WO2003078401A1

WO2003078401A1 - Preventive and/or therapeutic agent for hypoxic ischemic brain disorder

Info

Publication number: WO2003078401A1
Application number: PCT/JP2003/003067
Authority: WO
Inventors: Tomoaki Ikeda; Tsuyomu Ikenoue
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2002-03-15
Filing date: 2003-03-14
Publication date: 2003-09-25
Also published as: JP2005343789A; AU2003213364A1

Abstract

A medicine for use in the prevention of and/or treatments for hypoxic ischemic brain disorders, especially ones of newborns caused by labor. It contains as an active ingredient a substance selected from the group consisting of 3-methyl-1-phenyl-2-pyrazolin-5-one, pyralozone derivatives which are analogues thereof, physiologically acceptable salts thereof, and any hydrates and any solvates of these.

Description

Description Preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy

The present invention relates to a medicament useful for preventing or treating hypoxic-ischemic encephalopathy, more preferably neonatal hypoxic-ischemic encephalopathy. Background art

The fetus performs gas exchange in the uterus by the placenta, but when delivery approaches and labor becomes severe, gas exchange in the placenta stops. At this time, the partial pressure of carbon dioxide (PC o ₂ ) in the fetal blood increases and the partial pressure of oxygen (PO ₂ ) decreases. Normally, in this state, spontaneous respiration starts at the time of childbirth, so that the partial pressure of carbon dioxide (PC o ₂ ) decreases and the partial pressure of oxygen (PO ₂ ) increases and returns to normal.

Extremely small premature babies with low respiratory ability, large mature fetuses, large birth canals, narrow birth canal, abnormal pregnancy, prolonged labor due to forceps delivery, etc. This results in severe fetal asphyxia and severe neonatal asphyxia, which can result in extensive cerebral disability and developmental disorders such as cerebral palsy, mental retardation, visual / hearing impairment, and learning disability.

Although the involvement of active radical has been suggested to hypoxic-ischemic brain damage during labor, drug treatments methods for disorders of this has not been established _{(E spino Z a, M. I} , P arer, J T, Am. J. Obset Gyn ecol, 164 (1991) 1582-9; discussion 1589—91., Ha segawa, K. Yo shioka, H. Sawada, T., Nishikawa, H. Brain. De v., 13 (1 991) 101— 3., I keda, T., Choi, BH, Y ee, S., Mu rata, Y. Qu i 11 igan, EJ, Int. Neurosci., 17 (1999) 1—14 ·).

In addition, compared to the case of adult brain, the disease of asphyxia-induced Oxidative stress is given more importance as a cause.

It has been suggested that aloprinol (xanthine oxidase inhibitor), which exhibits antioxidant activity in vivo, reduces cerebral damage by pre-administration of hypoxic-ischemia, but it is effective for administration after hypoxic-ischemia Sex has not been confirmed.

In addition, deferoxamine (iron chelating agent), vitamin c, vitamin E and the like are well known as antioxidants, but all of these compounds have reached clinical trials as prophylactic agents for hypoxic-ischemic encephalopathy. Nothing has been found.

(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 R ¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ represents a hydrogen atom, alkyl having 1 to 5 carbon atoms, , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, or alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, total carbon number 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, The pyrazolone derivative represented by the formula (1) represents a phenyl substituted with 1 to 3 identical or different substituents selected from the group consisting of cyano, hydroxyl, nitro, amino and acetoamide. It has a function to normalize brain function (Japanese Patent Publication No. 5-315152), an inhibitory effect on lipid peroxide production (a compound of Japanese Patent Publication No. 5-31528, Example 1), an anti-ulcer effect (Japanese Unexamined Patent Application Publication No. 3-215425) and an effect of suppressing blood glucose elevation (Japanese Unexamined Patent Application Publication No. 3-215426) are known. In particular, various diseases and disorders that cause cerebral dysfunction are described as the brain function normalizing action (Japanese Patent Publication No. 5-315253), but these diseases are all intrinsic factors. It is understood to be due to.

However, each of these publications does not suggest that this compound is useful as a prophylactic and / or therapeutic agent for hypoxic-ischemic encephalopathy, which is thought to be triggered by external factors. Not taught.

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 (trade name: Radicut: manufactured and sold by Mitsubishi Pharma Corporation), but there are still no reports that this formulation is useful for prevention and / or treatment of hypoxic-ischemic encephalopathy. It has never been done. Disclosure of the invention

An object of the present invention is to provide a medicament useful for prevention and / or treatment of hypoxic-ischemic encephalopathy.

The inventors of the present invention have made intensive efforts to solve the above-mentioned problems. And / or found to be useful for treatment, and completed the present invention.

