JP2010229051A - Agent for preventing or treating living body damage by radiation exposure and administration kit thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for preventing or treating living body damage by radiation exposure. <P>SOLUTION: Administration of a farnesol amino acid derivative represented by formula (1) (wherein R is a nitrogen-substituent group-containing carboxylic acid residue; and geometric isomerism of 2-position and 6-position of farnesyl group is 2E, 6E isomer, 2Z/E, 6Z/E isomer) to a subject of radiation exposure effectively prevents or treats living body damage by radiation exposure. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel drug for the prevention or treatment of biological damage caused by radiation exposure and a kit for its administration.

Farnesol is a linear sesquiterpene alcohol contained in essential oils of plants such as roses and lemongrass, and is an aromatic component of flower essential oils. Farnesol is used as a fragrance or skin protection agent (Patent Document 1), and as a medicine, effects such as hyperlipidemia prevention effect and antifungal action have been reported (Non-Patent Document 1). More recently, an effect of increasing the activity of a nuclear receptor type transcription factor called peroxisome proliferator-responsive receptor (PPAR) has been reported (Non-patent Documents 2 and 3). It has also been reported that farnesol and its derivatives have anticancer activity that causes apoptosis in cancer cells (Non-patent Documents 4 and 5).
On the other hand, farnesol is a liquid but a volatile compound that does not dissolve in water at all. For this reason, solubilization methods such as the addition of a large amount of nonionic surfactants have been studied for the preparation of water-soluble preparations or aqueous cosmetics of farnesol, but a large amount of surfactants are a serious problem such as anaphylactic shock. May occur. A series of derivatives of farnesol has been created to improve on this point.
On the other hand, workers / engineers engaged in nuclear power generation, operators of measuring instruments using radiation, and doctors / engineers who perform radiation therapy for cancer always face health problems due to radiation exposure. Also, cosmic ray exposure of aircraft pilots and crew has become a problem. Furthermore, cancer patients undergoing radiation therapy often suffer from side effects such as nausea and diarrhea. The risk of carcinogenesis caused by a small amount of radiation exposure is also a problem for people who undergo medical examinations using radiation such as X-ray CT. Thus, research and development of anti-radiation exposure agents that overcome the risk of biological damage from radiation exposure is an important issue for society, regardless of whether they are professionals or ordinary people. However, there are very few drugs that have been put to practical use as anti-radiation exposure disorder agents for preventing and treating biological damage due to radiation exposure. For example, in the United States, amifostine has been approved for the prevention of xerostomia in the treatment of radiation cancer in the head and neck (see Non-Patent Document 6). Various aminothiols have been reported as radiation protective agents that effectively protect against biological damage caused by radiation exposure (see Non-Patent Document 7). The effectiveness of lactobacilli as a radioprotective agent has also been reported (see Non-Patent Document 8).

Patent No. 3811112

Biochem J., 144, 585-592 (1974). Au-Yeung KK, Liu PL, Chan C, Wu WY, Lee SS, Ko JK, Cancer Invest. 2008 Aug; 26 (7): 708-17. Duncan RE, Archer MC, Lipids. 2008 Jul; 43 (7): 619-27. Mo H. and C.E.Elson, Exp. Biol. Med. 229, 567-585, 2004. Hamada M, Ohata I, Fujita K, Usuki Y, Ogita A, Ishiguro J, Tanaka T., J Biochem. 2006 Dec; 140 (6): 851-9. J. Cancer Research, 1807-1812 (2004). Tsutomu Sugawara et al., “Radiation and Medicine”, Kyoritsu Publishing Co., Ltd., 1986 Radiat.Res. 125, 293-297 (1991)

An object of the present invention is to provide a drug for effectively preventing or treating a biological disorder caused by radiation exposure.
Another object of the present invention is to provide a drug administration kit capable of rapidly administering a drug for preventing or treating a biological disorder caused by radiation exposure after the radiation exposure.

  The present inventors have found that administration of an amino acid derivative of farnesol has an effect of effectively preventing or treating biological damage due to radiation exposure.

