JP2003267871A - Radiation hazard-preventing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine which is useful for preventing radiation hazards caused by radiation exposure accidents or radiotherapy. <P>SOLUTION: This radiation hazard-preventing agent contains a pyrazolone derivative represented by formula (I) (symbols in the formula are the same as those described in the specification), its physiologically acceptable salt, its arbitrary hydrate or solvate, its arbitrary hydrate physiologically acceptable salt, or its arbitrary solvate physiologically acceptable salt as an active ingredient. The compound is useful for preventing acute radiation hazards, late radiation hazards, and the like. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug useful for preventing radiation exposure accidents and radiation damage due to radiation treatment.

2. Description of the Related Art The damage that a living body receives due to ionizing radiation can be divided into acute damage and late damage. In acute injury at the time of whole body exposure, epidermal findings such as hair loss and skin inflammation were observed, and bone marrow hematopoietic system failure was observed at 3 to 8 Gy.
At -100 Gy, gastrointestinal disorders cause bleeding in multiple organs, infectious diseases, and the like, which cause death for about 3 weeks and several days. Furthermore, exposure to high doses of 100 Gy or more causes disturbance of consciousness due to disorders of the central nervous system, resulting in death within a few hours. Even after overcoming the acute phase of radiation injury, late-onset disorders may develop. Currently there is no effective way to prevent these disorders. Also in the radiation therapy for cancer, in order to prevent the occurrence of the radiation damage as described above, the dose is concentrated in the cancer lesion to reduce the exposure of the surrounding normal tissue, but the damage to this normal tissue is conversely. It is no exaggeration to say that the therapeutic dose is limited for prevention. However, there is no known drug that can prevent these radiation damages without limiting the therapeutic dose, and its development is eagerly awaited (Hauer-Jensen,
M. et al. , Acta Oncologica,
29, 401, 1990, Geraci, j. P. et
al. , RadiationResearch, 12
9, 61, 1992, Brook, i. et al. ，
Military Medicine, 157, 13
0,1992, Kokunai, t. et al. , N
eurologia Medico-Chirurgi
ca, 30, 36, 1990, Fajardo, l.
F. , Seminars in Rotengenol
(Ogy, 28, 297, 1993).

On the other hand, the following formula (I)

[Chemical 2] (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 As far as the inventor is aware, the pyrazolone derivative represented by the formula ()) has a function of normalizing brain function (Japanese Patent Publication No. 5-31523) and a lipid peroxide production inhibitory action (Japanese Patent Publication No. 35128/1993) as far as the inventors know. , The compound of Example 1),
It is known to have an anti-ulcer effect (JP-A-3-215425) and an inhibitory effect on blood glucose increase (JP-A-3-215426). However, in each of these publications, it is indicated that this compound is useful as a preventive agent for radiation damage.
Not suggested or taught. In addition, the compound of the above formula (I) has been marketed since June 2001 as a brain protectant (generic name "edaravone", trade name "Radicut": manufactured and sold by Mitsubishi Wel Pharma Co., Ltd.). Has not yet been reported to be useful in preventing radiation injuries.

[0002]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention relates to disorders associated with radiation exposure and radiation treatment, more specifically, acute local radiation injury, acute systemic radiation injury, late-onset local radiation injury, and late-onset radiation. It is intended to provide a preventive agent for systemic radiation damage.

[0003]

As a result of diligent efforts to solve the above problems, the present inventor has found that pyrazolone derivatives, which are conventionally known to have a brain-protecting action, and physiologically acceptable salts thereof, A hydrate or solvate thereof, a physiologically acceptable salt of the hydrate thereof, and a pharmaceutical composition containing a physiologically acceptable salt of the solvate thereof as an active ingredient They have found that they are useful in preventing radiation damage and have completed the present invention.

