JP2008001605A - Aqueous solution containing pyrazolone compound - Google Patents

Abstract

An aqueous solution containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and suppresses coloring of the solution over time when stored for a long period of time. And providing a stable aqueous solution.
An aqueous solution containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, ethylenediaminetetraacetate, an alcohol, and a compound that generates bisulfite ion in an aqueous solution.
[Selection figure] None

Description

  The present invention relates to an aqueous solution containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

（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）、血糖上昇抑制作用（特許文献４参照）等が知られている。 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. ing.

  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.

  The compound of the above formula (I) is extremely stable in the solid state, but in the case of an aqueous solution, it is easily oxidized by dissolved oxygen to form insoluble foreign matter, particularly at pH 2.5 or lower and pH 6.0 or higher. It was found that it was accelerated, and considerable difficulty was expected in formulating the liquid preparation. In particular, in the case of an injection, the generation of insoluble foreign substances adversely affects the living body and becomes a fatal defect. In order to solve this problem, Patent Document 5 discloses 3-methyl-1-phenyl-2-pyrazolone-containing one or more selected from sulfites, bisulfites and pyrosulfites and cysteines. An injectable solution is proposed, which is an aqueous solution of 5-one and the pH of the solution is in the range of 2.5 to 6.0. However, it has been desired to develop a stable 3-methyl-1-phenyl-2-pyrazolon-5-one-containing aqueous solution that suppresses coloring of the solution over time, particularly when stored for a long period of time.

Japanese Patent Publication No. 5-31523 Japanese Patent Publication No. 5-35128 Japanese Patent Laid-Open No. 3-215425 JP-A-3-215426 JP-A-63-132833 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 an aqueous solution containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and the solution of the solution over time when stored for a long time. It was set as the problem which should be solved to provide the stable aqueous solution agent which suppressed coloring.

  In order to solve the above problems, the present inventors have intensively studied the formulation of an aqueous solution containing a pyrazolone derivative represented by the formula (I), and as a result, an aqueous solution containing the pyrazolone derivative represented by the formula (I). In addition, it has been found that by adding ethylenediaminetetraacetate, alcohol and a compound that generates hydrogen sulfite ion in an aqueous solution, a stable aqueous solution that suppresses coloring of the solution over time even when stored for a long time can be provided. It came to complete.

（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のアルキル又は炭素数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若しくはその生理的に許容される塩、又はそれらの水和物若しくは溶媒和物、エチレンジアミンテトラアセテート、アルコール、及び水溶液中で亜硫酸水素イオンを発生する化合物を含有する水溶液剤が提供される。 That is, according to the present invention, the following formula (I):

(In the formula, R ¹ represents a hydrogen atom, 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 hydroxyalkyl having 1 to 3 carbon atoms, 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. , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, 2 to 5 carbon atoms in total Alkoxycarbonyl, alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, alkyl This represents phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of ruboxyl, cyano, hydroxyl, nitro, amino, and acetamide.
An aqueous solution containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, ethylenediaminetetraacetate, alcohol, and a compound that generates bisulfite ion in an aqueous solution. Provided.

Preferably, the compound that generates bisulfite ions in an aqueous solution is sulfite, bisulfite or pyrosulfite.
Preferably, the compound that generates bisulfite ions in an aqueous solution is sodium pyrosulfite.

Preferably, the ethylenediaminetetraacetate is sodium edetate.
Preferably, the alcohol is ethanol.
Preferably, the pH is 3.0 to 7.0.

Preferably, the pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained in an amount of 0.1 to 20 mg / ml.
Preferably, the pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained at 10 mg / ml.

Preferably, the pyrazolone derivative of formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
Preferably, the aqueous solution of the present invention further contains an isotonic agent.
Preferably, the isotonic agent is sodium chloride.
Preferably, in the aqueous solution of the present invention, the coloration of the solution over time is suppressed.

（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のアルキル又は炭素数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若しくはその生理的に許容される塩、又はそれらの水和物若しくは溶媒和物；エチレンジアミンテトラアセテート；アルコール；及び亜硫酸塩、亜硫酸水素塩又はピロ亜硫酸塩の何れか１種以上、を含有する液剤が提供される。 According to another aspect of the present invention, 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 hydroxyalkyl having 1 to 3 carbon atoms, 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. , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, 2 to 5 carbon atoms in total Alkoxycarbonyl, alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, alkyl This represents phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of ruboxyl, cyano, hydroxyl, nitro, amino, and acetamide.
Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof; ethylenediaminetetraacetate; alcohol; and any one or more of sulfite, bisulfite or pyrosulfite , Containing a liquid.

