnormal urinalysis, blood lactate 2.4 mM
Progression: MELAS recurrence was suspected since admission, Neuquinone (10) 21 tablets / day, uberanicotinate 3Cap / day was started. Extensive edematous lesions were observed in the right occipital lobe on T2-weighted and FLAIR images (FIG. 1). It was thought that there was no contradiction when it was considered to be a responsible focus of consciousness disorder, visual field disorder, and topographical disorder. This case has developed encephalopathy twice, and all have been relieved by the above treatment, but this time the disease was nevertheless progressing and it was thought that some additional therapy was necessary.

  Therefore, on the fifth day of illness, Radicut infusion treatment was started. Radicut was administered by instilling 30 mg of Radicut Injection diluted with 100 ml of physiological saline into a vein twice a day (morning and evening) (the time of one infusion is within 30 minutes). Radicut infusion treatment was performed for 2 weeks. Until 7 days after the start of Radicut administration, clinical symptoms did not change, disturbance of consciousness persisted, and sudden abnormalities were detected from the right hemisphere in the EEG on the 9th disease. MRI did not show lesion enlargement. From the 8th day (13th illness day) after the start of radiocut administration, meaningful conversation was established, visual acuity was improved, and single walking became possible. The MRI on the 13th disease day (FIG. 2) reduced edema at the lesion, and the MRI on the 20th disease day (FIG. 3) showed a marked reduction in the lesion. The left homonymous half-blindness and topographical disorder remained even on the 20th day of illness, but recovered to a state where it could be treated at home.

FIG. 1 shows an MRI image of a patient before administration of radicut. FIG. 2 shows an MRI image of a patient on the eighth day after administration of radicut. FIG. 3 shows an MRI image of a patient on the 14th day after administration of radicut.

Claims (5)

The following formula (I):

(In the formula, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms in total; R ² represents a hydrogen atom, an aryloxy group, or an aryl mercapto group. group, an alkyl group or hydroxyalkyl group having 1 to 3 carbon atoms of 1 to 5 carbon atoms; or, R ¹ and R ² are combined with each other to represent an alkylene group having 3 to 5 carbon atoms; R ³ is Hydrogen atom, alkyl group having 1 to 5 carbon atoms, cycloalkyl group having 5 to 7 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, benzyl group, naphthyl group, phenyl group, or alkyl group having 1 to 5 carbon atoms , An alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 total carbon atoms, an alkyl mercapto group having 1 to 3 carbon atoms, and an alkylamino group having 1 to 4 carbon atoms , Coal 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group having a prime number of 2 to 8, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group Represents a substituted phenyl group.)
A pharmaceutical agent for treating and / or preventing mitochondrial encephalomyopathy, comprising a pyrazolone derivative represented by the above or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. The pharmaceutical according to claim 1, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one. The medicament according to claim 1 or 2, wherein the mitochondrial encephalomyopathy is mitochondrial disease (MERAS) with stroke-like symptoms. The following formula (I):

(In the formula, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms in total; R ² represents a hydrogen atom, an aryloxy group, or an aryl mercapto group. group, an alkyl group or hydroxyalkyl group having 1 to 3 carbon atoms of 1 to 5 carbon atoms; or, R ¹ and R ² are combined with each other to represent an alkylene group having 3 to 5 carbon atoms; R ³ is Hydrogen atom, alkyl group having 1 to 5 carbon atoms, cycloalkyl group having 5 to 7 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, benzyl group, naphthyl group, phenyl group, or alkyl group having 1 to 5 carbon atoms , An alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 total carbon atoms, an alkyl mercapto group having 1 to 3 carbon atoms, and an alkylamino group having 1 to 4 carbon atoms , Coal 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group having a prime number of 2 to 8, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group Represents a substituted phenyl group.)
Inhibiting the expansion of infarction and / or suppressing edema in patients with mitochondrial encephalomyopathy, comprising the pyrazolone derivative represented by the above or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient For medicine. The pharmaceutical according to claim 4, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.

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