WO2004037249A1

WO2004037249A1 - Agent for alleviation of functional disorder after cardiopulmonary resuscitation

Info

Publication number: WO2004037249A1
Application number: PCT/JP2003/013769
Authority: WO
Inventors: Katsunori Akiyama
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2002-10-28
Filing date: 2003-10-28
Publication date: 2004-05-06
Also published as: AU2003275707A1

Abstract

A medicine useful for the alleviation of functional disorders after cardiopulmonary resuscitation. The agent for alleviation of functional disorders after cardiopulmonary resuscitation contains as an active ingredient a pyrazolone derivative represented by the following formula (I): (I) (wherein R1 represents hydrogen, aryl, etc. and R2 represents hydrogen, aryloxy, etc. or R1 and R2 in cooperation represent C3-5 hydroxyalkyl; and R3 represents hydrogen, C1-5 alkyl, phenyl, etc.), a physiologically acceptable salt of the derivative, or a hydrate or solvate of either.

Description

Specification

Agent for improving dysfunction after cardiopulmonary resuscitation

The present invention relates to an agent for improving dysfunction after cardiopulmonary resuscitation, comprising a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Background art

Within a few tens of seconds after cardiac arrest, consciousness disappears, and then breathing stops. It is generally believed that irreversible changes occur in the brain if blood flow resumes within three to five minutes and oxygen is not supplied. Therefore, how to resume effective circulation and respiration as quickly as possible is the point of the 月 resuscitation method. Cardiopulmonary resuscitation includes primary life support using hands and mouth without using assistive devices, and secondary life support using drugs or medical devices. Will continue without distinction. Primary rescue treatment for cardiopulmonary resuscitation includes securing the airway, artificial respiration and heart massage.

If the cardiopulmonary function is restored but the cardiopulmonary is stopped for a long period of time, the cerebral nerve cells will have secondary tissue damage after cerebral blood flow resumes, and eventually irreversible tissue damage Cause No definitive treatment for cerebral resuscitation has been established today, and therapies to improve dysfunction after cardiopulmonary resuscitation are awaited.

On the other hand, 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, Aryl mercapto, alkyl having 1 to 5 carbons or hydroxyalkyl having 1 to 3; or R ¹ and R ² together represent alkylene having 3 to 5 carbons; R ³ is a hydrogen atom, carbon Alkyl having 1 to 5 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, 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, cyano, Represents a phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a nitro, an amino, and an acetoamide. The pyrazolone derivatives represented by the following formulas are used as pharmaceuticals: normalization of brain function (Japanese Patent Publication No. 5-315253), and inhibition of lipid peroxide production (Japanese Patent Publication No. 5-3512). No. 8), an anti-ulcer effect (Japanese Patent Application Laid-Open No. 3-215425), and a blood glucose elevation inhibitory effect (Japanese Patent Application Laid-Open No. 3-215425) are known.

In addition, among the compounds of the above formula (I), a preparation containing 3-methyl-1-phenyl-2-pyrazolin-15-one as an active ingredient has been a cerebral protective agent (generic name) since June 2001. "Edaravone", brand name "Radicut": manufactured and sold by Mitsubishi Pharma Corporation. This “pedaravone” has been reported to have high reactivity to active oxygen (Kawai, H., et al., J. Phamacol. Exp. Ther., 281 (2), 921, 1997; And Wu, TW. Et al., Life Sci, 67 (19), 2387, 2000). In this way, edaravone is a free radicals force venger that functions to prevent cell damage by eliminating various free radicals including active oxygen. However, to date, there has been no report on whether edaravone is effective in improving dysfunction after cardiopulmonary resuscitation. Disclosure of the invention

An object of the present invention is to provide a medicament useful for improving dysfunction after cardiopulmonary resuscitation.

In order to solve the above-mentioned problems, the present investigators have given patients with cardiopulmonary arrest The pyrazolone derivative represented by the formula (I) was administered, and the effect was examined. As a result, they found that administration of the pyrazolone derivative could improve dysfunction after cardiopulmonary resuscitation and completed the present invention.

