JP2003335674A - Prophylactic and therapeutic agents for radiation damage - Google Patents

Abstract

(57) [Solution] A therapeutic agent for radiation damage, more specifically, a preventive agent for vascular damage caused by exposure to radiation, and / or
Or a therapeutic agent, a prophylactic and / or therapeutic agent for postoperative complications due to exposure to radiation, and for suppressing a decrease in vascular endothelial-derived nitric oxide synthase due to exposure to radiation Provide the drug to be used. SOLUTION: The following formula: (Each symbol in the formula has the same meaning as that described in the specification.) Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to treatment of radiation disorders,
More specifically, the prevention and / or treatment of vascular disorders caused by exposure to radiation, the prevention and / or treatment of postoperative complications caused by exposure to radiation, and the exposure to radiation The present invention relates to a useful medicine used for suppressing the decrease of vascular endothelium-derived nitric oxide synthase.

[0002]

2. Description of the Related Art It is known that postoperative complications such as susceptibility to infection and delay of wound healing are high in surgical treatment on tissues after receiving radiotherapy. One of the causes is considered to be a marked vascular disorder after irradiation, and in particular, vascular endothelial cells are more likely to absorb a higher radiation dose than other tissues, so that functional or functional vascular endothelial cells may be absorbed. It has been pointed out that morphological half price may be related to this. The present inventors previously irradiated with ⁶⁰ Co that the irradiation specifically impairs the expression of vascular endothelium-derived nitric oxide synthase (eNOS) without causing morphological changes in vascular endothelial cells. Experimentally demonstrated using rabbit ear artery and carotid artery removed intraoperatively from patients undergoing radiotherapy for malignant cervical tumors (Br. J. P.
harmacol. 123: 653-660, 1998, Circulation 100: 635-
641, 1999).

On the other hand, the following formula (I)

[0004]

[Chemical 5]

(Wherein R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents hydrogen atom, aryloxy, arylmercapto, carbon Represents an alkyl of the number 1 to 5 or a hydroxyalkyl of the number 1 to 3, or R
¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is 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, alkoxycarbonyl having 2 to 5 carbon atoms, and 1 carbon atom
Selected from the group consisting of alkylmercapto of 3 to 3, alkylamino having 1 to 4 carbons, dialkylamino having 2 to 8 carbons, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 substituents which are the same or different. Regarding the pyrazolone derivative represented by the formula (4), as a pharmaceutical use, a brain function normalizing action (Japanese Patent Publication No. 5-31523), a lipid peroxide production inhibitory action (Japanese Patent Publication No. 5-35128, compound of Example 1) , An anti-ulcer action (JP-A-3-215425), a blood glucose elevation inhibitory action (JP-A-3-215426), and the like are known. However, none of these publications suggests or teaches that this compound is useful as a preventive or therapeutic agent for radiation damage.

The compound of the above formula (I) is
It has been marketed as a brain protectant (generic name "edaravone", trade name "Radicut": manufactured and sold by Mitsubishi Welpharma Co., Ltd.) since June, 2012. No report has been made yet.

[0007]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a therapeutic agent for radiation damage, more specifically, a preventive and / or therapeutic agent for vascular damage resulting from exposure to radiation, and exposure to radiation. It is intended to provide a prophylactic and / or therapeutic agent for postoperative complications caused by thyroid gland, and a drug used for suppressing the decrease in vascular endothelium-derived nitric oxide synthase caused by exposure to radiation. .

[0008]

As a result of diligent efforts to solve the above problems, the present inventor has obtained a pyrazolone derivative or a physiologically acceptable salt thereof, which has hitherto been known to have a brain protecting action, Further, they have found that a pharmaceutical composition containing a hydrate or solvate thereof as an active ingredient is useful for the prevention and / or treatment of the above-mentioned radiation disorders, and have completed the present invention.

That is, the present invention relates to the following preventive agents and therapeutic agents for radiation damage.

(1) The following formula (I)

[0011]

[Chemical 6]

(Wherein R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents a hydrogen atom, aryloxy, arylmercapto, carbon Represents an alkyl of the number 1 to 5 or a hydroxyalkyl of the number 1 to 3, or R
¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is 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, alkoxycarbonyl having 2 to 5 carbon atoms, and 1 carbon atom
Selected from the group consisting of alkylmercapto of 3 to 3, alkylamino having 1 to 4 carbons, dialkylamino having 2 to 8 carbons, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 substituents which are the same or different. ) A therapeutic agent for radiation disorders containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

(2) Radiation damage containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient Therapeutic agent.

