WO2003064395A1 - Preventive or therapeutic agents for neurodegenerative diseases - Google Patents

Abstract

The invention aims at providing drugs effective in the prevention and/or treatment of neurodegenerative diseases, particularly, intractable or immune neurodegenerative diseases. The invention provides preventive or therapeutic agents for neurodegenerative diseases caused by increased cerebrospinal fluid 3-NT (3-nitrotyrosin) which contain as the active ingredient pyrazolone derivatives represented by the general formula (I) or physiologically acceptable salts thereof, or hydrates or solvates of both: (I) wherein R1 is hydrogen, aryl, or the like; R2 is hydrogen, aryloxy, or the like; and R3 is phenyl bearing one to three substituents.

Description

 Specification

 Agent for preventing or treating neurodegenerative diseases

 The present invention relates to a preventive or therapeutic agent for a neurodegenerative disease. Background art

 The definition of a neurodegenerative disease is unclear, and if it were to be defined, clinical manifestations of disorders of one system (for example, the pyramidal tract, the posterior chordal system, the spinocerebellar system, etc.) alone or in combination A disease that gradually develops and gradually progresses, and whose true cause is unknown, is collectively referred to as a neurodegenerative disease. [Kanazawa, Ichiro: Latest. College of Internal Medicine, 68: p. 3, Nakayama Shoten (1 997)].

 Representative of intractable neurodegenerative diseases or immune neurological diseases include Guillain-Barre syndrome (GBS: Guil 1 ia nBarre Syndrome), chronic demyelinating inflammatory polyneuropathy (CI DP) : Chronic Demyelinating In Irammatory Pollyneuropathy), Fisher syndrome, spinocerebellar degeneration, and Alzheimer's disease.

 GBS affects about 2 in 100,000 people, and not only does paralysis of the limbs progress, but a quarter of the patients cannot breathe and may need a ventilator.

 The onset of CIDP may be acute, subacute, or chronic, but refers to neuritis that progresses slowly or recurs or recurs repeatedly. The affected area is the motor paralysis of the extremities, sensory paralysis (dullness, abnormal sensation) due to impairment of the motor nerves connected to the limbs and trunk muscles from the spinal cord and the sensory nerves entering the spinal cord from the skin and joints. Etc.) occur. Occasionally, cranial nerve dysfunction causes eye movement paralysis (such as diplopia) and, rarely, respiratory paralysis.

In Fisher's syndrome, the eyes become stuck, the body sways, and you cannot walk well It is considered a disease similar to GBS.

 Spinocerebellar degeneration is a general term for an unexplained degenerative disease whose main symptom is cerebellar or spinal ataxia, and whose lesion is located in the nucleus or conduction pathway of the cerebellum or spinal cord. In general, the onset is slow but progressive, and some types of disease are hereditary. Head C T and MR I often cause atrophy of the cerebellum and brain stem. The main symptom is cerebellar or retrospinal ataxia, but some types have autonomic and spastic paraplegia as the main symptoms, as well as pyramidal and extrapyramidal symptoms. In some cases, the symptoms are variable.

 Alzheimer's disease is a progressive dementia that develops in the elderly (45-65 years old). Pathologically, there are numerous senile plaques and neurofibrillary tangles in the brain. Senile dementia due to so-called spontaneous aging, which occurs in the senile period of 65 years or older, is called Alzheimer-type senile dementia because there is no essential difference in pathological conditions. The number of patients with this disease is increasing with the elderly population, making it a socially important disease.

 Treatment of immune neurological disorders includes corticosteroid therapy, plasma exchange therapy, and immunoglobulin intravenous therapy. The efficacy of high-dose intravenous immunoglobulin therapy and simple plasmapheresis has been established, but there is no effective therapeutic agent using a compound, and the development of an immediate therapeutic agent is desired. Disclosure of the invention

 An object of the present invention is to provide a medicament useful for preventing and / or treating a neurodegenerative disease, preferably a refractory neurodegenerative disease or an immune neurological disease.

 The present inventors have found that a medicament containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient has an inhibitory action on 3-NT level increase in cerebrospinal fluid, The present inventors have found that they are useful as agents for preventing and treating neurodegenerative diseases, and completed the present invention.

