JP2008037753A - Therapeutic and/or preventive agent for pruritus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical useful for therapy and/or prevention of pruritus. <P>SOLUTION: The pharmaceutical for therapy and/or prevention of pruritus includes as an effective ingredient a pyrazolone derivative represented by formula (I) (wherein R<SP>1</SP>is a hydrogen atom, an aryl group, a 1-5C alkyl group or an alkoxycarbonylalkyl group having a total of 3-6 C atoms; R<SP>2</SP>is a hydrogen atom, an aryloxy group, an arylmercapto group, a 1-5C alkyl group or a 1-3C hydroxyalkyl group; or R<SP>1</SP>and R<SP>2</SP>are jointly a 3-5C alkylene group; R<SP>3</SP>is a phenyl group substituted with the same or different 1-3 substituent groups selected from the group of a hydrogen atom, a 1-5C alkyl group, a 5-7C cycloalkyl group, a 1-3C hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group) or a physiologically acceptable salt thereof, or a hydrate or a solvate thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a medicament for treating and / or preventing pruritus comprising a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

  Pruritus is an unpleasant sensation that makes you want to scratch or rub the skin and is an important symptom in many skin diseases. In many skin diseases involving pruritus, the problem is that symptoms worsen or become chronic due to the patient himself scratching the affected area (also called scratching behavior).

  Known factors that cause pruritus include neuropeptides such as histamine, bradykinin, and substance P, proteolytic enzymes, prostaglandins, platelet activating factors, leukotriene B4, and lymphokines. For example, antihistamines, antiallergic agents, steroids, moisturizers and the like are known as drugs for suppressing pruritus of atopic dermatitis.

  It is also known that nitric oxide (NO) produced by nitric oxide synthase (NOS) is involved in pruritus caused by atopic dermatitis. Patent Document 1 describes an agent for treating pruritus comprising a compound that selectively inhibits neuronal nitric oxide synthase (nNOS) as an active ingredient.

  Furthermore, ion channel glutamate receptors are classified into NMDA type, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type, and kainate type subunits. These receptors are distributed not only in the central nervous system but also in the sensory nerve endings of the skin in humans and animals, and are suggested to be involved in, for example, transmission of pain (noxious stimuli). Patent Document 2 describes an agent for treating pruritus comprising a compound that selectively inhibits a glutamate receptor 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３参照）、過酸化脂質生成抑制作用（特許文献４参照）、抗潰瘍作用（特許文献５参照）、及び血糖上昇抑制作用（特許文献６参照）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 3), lipid peroxide production inhibitory action (see Patent Document 4), anti-ulcer action (see Patent Document 5), blood glucose elevation inhibiting action (see Patent Document 6), 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 pruritus.

JP 2002-138052 A JP 2003-81872 A 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 pruritus. The subject of this invention is providing the said pharmaceutical which has mechanisms other than an antihistamine action especially.

  In order to solve the above-mentioned problems, the present inventors examined the therapeutic effect on pruritus using a pyrazolone derivative represented by the formula (I). As a result, it was found that itching can be suppressed by administration of the pyrazolone derivative, and the present invention has been completed.

（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、掻痒の治療及び／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 pruritus which contains the pyrazolone derivative | guide_body 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 invention, the pruritus is cutaneous pruritus.
According to a preferred embodiment of the present invention, the pruritus is pruritus by artificial dialysis.
According to a preferred embodiment of the present invention, pruritus is pruritus caused by dermatitis, urticaria, eczema, insect bites, itch caused by hay fever or food allergy; pruritus associated with jaundice; renal disease, diabetes, collagen disease or malignant tumor Pruritus as a symptom; or pruritus caused by heat and cold stimulation.
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 another aspect of the present invention, there is provided an anti-pruritic agent comprising a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Provided.

  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 pruritus comprising the step of administering to a mammal, including a human, is provided.

  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. There is provided a method for inhibiting pruritus comprising the step of administering to a mammal, including a human.

  According to still another aspect of the present invention, a pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or water thereof for the manufacture of a medicament for the treatment and / or prevention of pruritus Use of a solvate or solvate is provided.

  According to still another aspect of the present invention, use of a pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof for the manufacture of an antipruritic agent Is provided.

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

  The medicaments for the treatment and / or prevention of pruritus according to the present invention, and anti-pruritic agents (in the present specification, these may be collectively referred to as the medicament of the present invention) are defined in the present specification. The pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate 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 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 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, 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.

  The dose of the medicament of the present invention is not particularly limited, but is usually 0.1 to 100 mg / kg body weight per day in the case of oral administration in general as the weight of the compound represented by formula (I) as an active ingredient, In the case of parenteral administration, it is 0.1 to 100 mg / kg body weight per day. 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, capsules, powders, fine granules, granules, etc. can be prepared using solid pharmaceutical additives, and syrups using liquid pharmaceutical additives Etc. can be prepared. In addition, injections, infusions, suppositories, transdermal 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 or intraarterially.