式中、Ｒは窒素置換基を有するカルボン酸残基を表す。ファルネシル基の２位と６位の幾何異性は2E、6E体、2Z/E、6Z/E体を表す。 The present invention provides an agent for preventing or treating biological damage caused by radiation exposure, which comprises an amino acid derivative of farnesol represented by the following formula.

In the formula, R represents a carboxylic acid residue having a nitrogen substituent. The geometrical isomerism at the 2nd and 6th positions of the farnesyl group represents 2E, 6E, 2Z / E, 6Z / E.

上記式において、Ｒ₁は同じでも異なっていてもよく、水素原子またはメチル基を表し、Ｒ₂は同じでも異なっていてもよく、水素原子またはメチル基を表し、Ｘは酸付加塩を形成する酸を表す。ファルネシル基の２位と６位の幾何異性は2E、6E体、2Z/E、6Z/E体を表す。
本発明はまた、上記薬剤を含む、放射線被ばくによる生体障害の予防または治療用薬剤投与キットを提供する。 The present invention further provides an agent for preventing or treating biological damage caused by radiation exposure, which comprises an amino acid derivative of farnesol represented by the following formula.

In the above formula, R ₁ may be the same or different, represent a hydrogen atom or a methyl group, R ₂ may be the same or different, represent a hydrogen atom or a methyl group, X is form acid addition salts Represents an acid. The geometrical isomerism at the 2nd and 6th positions of the farnesyl group represents 2E, 6E, 2Z / E, 6Z / E.
The present invention also provides a drug administration kit for preventing or treating biological damage caused by radiation exposure, comprising the above drug.

The agent of the present invention can effectively prevent or treat biological damage due to radiation exposure. For example, by administering the agent of the present invention, workers / engineers engaged in nuclear power generation, operators of measuring instruments using radiation, and doctors / technologists who perform radiation therapy for cancer are always in good health due to radiation exposure. It can prevent or treat obstacles or cosmic radiation exposure of aircraft pilots and crew. In addition, various disorders caused by radiation exposure can be prevented or treated for cancer patients undergoing radiation therapy and those who undergo medical examination using radiation such as X-ray CT.
In addition, by using an administration kit for administering the drug of the present invention, after the radiation exposure occurs in a nuclear power plant or the like, the drug of the present invention can be quickly administered to prevent biological damage due to radiation exposure or Can be treated.

It is a figure which shows the survival rate of the radiation exposure mouse | mouth which administered the chemical | medical agent of this invention. It is a figure which shows the correlation with the time which administers the chemical | medical agent of this invention, and the prevention or treatment effect of a biological disorder.

(1) Agent for Preventing or Treating Radiation Exposure Disorder The agent for preventing or treating biological damage (hereinafter also simply referred to as “radiation exposure disorder”) of the present invention is an amino acid derivative of farnesol represented by the following formula: It is essential to include.

式中、Ｒは窒素置換基を有するカルボン酸残基を表す。ファルネシル基の２位と６位の幾何異性は2E、6E体、2Z/E、6Z/E体を表す。

In the formula, R represents a carboxylic acid residue having a nitrogen substituent. The geometrical isomerism at the 2nd and 6th positions of the farnesyl group represents 2E, 6E, 2Z / E, 6Z / E.

In the present specification, the “carboxylic acid residue” means a residue obtained by removing an OH group from a carboxyl group (COOH) of a carboxylic acid.
Preferred examples of the “carboxylic acid having a nitrogen substituent” giving the “carboxylic acid residue having a nitrogen substituent” of R ¹ include amino acids, N-acyl amino acids, N-alkyl amino acids, N, N-dialkyl amino acids, Examples thereof include those selected from the group consisting of residues of pyridinecarboxylic acids and their physiologically acceptable hydrohalides, alkylsulfonates, and acidic sugar salts.

In the “carboxylic acid residue having a nitrogen substituent”, the alkyl group of the alkyl-substituted amino group is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, n -Pentyl group, n-hexyl group, isopropyl group, isobutyl group, 1-methylpropyl group, tert-butyl group, 1-ethylpropyl group, isoamyl group, etc. can be exemplified, especially methyl group, ethyl group Is preferred.
The acyl group of the acyl-substituted amino group is preferably an acyl group in which a linear or branched alkyl group having 1 to 6 carbon atoms is a hydrocarbon chain, and specific examples of the alkyl group moiety are as described above.