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 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, and carbon atoms having 1 to 5 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, and 1 to 5 carbon atoms. Alkyl, 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, total carbon Alkoxycarbonyl having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms, alkynoleamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, A phenyl substituted with 1 to 3 identical or different substituent (s) selected from the group consisting of cyano, hydroxyl, nitro, amino, and acetoamide; or a physiologically acceptable salt thereof. Or 3-hydrate in cerebrospinal fluid containing hydrate or solvate thereof as an active ingredient

(3—Nitrotyrosin) An agent for preventing or treating a neurodegenerative disease caused by an increase in the value is provided.

 Preferably, the prophylactic or therapeutic agent for a neurodegenerative disease of the present invention comprises 3-methyl-1-phenyl-2-pyrazolin-15-one or a physiologically acceptable salt thereof, or a hydrate or solvent thereof. It contains a sum as an active ingredient.

 Preferably, the preventive or therapeutic agent for a neurodegenerative disease of the present invention is a 3-NT value increase inhibitor.

 Preferably, the neurodegenerative disease caused by an increase in 3-NT level in the cerebrospinal fluid is an intractable neurodegenerative disease or an immune neurological disease.

Preferably, the refractory neurodegenerative disease or immune neurological disease is Guillain-Barre syndrome Group, chronic demyelinating inflammatory polyneuritic peripheral neuritis, Fisher syndrome, spinocerebellar degeneration, and Alzheimer's disease.

 According to another aspect of the present invention, a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained as an active ingredient. —An NT value increase inhibitor is provided.

 Preferably, a 3-NT value increase inhibitor comprising 3-methinolay 1-phenyl-12-pyrazolin-15-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Is provided.

 According to still another aspect of the present invention, there is provided a mammal comprising a human containing an effective amount of the pyrazolone derivative represented by the above formula (I), a physiologically acceptable salt thereof, or a hydrate or solvate thereof. There is provided a method for preventing or treating a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid, comprising a step of administering to a animal.

 According to still another aspect of the present invention, a pyrazolone derivative represented by the formula (I) or a physiology thereof for producing a preventive or therapeutic agent for a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid. The use of chemically acceptable salts, or hydrates or solvates thereof, is provided. BEST MODE FOR CARRYING OUT THE INVENTION

 The agent for preventing or treating a neurodegenerative disease according to the present invention (hereinafter also referred to as the agent of the present invention) is a pyrazolone derivative represented by the formula (I) defined herein or a physiologically acceptable salt thereof, or Includes hydrates or solvates thereof. Among these, it is preferable to use the above-mentioned monohydrate of the pyrazopine derivative.

 The compound represented by the formula (I) used in the present invention has the following formula

It can also have the structure represented by (II) or (I "). For convenience, one of the tautomers is shown in the formula (I) in the present specification, but those skilled in the art will recognize the following tautomers. The active ingredient of the drug of the present invention is represented by the following formula () or

(1 ") or a physiologically acceptable salt thereof, or a compound thereof. Hydrates or solvates may be used.

式 （I ) において、 R ¹の定義におけるァリール基は単環性又は多環性ァリール 基のいずれでもよレ、。 例えば、 フエニル基、 ナフチル基などのほか、 メチル基、 ブチル基などのアルキル基、 メ トキシ基、 ブトキシ基などのアルコキシ基、 塩素 原子などのハロゲン原子、 又は水酸基等の置換基で置換されたフエニル基等が挙 げられる。 ァリール部分を有する他の置換基 （ァリールォキシ基など） における ァリール部分についても同様である。 (In,)

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

R \ R ² and alkyl groups of 1 to 5 carbon atoms in the definition of R ³ are straight chain, it may be either branched. Examples 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, a pentyl group and the like. The same applies to the alkyl moiety in other substituents having an alkyl moiety (alkoxycarbonylalkyl group).

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

The aryloxy group in the definition of R ² includes p_methylphenoxy group, p-methoxyphenoxy group, p-chlorophenoxy group, p-hydroxyphenoxy group and the like. And a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorophenylmercapto group, and a p-hydroxyphenylmercapto group.