(3) The following formula (I)

[0015]

[Chemical 7]

(In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents hydrogen atom, aryloxy, aryl mercapto, carbon Represents an alkyl of the number 1 to 5 or a hydroxyalkyl of the number 1 to 3, or R
¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is 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, alkoxycarbonyl having 2 to 5 carbon atoms, and 1 carbon atom
Selected from the group consisting of alkylmercapto of 3 to 3, alkylamino having 1 to 4 carbons, dialkylamino having 2 to 8 carbons, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 substituents which are the same or different. ), A preventive agent for a vascular disorder caused by exposure to radiation, which comprises a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and / or Or a therapeutic agent.

(4) Radiation containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient A preventive and / or therapeutic agent for vascular disorders resulting from exposure.

(5) The following formula (I)

[0019]

[Chemical 8]

(In the formula, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, carbon Represents an alkyl of the number 1 to 5 or a hydroxyalkyl of the number 1 to 3, or R
¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is 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, alkoxycarbonyl having 2 to 5 carbon atoms, and 1 carbon atom
Selected from the group consisting of alkylmercapto of 3 to 3, alkylamino having 1 to 4 carbons, dialkylamino having 2 to 8 carbons, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 substituents which are the same or different. ) A pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, which is a preventive agent for postoperative complications resulting from exposure to radiation. and/
Or a therapeutic agent.

(6) Radiation containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient A preventive and / or therapeutic agent for postoperative complications resulting from exposure.

(7) The prophylactic and / or therapeutic agent as described above, wherein the postoperative complications resulting from exposure to radiation are immunocompromised or delayed wound healing in the irradiated tissue.

(8) The following formula (I)

[0024]

[Chemical 9]

(Wherein R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbon atoms or alkoxycarbonylalkyl having 3 to 6 carbon atoms, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, carbon Represents an alkyl of the number 1 to 5 or a hydroxyalkyl of the number 1 to 3, or R
¹ and R ² together represent alkylene having 3 to 5 carbon atoms, R ³ is 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, alkoxycarbonyl having 2 to 5 carbon atoms, and 1 carbon atom
Selected from the group consisting of alkylmercapto of 3 to 3, alkylamino having 1 to 4 carbons, dialkylamino having 2 to 8 carbons, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino, and acetamide. Represents phenyl substituted with 1 to 3 substituents which are the same or different. ) A pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained as an active ingredient, and vascular endothelium-derived nitric oxide synthesis resulting from exposure to radiation A drug used to suppress the reduction of enzymes.

(9) Radiation containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient A drug used for suppressing the decrease in vascular endothelium-derived nitric oxide synthase due to exposure.

The pyrazolone derivative of formula (I) contained in the preventive and / or therapeutic agent for radiation damage of the present invention can be synthesized by any purposeful method. JP-A-62-108814
The method described in Japanese Patent Laid-Open Publication No. 2004-242242 can be mentioned.

The active ingredient of the preventive and / or therapeutic agent for radiation damage of the present invention is a free form of the above formula (I).
The pyrazolone derivative of 1 may be used, but a physiologically acceptable salt thereof, or any hydrate or solvate thereof can also be used.

The pyrazolone derivative is described in Japanese Patent Publication No.
Although there are tautomers (the following formula (I ′) or (I ″)) as shown in the chemical structural formula in the upper column of column No. 31523, the active ingredient of the medicament of the present invention contains these tautomers. It goes without saying that all isomers of are included.

[0030]

[Chemical 10]

In the above formula (I), the aryl group in the definition of R ¹ includes 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. Is mentioned.

The number of carbon atoms in the definition of R ¹ , R ² and R ³ is 1 to
As the alkyl group of 5, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec
-Butyl group, tert-butyl group, pentyl group and the like.

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

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 of the mercapto group include a phenylmercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorophenylmercapto group and a p-hydroxyphenylmercapto group.

The hydroxyalkyl group having 1 to 3 carbon atoms in the definition of R ² and R ³ is hydroxymethyl group, 2
-Hydroxyethyl group, 3-hydroxypropyl group and the like can be mentioned. Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R ³ include a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

In the definition of R ³ , examples of the alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and a pentyloxy group. Total carbon number 2
Examples of the alkoxycarbonyl group of ~ 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like, having 1 to 3 carbon atoms.
Examples of the alkylmercapto group include a methylmercapto group, an ethylmercapto group, a propylmercapto group, and the like, and an alkylamino group having 1 to 4 carbon atoms includes 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, a diethylamino group, a dipropylamino group and a dibutylamino group.