  Further, the amino group and the carbonyl group in the “carboxylic acid residue having a nitrogen substituent” are preferably bonded with a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. The branched alkylene group means an alkylene group derived from an alkyl group such as isopropyl group, isobutyl group, 1-methylpropyl group, tert-butyl group, and 1-ethylpropyl group. The cyclic alkylene group means an alkylene group containing a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring or the like in the structure. Particularly preferred as the alkylene group is a methylene group or an ethylene group.

  The nitrogen substituent in the “carboxylic acid residue having a nitrogen substituent” may form a salt. For example, as the hydrohalide, hydrochloride, hydrobromide and the like are preferable. In the present invention, the hydrohalide salt has an advantage that the melting point is higher than that of the original farnesol, and it is easy to handle the preparation. Examples of the alkyl sulfonate include methane sulfonate. Examples of the saccharide salt include gluconate, glucoheptanoate, and lactobionate.

Further, as the farnesol carboxylic acid ester, a compound represented by the following general formula (1 ′) is preferable.

In the above formula, R ₁ may be the same or different and represents a hydrogen atom or a methyl group, R ₂ may be the same or different and represents a hydrogen atom or a methyl group, and X forms an acid addition salt. Represents a pharmaceutically acceptable acid.
R ₁ is preferably a hydrogen atom. R ₂ is preferably a methyl group.
X means a pharmaceutically acceptable acid that forms an acid addition salt to the amino moiety. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, as well as acetic acid, propionic acid, glycolic acid, benzoic acid, cinnamic acid, mandelic acid, methane Organic acids such as sulfonic acid, p-toluenesulfonic acid, salicylic acid and the like can be mentioned.
Particularly preferred is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid and hydrofluoric acid.

The compound of the present invention can be produced by the following method.
By carrying out an esterification reaction by a conventional method with farnesol represented by the following general formula (2) and a carboxylic acid having a nitrogen substituent, or a reactive acid derivative thereof, or a hydrohalide thereof. The farnesol carboxylic acid ester (1) of the invention can be obtained. The geometric isomerism of the farnesyl group in the general formula (2) is as described in the general formula (1). (There is no description about stereoisomerism in the explanation of general formula (1). Please replenish.)

  The esterification reaction of farnesol follows a conventional method. When esterification is performed using a primary or secondary amino group or an amino acid having a hydroxyl group or a thiol group in the side chain, a tert-butoxycarbonyl group (hereinafter t-BOC) is used. These primary or secondary amino groups, hydroxyl groups, and thiol groups are preferably protected and used with an appropriate protective group such as a benzyloxycarbonyl group (hereinafter abbreviated as Z group).

In addition, N, N-dialkylamino acids are dihalogenated using dicyclohexylcarbodiimide (hereinafter abbreviated as DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N, N -The reaction is preferably carried out in the presence of an active esterification reagent such as disuccinimide oxalate (hereinafter abbreviated as DSO). In this case, anhydrous pyridine is preferred as the solvent.
In the method using a reactive acid derivative, a method using acid halogenite, particularly acid chloride is preferable. In this case, an anhydrous benzene / anhydrous pyridine mixture is preferred as the solvent.

  Hydrohalates, alkyl sulfonates, and acidic sugar salts are produced by reacting free amino acid esters with hydrolactones, alkyl sulfonic acids, and acidic sugar lactones by conventional methods. Further, after the N-acylamino acid ester is produced, a hydrohalide can be produced by deprotection with hydrohalic acid by a conventional method.

  The hydrohalide salt of farnesol carboxylate ester (1) is a crystalline powder having a high melting point, is easy and easy to handle in terms of pharmaceutical technology, and has high water solubility.

Radiation is a beam produced by particles (including photons) emitted by radioactive decay, and includes α-rays, β-rays, γ-rays, etc., and also emitted by X-rays, nuclear reactions, and interconversion of elementary particles. Includes particle beams and cosmic rays.
The radiation exposure disorder is a disorder that develops due to radiation irradiation, that is, external radiation directly penetrates the body. There are acute disorders that develop immediately after exposure (acute radiation damage) and delayed disorders such as cancer and congenital congenital damage, especially when exposed to large amounts of radiation.
In the present specification, the drug for the prevention or treatment of biological damage caused by radiation exposure refers to biological damage caused by radiation exposure (especially before or during irradiation before or after irradiation, or after irradiation). It means drugs that suppress or alleviate acute radiation damage.