Preferably, the pyrosulfite is sodium pyrosulfite.
Preferably, the ethylenediaminetetraacetate is sodium edetate.
Preferably, the alcohol is ethanol.
Preferably, the pH is 3.0 to 7.0.

Preferably, the pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained in an amount of 0.1 to 20 mg / ml.
Preferably, the pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained at 10 mg / ml.

Preferably, the pyrazolone derivative of formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
Preferably, the liquid preparation of the present invention further contains an isotonic agent.
Preferably, the tonicity agent is sodium chloride.
Preferably, in the liquid preparation of the present invention, coloring of the solution over time is suppressed.

  According to the present invention, an aqueous solution and solution containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, which suppresses coloring of the solution over time. Stable aqueous solutions and solutions are provided. Since the aqueous solution and solution of the present invention contain a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, normalization of brain function, suppression of lipid peroxide production, It can be used for various purposes such as anti-ulcer and blood glucose elevation suppression.

  The aqueous solution or solution of the present invention contains a pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient as defined herein. .

  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 alkylene group having 3 to 5 carbon atoms in the definition of R ¹ and R ² include trimethylene group, tetramethylene group, pentamethylene group, methyltrimethylene group, ethyltrimethylene group, dimethyltrimethylene group, and methyltetramethylene group. Is mentioned.

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 like, and examples of the aryl mercapto group include 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 2-5 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group and the like, and 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 aqueous solution or solution 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, acetic acid, oxalic acid, citric acid, malic acid, Salts with organic acids such as fumaric acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium; ammonia, ethanolamine, 2-amino-2-methyl-1-propanol, etc. Examples include salts with amines. In addition, the type of salt is not particularly limited as long as it is physiologically acceptable.

  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.

  A pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof (hereinafter collectively referred to as pyrazolone) formulated in the aqueous solution or solution of the present invention. The concentration of (also referred to as a derivative) is generally about 0.1 mg / ml to about 20 mg / ml, preferably about 1 mg / ml to about 20 mg / ml.

  The aqueous solution or solution of the present invention includes ethylenediaminetetraacetate. As ethylenediaminetetraacetate, sodium edetate is preferably used. The amount of ethylenediaminetetraacetate used in the aqueous solution or solution of the present invention is not particularly limited, but is generally 0.01 mg / ml to 5 mg / ml, preferably 0.01 mg / ml to 1 mg / ml. Particularly preferred is 0.02 mg / ml or more and 0.5 mg / ml or less.

  The aqueous solution or solution of the present invention contains alcohol. As the alcohol, a lower alcohol having 1 to 6 carbon atoms is preferably used. For example, methanol, ethanol, n-propanol, 2-propanol, butanol and the like can be used, and ethanol is preferably used. it can. The amount of alcohol used in the aqueous solution or solution of the present invention is not particularly limited, but is generally 0.1 ml / ml to 0.8 ml / ml, preferably 0.2 ml / ml to 0.8 ml / ml. ml or less, more preferably 0.3 ml / ml or more and 0.7 ml / ml or less.

The aqueous solution of the present invention includes a compound that generates bisulfite ions in an aqueous solution. The compound that generates bisulfite ions in an aqueous solution is preferably sulfite, bisulfite, or pyrosulfite. The liquid preparation of the present invention includes sulfite, hydrogen sulfite or pyrosulfite. Examples of the sulfite used in the present invention include sodium sulfite (Na ₂ SO ₃ ), potassium sulfite (K ₂ SO ₃ ), calcium sulfite (CaSO ₃ ), and the like. Examples thereof include sodium (NaHSO ₃ ), potassium hydrogen sulfite (KHSO ₃ ), ammonium hydrogen sulfite (NH ₄ SO ₃ ), and examples of the pyrosulfite include sodium pyrosulfite (Na ₂ S ₂ O ₅ ), potassium pyrosulfite ( K ₂ S ₂ O ₅ ) and the like. The amount of the compound that generates bisulfite ions in the aqueous solution in the aqueous solution of the present invention and the amount of sulfite, hydrogen sulfite, or pyrosulfite used in the liquid of the present invention are not particularly limited. It is 0.01 mg / ml or more and 5 mg / ml or less, preferably 0.1 mg / ml or more and 2 mg / ml or less, and particularly preferably 0.1 mg / ml or more and 1 mg / ml or less.