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

3-Methyl-1-phenyl-2-pyrazolin-5-one, 3-methyl-1- (2-methylphenyl) -2-pyrazolin-5-one, 3-methyl-1-
(3-methylphenyl) -2-pyrazolin-5-one,
3-Methyl-1- (4-methylphenyl) -2-pyrazolin-5-one, 3-methyl-1- (3,4-dimethylphenyl) -2-pyrazolin-5-one, 1- (4-ethyl Phenyl) -3-methyl-2-pyrazolin-5-one, 3-methyl-1- (4-propylphenyl) -2-
Pyrazolin-5-one, 1- (4-butylphenyl)-
3-Methyl-2-pyrazolin-5-one, 1- (3-trifluoromethylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-trifluoromethylphenyl) -3-methyl- 2-pyrazolin-5-one, 1-
(2-Methoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (3-methoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-methoxyphenyl) -3 -Methyl-2-pyrazolin-5-one,
1- (3,4-dimethoxyphenyl) -3-methyl-2
-Pyrazolin-5-one, 1- (4-ethoxyphenyl) -3-methyl-2-pyrazolin-5-one, 3-methyl-1- (4-propoxyphenyl) -2-pyrazolin-5-one, 1 -(4-butoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (2-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1
-(3-Chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (3,4-dichlorophenyl) -3 -Methyl-2-pyrazolin-5-one, 1- (4-bromophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-fluorophenyl)-
3-Methyl-2-pyrazolin-5-one, 1- (3-chloro-4-methylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (3-methylmercaptophenyl) -3-methyl -2-Pyrazolin-5-one, 1-
(4-methylmercaptophenyl) -3-methyl-2-
Pyrazolin-5-one, 4- (3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid, 1- (4-ethoxycarbonylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-nitrophenyl) -3-methyl-2-pyrazolin-5-one, 3-ethyl-1-phenyl-2-pyrazolin-5-one, 1-phenyl-3
-Propyl-2-pyrazolin-5-one, 1,3-diphenyl-2-pyrazolin-5-one, 3-phenyl-1
-(P-tolyl) -2-pyrazolin-5-one, 1-
(4-Methoxyphenyl) -3-phenyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-phenyl-2-pyrazolin-5-one, 3,4-dimethyl-1-phenyl-2 -Pyrazolin-5-one, 4-isobutyl-3-methyl-1-phenyl-2-pyrazolin-
5-one, 4- (2-hydroxyethyl) -3-methyl-1-phenyl-2-pyrazolin-5-one, 3-methyl-4-phenoxy-1-phenyl-2-pyrazolin-
5-one, 3-methyl-4-phenylmercapto-1-
Phenyl-2-pyrazolin-5-one, 2,3a, 4
5,6,7-Hexahydro-2-phenylindazol-3-one, 3- (ethoxycarbonylmethyl) -1-
Phenyl-2-pyrazolin-5-one, 1-phenyl-
2-pyrazolin-5-one, 3-methyl-2-pyrazolin-5-one, 1,3-dimethyl-2-pyrazolin-5
-One, 1-ethyl-3-methyl-2-pyrazolin-5
-One, 1-butyl-3-methyl-2-pyrazolin-5
-One, 1- (2-hydroxyethyl) -3-methyl-2
-Pyrazolin-5-one, 1-cyclohexyl-3-methyl-2-pyrazolin-5-one, 1-benzyl-3-
Methyl-2-pyrazolin-5-one, 1- (α-naphthyl) -3-methyl-2-pyrazolin-5-one, 1-methyl-3-phenyl-2-pyrazolin-5-one, 3-
Methyl-1- (4-methylphenyl) -2-pyrazolin-5-one, 1- (4-butylphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-methoxyphenyl) -3 -Methyl-2-pyrazolin-5-one, 1-
(4-Butoxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-chlorophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-hydroxyphenyl) -3- Methyl-2-pyrazolin-5-one,
1- (3,4-dihydroxyphenyl) -3-methyl-
2-pyrazolin-5-one, 1- (2-hydroxyphenyl) -3-methyl-2-pyrazolin-5-one, 1-
(3-Hydroxyphenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-hydroxyphenyl) -3
-Methyl-2-pyrazolin-5-one, 1- (3,4-
Hydroxyphenyl) -3-methyl-2-pyrazoline-
5-one, 1- (4-hydroxyphenyl) -3-phenyl-2-pyrazolin-5-one, 1- (4-hydroxymethylphenyl) -3-methyl-2-pyrazolin-5
-One, 1- (4-aminophenyl) -3-methyl-2
-Pyrazolin-5-one, 1- (4-methylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1-
(4-Ethylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-butylaminophenyl)
-3-Methyl-2-pyrazolin-5-one, 1- (4-
Dimethylaminophenyl) -3-methyl-2-pyrazolin-5-one, 1- (acetamidophenyl) -3-methyl-2-pyrazolin-5-one, 1- (4-cyanophenyl) -3-methyl-2 -Pyrazolin-5-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 an organic acid salt such as a fumarate; a metal salt such as a sodium salt, a potassium salt, or a magnesium salt; an ammonium salt; or an organic amine salt such as ethanolamine 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.