That is, according to the present invention, 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; R ² represents a hydrogen atom, R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms, an aryl mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; R ³ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a carbon atom; Alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms Group, alkylamino group with 1-4 carbon atoms, total carbon number 2 8 substituted with 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group, a halogen atom, a trifluoromethyl group, a propyloxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetoamide group. Represents a phenyl group.)

Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, for improving a dysfunction after cardiopulmonary resuscitation.

According to a preferred embodiment of the present invention, the dysfunction is a cerebral dysfunction.

According to another preferred embodiment of the present invention, the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-pyrazolin-15-one or a physiologically acceptable salt thereof, or water thereof. Or a solvate. According to still another aspect of the present invention, a prophylactically and / or therapeutically effective amount of a pyrazolone derivative represented by the above formula (I), a physiologically acceptable salt thereof, or a hydrate or solvate thereof is determined. Provided is a method for ameliorating post-cardiopulmonary resuscitation dysfunction, comprising administering to a mammal, including a human.

According to still another aspect of the present invention, a pyrazoopene derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a salt thereof, for producing an agent for improving a dysfunction after cardiopulmonary resuscitation: Use of a hydrate or solvate is provided. BEST MODE FOR CARRYING OUT THE INVENTION

The agent for improving dysfunction after cardiopulmonary resuscitation according to the present invention (hereinafter also referred to as “the agent for improving the present invention”) is a pyrazolone derivative represented by the formula (I) or a physiologically acceptable derivative thereof as defined herein. Or a hydrate or solvate thereof.

The compound represented by the formula (I) used in the present invention may also have a structure represented by the following formula (I ′) or (′) due to tautomerism. In formula (I) of the present specification, one of the tautomers is shown for convenience, 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, a compound represented by the following formula (1 ′) or (′) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is used. Is also good.

In the formula (I), the aryl group in the definition of R ¹ may be either a monocyclic or polycyclic aryl group. For example, it is substituted with a substituent such as a phenyl group, a naphthyl group or the like, 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 hydroxyl group. Phenyl groups, etc. I can do it. The same applies to the aryl moiety in other substituents having an aryl moiety (such as an aryloxy group).

R \ R ²及Pi: alkyl group having 1 to 5 carbon atoms in the definition of R ³ may be either straight-chain, branched-chain. 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 (alkoxycarboylalkyl groups).

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

Examples of the aryloxy group in the definition of R ² include a phenoxy group, a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy group, a p-hydroxyphenoxy group, and the like. Examples thereof include a dimercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorophenylmercapto group, and a p-hydroxyphenylmercapto group.

Examples of the alkylene group having 3 to 5 carbon atoms in the definition of R ² and R ³ include a trimethylene group, a tetramethylene group, a pentamethylene group, a methyltrimethylene group, an ethyltrimethylene group, a dimethyltrimethylene group, a methyltetramethylene group, and the like. Are mentioned.

The hydroxycarboxylic alkyl group having 1 to 3 carbon atoms in the definition of R ² and R ^3, human Dorokishimechiru group, 2-arsenide Dorokishechiru group, and 3-hydroxycarboxylic propyl 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, the alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group, main butoxy group, an ethoxy group, a propoxy group, isopropoxy group, butoxy sheet group, Penchiruokishi group and the like, total carbon Alkoxy group Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group.Examples of the alkylmercapto group having 1 to 3 carbon atoms include a methylmercapto group, an ethylmercapto group, and a propylmercapto 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.Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group. And a dimethylamino group, a dipropylamino group, a dibutylamino group and the like.