  The medicament of the present invention can be administered prophylactically prior to the onset of pruritus. In addition, for the patient who develops pruritus, 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.

  Pruritus to be administered with the medicament of the present invention is interpreted in the broadest sense. Pruritus includes all unpleasant sensations that make you want to scratch or rub the skin, and includes pruritus that occurs in the mucous membrane and cornea in addition to itching that occurs in the skin. For pruritus, itchy skin (for example, when the skin is itchy without showing any obvious skin symptoms; including senile skin pruritus); pruritus by artificial dialysis; dermatitis (atopic skin Inflammation, contact dermatitis, etc.), urticaria, eczema, insect bites, pruritus caused by hay fever or food allergy (preferably dermatitis, urticaria, pruritus due to eczema); pruritus associated with jaundice; kidney disease, Examples include, but are not limited to, pruritus as a complication of diabetes, collagen disease, or malignant tumor; and pruritus caused by heat and cold stimulation. The medicament of the present invention can be used for the treatment and / or prevention of pruritus as described above, and can also be used as an anti-pruritic agent for inhibiting pruritus as described above.

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

Synthesis Example: 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

Test example: Test using animal experiment model (1) Animals used
BALB / c mice (male, 6 weeks old, SEAC Yoshikazu) were bred for 1 week in the controlled area and then used for the test.

(2) Drugs used Weighed edaravone was completely dissolved with a small amount of 1N NaOH, then neutralized with HC1 to pH 7.2 to 7.6, and a solution obtained by measuring the volume with physiological saline was used as an injection solution.

(3) Test method Nine groups of BALB / c mice were used. Mice are sensitized by intravenous administration of 10 μg / 0.3 mL of anti-trinitrophenyl (TNP) monoclonal IgE in advance. 24 hours after the sensitization, 5 μL of an antigen solution (acetone / olive oil (3: 1) containing 0.75% dinitrofluorobenzene (DNFB)) was applied to both sides of the right auricle. Edaravone was intravenously administered at 10 mL / kg twice before the antigen application and 30 minutes after the antigen application. Exactly 1 hour after antigen application, each mouse is housed in a glass container for observation of behavior (diameter 18cm x height 20cm) that has been acclimatized in advance, and then the camera is photographed for 30 minutes in an unattended environment. did. Later, the number of pruritus behaviors for 30 minutes was counted and evaluated from the replay image of this video. In addition, the scratching behavior of the mouse was a scratching action for 1 second or more around the right auricle or around the right auricle by a hind leg, and facial scratching (grooming) by a front leg was excluded.

  In addition, immediately after video recording, the thickness of the right auricle of the mouse was measured using a dial gauge, and the amount of immediate edema was evaluated as a difference from the previously measured previous value.

(4) Test results
Table 1 shows the measurement results of the number of pruritus actions for 30 minutes.

  Intravenous administration of edaravone (0.1-10 mg / kg) suppressed IgE-dependent (allergic) pruritus behavior in a dose-dependent manner and was significant at doses of 1 mg / kg and higher. In the state observation, no sedation / somnolence or the like caused by drug administration was observed.

  Table 2 shows the results of evaluating the amount of immediate edema.

  Edaravone significantly inhibited the immediate skin edema response observed at the same time as pruritus at a dose of 1 mg / kg.

(5) Summary A dose-dependent and significant pruritus inhibitory effect was observed by intravenous administration of edaravone. On the other hand, in this administration schedule, the immediate edema response was confirmed to be suppressed at a dose of 1 mg / kg. It is considered that this edema inhibitory action was caused by a mechanism different from the pruritus inhibitory action. The BALB / c mice used in the experiment have little involvement of histamine in pruritus, but mast cell degranulation and histamine are involved in the immediate edema response of the skin (increased vascular permeability) observed simultaneously with pruritus. It is said that there is. Therefore, edaravone may suppress the edema reaction of the skin by a mechanism mediated by histamine including degranulation of mast cells in addition to the action of suppressing pruritus by a mechanism not mediated by histamine.

Claims (7)

The following formula (I):

(Wherein 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.)
Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, for treating and / or preventing pruritus. The medicament according to claim 1, wherein the pruritus is skin pruritus. The medicament according to claim 1, wherein the pruritus is pruritus by artificial dialysis. Pruritus is dermatitis, hives, eczema, insect bites, hay fever or pruritus caused by food allergy; pruritus associated with jaundice; pruritus as a complication of kidney disease, diabetes, collagen disease or malignant tumor; The medicament according to claim 1, wherein The pharmaceutical according to any one of claims 1 to 4, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one. 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 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 antipruritic agent which contains the pyrazolone derivative | guide_body shown by these, its physiologically acceptable salt, or those hydrates or solvates as an active ingredient. The antipruritic agent according to claim 6, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.