That is, the present invention relates to the following preventive agents. (1) The following formula (I)

[Chemical 3] (Wherein each symbol has the same meaning as defined above), a pyrazolone derivative represented by the formula, a physiologically acceptable salt thereof, any hydrate or solvate thereof, physiologically any hydrate thereof. An agent for preventing radiation damage, which comprises an acceptable salt and a physiologically acceptable salt of any solvate thereof as an active ingredient. (2) 3-methyl-1-phenyl-2-pyrazoline-5
-One, a physiologically acceptable salt thereof, any hydrate or solvate thereof, a physiologically acceptable salt of any hydrate thereof, and a physiologically acceptable salt of any solvate thereof. A preventive agent for radiation damage, which comprises a salt as an active ingredient. (3) The radiation damage is one or more radiation damages selected from the group consisting of acute local radiation damage, acute systemic radiation damage, late focal local radiation damage, and late systemic radiation damage. The preventive agent according to 1 or 2.

The compound of the above formula (I) contained in the agent for preventing radiation damage of the present invention can be synthesized by any purposeful method, and as a preferable example, there is JP-A-62-62.
The method described in JP-A-108814 can be mentioned.

As the active ingredient of the preventive agent for radiation damage of the present invention, a free form of the compound of the above formula (I) may be used, but its physiologically acceptable salt, any hydrate or solvent thereof. A solvate, a physiologically acceptable salt of any hydrate thereof, and a physiologically acceptable salt of any solvate thereof can also be used. It should be noted that Japanese Patent Publication No. 5-31
Although there are tautomers (the following formula (I ′) or (I ″)) as shown in the chemical structural formula in the upper column of column No. 523 of 523 publication, these are included in the active ingredient of the medicine of the present invention. It goes without saying that all isomers of are included.

[Chemical 4]

As the salt of the above compound, 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 acid salts such as fumarate; sodium salt, potassium salt,
Or a metal salt such as a magnesium salt; an ammonium salt; or ethanolamine or 2-amino-2-
An organic amine salt such as methyl-1-propanol can be used, but the type of salt is not particularly limited as long as it is physiologically acceptable.

The dosage form of the agent for preventing radiation damage of the present invention is not particularly limited, and it can be administered orally or parenterally. Preferably, it may be parenterally administered intravenously by injection or drip. The compound of the above formula (I) which is an active ingredient as a preventive agent for radiation damage of the present invention, a physiologically acceptable salt thereof, any hydrate or solvate thereof, physiologically any hydrate thereof Of the acceptable salts and physiologically acceptable salts of any solvates thereof, one or more species may be directly administered to the patient, but preferably,
The active ingredient and pharmacologically and pharmaceutically acceptable additives should be added to provide the preparation in a form well known to those skilled in the art. The pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizing agents or A solubilizing agent, an isotonicity agent, a pH adjusting agent, a stabilizer, a propellant, an adhesive 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.

For the preparation suitable for oral administration, as additives, for example, excipients such as glucose, lactose, D-mannitol, starch or crystalline cellulose; disintegrants such as carboxymethyl cellulose, starch or carboxymethyl cellulose calcium, 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 infusion include, for example, distilled water for injection, physiological saline, and solubilizers or solubilizers that can compose aqueous or injection-soluble injections such as propylene glycol; glucose, sodium chloride, D-mannitol. , Isotonic agents such as glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases 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 may be added. The brain protectant (drip) containing the compound of the above formula (I) as an active ingredient has already been used clinically (generic name "edaravone", trade name "RADICAT": manufactured by Mitsubishi Wel Pharma Co., Ltd.・ Sale),
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 preventive agent of the present invention can be applied to, for example, acute and / or late radiation damage caused by systemic radiation exposure due to a nuclear accident or nuclear explosion,
Alternatively, there may be mentioned acute and / or late radiation damage due to local radiation exposure due to radiation irradiation or radiation exposure accident for medical purposes such as cancer treatment.
Of these, it is preferably used for the prevention of local or systemic late radiation damage.

In the present specification, the treatment period of the radiation treatment includes a treatment preparation period prior to the first radiation irradiation, a whole period from the first radiation irradiation to the last radiation irradiation, or any one of the above whole periods. Or two or more periods or days are included. For example, administration of the medicament of the present invention prior to the first irradiation is preferable for prevention of radiation damage caused by radiation treatment. It is also preferable to intermittently administer the medicament of the present invention in accordance with the radiation irradiation schedule of the above treatment period.