(2) Administration Form and Administration Method The agent for preventing or treating radiation exposure disorders of the present invention can be administered in various dosage forms. Examples of the administration route include oral, intravenous, subcutaneous, intramuscular and intraperitoneal administration. From the viewpoint of the preventive effect, oral administration is preferred because the administration method is simple. In addition, from the viewpoint of obtaining an effect quickly after radiation exposure, administration by a route that exhibits an effect similar to that of vein, subcutaneous, muscle, abdominal cavity or the like is preferable.
Examples of the dosage form of the drug of the present invention include oral preparations such as powders, liquids, powders, granules, tablets, intestinal solvents and capsules, injections such as intravenous, subcutaneous, intramuscular and intraperitoneal, and suppositories. And parenteral preparations. When used in the form of orally administered drugs, injections, and the like, various excipients and additives usually used in these dosage forms can be used within a range not inhibiting the effects of the present invention.
In addition, since the compound of the present invention has particularly high water solubility, it can be suitably used as a preparation that can be administered intravenously, an eye drop, an oral preparation, an aqueous coating agent, a spray, and the like.

The amino acid derivative of farnesol, which is an active ingredient of the agent for preventing or treating radiation exposure damage of the present invention, is preferably used together with a stabilizer for stabilization. Examples of the stabilizer include celluloses such as methyl cellulose and carboxymethyl cellulose.
The agent for preventing or treating radiation exposure disorders of the present invention can be used as a composition containing a pharmaceutically acceptable carrier or diluent. Examples of such carriers or diluents include, for example, starches, lactose, sucrose, glucose, dextrin, mannitol, sorbit, calcium phosphate, calcium sulfate, tragacanth gum, gelatin, gum arabic, methylcellulose, sodium carboxymethylcellulose, polyvinyl Solid diluents such as pyrrolidone, microcrystalline cellulose, magnesium stearate, talc, polyethylene glycol, agar, sodium alginate and kaolin, such as water, saline, ethanol, propylene glycol, polyethylene glycol, glycerin, Hartmann's solution And liquid diluents such as Ringer's solution.

  The dose of the drug for exerting the desired effect of the drug for preventing or treating radiation exposure according to the present invention varies depending on the age, body weight, degree of exposure, administration route, administration method, etc. of the subject and is appropriately determined. However, a high effect is recognized by using, for example, farnesol dimethylglycine in a range of about 50 to 200 mg / kg per day.

The drug of the present invention can be administered to nuclear power plant workers and radiographers who are expected to receive whole body exposure, and cancer patients to whom radiation such as X-rays and heavy particle beams are irradiated locally. it can.
The agent of the present invention may be administered before radiation exposure, before exposure during exposure, or immediately after exposure to 2 hours. Preferably, the dose is administered immediately after exposure to 2 hours, more preferably immediately after exposure to 1 hour, most preferably immediately after exposure. The term “immediately after exposure” refers to administration within 10 minutes after exposure and further within 5 minutes.

Since the drug of the present invention is administered after radiation exposure and has a preventive or therapeutic effect, the drug of the present invention is promptly administered after radiation exposure occurs by always providing it as an administration kit, for example, a nuclear power plant. Thus, biological damage caused by radiation exposure can be prevented or treated.
The administration kit contains the drug of the present invention, and further includes predetermined administration means for administering the drug to the subject, although it varies depending on the administration form or administration method of the drug.
Examples of means for administering a drug to a subject include liquid diluents such as syringes and physiological saline. Also, administration kits are administered within 2 hours immediately after the subject is exposed to radiation. It is preferable to include an instruction for instructing

(3) Effect on radiation exposure injury As an experiment for confirming the effect of the drug of the present invention on radiation exposure injury, immediately after 7.5 Gy X-rays were irradiated to mice at a dose rate of 0.48 Gy / min, Observation was performed by intraperitoneally administering a drug dissolved in a 0.5% methylcellulose solution (5.48 mg / ml). In the control group using a 0.5% methylcellulose solution containing no drug, the survival rate after 30 days of irradiation was 5%, whereas those administered with the drug of the present invention showed a high survival rate of 70% or more.
In addition, drugs were administered immediately after irradiation, 1 hour, 2 hours, and 4 hours after irradiation to examine whether radiation exposure damage can be prevented or treated. Control was performed immediately after irradiation until 2 hours after administration. The survival rate was significantly improved for the group.