Examples of the hydroxyalkyl group having 1 to 3 carbon atoms in the definition of R ² and R ³ include hydr Roxymethyl group, 2-hydroxyl group, 3-hydroxypropyl group and the like. 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, it is a alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group, main butoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, Penchiruokishi group and the like, total Examples of the alkoxycarbonyl group having 2 to 5 carbon atoms include a methoxycanolebonyl group, an ethoxycanoleboninole group, a propoxycarboninole group, and a butoxycarbonyl group, and an alkylmercapto group having 1 to 3 carbon atoms. Examples thereof include a methyl mercapto group, an ethyl mercapto group, and a propyl mercapto group.Examples of the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, and a butylamino group. As the aralkylamino group having a total of 2 to 8 carbon atoms, a dimethylamino group, a getylamino group, Puropirua amino group, Jibuchiruamino group and the like.

 As the compound (I) suitably used as an active ingredient of the drug of the present invention, for example, the following compounds can be mentioned.

 3-Methinole 1-phenyl-1-birazolin-1 5-one;

 3-Methyl-1 _ (2-methylphenyl) -1-2-pyrazolin-1-5-

 3-Methinole 1- (3-Methylphenyl) _2-Pyrazolin-1-5-one

 3-Methyl-1- (4-methylphenyl) -1-2-pyrazolin-1-5-

 3-methyl-1- (3,4-dimethylphenyl) -12-pyrazolin-15-one;

 1- (4-Ethynolephenyl) -1-3-Methyl-1-pyrazolin-1-5-one; 3-Methyl-1- (4-propylphenyl) -1-2-pyrazolin-1-5-one; 1- (4-butylphenyl) -1 3-Methyl-1-pyrazolin-5-one; 1- (3-Triphnorelolomethylpheninole) -1-3-methyl-12-pyrazolin-1-5-one;

1- (4-trifluoromethylphenyl) 1 3-methyl-1 2-pyrazolin-1 5 —On;

 1- (2-Methoxyphenyl) 1-3-methyl-2-pyrazolin-1-5-one 1- (3-Methoxyphenyl) 1-3-Methyl-2-pyrazolin-1-5-one 1-1 (4-Methoxyphenyl) 1-3 —Methyl-1-pyrazolin-15-one-11- (3,4-dimethoxyphenyl) -1-3-methyl1-2-pyrazolin-15-one;

 1- (4-ethoxyphenyl) -1-3-methyl-2-pyrazolin-15-one;

3-Methyl-11- (4-propoxyphenyl) 1-2-pyrazolin-15-one; 1- (4-butoxyphenyl) -1-3-Methyl-1-pyrazolin-15-one; 1- (2-chlorophenyl) 1-Methinole 1-Pyrazolin-5-one 1- (3-Chlorophenyl) 1-3-Methyl-1 2-pyrazolin-1-5-one 1- (4-Chlorophenyl) 1-3-Methinole 1-Pyrazolin One 5-one 1- (3,4-dichloropheninole) one 3-methinole 2-pyrazolinone 5-one;

 1- (4-bromophenyl) 1-3-methynole-1-pyrazolin-1 5-one; 1- (4-fluorophenyl) 1-3-methyl-1-pyrazolin-1 5-one; 1- (3-chloro-1-4 —Methinolephenyl) -1-methyl-1-2-pyrazolin-15-one;

 1- (3-methylmercaptophenyl) 1-3-methyl-12-pyrazolin-1 5-one;

 1- (4-methylmercaptophenyl) -1-3-methyl-1-pyrazolin-1-one;

 4- (3-Methyl-15-oxo-1 2-pyrazoline-1 T) Benzoic acid; 1- (4-Ethoxycarbinolephenine) 1-3-Methyl-1-2-pyrazolin-1 5

—On;

1- (4-Nitrophenyl) -1-3-methyl-1-pyrazolin-1-5-one; 3-ethyl-11-phenyl-1-birazolin-1-one; 1-phenyl-1-propynole 2-birazolin-1-5-one; 1,3-diphenyl-2-pyrazolin-1- 5-one;

 3-phenyl-1- (p-tolyl) -1-pyrazolin-5-one;

 1- (4-Methoxyphenyl) 1-3-phenyl 2-pyrazolin-1-5-one; 1- (4-chloropheninole) 1-3-phenylinole 2-pyrazolin-5-one; 3,4-dimethinole 1 1-Feninore 1-Birazolin-5-one;

 4-isobutyl-1-methynole-1-phen-2-ole-2-pyrazolin_5_one;