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

3-Methinole 1-Feninole 2-Pyrazolin-5-one;

3-methyl-1- (2-methylphenyl) -1-pyrazolin-1-5-one; 3-methyl-1- (3-methylphenyl) -1-2-pyrazolin-15-one; 3-methyl-1- (4-methylphenyl) -1- 2-pyrazolin-1-5-one; 3-methyl-1- (3,4-dimethylphenyl) — 2-pyrazolin-1-5-one; 1-1 (4-ethynolephen-2-ole) 1-3-methinole 2-pyrazolin-1-5- 1; (4-propylpheninole) 1-2-pyrazolin-1 5-one; 1- (4-butylphenyl) 1-3-methyl-1 2-pyrazolin-1 5-one; 1-(3-trif Norelomethinolefeninole) 1-3-methinole 2-pyrazolin-one-one;

1- (4-trifluoromethylphenyl) -1-3-methyl-2-pyrazolin-1-one;

1- (2-methoxyphenyl) 1-3-methyl-2-pyrazolin-1 5-one; 1-1 (3-methoxyphenyl) 1-3-methyl-2-pyrazolin-1 5-one; 1- (4-meth 1- (3,4-dimethoxyphenyl) -13-methyl-2-pyrazolin-5-one; 1-3-methyl-2-pyrazolin-5-one;

1- (4-ethoxyphenyl) -1-3-methyl-2-pyrazolin-5-one; 3-methyl-11- (4-propoxyphenyl) 1-2-pyrazolin-15-one; 1- (4-butoxyphenyl) 1-3-methyl-1-pyrazolin-1-5-one; 1-1 (2-chlorophenyl) 1-3-methyl-1-pyrazolin-1-5-one; 1-1 (3-chlorophenyl 1-Methyl-2-pyrazolin-1-one; 1- (4-chlorophenol-1) -1-Methyl-2-pyrazolin-1-5-one; 1- (3,4-Dichlorophenyl) -1 3-methyl-2-birazolin-1-5-one; 1- (4-bromopheninole) 1-3-methinole 2-pyrazolin_5-one; 11- (4-funoleolopheninole) 1-3-methinole 1- 1- (3-chloro- 4-methylphenyl) 1- 3-methinole 2-pyrazolin 1-one;

1- (3-methylmercaptophenyl) -1-3-methyl-2-pyrazolin-15-one;

1- (4-methylmercaptophenyl) 1-3-methinole 2-pyrazolin-1 5-one;

4- (3-methyl-5-oxo-12-pyrazolin-1-yl) benzoic acid; 1- (4_ethoxycanolepodinolephenyl) 1-3-methinole 2-pyrazolin-1-one;

1- (4-nitropheninole) 1-3-methinole 2-pyrazolin-1 5-one; 3-ethinole 1-phenylenole 2-pyrazolin-1 5-one;

1-Feninole 3-propynolee 2-pyrazolin-5-one;

1,3-dipheninole 2-pyrazolin-5-one;

3-Fueneru 11 (ρ-tolyl) 1 2-pyrazolin-1 5-one;

1- (4-Methoxyphenyl) _3-phenyl-2-pyrazolin-1-5-one; 1- (4-chlorophenyl) -1-phenyl-2-pyrazolin_5-one; 3,4-dimethyl-1- 1-Feunru 2-Pyrazolin-5-On;

4-isobutyl-1-methyl-1-phenyl-2-pyrazolin-1-one;

4-I (2-Hydroxyshetyl) 1-3-Methinole 1-Feninole 2 _Pyrazoline _5-ON;

3-Methinole 4-Phenoxy 1-Feninole 2-Pyrazolin-5-one; 3-methyl-1-phenylmercapto-11-phenyl / le 2-pyrazolin-1-one;

3,3,3,4,5,6,7-hexahydro-12-phenyl-12H-indazole-3-one;

3- (ethoxycarbonylmethyl) _ 1-phenyl 2-pyrazolin-1 5-one;

1-Feunru 2-Pyrazolin-5-On;

3-Methyl-2-virazoline-5-one;

1,3-dimethyl-1-2-pyrazolin-1-5-one;

1-Ethyl-1-methyl-2-birazolin-5-one;

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

1- (2-hydroxyethyl) 1-3-methyl-2-pyrazolin-5-one; 1-hexanol-1-methynole_2-pyrazolin-5-one;