Production Example A method for producing a farnesol derivative is shown below.
Manufacturing method A
Add N, N-dialkylamino acid hydrochloride (3.1 mmol), DCC (3.1 mmol) and anhydrous pyridine (30 ml), stir for 30 minutes, add farnesol (3.1 mmol), and stir at room temperature for 16 hours. The solvent is distilled off under reduced pressure, the residue is suspended in distilled water, and the soluble fraction is extracted with ethyl acetate. The extract was dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was separated and purified by flash chromatography on silica gel (eluent: n-hexane: ethyl acetate) to give oily N, N-dialkylamino acid farnesol ester. obtain.

Manufacturing method B
The N, N-dialkylamino acid farnesol ester obtained by Production Method A or E is dissolved in a small amount of acetone, 2-fold molar amount of hydrochloric acid-dioxane is added, and the solvent is distilled off under reduced pressure. Crystallize to obtain the hydrochloride salt of N, N-dialkylamino acid farnesol ester.

Manufacturing method C
Dissolve 0.1 mol of amino acid in 100 ml of distilled water-dioxane (1: 1, v / v), add 30 ml of triethylamine, gradually add di-tert-butyl dicarbonate and stir for 30 minutes at room temperature. Dioxane is distilled off under reduced pressure, 50 ml of aqueous sodium hydrogen carbonate solution (0.5 M) is added, and the mixture is washed with 100 ml of ethyl acetate. The ethyl acetate layer was washed with 50 ml of sodium bicarbonate solution, and the aqueous layers were combined and acidified (pH 3) with an aqueous citric acid solution (0.5 M) under ice-cooling. After saturating sodium chloride, ethyl acetate was added. Extract with (100 ml x 3 times). The extract is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the oily residue or it is crystallized by cooling to obtain an Nt-BOC amino acid.
Farnesol 5 mmol, Nt-BOC amino acid 5 mmol, and DCC 5 mmol are added to 30 ml of anhydrous pyridine and stirred at room temperature for 20 hours. The solvent is distilled off under reduced pressure, and ethyl acetate is added to the residue to extract a soluble fraction (100 ml x 2 times). The extract is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate) to obtain farnesol Nt-BOC-amino acid ester.
Dissolve farnesol Nt-BOC-amino acid ester in a small amount of acetone, add hydrochloric acid-dioxane (2.5-4.0 N) in an amount equivalent to 20 times the molar amount of hydrochloric acid and stir for 1 hour, and then evaporate the solvent under reduced pressure. To do. The residue is recrystallized with acetone-methanol system or ethyl acetate-methanol system to obtain farnesol amino acid ester hydrochloride.

Manufacturing method D
Add 3 mmol of farnesol amino acid ester hydrochloride obtained in production method C to 150 ml of water, add sodium bicarbonate to adjust the pH of the solution to 7-8, and then extract with ethyl acetate (100 ml x 3 times) . The extract is dehydrated with anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure to obtain oily farnesol amino acid ester.

Manufacturing method E
Dissolve 3.1 mmol of farnesol in 30 ml of anhydrous pyridine-anhydrous benzene (1: 1, v / v), add 3.1 mmol of N, N-dialkylaminoalkanoyl chloride hydrochloride, stir for 1 hour, and suspend in distilled water. Sodium hydrogen is added to bring the pH of the solution to 7-8, followed by extraction with ethyl acetate (3 x 100 ml). The extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel flash chromatography (eluent: n-hexane: ethyl acetate) to obtain oily farnesol N, N-dialkylamino acid ester. obtain.

  Examples of compounds produced by the above production methods A to E are shown in Tables 1 to 3 below.