4- (2-Hydroxyshetyl) -1-3-Methyl-1-phenyl-1-pyrazolin-1-one;

 3-Methinole 4-phenoxy 1 1-Feninole 2 _pyrazolin-1-5-one; 3-Methinole 4-Feninolemercapto 1 1 -Feninole 2 -Vilazoline 1 5-one;

 3,3 ', 4,5,6,7-hexahydro-2-phenyl-2-H-indazole-3-one;

 3- (ethoxycarboninolemethyl) _ 1-Feninole _ 2-pyrazolin-1-one;

 1-Phenyl-1-birazolin-5-one;

 3-methyl-1-pyrazolin-1-5-one;

 1,3-dimethyl-1-pyrazolin-15-one;

 1-Echinore 1-Metinole 2-Vilazoline-5-one;

 1-butyl-1-methyl-1-birazolin-5-one;

 1-(2-Hydrochietinole) 1-3_methyl-1 2-pyrazolin-1 5-one;

1-Cyclic hexyl 3-Methinole 2-Virazoline 1 5-one;

 1-benzyl-1-methinole 2-birazolin-1-5-one;

 1- (α-naphthyl) _3_methyl_2-pyrazolin-1-5-one;

 1-methyl-1-3-phenyl-1-birazolin-1-5-one;

3-methyl-1- (4-methylphenyl) -1-pyrazolin-15-one; 1- (4-butylphenyl) 1-3-methyl-12-pyrazolin-1 5-one; 1- (4-methoxyphenyl) 1-3-methyl-1 2-pyrazolin-1 5-one; 1- (4-butoxyphenyl) 13 —Methyl-2-pyrazolin-1-5-one; 1- (4-chlorophenyl) -1-3-methyl-1-pyrazolin-15-one; 1- (4-hydroxyphenyl) -1-3-methyl-1-pyrazolin-1-5 1- (3,4-dihydroxyphenyl) -1-3-methyl-1-pyrazolin-1-on;

 1- (2-Hydroxyphenyl) 1-3-Methyl-1 2-pyrazolin-1 5-one 1- (3-Hydroxyphenyl) 1-3-Methyl-1 2-pyrazolin-1 5-one 1- (4-Hydroxyphenyl) 1-Methyl_2-Pyrazolin-1-5-one 1- (3,4-Hydroxyphenyl) -1-Methyl-2-pyrazolin-15-one;

 1- (4-hydroxyphenyl) -1-3-phenyl-1-pyrazolin-5-one;

 1- (4-hydroxymethylpheninole) 1-3-methyl-1 2-pyrazolin-1 5-one;

 1- (4-aminophenyl) 1-3-methyl-2-pyrazolin-1-5-one; 1- (4-methylaminophenyl) 1-3-methyl-12-pyrazolin-15-one;

 1- (4-ethylaminophenyl) 1-3-methyl-1-pyrazolin-5-one;

 1- (4-butylaminophenyl) 1-3-methyl-12-pyrazolin-15-one;

 1- (4-dimethylaminophenyl) -1-3-methyl-2-pyrazolin-15-one;

1- (acetamidophenyl) -1-3-methyl-2-pyrazolin-15-one; and 11- (4-Cyanophenyl) -13-methyl-12-pyrazolin-15-one As an active ingredient of the drug of the present invention, a free form compound represented by the formula (I) is physiologically acceptable. Salts may be used. Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, and phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, and glucuronic acid. Salts with organic acids such as maleic acid, fumaric acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, nicotinic acid, tartaric acid; Salts with alkali metals such as sodium and potassium; Salts with earth metals; ammonia, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyxethylene) piperazine, 2-amino-1-methyl-11-propanol, ethanolamine, N— And salts with amines such as methylglutamine and L-glutamine. Further, a salt with an amino acid such as glycine may be used.

 As an active ingredient of the drug of the present invention, a hydrate of the compound represented by the above formula (I) or a physiologically acceptable salt thereof, or a compound represented by the above formula (I) or a compound thereof A solvate of a physiologically acceptable salt may be used. The type of the organic solvent that forms the solvate is not particularly limited, and examples thereof include methanol, ethanol, ether, dioxane, and tetrahydrofuran. Further, the compound represented by the above formula (I) may have one or more asymmetric carbons depending on the type of the substituent, and may have a stereoisomer such as an optical isomer or a diastereomer. is there. As the active ingredient of the medicament of the present invention, pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used.