That is, the present invention relates to the following prophylactic and / or therapeutic agents for hypoxic-ischemic encephalopathy. '

(1) The following equation (I)

(Wherein each symbol has the same meaning as described above) A preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy comprising, as an active ingredient, a substance selected from the group consisting of an acceptable salt thereof, an arbitrary hydrate thereof, and an arbitrary solvate thereof. .

(2) a pyrazolone derivative,

3-Methyl-1-Fenuru 2-Birazolin-5-one,

3-methyl-11- (2-methylphenyl) -1-2-pyrazolin-1-5-,

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

3-Methyl-1- (4-methinolephenyl) -2-birazolin-5-one,

3-methyl-1- (3,4-dimethylphenyl) _2-pyrazolin-1-5-,

1- (4-ethynolephenine) 1-3-methyl-1 2-pyrazolin-1 5-one,

3_methyl-1- (4-propylphenyl) -1-pyrazolin-1-5-,

1- (4-butynolephenone) 1-3-methyl-2-pyrazolin-1 5-one,

1-one (3-triphnoleolomethinorefue-norre) 1-3-methinole 2-pyrazolin-5-one,

1- (4-trifluoromethylphenyl) — 3-methyl-2-pyrazolin-1-one,

1- (2-Methoxyphenyl) 1-3-Methyl-1-pyrazolin-5-one, 1- (3-Methoxyphenyl) _3-Methyl1-2_pyrazolin-1 5-one, 1- (4 1-Methyl-2-phenyl-5-one, 1- (3,4-dimethoxyphenyl) -1-methyl-3-pyrazolin-5-one, 1-1- (4-ethoxyphenyl) 1-Methyl-2-pyrazolin-1-5-one, 3-Methyl-11- (4-propoxyphenyl) 1-2-Pyrazolin-5-one, 1- (4-butoxyphenyl) 1-3-Methyl1-2-pyrazolin-15 —One, 1— (2-chlorophenyl) 1-3-methyl-12-pyrazolin-1-5-one, 1— (3-chlorophenyl) 1-3-methyl-1-2-pyrazolin-5-one, 1-1 ( 4-Monophenyl) —3-Methyl-1-pyrazolin-1-5-one, 1- (3,4-Dichlorophenyl) 3-Methyl-2-pyrazolin-1-5-one, 1- (4-bromopheninole) 1-3-methinole 2-pyrazolin-15-one, 1- (4-fluoropheninole) 1-3-methinole 2-pyrazolin-15-one, 1- (3-chloro-4-methylphenyl) 1-3-methyl_2-pyrazolin-15-one,

1- (3-methylmercaptophenyl) -1-methyl-2-pyrazolin-5-one,

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

4- (3-Methyl-5-oxo-1-2-pyrazolin-1-yl) benzoic acid, '11-(4-ethoxycarpoylphenyl) -1-3-methyl-1-2-pyrazolin-1-one,

1 1 (4 12 Trofe 2) 1 3-Methynole 2-Pyrazolin 1 5-one,

3-Echinole 1 1-Phenyl 2-Pyrazolin-5-one,

1-phenyl-1-3-propyl-1-birazolin-5-one,

1,3-diphenyl-1-birazolin-5-one,

3-Feuniru 1- (ρ-Trinore) 1 2-pyrazolin-5-one,

1- (4-methoxyphenyl) 1-3-phenylenol 2-pyrazolin-5-one,

1-(4 口 1 口二 2 ビニニ 2 レービラ — — —

3,4-Dimethyl 1-Feneru 2-Vilazoline-5-one,

4-isobutyl-1-3-methyl-1-phenyl-1-pyrazolin-1-5-

4 1 (2—Hydroxyshechnole) 1 3—Methinole 1 1 Fenru 2 2-Pyrazolin 1 5 1

3-methyl-1-phenoxy-1-phenyl-2-birazolin-5-one,

3-Methinole 4--1-mercapto 1-phenyl 2-pyrazolin-5-one,

2,3a, 4,5 +, 6,7-hexahydrol 2-pheninoleindazole_3-one,

3— (ethoxycarponinolemethinole) 1—11 phenol 2—birazolin-5—one, 1—phenyl 2-birazolin-5— 3—Methinole 2—Pyrazolin-5—one,