A drug (5.48 mg / ml) prepared by dissolving farnesol dimethylglycine hydrochloride having the following structure (hereinafter also referred to as “FODMG · HCl”) in a 0.5% methylcellulose solution was prepared as a test drug for effects on radiation exposure injury .

(1) Measurement of 30-day survival rate in administration group immediately after irradiation C3H, male, 10-week-old mice were used. Mice were divided into two groups as follows.
Group 1 20 FODMG · HCl administered immediately after irradiation Group 2 Control group: 20% 0.5% methylcellulose solution administered immediately after irradiation (2) Mean survival days when the time to administration after irradiation was changed (protection) Measurement of effect) Mice used were C3H, male, and 10 weeks old. The mice were divided into 5 groups as follows.
Group 1 FODMG / HCl administered immediately after irradiation 10 animals Group 2 FODMG / HCl administered 1 hour after irradiation 11 animals Group 3 FODMG / HCl administered 2 hours after irradiation 11 animals Group 4 4 hours after irradiation After administration of FODMG · HCl 10 animals Group 5 Control group: Immediately after irradiation, 0.5% methylcellulose solution was administered 10 animals

In the above administration, the dose of the drug was 64 mg / kg (0.3 ml) and was administered intraperitoneally.
For X-ray irradiation, Shimadzu Pantak HF-320 was used. The whole body was irradiated with 7.5 Gy at a dose rate of 0.48 Gy / min.
After X-irradiation, FODMG · HCl was administered at various times as described above. In addition, “immediately after irradiation” in the first group of (1) and (2) was within 5 minutes after irradiation. After administration of the drug, the mice were returned to their cages and reared for 30 days for observation.

Data analysis was performed as follows.
-Survival curve, 30-day survival rate and average survival days were determined.
-Mantel-Cox test and Breslow-Gehan-Wilcoxon test were used to test the significance of the survival curve of each group relative to the control group (using Stat View software).

The relationship between the survival days and survival rates of the first group and the second group (control group) in the experiment of (1) is shown in a graph (FIG. 1).
The mean survival days of mice in each group are shown with the mean survival days (13.2 days) in the experiment of (2) as the standard (0%) and the average survival days of 30 days as 100%. The graph shows the relative protective effect of each group of mice (FIG. 2).
From FIG. 1, when the drug of the present invention was administered immediately after radiation exposure, the survival rate for 30 days was 70% or more (75%), whereas in the control group, it was 5%. It turns out that there exists a remarkable effect in the prevention or treatment of the biological disorder by exposure.
In addition, as can be seen from FIG. 2, the survival curve after administration for 1 hour and 2 hours after irradiation was significantly higher than that of the control group at P <0.05. Regarding the administration after 4 hours, the survival rate was higher than that of the control group, but there was no significant difference.

Claims (8)

A drug for preventing or treating biological damage caused by radiation exposure, comprising an amino acid derivative of farnesol represented by the following formula.

In the formula, R represents a carboxylic acid residue having a nitrogen substituent. The geometrical isomerism at the 2nd and 6th positions of the farnesyl group represents 2E, 6E, 2Z / E, 6Z / E. The drug according to claim 1, wherein the amino acid derivative of farnesol is further represented by the following general formula (1 ').

In the formula, R ₁ may be the same or different and represents a hydrogen atom or a methyl group; R ₂ may be the same or different and represents a hydrogen atom or a methyl group; and X represents an acid that forms an acid addition salt. Represents. The geometrical isomerism at the 2nd and 6th positions of the farnesyl group represents 2E, 6E, 2Z / E, 6Z / E. The drug according to claim 2, wherein R ₁ is a hydrogen atom. The drug according to claim 2 or 3, wherein each R ₂ is a methyl group. The drug according to any one of claims 2 to 4, wherein X is selected from the group consisting of hydrochloric acid, hydrobromic acid and hydrofluoric acid. A drug administration kit for preventing or treating a biological disorder caused by radiation exposure, comprising the drug according to any one of claims 1 to 5. The administration kit according to claim 6, further comprising means for administering the drug to a subject. The administration kit according to claim 6 or 7, comprising an instruction for instructing to administer the drug according to any one of claims 1 to 4 within 2 hours immediately after the subject is exposed to radiation.

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