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

1- (α-naphthyl) — 3-methyl-1-pyrazolin-1-5-one;

1-methyl-1-3-phenylenol 2-birazolin-5-one;

3-Methyl-1- (4-methylphenyl) -1-2-pyrazolin-15-one; 1-1- (4-butylphenyl) _3-methyl-2-pyrazolin-1-5-one; 1- (4-Methoxyphenyl) -1-3- Methyl-2-pyrazolin-1-5-one; 1-1 (4-butoxyphenyl) -1-3-methyl-12-pyrazolin-1-5-one; 1-1 (4-chlorophenyl) -1-methyl-1-pyrazolin-1-5-one 1- (4-hydroxyphenyl) -3- 3-methynole-1-pyrazolin-1-one; 1- (3,4-dihydroxyphenyl) -3-methyl-2-pyrazolin-1-one;

1- (2-hydroxyphenyl) -1-3-methyl-2-pyrazolin-15-one; 1- (3-hydroxyphenyl) 1-3-methyl-1 2-pyrazolin-15-one; 1- (4-hydroxyphenyl) 1-Methyl-2-pyrazolin-5-one; 1- (3,4-hydroxyphenyl) 1-3-Methyl-2-pyrazolin-5-one N;

1- (4-Hydroxyphenyl) -1-3-phenyl 2-virazoline-1 5-one; 1- (4-Hydroxymethylphenyl) 1-3-methyl-2-pyrazolin-1 5-one;

1- (4-aminophenyl) 1-3-methyl-1-pyrazolin-5-one; 1- (4-methylaminophenyl) -3-methyl-1-2-virazoline-5-one; 1- (4-ethylamino) 1- (4-Butylaminophenyl) -1 3- (methylamino-2-pyrazoline) 5-one; 1- (4-Dimethylaminophenyl) 1-3 —Methyl-1-pyrazolin-5-one;

1- (acetoamidophenyl) -1-methyl-2-pyrazolin-1-one; and ぴ

1- (4-cyanophenyl) -1-methyl-2-pyrazolin-15-one The active ingredient of the improving agent of the present invention includes, in addition to the free-form compound represented by the formula (I), a physiologically acceptable compound. 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; alkaline earths such as magnesium and calcium Salts with metals: ammonia, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyxethyl) piperazine, 2-amino-12-methyl-11-propanol, ethanolamine, N-methyldaltamine, L — Salts with amines such as glutamine. Further, a salt with an amino acid such as glycine may be used.

As an active ingredient of the improving agent of the present invention, a hydrate of the compound represented by the above formula (I) or a physiologically acceptable salt thereof, or a compound or a compound represented by the above formula (I) A solvate of the physiologically acceptable salt may be used. The type of the organic solvent that forms the solvate is not particularly limited. For example, methanol, ethanol, Monoter, dioxane, tetrahydrofuran and the like can be exemplified. 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 stereoisomers such as optical isomers and diastereoisomers. is there. As the active ingredient of the improving agent of the present invention, pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used.

The compounds represented by the formula (I) are all known compounds, and can be easily synthesized by those skilled in the art by the method described in Japanese Patent Publication No. 5-31523.

The dose of the ameliorating agent of the present invention is not particularly limited, but is usually from 0.:! To 1000 mg / kg per day in the case of oral administration generally as the weight of the compound represented by the formula (I) as an active ingredient. Body weight, preferably 0.5 to 50 mg / kg body weight per day; for parenteral administration, 0.01 to 100 mg / kg body weight per day, preferably 0.1 to 10 mg / kg body weight. You. The above dose is preferably administered once a day or divided into two or three times a day. The dose may be appropriately increased or decreased depending on age, disease state and symptoms.

As the ameliorating agent 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 administer and administer a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmacologically and pharmaceutically acceptable additive.

Pharmaceutically and pharmaceutically acceptable excipients include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, dissolutions agents or dissolving aids, isotonic agents, _P H adjusting agents, stabilizers, propellants, and can be used an adhesive or the like.