1,3-dimethyl-2-birazolin-5-one,

1-ethyl-3-methyl-2-birazolin-5-one,

1-butyl-3-methyl-2-pyrazolin-5-one,

1- (2-hydroxyethyl) -1-3-methyl-2-pyrazolin-5-one,

1-Silicone hexinole 3-methyl-2-birazolin-5-one,

1-benzyl-1-3-methyl-1-pyrazolin-1-5-one,

1- (α-naphthyl) -1 3-methyl-2-pyrazolin-5-one,

1-Methyl-3 -Fenil 2-Pyrazolin-5-one,

3-methyl-11- (4-methylphenyl) -1-2-pyrazolin-15-one,

1- (4-butylphenyl) -1-3-methyl-2-pyrazolin-15-one,

1- (4-methoxyphenyl) -1-3-methyl-2-pyrazolin-15-one,

1- (4-butoxyphenyl) _3_methyl-1-2-pyrazolin_5-one,

1-(4-phenyl phenyl) 1-3-methinolate 2-pyrazoline _ 5-one,

1- (4-hydroxyphenyl) 1 3-methinole 2-pyrazolin-5-one,

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

1- (2-Hydroxyphenyl) -1-3-Methylenol 2-1-Vilazoline-1 5-one, 1-1 (3-Hydroxyphen-2-ole) 1 3- (Methylenolate 2-pyrazolin-1-5-one, 1- (4-Hydroxyphenyl) -1 3-Methyl-2-pyrazolin-1-5-one, 1-1 (3,4-hydroxyphenyl) -3-methinole 2-virazolin-1-51-one, 1- (4-hydroxyphenylene) 1-3-Phenazolin 2-pyrazolin One 5-one, one-one (4-hydroxymethylpheninole) one three-methinole two-pyrazolinone five-one,

1- (4-aminophenyl) 1-3-methyl-1 2-pyrazolin-1 5-one, 1-1 (4-methylaminophenyl) 1-3-methyl-1 2-pyrazolin-1 5-one, 1-1 (4-ethyla) Minophenyl) 1-3-methyl-2-pyrazolin-15-one, 1-1 (4-butylaminophenyl) -3-methyl-2-pyrazolin-15-one, 1- (4-Dimethyl / reaminophenyl) -1-3-methyl-1-pyrazolin-1-5-one, 1- (acetoamidophenyl) 1-3-methyl-2-pyrazolin-15-one, 1- (4-cyanophenyl) -1-3-methyl The prophylactic and / or therapeutic agent according to claim 1, which is a compound selected from the group consisting of 1-2-pyrazolin-15-one.

(3) selected from the group consisting of 3-methyl-1-phenyl-2-birazolin-5_one and physiologically acceptable salts thereof, and any hydrates and solvates thereof And / or an agent for preventing or treating hypoxic-ischemic encephalopathy containing a substance as an active ingredient.

(4) The preventive and / or therapeutic agent according to any one of (1) to (3), wherein the hypoxic-ischemic encephalopathy is neonatal hypoxic-ischemic encephalopathy.

(5) Birazolone derivative represented by the above formula (I) and a physiologically acceptable salt thereof, and any hydrates and any hydrates thereof, for the production of the above prophylactic and / or therapeutic agents Use of a substance selected from the group consisting of solvates.

(6) A method for preventing and / or treating hypoxic-ischemic encephalopathy, comprising a pyrazolone derivative represented by the above formula (I), a physiologically acceptable salt thereof, and any hydrate thereof. And administering a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of any solvates thereof to mammals including humans. BEST MODE FOR CARRYING OUT THE INVENTION

The entire disclosure of Japanese Patent Application No. 2002-71595 filed on Mar. 15, 2002 is incorporated herein by reference.

The pyrazolone derivative of the formula (I) contained in the prophylactic and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention can be synthesized by any suitable method. Examples of preferable synthetic methods Examples thereof include a method described in JP-A-62-108814.

As an active ingredient of the prophylactic and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention, a pyrazolone derivative of the above formula (I) in a free form may be used. In addition, any hydration of the above pyrazolone derivative or physiologically acceptable salt Or any solvate thereof can also be used.

The pyrazolone derivative has a tautomer (() or (1 ′)) represented by the chemical structural formula shown in the upper part of column 5 of JP-B-5-311523. Any of these isomers may be used as an active ingredient of the medicament of the present invention.

In the formula (I), examples of the aryl group in the definition of R ¹ include a phenyl group and a phenyl group substituted with a substituent such as a methyl group, a butyl group, a methoxy group, a butoxy group, a chlorine atom and a hydroxyl group. Can be

Examples of the alkyl group having 1 to 5 carbon atoms in the definition of RR ² and R ³ 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. Is mentioned.

Examples of the alkoxycarbonylalkyl group having a total of 3 to 6 carbon atoms in the definition of R ¹ include a methoxycanoleponylmethyl group, an ethoxycarbonylmethyl group, a propoxycanoleponylmethyl group, a methoxycarbonylethyl group, and a methoxycarbonylpropyl group. And the like.

The aryloxy group in the definition of R ² includes a phenoxy group, a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy group, a p-hydroxyphenoxy group, and the like. Examples include a phenylmercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorobutyrmercapto 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 a hydroxymethyl group, a 2-hydroxyethyl group, a 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, 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 Examples of the alkoxycarbonyl group having 2 to 5 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, Ethyl mercapto group, propyl mercapto group, and the like.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. Dialkylamino groups include dimethylamino, getylamino, and dipropylamino. Amino group, Jibuchiruamino group, and the like.