One or more compounds of the formula (I) or a salt thereof, which is an active ingredient of the preventive and / or therapeutic agent for radiation damage of the present invention, may be directly administered to a patient. Preferably, the active ingredient and pharmacologically and pharmaceutically acceptable additives should be added and the preparation should be provided in a form well known to those skilled in the art.

The pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids,
Binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters,
Stabilizers, propellants, adhesives and the like can be used. Examples of the formulation suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, syrups, etc., and examples of the formulation suitable for parenteral administration include injection. An agent, a drip, a suppository, etc. can be mentioned.

In the preparation suitable for oral administration, as an additive, for example, an excipient such as glucose, lactose, D-mannitol, starch or crystalline cellulose; a disintegrating agent such as carboxymethylcellulose, starch or calcium carboxymethylcellulose, or Disintegration aids; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc;
A coating agent such as hydroxypropylmethyl cellulose, sucrose, polyethylene glycol or titanium oxide; a base such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.

Formulations suitable for injection or drip include solubilizers or solubilizers that can constitute aqueous or in-use dissolution-type injections such as distilled water for injection, physiological saline, and propylene glycol; glucose, sodium chloride, Tonicity agents such as D-mannitol and glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases can be used.

A brain protectant (drip solution) containing the compound of the above formula (I) as an active ingredient has already been used clinically (generic name "edaravone", trade name "Radicut": Mitsubishi Wel Pharma Manufacturing and sales)
As the preventive / therapeutic agent for radiation damage of the present invention, the above-mentioned commercially available preparation can be used as it is.

The radiation damage of the present invention includes, for example, vascular damage caused by exposure to radiation, postoperative complications caused by exposure to radiation, and wound healing caused by exposure to radiation. Examples include delay and decrease in vascular endothelium-derived nitric oxide synthase due to exposure to radiation. Of these, specific examples of postoperative complications resulting from exposure to radiation include immunocommunicability in irradiated tissues or delayed wound healing.

The prevention and / or treatment of radiation damage is
It is suitable to carry out at an appropriate time before and after exposure to radiation. Examples of the case of being exposed to radiation include a case of performing radiation treatment on a cancer patient (including a case of using a radium needle), a nuclear power plant accident, and the like. It can also be used for patients suffering from aftereffects of atomic bombs.

The pharmaceutical agent of the present invention has a function as a preventive agent for preventing radiation damage and a function as a therapeutic agent for recovering radiation damage to a normal state, but it is preferably used as a therapeutic agent.

The route of administration of the medicament of the present invention is not particularly limited, and it can be administered orally or parenterally. For example, it is preferable to administer the medicament of the present invention to a patient exposed to a large amount of radiation due to an accident by intravenous, intraarterial, or intracardiac injection. When it is clear that the patient is exposed to radiation, such as when performing radiation treatment on a cancer patient, the drug of the present invention should be orally administered, or injection or infusion should be performed before exposure to radiation. It is preferable to administer parenterally during or before the radiation treatment. For patients who have developed vascular disorders or postoperative complications due to exposure to radiation or for patients who have decreased vascular endothelium-derived nitric oxide synthase due to exposure to radiation For the purpose of preventing worsening of symptoms or alleviating symptoms, it is preferable to administer by intravenous injection, intraarterial injection, or intracardiac injection.