 All of the compounds represented by the formula (I) are known compounds, and are described in Japanese Patent Publication No. 5-31523, JP-A-62-108814, and the like. Thus, a person skilled in the art can easily synthesize.

The administration form of the agent for preventing or treating a neurodegenerative disease of the present invention is not particularly limited, and it can be administered orally-parenterally. Preferably, it may be administered parenterally, intravenously by injection or infusion. As the prophylactic or therapeutic agent for a neurodegenerative disease of the present invention, one or more of the pyrazolone derivative of the formula (I) or a salt thereof may be administered as it is to a patient. And a pharmacologically and pharmaceutically acceptable additive, and are preferably provided as a formulation in a form known to those skilled in the art.

Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, dissolving agents or dissolving aids, isotonic agents, _P H adjusting agents, stabilizers, propellants, and can be used an adhesive or the like. Examples of preparations suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups.Examples of preparations suitable for parenteral administration include: Examples include injections, drops, and suppositories.

 Formulations suitable for oral administration include, as excipients, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; Disintegration aid; Binder such as hydroxypropynolecellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; Lubricant such as magnesium stearate or talc; Hydroxypropylmethylcellulose , Sucrose, polyethylene dalicol or titanium oxide; and base materials such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat.

 Suitable formulations for injection or infusion include: solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, propylene glycol, etc .; glucose, sodium chloride, Pharmaceutical additives such as D-mannitol, glycerin and other tonicity agents; pH regulators such as inorganic acids, organic acids, inorganic bases and organic bases can be used.

Formulations suitable for injection or infusion include dissolving agents or dissolving agents which can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and propylene glycol. Auxiliaries; isotonic agents such as glucose, sodium salt, D-mannitol, glycerin, etc .; additives for pharmaceutical preparations such as pH adjusters such as inorganic acids, organic acids, inorganic bases or organic bases may be added. Les ,.

 It should be noted that a brain protectant (drip) containing the pyrazolone derivative of the formula (I) as an active ingredient is already used in clinical practice (generic name: edaravone, trade name)

"Radicut": manufactured and sold by Mitsubishi Pharma Corporation. As the agent for preventing and treating neurodegenerative diseases of the present invention, the above-mentioned | S preparation can be used as it is.

The dose of the medicament of the present invention can be appropriately selected depending on the purpose of preventing or treating a neurodegenerative disease, the age and condition of a patient, and the like. : Ability to administer about L0 OmgZkg by injection or infusion It is preferable to orally administer about 0.1 to 100 mg / kg. In the case of administration by injection, it is preferable to use, for example, injections described in JP-A-63-132833. The above compound as an active ingredient of the medicament of the present invention is highly safe (mouse intraperitoneal LD ₅ 2012 mgZk g; rat oral _{LD 50 3, 500mg / kg:} . R egistryof To xic E ifectsof Ch em ical Su bstances, 1981–1982), has also been shown to be noncarcinogenic (National Cancer Institute Report, 89, 1978).

The agent of the present invention may be a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid, preferably a refractory neurodegenerative disease or an immune neurological disease, more preferably Guillain-Barre syndrome group, or chronic demyelinating inflammation. It is effective for the prevention or treatment of polyneuritis nervosa, Fisher syndrome, spinocerebellar degeneration, or Alzheimer's disease. That is, the cryogen of the present invention can be administered prophylactically prior to the onset of the above-mentioned neurodegenerative disease. The agent of the present invention can be administered to the patient for the purpose of reduction or the like. Furthermore, the agent of the present invention is also useful as an inhibitor of 3-NT level elevation in cerebrospinal fluid. The present invention will be described in more detail with reference to the following examples. It is not limited to the examples. Example

Synthesis example: Synthesis of 1-phenyl_3-methyl-12-pyrazolin-15_one (hereinafter referred to as edaravone)

 13.0 g of ethyl acetate acetate and 10.8 g of phenylhydrazine were added to 5 Om1 of ethanol, and the mixture was stirred under reflux for 3 hours. After allowing the reaction solution to cool, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the title compound (11.3 g) as colorless crystals.