Pharmaceutical compositions suitable for oral administration include, as additives, excipients such as glucose, lactose, D-mannitol, starch, and crystalline cellulose; disintegrants such as carboxymethylcellulose, starch, and calcium carboxymethylcellulose Or a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; a lubricant such as magnesium stearate or talc; hydroxypropylmethylcellulose, sucrose Coating agents such as polyethylene glycol or titanium oxide; Bases such as raffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat can be used.

Pharmaceutical compositions suitable for injection or infusion include solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injectables such as distilled water for injection, physiological saline, and oral pyrendalcol; glucose, chloride Additives such as isotonic agents such as sodium, D-mannitol, and glycerin; pH regulators such as inorganic acids, organic acids, inorganic bases and organic bases can be used.

The form of the improving agent of the present invention is not particularly limited, and can take various forms available to those skilled in the art. Pharmaceuticals suitable for oral administration include, for example, coagulants, powders, granules, hard gelatin capsules, suppositories, and troches using solid pharmaceutical additives. A syrup, an emulsion, a soft gelatin capsule or the like can be prepared using the product. In addition, injections, drops, inhalants, suppositories, transdermal absorbents, transmucosal absorbents, and the like can be prepared as pharmaceuticals suitable for parenteral administration. In addition, a brain protectant (intravenous solution) 1S containing a compound of the above formula (I) as an active ingredient. 1S Since it has already been used in clinical practice (generic name: edaravone, trade name: Radicut: manufactured by Mitsubishi Perpharma Co., Ltd.) 'Sales), and the above-mentioned commercial preparations can be used as they are in the medicament of the present invention.

The improving agent of the present invention is effective for improving dysfunction after cardiopulmonary resuscitation. That is, the ameliorating agent of the present invention has a function as a prophylactic agent for preventing deterioration of dysfunction and / or a therapeutic agent for restoring dysfunction to a normal state.

In addition, the improving agent of the present invention may have an effect of extending the curable time during cardiopulmonary arrest (the time from cardiopulmonary arrest to resumption of circulation and respiration). Generally, it is thought that irreversible changes in the brain will occur unless circulation and respiration are resumed within 3 to 5 minutes after cardiopulmonary arrest, and it will not be possible to sufficiently improve dysfunction. However, the ameliorating agent of the present invention may have the effect of preventing irreversible changes in the brain even when the circulation and respiration are resumed for more than 3 to 5 minutes.

In the present specification, amelioration of dysfunction after cardiopulmonary resuscitation means that spontaneous exercise becomes possible, communication becomes possible, and furthermore, speech is possible, and ultimately rehabilitation is possible. To recover to a functional state.

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

The ameliorating agent of the present invention can also be administered prophylactically prior to dysfunction after cardiopulmonary resuscitation. The ameliorating agent of the present invention can be administered to a patient who has suffered a dysfunction after cardiopulmonary resuscitation for the purpose of preventing the worsening of symptoms or reducing the symptoms. Example

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples. The Radicut (registered trademark) used in the following examples was Radicut (registered trademark) Note 3 O mg sold by Mitsubishi Pharma Corporation. Example 1:

The case was an 81-year-old woman. A feeling of food cling appeared, and an examination of the upper gastrointestinal tract was performed. As a result, the patient was diagnosed with cancer of the esophagus and gastric junction. Under a right laparotomy, the lower esophagus, resection of the gastric cardia, reconstruction of the intrathoracic gastric fistula, and pyloroplasty were performed. One week after the operation, a tracheostomy was performed due to pulmonary complications, but he recovered steadily and was able to walk in the ward.