Specific examples of the compound of the formula (I) used in the present invention include the following compounds.

3-methyl-1-phenyl-2-ylazolin-5-one,

3-methyl-1- (2-methylphenyl) _2_pyrazolin _5—one,

3-methyl-11- (3-methylphenyl) -1-birazolin-5-one,

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

3-Methyl-1- (3,4-dimethylphenyl) -1-2-pyrazolin _5-one,

1- (4-ethynolepheninole) —3-methyl-2-pyrazolin-1-5-one,

3-methyl-11- (4-propynolephenyl) -1-2-pyrazolin-15-one,

1- (4-butylphenyl) 1-3-methyl-2-pyrazolin-1 5-one,

1- (3-trifluoromethylphenyl) -1-3-methinole _2-pyrazolin-5-one,

1- (4-trifluoromethylphenyl) — 3-methinole 2-pyrazolin-1-5- 1- (2-Methoxyphenyl) -1-3-Methyl-2-pyrazolin-1-5-one,

1- (3-methoxyphenyl) -1-3-methyl-2-pyrazolin-5-one,

1- (4-methoxyphenyl) 1-3-methyl-2-pyrazolin-15-one,

1- (3,4-dimethoxyphenyl) -1-3-methyl-2-pyrazolin-15-one,

1- (4-ethoxyphenyl) -1-3-methyl-2-pyrazolin-1-5-one,

3-methyl-1- (4-propoxyphenyl) -1-2-pyrazolin-1-one,

1- (4-butoxyphenyl) -1-3-methyl-2-pyrazolin-1-5-

1- (2-chlorophenyl) -1-3-methyl-2-pyrazolin-5-one,

1— (3—Mouth-Feninole) _ 3-Methyl-1-2-pyrazolin-1-5-

1-(4 phenyl) 1-3-methyl-2-pyrazolin-1 5-one,

1- (3,4-Dichroen feninole) 1-3-Methinole 2-pyrazolin-5-one,

1- (4-bromophenyl) _3-methyl-2-pyrazolin-1-5-

1- (4-Funoleolofeninole) one 3-methinole 2-pyrazolin one 5-one,

1-(3-Chloro-4-methinolephenone) 1-3-Methinole 1-Pyrazolin 1 5-On,

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

1-(4-Methyl Menolecaptopheninole) 1-3-Methinole _2 2-Pyrazolin-1 5-one,

4-(3-Methyl-5-oxo-1-2-pyrazolin-1-yl) benzoic acid,

1-1 (4-1 ethoxy canoleponinole fuinore) 1-3-methinolate 2-pyrazoline 1-5-on,

1- (4-12-trophenyl) 1-3-methyl-1-pyrazolin-1-5-

3—Echiru 1 1 2 Ru 2—Virazoline 1 5 1 on,

1-Feneru 3-Propyl 2- 2-Pyrazolin-1 5-one,

1,3-diphenyl-1-pyrazolin-5-one,

3—Feniru 1— (p—tolyl) 1-2—Pyrazolin-1 5—one,

1-(4-Methoxy ethoxy) 1 3-Feninole 2-pyrazolin 1 5-one, 1- (4 1-mouth) 2- 3-pyrazolin 1-