The dose of the drug of the present invention can be appropriately selected according to the purpose of prevention or treatment of radiation damage, the age and condition of the patient, and the like. It is preferable to administer about 1 to 100 mg / kg by injection or drip, or about 0.1 to 100 mg / kg orally. When administered by injection, it is preferable to use, for example, the injections described in JP-A-63-132833. The above-mentioned compound, which is the active ingredient of the medicine of the present invention, is highly safe.
(Intraperitoneal administration of mouse LD ₅₀ 2012 mg / kg; Oral administration of rat LD ₅₀ 3,500 mg / kg: Regis
try of Toxic Effects of C
chemical Substances, 1981-1
982), which has also been proved non-carcinogenic (Nat
ional Cancer Institute Re
(Port, 89, 1978).

[0050]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples. The following experiment was conducted using 1-phenyl-3-methyl-2-pyrazolin-5-one as a representative example of compound (I).

Synthesis example: 1-phenyl-3-methyl-2-
Synthesis of pyrazolin-5-one 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added to 50 ml 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 obtain 11.3 g of the title compound as colorless crystals. Yield 67% Melting point 127.5-128.5 ° C

Experimental Example 1 (Method) A male New Zealand white rabbit weighing 2 kg was used. Rabbit with pentobarbital
tal) was anesthetized by intravenous injection of 25 mg / kg, and the auricles on both sides were fixed with tape. RC as an external irradiation device for ⁶⁰ Co
Using R-120-C3 (manufactured by Toshiba), the irradiation dose of 45 Gy was applied once. Irradiation field is 10 × 10 cm, irradiation distance SSD (source-skin distanc
e) was set to 55 cm, and one ear was irradiated with 1.25 meV gamma ray. ^Since the build-up of ⁶⁰ Co gamma rays was 5 mm, one piece of gauze was placed on the ear of a rabbit, and the irradiation dose of the central artery was made to correspond to the calculated total dose. The other ear, which was not irradiated, served as a control group. 1-phenyl-3-methyl-2-pyrazolin-5-one is 3m
g / kg was intraperitoneally administered twice a day from the day before the irradiation, and was continuously performed until the day before the blood vessel was removed.

Two weeks after the irradiation, the rabbit was killed by an excessive injection of pentobarbital, and one central auricle was removed from one auricle without damaging the endothelium, and a microscope was used depending on the purpose of the experiment. Underneath, the soft tissue around the blood vessel was peeled off.
When observing the endothelium-dependent relaxation reaction of the ear artery, the blood vessel was made into a ring-shaped sample with a width of about 4 mm, and the temperature was 37 ° C. according to the usual method.
It was fixed in an organ bath filled with 25 ml of oxygenated physiological saline. For immunohistochemistry and immunofluorescence staining, tissues were fixed in formalin, embedded in paraffin, sectioned, and attached to slide glasses. The sections were blocked with normal goat serum to avoid nonspecific staining with secondary antibody, and then incubated with anti-human eNOS polyclonal antibody (Affinity Bioreagents) at 4 ° C. overnight, followed by horseradish peroxidase (horseradish). peroxidase) -bound secondary antibody. Pixel intensity
Quantitative analysis of immunoreactivity according to y) was done using image-analyzing software. To obtain immunofluorescent staining, sections were stained with rhodamine-conjugated anti-rabbit IgG2.
Incubated for hours. Western blot (We
In the stern blot), the blood vessel was homogenized on ice, and an equal amount of the blood vessel was applied on a polyacrylamide gel and electrophoresed using a running buffer. After the migration, it was transferred to a polyvinylidine defluoride filter (PVDF) membrane and blocked, and then sequentially reacted with a primary antibody and a horseradish peroxidase-labeled secondary antibody. The obtained film was exposed to X-ray film after chemiluminescence, and was exposed to NIH image software (National Institute).
tute of Health, Bethesda, MD, USA).

The method described above is performed by Br. J. Pharmacol.
123: 653-660, 1998 and Circulation 100: 635-641,
It was performed according to the method described in 1999.

(Results) The endothelium-dependent relaxation reaction by acetylcholine when the ear artery was pre-contracted with 1 μM phenylphrine was significantly attenuated in the irradiation group. 1-Phenyl-3-methyl-2-pyrazolin-5-one treatment restored the relaxation response to almost the level of the control group (FIG. 1). In immunofluorescence staining, the expression of eNOS protein in the endothelium of the ear artery was clearly decreased in the irradiation group. This decrease in expression is due to 1-phenyl-3-
It was improved by treatment with methyl-2-pyrazolin-5-one (Fig. 2). When the immunoactivity was analyzed by immunohistostaining by pixel intensity, the above changes were statistically significant (Fig. 3). In Western blot analysis, the eNOS protein expression was reduced to about 50% after irradiation. Treatment with 1-phenyl-3-methyl-2-pyrazolin-5-one completely ameliorated the reduced eNOS expression (FIG. 4).

