JP2005314348A - Drug for treatment of facial paralysis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel drug for the treatment and/or prevention of facial paralysis. <P>SOLUTION: The drug for the treatment and/or prevention of facial paralysis comprises as an active ingredient a specified pyrazolone derivative (e.g., 3-methyl-1-phenyl-2-pyrazoline-5-one), a physiologically acceptable salt thereof, or a hydrate or solvate of one of the former two. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

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

  Facial paralysis is a symptom of sudden movement of a part of the face or distorted face, and in addition to the above, pain and dizziness, loss of taste, It may be difficult to hear. Facial nerve palsy can be categorized as Bell's Palsy, Ramsay-Hunt Syndrome, otitis median facial palsy, traumatic facial palsy, and others.

60-70% of peripheral facial palsy is Bell palsy and 10-15% is Ramsey Hunt syndrome. The main treatment for Bell's palsy is drug therapy. Specifically, steroid hormones (eg, prednisolone, hydrocortisone, dexamethasone, betamethasone, adrenocorticotropic hormone (ACTH)), plasma expanders (eg, dextran 40, hydroxyethyl starch, etc.), microcirculatory improvers (eg, Prostaglandin E ₁ , pinpocetine, etc.), peripheral vasodilators (eg, papaverine hydrochloride, nicotinic acid, histamine preparations, ergotamine preparations, carnacrine etc.), metabolic improvers (eg, ATP, pantothenic acid etc.), vitamins (eg, , Cocarboxylase, pyridoxine hydrochloride, mecobalamin, etc.), diuretics (eg, glycerol, mannitol, diamox, lasix, etc.), antiviral agents (eg, acyclovir, vitarabine, etc.), and gamma globulin Such as are used formulation. However, it is desired to develop a drug that can more effectively treat and / or prevent facial nerve palsy and has fewer side effects.

（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. In addition, it is known that the present compound improves left hemiplegia (motor nerve palsy) (Non-patent Document 3). However, there has been no report on whether edaravone is effective for the treatment and / or prevention of facial palsy.

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 Inui Nagata, Drugs and Clinical Studies, Vol. 51, No. 10, 1009-1018, 2002

  An object of the present invention is to provide a medicament useful for treating and / or preventing facial nerve palsy, preferably peripheral facial palsy.

  In order to solve the above-mentioned problems, the present inventors examined the effect of suppressing the incidence of facial nerve palsy and the effect of recovering the numbness caused by using the pyrazolone derivative represented by the formula (I). As a result, it has been found that administration of the above-mentioned pyrazolone derivative can achieve the suppression of the incidence of facial nerve paralysis and the recovery of the onset of the paralysis, 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、顔面神経麻痺の治療及び／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.)
And a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient is provided.

According to a preferred embodiment of the present invention, the pyrazolone derivative of formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
According to a preferred embodiment of the present invention, the facial palsy is peripheral facial palsy. Specific examples of facial palsy include Bell palsy, Ramsey Hunt syndrome, otitis median facial palsy, and traumatic facial palsy.

  According to still another aspect of the present invention, there is provided a prophylactic and / or therapeutically effective amount of a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. Provided is a method of treating and / or preventing facial nerve palsy comprising 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 for the manufacture of a medicament for the treatment and / or prevention of facial palsy, or a salt thereof, Use of a hydrate or solvate of is provided.

  The medicament for treatment and / or prevention of facial nerve palsy according to the present invention can effectively prevent and suppress facial nerve palsy.

  The medicament for the treatment and / or prevention of facial palsy 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 the physiological Pharmaceutically 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 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, 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. And 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 dissolution-type 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 be administered prophylactically prior to the onset of facial nerve palsy. In addition, for the patient who developed facial nerve palsy, 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.

  Facial nerve palsy to be administered with the medicament of the present invention is interpreted in the broadest sense. Facial nerve palsy shall include all of Bell's Palsy, Ramsay-Hunt Syndrome, otitis median facial palsy, traumatic facial palsy, and other facial palsy. Facial nerve palsy can be classified into central facial palsy, where nerves close to the brain are numbing, and peripheral facial nerve palsy, where nerves far from the brain are numb, and the medicament of the present invention is as described above. Any of them can be applied. A preferred embodiment of facial nerve palsy to be administered with the medicament of the present invention is peripheral facial palsy, and the most preferred embodiments are Bell palsy and Ramsey Hunt syndrome.

  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

Example 1: Incidence of facial nerve palsy (method)
We investigated the effects of edaravone on the incidence of ischemic facial nerve palsy after block of the mesophyllous animals.
In the experiment, 53 Hartley normal white guinea pigs weighing 250 to 350 g were used. In all cases, blocking of the middle dural arterial rock-like branch was performed, and follow-up of the facial nerve function after blocking was continued for 2 weeks to evaluate the degree of paralysis. Blood blockage of the rock-like branch of the middle dural artery was performed under general anesthesia with intramuscular injection of Ketamin (35 mg / kg) and Xylazine (5 mg / kg). Blockage was performed as previously reported (Takeda T, Takeda S, Kozakura K, Saito H. An animal model of ischemic facial palsy. Eur Arch Otorhinolaryngol [Suppl]: S418-9, 1994).