3,4 dimethyl 1-phenyl 2-birazolin-5-one,

4-isoptyl-3—methyl-1 1-Fe2ru 2-birazolin-5-one,

4-I (2-Hydroxyshetyl) _ 3-Methyl- 1-Pheninolee 2-Pyrazoline 1

5 one on,

3-Methinole 4- 1-phenoxy 1- 1-phenyl-2- 1-pyrazolin-5-one,

3-Methyl-4 1-pheninolemenolecapto 1- 1-phenyl-2-ene 2-pyrazolin-5-one,

2,3a, 4,5,6,7—hexahydro-2-3-phenylindazo-1-one,

3- (ethoxyethoxyvinylmethinole) -1 1-phenyl-1 2-birazolin-1 5-one,

1 Hue-ru 2-Birazolin-5-on,

3-methyl-1-pyrazolin-5-one,

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

1-etizole _ 3—methinole 1 2-pyrazolin-5-one,

1-butyl-3-methyl-2-birazolin-5_one,

1- (2-hydroxyethyl) -1-3-methyl-1-pyrazolin-15-one,

1—Mouth hexinole 3—Methinole 2—Vilazoline 1

1 Benzyl 3-methyl-2-pyrazolin-5-one,

1- (α-Naphtinol) -1-3-Methyl-2-pyrazolin-1-5-one,

1-methyl-3-phenyl-1 -2-pyrazolin-1 5-one,

3-methyl-11- (4-methylphenyl) -1-2-pyrazolin-15-one,

1- (4-butylphenyl) 1-3-methyl-2-pyrazolin-5-one,

11- (4-methoxyphenyl) 13-methyl-12-pyrazolin-15-one,

1- (4-butoxyphenyl) -1-3-methyl-2-pyrazolin-1-5-one,

1-one (4—Mouth Feninole) _ 3—Methyl-2-pyrazolin-1-one,

1- (4-Hydroxypheninole) 1-3-methinole _2-pyrazolin_5-one,

1- (3,4-dihydroxyphenyl) 1-3-methyl-12-pyrazolin _5— ,

1- (2-hydroxyphenyl) _3-methyl-1-2-pyrazolin_5—one, 1- (3-hydroxyphenyl) -1-3-methyl_2-pyrazolin-1-5-one, 1- (4— Hydroxyphenyl) 1-Methyl_2-Pyrazolin-15-one, 1-1 (3,4-Hydroxyphenyl) -13-Methyl-12-birazolin-5-one, 1- (4-Hydroxyphenyl) 1 3 _ phenyrol 2 _ pyrazoline 1 5 -one, 1-(4-hydroxymethinolephen 2) 1 3 methinole 1 2-pyrazoline 1 5 ォ

1- (4-aminophenyl) 1 3-methyl-2-pyrazolin-5-one, 1- (4-methylaminophenyl) _3-methyl-2-pyrazolin-5-one, 1- (4-ethyl) 1-Methyl-2-pyrazolin-15-one, 1- (4-Butylamino) _3-methyl-4-pyrazolin-5-one, 1- (4-dimethylaminophenyl) -1-methyl One 2-birazolin-5-one, 1- (acetoamidophen-2-ole) —3-methinole 2-birazolin-1-5-one, 1- (4-1 cyanophenyl) -3-methyl-2-pyrazolin-1-one.

As the salt of the pyrazolone derivative of the formula (I), an acid addition salt or a base addition salt can be used. For example, mineral salts such as hydrochloride, sulfate, hydrobromide, or phosphate; methanesulfonate, paratoluenesulfonate, acetate, oxalate, citrate, malate Or organic salts such as fumarate; metal salts such as sodium, potassium or magnesium salts; ammonium salts; or organic amine salts such as ethanolanol or 2-amino-2-methyl-1-propanol. Although it can be used, the type of salt is not particularly limited as long as it is physiologically acceptable.

As the preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention, the compound of formula (I) as an active ingredient, a physiologically acceptable salt thereof, and a hydrate or a hydrate thereof are provided. One or more of the substances selected from the group consisting of these solvates may be administered to the patient as they are, but preferably the pharmacologically and pharmaceutically And a pharmaceutical composition in a form well known to those skilled in the art. Should be provided as a thing.

Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coatings, pigments, diluents, bases, solvents A peptizer or a solubilizing agent, a tonicity agent, a pH regulator, a stabilizer, a propellant, an adhesive, or the like can be used. Examples of pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups. Pharmaceutical compositions suitable for parenteral administration Examples thereof include an injection, a drip, and a suppository.

Pharmaceutical compositions suitable for oral administration include, as excipients, excipients such as pudose, lactose, D-mannitol, starch, and crystalline cellulose; carboxymethyl cellulose, starch, and calcium carboxymethyl cellulose. Disintegrant or disintegration aid; binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or gelatin; lubricant such as magnesium stearate or talc; hydroxypropylmethylcellulose, sucrose, polyethylene Coating agents such as glycol or titanium oxide; bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, dextrin, 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 Pharmaceutical 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.

Pharmaceutical compositions suitable for injection or infusion include solubilizers or dissolution aids that can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and oral pyrendalcol; glucose, Pharmaceutical additives such as isotonic agents such as sodium chloride, D-mannitol, and glycerin; PH regulators such as inorganic acids, organic acids, inorganic bases and organic bases may be added.

Brain protective agents (drops) containing the compound of the above formula (I) as an active ingredient are already available. (Generic name "Edaravone", trade name "Radicat": manufactured and sold by Mitsubishi Pharma Corporation) as a preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention. The above commercial preparations can be used as they are.

More preferably, the hypoxic-ischemic encephalopathy includes neonatal hypoxic-ischemic encephalopathy. _fl

The administration form of the preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention is not particularly limited, and it can be administered orally or parenterally. Preferably, it is administered parenterally, for example, intravenously by injection or infusion. For example, it is preferable to administer the medicament of the present invention prophylactically intravenously, intraarterially or intracardially to patients who have suffered massive bleeding or acute circulatory failure due to accidents or the like. If a considerable amount of bleeding is expected at the time of surgery, prior to the operation, the drug of the present invention should be administered orally by parenteral administration such as injection or infusion. Alternatively, it is preferable to administer prophylactically before and after that. For patients who have developed hypoxic-ischemic encephalopathy, it is preferable to administer intravenously, intraarterially or intracardially by injection for the purpose of preventing the worsening of symptoms or reducing the symptoms.