He was found 23 days after the operation at 6:15 am, with a pulse rate of 30 bradycardia, and at 6:17, cardiopulmonary arrest and cardiac massage and assisted breathing were started. At 6:25, the pulse became 180 units, but blood pressure could not be measured due to ventricular tachycardia. She underwent defibrillation and sinus rhythm, and her blood pressure recovered to 100 units. At this time, the pupil was 3 mm on the right and 4 mm on the left, and the light reflex was almost eliminated. Cranial CT showed no cerebral hemorrhage or subarachnoid hemorrhage, and echocardiography showed extensive hypokinesia outside the basal heart. The patient was diagnosed as having cardiac arrest as a result of a sudden decline in cardiac function due to a takotsubo-shaped myocardial disorder. Force tecora Administration of edaravone was started at 11:00 on the same day for hypoxic encephalopathy and blood pressure control by min administration. The administration method is the same as in the case of normal cerebral infarction. Dissolve 20 ml of Radicat (registered trademark) (100 mg as edaravone) in 100 ml of physiological saline and instill for 30 minutes. The dose was administered twice a day, every 12 hours. The light reflex began to appear around 16 o'clock on the same day, and at 0 o'clock the next day (the second day from the start of edaravone administration), movements such as leftward and downward displacement of the eyeball began to be observed. Myoclonus was observed in both upper limbs. On the morning of the third day after the start of edaravone administration, slight locomotor activity was observed in the neck and upper extremities. On the fourth day after the start of edaravone administration, spontaneous eye opening and pursuit movement of the eyes were observed, but no fate was possible and no speech was made. On the morning of the sixth day after starting administration of Edaravone, a handshake was possible, and on the eighth day, the dial was used to allow communication. On the same day, on the 15th day, the ventilator was still attached, but it could be generated using the vocaloid cannula. Now you can do it. At this time, no apparent paralysis of the limbs was observed, and no ischemic changes were observed on the head CT. The above results showed that no activity other than myoclonus was observed for 2 days after cardiac arrest, but then recovered to a state in which spontaneous exercise, communication, and speech were possible. Industrial potential

The medicament of the present invention is useful for improving dysfunction after cardiopulmonary resuscitation.

US provisional application 60 0 4 2 1, 6 which is the application on which the priority claimed in this application is based

The entire contents of the specification of 19 are incorporated herein by reference as a part of the disclosure of the specification.

Claims

Claims 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; R ² represents a hydrogen atom, an aryloxy group, an aryl group) R represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a carbon number. Alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkyl mercapto group having 1 to 3 carbon atoms , An alkylamino group having 1 to 4 carbon atoms, a total carbon number of 2 1 to 3 substituents selected from the group consisting of dialkylamino group, halogen atom, trifluoromethyl group, carboxyl group, cyano group, hydroxyl group, nitro group, amino group and acetoamide group Represents a substituted phenyl group.)

An agent for improving dysfunction after cardiopulmonary resuscitation, comprising, as an active ingredient, a pyrazolone derivative represented by or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

2. The drug according to claim 1, wherein the dysfunction is a cerebral dysfunction.

3. The improving agent according to claim 1, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-pyrazolin-15-one.

4. 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; R ² represents a hydrogen atom, an aryloxy group, an aryl group) R ³ represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; Represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a 1 to 5 carbon atoms. An alkyl 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 a carbon number 1-4 alkylamino groups, total carbon number 2- 8 substituted with 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetoamide group. Represents a phenyl group.)

Administering a prophylactically and / or therapeutically effective amount of a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, to a mammal containing human, after cardiopulmonary resuscitation. How to improve your dysfunction.

5. The method of claim 4, wherein the dysfunction is a cerebral dysfunction.

6. The method according to claim 4, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-12-pyrazolin-15-one.

7. Formula (I) for the manufacture of an agent for improving dysfunction after cardiopulmonary resuscitation:

(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; R ² represents a hydrogen atom, an aryloxy group, an aryl group) Represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; R ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a carbon atom; Alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms Group, alkylamino group with 1-4 carbon atoms, total carbon number 2 8 substituted with 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetoamide group. Represents a phenyl group.)

Use of a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

8. The use according to claim 7, wherein the dysfunction is a cerebral dysfunction.

9. The use according to claim 7 or 8, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-12-pyrazolin-15-one.