  33 animals were given edaravone and the remaining 20 animals were given to control animals (group not receiving edaravone). The edaravone-administered animals were divided into two groups: edaravone-administered group I (21 animals) administered immediately after blockade and edaravone-administered group II (12 animals) administered from the second day after blockade. Edaravone was injected intraperitoneally at 3.0 mg / kg / day for one week. The evaluation of the degree of paralysis was normal (0): movement of both eyelids and lips was quick and strong, mild paralysis (1+): eyelid movement was weak but movement of eyelids was weak compared to the healthy side, moderate paralysis (2+ ): The movement of the eyelids was weak, the eyes could not be closed sufficiently, and severe paralysis (3+): The eyelids and lips did not move at all.

(result)
The distribution of the degree of facial nerve palsy in the edaravone non-administered group, the edaravone administered group I, and the edaravone administered group II is shown in FIG. In the edaravone non-administration group, onset 4th day, 80% of animals (six mild paralysis, five moderate paralysis, five severe paralysis) developed paralysis. From the 7th day onwards, the degree of paralysis showed a somewhat decreasing tendency, but there were 50% of animals with paralysis even in the 2nd week (3 mild paralysis, 4 moderate paralysis, 3 severe paralysis). On the other hand, the incidence of paralysis was significantly reduced in the edaravone administration group. In the edaravone administration group I administered edaravone immediately after blockade, 42.9% (2 mild palsy, 2 moderately palsy, 5 severely palsy) appear onset of paralysis with a considerable frequency 1/2 day after the blockade However, the incidence of paralysis subsequently declined, and the onset of paralysis markedly decreased to 19.0% in the second week of blockade. The rate of paralysis in the edaravone-administered group I is 1% risk on the 3rd and 4th days of blockage, 0.1% risk on the 5th day, 5% risk on the 6th day, and 7th to 13th day. The risk rate was 1% until the eyes and the risk rate was 5% on the 14th day (Fisher's direct probability method). In the edaravone administration group II in which edaravone was administered from the second day after blocking, 75% of animals (six mild paralysis, zero moderate paralysis, three severe paralysis) developed paralysis on the first day of blocking. After the third day of blockage, the incidence of paralysis declined and only 16.7% had paralysis in the second week. Statistically, the incidence of paralysis between the edaravone non-administered group and the edaravone-administered group II was significantly different on the 4th and 5th days with a risk rate of 1% or less and on the 13th day with a 5% risk rate (Fisher). Direct probability method).

Example 2: Detection of Reactive Oxygen Species (ROS) (Method)
We investigated the production of ROS in the facial nerve by blocking the branch of the middle dura of the animal. In this experiment, two medium dural vertebrate rock-like branch-branched animals (hereinafter referred to as animals indicate guinea pigs) prepared in the same manner as in Example 1 were used. In one animal, edaravone (3.0 mg / kg / day) was intramuscularly injected for 2 days immediately after the middural vein block-like branching. For detection of ROS, dihydrotetramethylrosamine (DHTMRos) from Molecular Probes was used as a detection probe. Excitation light is 550 nm and fluorescence is 574 nm. ROS was detected 6 hours after the second day of edaravone intramuscular injection. Under deep anesthesia with Nembutal, the cochlea was removed, the cochlear bone wall was removed under a stereomicroscope, and the cochlear outer wall and cochlear basement plate were collected. After loading with DHTMRos, the specimen was washed with artificial perilymph and placed in a chamber kit filled with artificial perilymph, and observed with a fluorescence microscope (Nikon Eclipse E600) (FIG. 3).

(result)
FIG. 2 shows a comparison of ROS production with and without edaravone administration. In the edaravone-untreated animals, production of extremely prominent ROS was observed in the facial nerve on the blocking side of the middle dural arterial rock-like branch. Such excessive ROS expression was not seen on the non-blocking side. In edaravone-treated animals, production of ROS was not significant on both the non-blocking and non-blocking sides. The production of this ROS was measured at 30 points of fluorescence emission intensity arbitrarily selected from the facial nerve, and the average value and standard deviation were obtained. Although the fluorescence intensity of the facial nerve is significantly increased by blocking (p <0.01, t-test), there is no increase in ROS production in animals treated with edaravone, and there is a significant difference compared to the fluorescence intensity on the non-blocking side. No (t-test).