The dose of the medicament of the present invention can be appropriately selected depending on the purpose of prevention or treatment of hypoxic-ischemic encephalopathy, the age and condition of the patient, and the like. About 0.01 to 10 Omg / kg, preferably 0.1 to: about L Omg / kg by injection or infusion, or about 0.1 to 100 Omg / kg, preferably 0.5 to 5 It is preferable to administer about OmgZkg orally. For administration by injection, it is preferable to use, for example, injections described in JP-A-63-132833. The above compound, which is an active ingredient of the medicament of the present invention, is highly safe (LD ₅ intraperitoneally administered to mice; 2012 mg / kg; LD orally administered to rats; 3,500 mg / kg: Registry of Toxiceffects of Chemical Sub stances, 1981-1982), and has also been shown to be non-carcinogenic (National Caneer Institute Report, 89, 1978). Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example of synthesis: Synthesis of 1-phenyl-2-methyl-2-pyrazolin-15-one (hereinafter referred to as "edaravone")

15.0 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 mixture 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 6 7%

Melting point 1 27.5-128.5 ° C

(A) Animal

Seven-day Wistar rats were used. Pregnant rats were purchased (Kudo Co., Ltd.), and the newborn rats that gave birth were divided into an experimental group and a control group on day 7 of life. Only rats in the normal weight range were used for the experiments. In addition, it was adjusted to have 7 to 12 pups per parent rat.

Based on the report (Ann. Neurol., 1983, 13, 51-518.) That the maturity of the 7-day-old rat brain corresponds to the maturity of the term term infant (37-41 weeks of gestation). In this experiment, 7-day-old rats were used.

(B) Hypoxic ischemic load

A modified version of LeViline (Levin, S., Am. J. Pathol., 36 (1960) 1-17) was used.

That is, after ligating the rat left carotid artery (with 4-0 silk thread), stabilize it for 1 to 2 hours, and then apply 8% hypoxic load in a 6 liter chamber at 33 ° C. It took time. (With this model, brain injury in the left hemisphere can be created in 70-90% of cases, and mortality under this condition is less than 10%.)

(C) Evaluation method: Histological evaluation 7 days after hypoxic-ischemic challenge, the brain was removed under pentobarbital anesthesia, fixed with alcohol, and embedded in paraffin. At 2 mm anterior to the external ear canal, a forehead section specimen (5 μ thick) was prepared and stained with hematoxylin-eosin.

Ota et al.'S method (Ota, A., I keda, Τ ·, I kenoue, T., To shimori, K., Am. J. Obset Gyn ecol, 177 (1997) 519-26) The evaluation was judged as having neuropathy of 50% or more of the hemisphere area (severe), 25-50% (moderate), less than 25% (mild) and no neuropathy. The test was performed using M a n n -W h i t n e y t e st, and p <0.05 was significant.

The evaluation sites were the cerebral cortex, hippocampus (C A1, C A3, dentate gyrus), thalamus, and striatum.

(D) The method of administration of the prophylactic and Z or therapeutic agents of the present invention

As a prophylactic and / or therapeutic agent of the present invention, 3, 6 and 9 mg / kg of edaravone were dissolved in physiological saline, and 0.1 ml of this solution was injected intraperitoneally immediately after the hypoxic-ischemic load in the experimental group. The same dose was administered 30 minutes later. The control group received saline in the same manner.

(E) Result

The results are shown in Table 1. In the 6 mgZkg group, alleviation of damage was observed at three sites in the hippocampus CA at the 9 mg / kg group, and at the 9 mg / kg group, obvious damage reduction was observed at all evaluation sites. These results indicate that the prophylactic and / or therapeutic agents of the present invention reduce the onset of brain damage due to low oxygen ischemic load.