  An isotonic agent can be included in the aqueous solution or solution of the present invention as desired. The isotonic agent can be made isotonic using sodium chloride or the like.

  The pH adjuster used for the preparation of the aqueous solution or solution of the present invention can be used without particular limitation as long as it is generally used as a pH adjuster for injections. For example, sodium hydroxide is used. Can do.

  The liquidity of the aqueous solution or solution of the present invention, that is, the pH, can be arbitrarily adjusted by using the above pH adjuster. The pH of the aqueous solution or solution of the present invention is preferably pH 3.0 to 7.0, more preferably pH 3.0 to 6.0, and particularly preferably pH 4.0 to 5.5.

  As other additives used for the preparation of the aqueous solution or solution of the present invention, any additive that is generally used as an additive for injections can be used without particular limitation. In the present invention, preferable other additives include, for example, pharmaceutical additives as described in Yakuji Nippo Co., Ltd. 2000 “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association). These additives may be added as a salt (for example, a monovalent alkali metal salt such as a sodium salt or a potassium salt) or may be added as a hydrate as desired. These additives are generally blended in a proportion usually used for injections. It is easy for those skilled in the art, and these additives may be used according to the purpose of use, as described in “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association) published in 2000. For example, stabilizers, surfactants, buffers, solubilizers, antioxidants, antifoaming agents, emulsifiers, suspending agents, preservatives, soothing agents, solubilizers, solubilizers, etc. It is possible. These additives can be added in combination of two or more components as desired.

  Addition and mixing operations in the preparation of the aqueous solution or solution of the present invention can be carried out according to ordinary pharmaceutical methods. For example, a pyrazolone derivative, ethylenediaminetetraacetate, alcohol, and a compound that generates hydrogen sulfite ions in an aqueous solution may be weighed, mixed and then dissolved in water, or weighed into an aqueous solution containing a pyrazolone derivative. You may melt | dissolve the compound which generate | occur | produces a bisulfite ion in ethylenediaminetetraacetate, alcohol, and aqueous solution. Further, the weighed pyrazolone derivative may be dissolved in an aqueous solution containing ethylenediaminetetraacetate, alcohol, and a compound that generates hydrogen sulfite ions in the aqueous solution. Prepare an aqueous solution containing ethylenediaminetetraacetate, alcohol, and a compound that generates hydrogen sulfite ion in an aqueous solution, and an aqueous solution containing a pyrazolone derivative, respectively, so that the concentration of the pyrazolone derivative is the above-mentioned concentration. It is also possible to prepare by mixing aqueous solutions of Also, when other additives are included, it can be similarly prepared.

  The aqueous solution or solution of the present invention can be used by filling a container such as a plastic container or a glass container. The container may be in any form as long as it is sealable and can maintain the sterility of the contents. Infusion bags, syringes, ampoules generally used for filling injection solutions Containers such as vials are preferable, and containers such as infusion bags, syringes, and ampoules are more preferable. Further, these containers are preferably transparent and non-colored in order to confirm the presence or absence of insoluble foreign matter generation, but may be opaque and colored.

  The administration route of the pyrazolone compound contained in the aqueous solution or solution of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered parenterally.

  The dose of the pyrazolone compound contained in the aqueous solution or solution of the present invention can be appropriately selected depending on the type of active ingredient and the degree of action. Usually, however, the compound represented by the formula (I) which is an active ingredient is used. The weight is generally 0.1 to 100 mg / kg body weight per day for oral administration and 0.1 to 100 mg / kg body weight per day for parenteral administration.

The aqueous solution or solution of the present invention may be used as an amyotrophic lateral sclerosis, an anti-ulcer agent, or an inhibitor of blood sugar elevation, in addition to the improvement of neurological symptoms associated with acute cerebral infarction, daily life movement disorder, and functional disorder. it can.
The administration time and administration period of the aqueous solution or solution of the present invention are not particularly limited, and can be appropriately selected. For example, the aqueous solution or solution of the present invention may be administered prophylactically prior to the onset of the target disease, or may be administered for the purpose of treatment, improvement of symptoms, or prevention of deterioration of symptoms after onset. Good.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited by the following Example.