1-Phenyl-3-methyl-2-pyrazolin-5-one significantly reduced endothelium-dependent relaxation response and eN in rabbit ear artery by irradiation.
The expression of OS protein was significantly improved to the control level. From this, the pharmaceutical of the present invention is effective in preventing and / or treating radiation damage, more specifically, vascular damage caused by exposure to radiation, and postoperative complications caused by exposure to radiation, It was also found to be effective in suppressing the decrease in vascular endothelium-derived nitric oxide synthase due to exposure to radiation.

[0057]

INDUSTRIAL APPLICABILITY The medicament of the present invention is a therapeutic agent for radiation disorders, more specifically, a preventive and / or therapeutic agent for vascular disorders caused by exposure to radiation, and postoperative treatment caused by exposure to radiation. It is useful as a preventive and / or therapeutic agent for complications, and an agent used for suppressing the decrease in vascular endothelium-derived nitric oxide synthase due to exposure to radiation.

[0058]

[Brief description of drawings]

FIG. 1 is a graph showing the effect of the pharmaceutical preparation of the present invention on the endothelium-dependent relaxation reaction induced by acetylcholine in the ear artery.

FIG. 2 is a view showing a micrograph of an eNOS protein in the endothelium of an ear artery which was subjected to immunofluorescence staining.

FIG. 3 is a diagram showing the results of analysis of eNOS protein in the endothelium of the ear artery by pixel intensity.

FIG. 4 is an actual record (left) in which eNOS protein in the endothelium of the ear artery was analyzed by immunoblotting and a diagram (right) showing the result.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 231/20 C07D 231/20 C F term (reference) 4C086 AA01 AA02 BC36 MA01 MA04 MA17 MA22 MA23 MA31 MA35 MA37 MA41 MA43 MA52 MA60 MA66 NA14 ZA36 ZA89 ZB32 ZC41

Claims (9)

[Claims] 1. 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 in total, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² are
Together, they represent alkylene having 3 to 5 carbon atoms, R ³ is 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 2
~ 5 alkoxycarbonyl, C1-3 alkylmercapto, C1-4 alkylamino, total C2-8 dialkylamino, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino , And phenyl substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ) A preventive and / or therapeutic agent for a radiation disorder containing a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. 2. Prevention of radiation damage containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Agents and / or therapeutic agents. 3. 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 in total, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² are
Together, they represent alkylene having 3 to 5 carbon atoms, R ³ is 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 2
~ 5 alkoxycarbonyl, C1-3 alkylmercapto, C1-4 alkylamino, total C2-8 dialkylamino, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino , And phenyl substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ), A preventive agent for a vascular disorder caused by exposure to radiation, which comprises a pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and / or Or a therapeutic agent. 4. Exposure to radiation, comprising 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. A preventive and / or therapeutic agent for vascular disorders resulting from the treatment. 5. 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 in total, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² are
Together, they represent alkylene having 3 to 5 carbon atoms, R ³ is 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 2
~ 5 alkoxycarbonyl, C1-3 alkylmercapto, C1-4 alkylamino, total C2-8 dialkylamino, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino , And phenyl substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ) A pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, which is a preventive agent for postoperative complications resulting from exposure to radiation. And / or therapeutic agents. 6. Radiation exposure containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. A preventive and / or therapeutic agent for postoperative complications resulting from the above. 7. The prophylactic and / or therapeutic agent according to claim 5 or 6, wherein the postoperative complication resulting from exposure to radiation is immunocompromised or delayed wound healing in the irradiated tissue. 8. 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 in total, and R ² represents a hydrogen atom, aryloxy, arylmercapto, 1 to 1 carbons. 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² are
Together, they represent alkylene having 3 to 5 carbon atoms, R ³ is 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 2
~ 5 alkoxycarbonyl, C1-3 alkylmercapto, C1-4 alkylamino, total C2-8 dialkylamino, halogen atom, trifluoromethyl, carboxyl, cyano, hydroxyl group, nitro, amino , And phenyl substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ) A pyrazolone derivative represented by the formula (1) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained as an active ingredient, and vascular endothelium-derived nitric oxide synthesis resulting from exposure to radiation A drug used to suppress the reduction of enzymes. 9. Radiation exposure containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. A drug used for suppressing the decrease in vascular endothelium-derived nitric oxide synthase due to the above-mentioned action.