Yield 67%

Melting point 127.5-128.5 ° C Experimental example 1

 ALS patients were infused intravenously with edaravone at 30 mgZ days for 2 weeks, and cerebrospinal fluid was collected before and after administration, and the 3-NT value in the cerebrospinal fluid was measured by enzyme immunoassay. A nitrotyrosine measurement kit (Cayman Chemical, domestic agent Funakoshi) was used for EIA measurement, and statistical analysis was performed by the usual paired t-test.

The results are shown in Table 1 below. 3_NT levels in cerebrospinal fluid of ALS patients who received edaravone decreased significantly.

3-NT concentration (ng / ml)

 Patient

 Before administration Difference after administration

 A 2.055 0.640 one 1.415

 B 3.504 0.763 -2.741

 C 0.488 0.958 0.470

 D 0.544 1.098 0.554

 E 1.533 0.407 one 1.126

 o

 F 0.588 -0.420

 G 0.981 0.870 -0.111

 H 0.800 0.393 --0.407

 I 1.937 0.482-1.455

 J 1.876 0.956 -0.920

 Number of cases 10 10 10

 Average 1.4306 0.6735 -0.7571

 S D 0.9509 0.3038 0.9942

 t value---2.408

 p- value-― 0.0394

Industrial applicability

 Since the pyrazolone derivative of the formula (I) described in the present specification has an action of suppressing an increase in 3-NT level in cerebrospinal fluid, it prevents neurodegenerative diseases, in particular, intractable neurodegenerative diseases or immune neurological diseases. Alternatively, a highly safe drug useful as a therapeutic agent can be provided.

The contents of the description of Japanese Patent Application No. 2002-24794, which is the application on which the priority claimed by the present application is based, are all incorporated herein by reference as a part of the disclosure of the present specification. ₍

Claims

Claims The following formula (I)

(Wherein, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, arylino remercapto, carbon number 1 Represents 5 alkyl or 1-3 hydroxyalkyl, or R ¹ and R ² together represent alkylene having 3-5 carbon atoms, R ³ is a hydrogen atom, and 1-5 carbon atoms. Alkyl, cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or pheninole, or alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, Alkoxycarbonyl having 2 to 5 carbon atoms, 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, carboxyl A pyrazolone derivative represented by the following formula: or a physiologically acceptable salt thereof, which is substituted with 1 to 3 identical or different substituents selected from the group consisting of cyano, hydroxyl, nitro, amino, and acetoamide. Or 3-hydrate in cerebrospinal fluid containing hydrate or solvate thereof as an active ingredient (3-Nitrotyrosin) An agent for preventing or treating a neurodegenerative disease caused by an increase in the value.  2. The nerve according to claim 1, comprising 3-methyl-1-phenyl-1-birazolin-15-one, a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Agent for preventing or treating degenerative diseases. 3.3. The preventive or therapeutic agent for a neurodegenerative disease according to claim 1 or 2, which is an inhibitor of an increase in NT value. 4. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 3, wherein the neurodegenerative disease caused by an increase in 3-NT level in the cerebrospinal fluid is an intractable neurodegenerative disease or an immune neurological disease. .  5. The group of intractable neurodegenerative diseases or immunological neurological diseases consisting of Guillain-Barre syndrome, chronic demyelinating inflammatory polymorphic peripheral disease ^ Fisher syndrome, spinocerebellar degeneration, and Alzheimer's disease The preventive or therapeutic agent according to claim 4, which is a disease selected from the group consisting of:  6. The following formula (I):

(In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, carbon number 1 to 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 , Cycloalkyl having 5-7 carbon atoms, carbon number: hydroxyalkyl having! -3, benzyl, naphthyl or phenyl, or alkoxy having 1-5 carbon atoms, hydroxyalkyl having 1-3 carbon atoms, total carbon Alkoxycarbonyl having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms, alkyl / reamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, A phenyl substituted with 1 to 3 identical or different substituent (s) selected from the group consisting of cyano, hydroxyl, nitro, amino and acetoamide, or a physiologically acceptable salt thereof. Or a hydrate or a solvate thereof as an active ingredient. 7.3_Methyl-1-phenyl-2-pyrazolin-1-one, its hydrate, Or the inhibitor of 3-NT value elevation according to claim 6, comprising a pharmacologically acceptable salt thereof as an active ingredient.