Table 1 Disorders after hypoxia / ischemia load

No impairment Mild Moderate Severe No impairment Mild Moderate Severe Solvent group (saline administration group) n = 14 Experimental group (edaravone 3 mg kg administration group) n = 14 Cerebral cortex 1 2 0 11 4 0 1 9 Hippocampus CA1 1 2 0 11 3 1 1 9 Sea ^] and Ao 1 0 0 13 3 0 0 11 Edentate gyrus 3 2 2 6 2 0 6 Thalamus 3 1 2 8 4 2 3 5 Striatum-2 1 1 10 4 0 4 6 Disorder None Mild Moderate Severe No obstruction Mild Moderate Severe _ Solvent group (saline administration group) n = 14 Experimental group (Edaravone 6 mgZkg administration group) n = 14 Cerebral cortex 3 1 0 10 0 6 Hippocampus CA1 3 1 0 10 1 5 Hippocampus CA3 * 2 1 0 11 0 6 ¾Horse dentate gyrus 4 2 0 8 1 3 Thalamus 4 3 0 0 5 Striatum-4 0 1 9 1 0 6 No obstruction Mild Moderate Severe No obstruction Mild Moderate Severe Solvent group (Normal diet administration group) n = 14 Experimental group (Edaravone 9 mg Zkg administration group) n = 14 Cerebral cortex * 3 1 0 10 7 2 1 4 Hippocampus GA1 * 3 1 0 10 7 1 2 4 Hippocampus CA3 * 2 1 0 11 8 0 1 5. Hippocampal dentate gyrus * 4 2 2 6 10 2 0 2 Thalamus * 4 2 2 6 9 3 1 1 Striatum * 3 1 1 9 8 2 2 _ 2 _ = = Obstacle "¥ None ΰ Mild = Hemisphere Area Less than 25% have neuropathy, moderate = 25-50% of hemisphere area has neuropathy,

Severe = Neuropathy is recognized in 50% or more of the hemisphere area

* = ρ <0.05 Industrial applicability

The medicament of the present invention are useful in the prevention and Ζ or treatment of hypoxic-ischemic encephalopathy _c

Difference. Replacement ¾ paper (Rule 2β

Claims

The scope of the claims

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 R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, R ³ represents a hydrogen atom, and a hydrogen atom having 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, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl A pyrazolone derivative represented by the formula: phenyl, substituted by 1 to 3 identical or different substituents selected from the group consisting of cyano, hydroxyl, nitro, amino and acetoamide; A preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy, comprising as an active ingredient a substance selected from the group consisting of a salt thereof, a hydrate thereof, and a solvate thereof.

2. The pyrazolone derivative is

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

3-methyl-11- (2-methylphenyl) -1-2-pyrazolin-15-one,

3-methyl-1- (3-methylphenol) -1-2-pyrazolin-5-one,

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

3-methyl-1- (3,4-dimethylphenyl) -1-pyrazolin-15-one, 1- (4-ethylphenyl) 1-3-methyl _2-pyrazolin-5-one,

3-methyl-11- (4-propylphenyl) -1-2-birazolin-5-one, 1- (4-butylphenyl) -1-3-methyl-1-pyrazolin-15-one,