Example 3: Morphological evaluation of facial neuropathy (method)
Four animals that developed severe paralysis due to blockage of the rock-like branch of the middle dural vein animal were divided into two groups, an edaravone non-administration group and an edaravone administration group. In the edaravone administration group, edaravone (3.0 mg / kg / day) was administered for one week from the day of onset of paralysis. After each month, the degree of paralysis was followed for 1 month, and then perfusion was fixed under deep anesthesia with Nembutal, and the temporal bone was removed. The excised temporal bone was decalcified like a mold, embedded in paraffin and celloidin, then sliced, a tissue specimen for light microscopy was prepared, triple-stained with Luxor First Blue, Hematoxylin, and Eosin, and microscopically examined .

(result)
One month after the onset of paralysis, facial facial muscle movement tended to improve regardless of whether or not edaravone was administered. FIG. 4 shows representative tissue changes in the facial nerves of the knee and mastoid area of the edaravone-administered animal and the edaravone-untreated animal. The animals treated with edaravone showed movements in the facial muscles from the third week. In animals not treated with edaravone, movements were seen in the facial muscles immediately before preparation of the tissue specimen, and the degree of paralysis was determined to be 2+. The degree of nerve damage was high in the mastoid, regardless of whether or not edaravone was administered, and myelin staining was reduced and neurodegeneration accompanied by detachment was observed. On the other hand, in the knee, both edaravone-administered and non-administered animals showed low staining throughout, indicating that neurodegeneration remains. It was suggested that the damage was in the process of recovery. A large difference between edaravone and non-edaravone animals was found in the cell bodies of the knee ganglia. In edaravone non-administered animals, ganglion cell bodies were highly denatured, but in edaravone-treated animals, cell bodies remained and did not show clear degeneration.

Summary of Examples 1-3:
By selectively blocking the rock-like branch of the middle dural artery of the guinea pig, an ischemic paralysis model animal can be created easily and at a high rate without directly damaging the facial nerve (Takeda T , Takeda S, Kozakura K, Saito H. An animal model of ischemic facial palsy. Eur Arch Otorhinolaryngol [Suppl]: S418-9, 1994; and Takeda T, Takeda S, Kozakura K, Saito H. Intratemporal facial nerve blood flow in guinea pigs. Am J Otol 18: 252-6, 1997). The paralysis process of this model animal follows a process very similar to that of human facial nerve paralysis (Setuko Takeda, Taizo Takeda, Haruo Saito: Progression of facial nerve paralysis in rock-like branch blockers. Oto-nose 42: 1082-1088, 1996 ). In Examples 1 to 3, the prophylactic / therapeutic effect on facial nerve palsy caused by edaravone was evaluated using this ischemic palsy model animal.

  In the edaravone-administered group I which received edaravone at the same time as rocky branch blockage, the incidence of facial nerves was significantly reduced. In addition, moderate / severe paralysis developed within 2 days of blockage, but the incidence of paralysis was also significantly reduced in the edaravone-administered group II administered edaravone at this time. However, there was no difference in the incidence of severe paralysis according to whether or not edaravone was administered in at least 2 weeks of follow-up. However, the tissue damage of the facial nerve in the animals that received edaravone for 1 week from the onset of severe paralysis was clearly milder in the knee than in the animals that did not receive edaravone. It is particularly noteworthy that the cell body of the knee ganglion was not significantly damaged in the edaravone-treated animals. There was no difference in tissue damage between the edaravone-treated animals and non-treated animals, although there was no significant difference in facial expression movement between the edaravone-treated animals and the non-treated animals. It is thought that reproduction is progressing. From the above results, edaravone can be expected to promote facial nerve regeneration.

FIG. 1 shows the distribution of edaravone administration and facial nerve paralysis. In the edaravone non-administered group, 80% of the animals showed onset of paralysis on the 4th day after blocking, but in the edaravone-administered group, the onset of paralysis was clearly reduced. Arrow indicates edaravone administration period. FIG. 2 shows a comparison of ROS production with and without edaravone administration. Blocking of the medial dural arterial rock-like branch leads to significant ROS production in the facial nerve, but administration of edaravone suppresses ROS production. FIG. 3 shows edaravone administration and facial nerve fluorescence intensity. ROS production is significantly increased on the rocky side, but ROS production decreases markedly when edaravone is administered. FIG. 4 shows edaravone administration and facial nerve tissue damage. Because of the development of severe paralysis, neurodegeneration is quite advanced in both the knee and mastoid. However, the cell body of the knee ganglion remains in the edaravone-administered animals, and further, the staining of the nerve tends to recover at the knee level. It is suggested that nerve regeneration has reached the level of the knee. A: Knee of edaravone administration group B: Knee of edaravone non-administration group C: Mastoid of edaravone administration group D: Mastoid of edaravone non-administration group

Claims (4)

Formula (I) below:

(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.)
Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, a medicament for the treatment and / or prevention of facial nerve palsy. 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 facial nerve palsy is peripheral facial palsy. The medicament according to claim 1 or 2, wherein the facial nerve palsy is Bell palsy, Ramsey Hunt syndrome, otitis median facial palsy, or traumatic facial palsy.

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