(1) Synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one (hereinafter referred to as edaravone) 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added to 50 ml of ethanol and stirred at reflux for 3 hours. did. After allowing the reaction solution to cool, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 11.3 g of the title compound as colorless crystals.
Yield 67%
Melting point 127.5-128.5 ° C

(2) Preparation of aqueous solution An aqueous solution 1 (invention) to which sodium pyrosulfite was added as a sulfite and an aqueous solution 2 (comparative example) to which sodium pyrosulfite was not added were prepared according to the formulation described in Table 1 below. Prepared.

(3) Evaluation of Stability of Aqueous Solution The aqueous solution 1 and the aqueous solution 2 prepared in the above (2) were stored at 60 ° C. for 1 month, and then quality evaluation was performed. Quality evaluation was performed by measuring absorbance (400 nm), observing properties, and measuring the amount of related substances produced. The production amount of the related substance was measured by the following method.

Measurement of production amount of related substances Sample preparation: 2 mL of sample was accurately weighed and 0.01 mol / L hydrochloric acid test solution was added to make 10 mL, which was used as a sample solution.
Test condition detector: UV absorption photometer (measurement wavelength: 240 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm filled with 5 μm octadecylsilylated silica gel for liquid chromatography Column temperature: 40 ° C
Mobile phase A: Water / trifluoroacetic acid mixture (1000: 0.5)
Mobile phase B: Methanol / trifluoroacetic acid mixture (1000: 0.5)
Transfer of mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phases A and B as follows.

Flow rate: 1mL per minute
Injection volume: 10μL

  Table 3 shows the results of the quality evaluation described above.

  As can be seen from the results in Table 3, in the aqueous solution 1 of the present invention to which sulfite was added, the coloration of the solution could not be confirmed visually, and the absorbance at 400 nm, which is a quantitative index of coloration, was suppressed, and the time course It was confirmed that coloring of a simple solution was suppressed.

Claims (23)

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 hydroxyalkyl having 1 to 3 carbon atoms, 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. , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, 2 to 5 carbon atoms in total Alkoxycarbonyl, alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, alkyl This represents phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of ruboxyl, cyano, hydroxyl, nitro, amino, and acetamide.
An aqueous solution containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, ethylenediaminetetraacetate, alcohol, and a compound that generates bisulfite ion in an aqueous solution. The aqueous solution agent of Claim 1 whose compound which generate | occur | produces bisulfite ion in aqueous solution is a sulfite, a bisulfite, or a pyrosulfite. The aqueous solution agent of Claim 1 or 2 whose compound which generate | occur | produces a bisulfite ion in aqueous solution is sodium pyrosulfite. The aqueous solution agent of any one of Claim 1 to 3 whose ethylenediaminetetraacetate is sodium edetate. The aqueous solution agent of any one of Claim 1 to 4 whose alcohol is ethanol. The aqueous solution agent of any one of Claim 1 to 5 whose pH is 3.0-7.0. The pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained in an amount of 0.1 to 20 mg / ml. The aqueous solution agent of any one. The pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained at 10 mg / ml according to any one of claims 1 to 7. The aqueous solution described. The aqueous solution agent according to any one of claims 1 to 8, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one. The aqueous solution according to any one of claims 1 to 9, further comprising an isotonic agent. The aqueous solution according to claim 10, wherein the tonicity agent is sodium chloride. The aqueous solution according to any one of claims 1 to 11, wherein coloring of the solution over time is suppressed. 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 hydroxyalkyl having 1 to 3 carbon atoms, 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. , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, 2 to 5 carbon atoms in total Alkoxycarbonyl, alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, alkyl This represents phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of ruboxyl, cyano, hydroxyl, nitro, amino, and acetamide.
Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof; ethylenediaminetetraacetate; alcohol; and any one or more of sulfite, bisulfite or pyrosulfite A liquid preparation containing The liquid agent of Claim 13 whose pyrosulfite is sodium pyrosulfite. The liquid agent according to claim 13 or 14, wherein the ethylenediaminetetraacetate is sodium edetate. The liquid agent according to any one of claims 13 to 15, wherein the alcohol is ethanol. The liquid agent according to any one of claims 13 to 16, which has a pH of 3.0 to 7.0. The pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained in an amount of 0.1 to 20 mg / ml. The liquid agent of any one. The pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained at 10 mg / ml according to any one of claims 13 to 17. The liquid preparation described. The liquid agent according to any one of claims 13 to 19, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one. The liquid preparation according to any one of claims 13 to 20, further comprising an isotonic agent. The liquid preparation according to claim 21, wherein the tonicity agent is sodium chloride. The liquid agent according to any one of claims 13 to 22, wherein coloring of the solution over time is suppressed.