1- (3-trifluoromethylphenyl) 1-3_ methyl _2 2-pyrazolin-1 5 _ one,

1- (4-triphnoleolomethinolephenyl) —3-methyl-1-pyrazolin-1-one,

1- (2-Methoxyphenyl) -3-methyl-2-pyrazolin-1-5-one,

1- (3-Methoxyphenyl) 1 3-Methinole 2-pyrazolin-1 5-one,

1- (4-methoxyphenyl) — 3-methyl-1-2-pyrazolin-1-one,

1_ (3,4-dimethoxyphenyl) 1-3-methyl-2-pyrazolin-15-one,

1- (4-ethoxyphenyl) _3-methyl-1-pyrazolin-5-one,

3-methyl-1- (4-propoxyphene) 1-2-pyrazolin-1-one,

1- (4-butoxyphenyl) -1-3-methyl-2-pyrazolin-1-5-

1- (2-chlorophenyl) 1-3-methyl-2-pyrazolin-5-one,

1-(3—Mouth iron) 1 3—Methinole 2 _Pyrazoline 1 5—On,

1- (4-chlorophenyl) 1-methyl 3--2-pyrazolin-5-one,

1-(3,4-diclomouth feninole) 1-3-methyl _ 2-pyrazoline 1 5-one,

1- (4-bromophenyl) -1-methyl-2-pyrazolin-5-one,

1-(4-Funoleolofeninole)-3-Methinole 2-pyrazolin-5-one,

1-(3-Chloro-4-methinolephenyl) _ 3 -Methinole 2_Pyrazoline 5_one,

1- (3-methylmercaptophenyl) _3-methyl-2-pyrazolin-1-one,

1- (4-methylmercaptophenyl) _3-methyl-2-pyrazolin-5-one,

4-(3-Methyl-5-oxo-1-2-pyrazolin-1-yl) benzoic acid,

1 1 (4 1 ethoxy canoleponinolefuinore) 1 3-methinolate 2-pyrazoline 1 5 _ on,

1- (4_Nitrophenol) 1-3-Methyl-1_2_Pyrazolin-5-one,

3-Ethyl-one 1-Feninole 2-1-Pyrazolin-5-on,

1-phenyl-1-3-propyl-1-birazolin-1-5-one,

1,3-diphenyl-2-pyrazolin-1-5-one,

3-phenyl-1- (p-tolyl) -2-pyrazolin_5—one,

1- (4-methoxyphenyl) -1-3-phenyl_2-pyrazolin-1-5-one,

1- 1 (4-—Fou-no-Feninore) — 3-—Fu-Nore 1—2-Pyrazolin-1 5—one,

3, 4—Dimethinole _1—Feninole 2—Pyrazolin-1-5-one,

4-isobutyl- 3-methinole 1-1-phenylenole 2-bilazoline 1-5-one,

4 1 (2-Hydroxishechnole) 1 3-Methinole 1 1 Phenyl _ 2-Pyrazolin 1

5 one on,

3-Methyl-4-phenoxy-1-phenylenol 2-birazolin-5-one,

3-Methyl-4-1-phenylmercapto-11-Phenyl-2-Vyrazolin-1-5-one,

2,3a, 4,5,6,7—hexahydrol 2 _phenylindazole_3—one,

3- (ethoxycarbonylmethyl) 1-1-phenyl 2-birazolin-5-one,

1—Feninole 2—Virazoline 5

3-methyl-2-birazolin-5-one,

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

1—Ethyru 3—Methinolay 2—Pyrazolin-5—On,

1-butyl-3-methyl-2-pyrazolin-1-5-one,

1- (2-hydroxyethyl) 1-3-methyl-2-pyrazolin-5-one,

1-Mouth hexinole 1-Methinole 2-Vilazoline-5-one,

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

1- (α-naphthyl) -1-3-methyl-2-pyrazolin-1-5-one,.

1-Methinolay 3-Feninole 2-Bilazoline-5-On, 3-Methyl-1- (4-methylphenyl) -1-2-pyrazolin-15-one, 1-1 (4-butylphenyl) -1-3-methyl-2-pyrazolin-15-one, 1-1 (4-methoxyphenyl) -1-3 —Methyl-1-2-pyrazolin-1-5-one, 1- (4-butoxyphenyl) 1-3-methyl-1-pyrazolin-1-5-one, 1-1 (4-chlorophen-2-ole) -1-3-Methyl-2-pyrazolin-1 5-one, 1- (4-hydroxyphenyl) -1-3-methyl-2-pyrazolin-1-5-one, 1_ (3,4-dihydro π-xyphenyl) 1-3-methyl-1-pyrazolin-15-one,

1- (2-Hydroxyphenyl) -1-3-Methyl-2-pyrazolin-1-5-one, 1- (3-hydroxyphenyl) — 3-Methyl-1-pyrazolin-1-5-one, 1- (4-Hydroxyphenyl) -1 3-Methyl-2-pyrazolin-1-5-one, 1_ (3,4-hydroxyphenyl) -1-3-methyl-2-pyrazolin-1-5_one, 1- (4-hydroxyphenyl) 1 3-phenylenol-2-pyrazolin One 5-one, one-one (4-hydroxymethylphenyl) one-three-methino-one two-pyrazolinone five-one,

1- (4-aminophenyl) -1-3-methyl-2-pyrazolin-5-one,

1- (4-methinoleaminopheninole) —3-methyl-1-2-pyrazolin-1-5-one,

1- (4-ethylaminophenyl) 1-3-methyl-2-pyrazolin-1 5-one,

1-(4-butynoleaminopheninole) one 3-methinole 2-pyrazolin one 5-one,

1- (4-dimethylaminophenyl) _3-methyl_2-birazolin-1-5-,

1-(acetoamidophenyl) _ 3 -methyl-2-pyrazolin _ 5 -one,

2. The prophylactic and / or Z or therapeutic agent according to claim 1, which is a compound selected from the group consisting of 1- (4-cyanophenyl) -13-methyl-12-pyrazolin-15-one.

3.3 selected from the group consisting of 3-methyl-1-phenyl-2-virazolin-1-one and physiologically acceptable salts thereof, and any hydrates and solvates thereof An agent for preventing and / or treating hypoxic-ischemic encephalopathy containing a substance as an active ingredient.

4. The hypoxic-ischemic encephalopathy is a neonatal hypoxic-ischemic encephalopathy. 4. The prophylactic and / or Z or therapeutic agent according to any one of paragraphs 3 to 3.

5. A pyrazolone derivative represented by the formula (I) according to claim 1 for the manufacture of a prophylactic and / or therapeutic agent according to any one of claims 1 to 4. Use of a substance selected from the group consisting of body and physiologically acceptable salts thereof, and any hydrates and solvates thereof.

6. A method for preventing and / or treating hypoxic-ischemic encephalopathy, wherein the pyrazoopene derivative represented by the formula (I) according to claim 1 and a physiologically acceptable salt thereof are provided. And administering a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of any hydrates and any solvates thereof to mammals including humans.