The dose of the preventive agent for radiation damage of the present invention is not particularly limited, and is appropriately selected depending on the administration form, the age of the patient, the degree and symptoms of acute or late radiation damage, age, body weight and other conditions. can do. The dose of the drug of the present invention is
It can be appropriately selected according to the purpose of preventing radiation damage and the condition such as age and condition of the patient, but generally, about 0.01 to 100 mg / kg is administered to an adult by injection or infusion. , 0.1 to 100 mg / kg is preferably orally administered. When administered by injection, it is preferable to use, for example, the injections described in JP-A-63-132833. When the preventive agent for radiation damage of the present invention is used as a preventive agent for acute radiation damage when it is expected to be exposed to radiation, it is preferable to start the pre-administration from 30 minutes before and continuously administer it several times. Further, as the preventive administration of the late-onset radiation injury, it is preferable to start the administration as soon as possible after the exposure is revealed, and thereafter to perform the administration once a week for several months.

The above-mentioned compound, which is an active ingredient of the medicament of the present invention, has high safety (intraperitoneal administration to mice LD ₅₀ 20).
12 mg / kg; Rat oral administration LD ₅₀ 3,500 m
g / kg: Registry of Toxic Ef
facts of Chemical Substan
ces, 1981-1982), and is also not carcinogenic (National Cancer In).
status Report, 89, 1978).

[0015]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

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 Mice were divided into 5 groups as follows, and 1-phenyl-3-methyl-2-pyrazolin-5-one was intraperitoneally administered before or after irradiation, and whole body irradiation with X-ray 8.0 Gy was performed. ,
Survival was assessed as the endpoint.

[Table 1]

The results are shown in FIG. 1 ("symbols in the figure" shown in Table 1 correspond to each group in FIG. 1). The survival rate (%) = (survival number / 10) × 100. As is clear from FIG. 1, irradiation was observed up to 30 days after irradiation, but irradiation 3
0 minutes before 1-phenyl-3-methyl-2-pyrazoline-
A clear improvement in the survival rate was observed in the groups administered with 5-one 300 mg / kg and 450 mg / kg as compared with the control group. In particular, in the 450 mg / kg administration group, 80% survived even 30 days after irradiation, showing a remarkable effect. 1 from this result
It was suggested that -phenyl-3-methyl-2-pyrazolin-5-one is effective in preventing radiation damage.

[0019]

[Brief description of drawings]

FIG. 1 shows that each group shown in Table 1 was treated 3 times after irradiation.
It is a graph showing the survival rate for 0 days.

[0020]

INDUSTRIAL APPLICABILITY The medicament of the present invention is useful for preventing radiation damage.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kei Moritake             1-1-1 Tennodai, Tsukuba City, Ibaraki Prefecture University of Tsukuba             Graduate School of Medicine (72) Inventor Kazunori Anzai             Radiation 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba             Line Medical Research Institute F-term (reference) 4C086 AA01 AA02 AA03 AA04 BC36                       MA01 MA04 NA14 ZC01 ZC02

Claims (3)

[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 pyrazolone derivative represented by the formula, a physiologically acceptable salt thereof, any hydrate or solvate thereof, a physiologically acceptable salt of any hydrate thereof, and any solvate thereof. A preventive agent for radiation damage containing a physiologically acceptable salt as an active ingredient. 2. 3-Methyl-1-phenyl-2-pyrazolin-5-one, a physiologically acceptable salt thereof, any hydrate or solvate thereof, physiologically any hydrate thereof. A preventive agent for radiation damage containing as an active ingredient a physiologically acceptable salt of a pharmaceutically acceptable salt thereof or an arbitrary solvate thereof. 3. The radiation damage is one or more radiation damages selected from the group consisting of acute local radiation damage, acute systemic radiation damage, late local radiation damage, and late systemic radiation damage. The preventive agent according to claim 1 or 2.